HK40020212A

HK40020212A - Ophthalmic composition

Info

Publication number: HK40020212A
Application number: HK42020010090.7A
Authority: HK
Inventors: 格雷戈里·I·奥斯特罗夫; 肯尼斯·J·威德; 大卫·S·贝克
Original assignee: 西德奈克西斯公司
Priority date: 2014-06-24
Filing date: 2020-06-29
Publication date: 2020-10-23

Description

Ophthalmic composition

This application is a divisional application of chinese patent application No. 201580045735.9 (international application No. PCT/US2015/037249) entitled "ophthalmic composition" filed on 23/06/2015.

Cross-referencing

This application claims benefit of U.S. provisional application No. 62/016,502 filed 24/6/2014, U.S. provisional application No. 62/096,433 filed 23/12/2014, and U.S. provisional application No. 62/151,926 filed 23/4/2015; and was filed as part of U.S. application No. 14/726,139 filed on 29/5/2015, which is incorporated by reference herein in its entirety.

Background

The pharmaceutical preparation has a useful life based on the degradation of the active ingredient.

Disclosure of Invention

Provided herein are ophthalmic compositions. In some embodiments, disclosed herein is an ophthalmic composition comprising from about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and deuterated water, at a pD of from about 4.2 to about 7.9.

In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the ophthalmic composition has a pD of one of: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, or less than about 4.8.

In some embodiments, the ophthalmic composition comprises a muscarinic antagonist that is one of the following based on initial concentrations after an extended period of time under storage conditions: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%. As described in the present disclosure, the percentage of the ophthalmic agent in the composition after storage is based on the amount of ophthalmic agent initially present in the composition (i.e., prior to storage conditions).

In some embodiments, the ophthalmic composition further has an efficacy of one of the following after an extended period of time under storage conditions: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99%. As described in the present disclosure, the efficacy of the ophthalmic agent in the composition after storage is based on the efficacy of the ophthalmic agent initially present in the composition (i.e., prior to storage conditions).

In some embodiments, the extended period of time is one of: about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 18 months, about 24 months, about 36 months, about 4 years, or about 5 years.

In some embodiments, the storage conditions have a storage temperature of from about 2 ℃ to about 10 ℃ or from about 16 ℃ to about 26 ℃. In some embodiments, the storage conditions have a storage temperature of about 25 ℃. In some embodiments, the storage conditions have a storage temperature of about 40 ℃. In some embodiments, the storage conditions have a storage temperature of about 60 ℃.

In some embodiments, the storage condition has a relative humidity of about 60%. In some embodiments, the storage conditions have a relative humidity of about 75%.

In some embodiments, the muscarinic antagonist is present in the composition at a concentration of one of: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.008 wt%, or about 0.001 wt% to about 0.005 wt%.

In some embodiments, the composition comprises less than 20% of a major degradant (degradant) based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition comprises less than 15% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent.

In some embodiments, the composition comprises less than 10% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 5% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 2.5% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 2.0% of the major degradant based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition comprises less than 1.5% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 1.0% of the major degradant based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition comprises less than 0.5% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 0.4% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 0.3% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 0.2% of the major degradant based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition comprises less than 0.1% of a major degradant based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the primary degradant is tropine. As described in the present disclosure, the percentage of the major degradants in the composition after storage is based on the amount of ophthalmic agent initially present in the composition (i.e., prior to storage conditions).

In some embodiments, the composition is in the form of an aqueous solution.

In some embodiments, the composition further comprises an osmolarity (osmolarity) adjusting agent. In some embodiments, the osmolality adjusting agent is sodium chloride.

In some embodiments, the ophthalmic composition further comprises a preservative. In some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium (cetrimonium), sodium perborate, stabilized oxy-chloride complexes, SofZia, polyquaternium-1, chlorobutanol, edetate disodium, polyhexamethylene biguanide, or combinations thereof.

In some embodiments, the ophthalmic composition further comprises a buffering agent. In some embodiments, the buffer is selected from borate, borate-polyol complex, phosphate buffer, citrate buffer, acetate buffer, carbonate buffer, organic buffer, amino acid buffer, or combinations thereof.

In some embodiments, the ophthalmic composition further comprises a tonicity adjusting agent. In some embodiments, the tonicity modifier is selected from the group consisting of sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerol, or combinations thereof.

In some embodiments, the composition is stored in a plastic container. In some embodiments, the material of the plastic container comprises Low Density Polyethylene (LDPE).

In some embodiments, the ophthalmic composition is substantially free of procaine and benactyzine, or a pharmaceutically acceptable salt thereof.

In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 50%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 40%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 30%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 20%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 10%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 5%. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 10 consecutive doses. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 8 consecutive doses. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 5 consecutive doses. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 3 consecutive doses. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 2 consecutive doses.

In some embodiments, the composition further comprises a pD modulator. In some embodiments, the pD modulator comprises DCl, NaOD, CD₃COOD or C₆D₈O₇。

In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the ophthalmically acceptable carrier further comprises at least one viscosity enhancing agent. In some embodiments, the viscosity enhancing agent is selected from a cellulose-based polymer, a polyoxyethylene-polyoxypropylene triblock copolymer, a dextran-based polymer, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycol, chitosan, collagen, gelatin, hyaluronic acid, or a combination thereof.

In some embodiments, the ophthalmic composition comprises one of: less than 60% of H₂O, less than 55% H₂O, less than 50% of H₂O, less than 45% of H₂O, less than 40% H₂O, less than 35% H₂O, less than 30% of H₂O, less than 25% of H₂O, less than 20% of H₂O, less than 15% of H₂O or less than 10% H₂O。

In some embodiments, the ophthalmic composition comprises one of: less than 5% of H₂O, less than 4% of H₂O, less than 3% of H₂O, less than 2% of H₂O, less than 1% of H₂O, less than 0.5% of H₂O, less than 0.1% of H₂O, or 0% of H₂O。

In some embodiments, the ophthalmic composition is stored at a temperature below room temperature prior to first use. In some embodiments, the ophthalmic composition is stored at a temperature between about 2 ℃ to about 10 ℃ prior to first use. In some embodiments, the ophthalmic composition is stored at a temperature between about 4 ℃ to about 8 ℃ prior to first use.

In some embodiments, the ophthalmic composition is stored at room temperature after first use. In some embodiments, the ophthalmic composition is stored at a temperature between about 16 ℃ to about 26 ℃ after first use.

In some embodiments, the ophthalmic composition is not formulated as an injectable formulation.

In some embodiments, the ophthalmic composition is formulated as an ophthalmic solution for treating an ophthalmic condition. In some embodiments, the ophthalmic disorder or condition is pre-myopia (pre-myopia), myopia, or myopia progression. In some embodiments, the ophthalmic composition is formulated as an ophthalmic solution for the treatment of pre-myopia, or myopia progression.

In some embodiments, the ophthalmic composition is a solution.

In some embodiments, disclosed herein is a method of preventing myopia progression comprising administering to an eye of an individual in need thereof an effective amount of an ophthalmic composition described herein. Also described herein is a method of preventing myopia progression comprising administering to an eye of an individual in need thereof an effective amount of an ophthalmic composition described herein. In some embodiments, described herein is a method of preventing or preventing the development of myopia, the method comprising administering to an eye of an individual in need thereof an effective amount of an ophthalmic composition comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and deuterated water, at a pD of about 4.2 to about 7.9. In some embodiments, the ophthalmic composition is administered at predetermined time intervals over an extended period of time. In some embodiments, the ophthalmic composition is administered once daily. In some embodiments, the ophthalmic composition is administered once every other day. In some embodiments, the ophthalmic composition is administered within 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, or 12-15 years. In some embodiments, the ophthalmic composition is stored at a temperature below room temperature prior to first use. In some embodiments, the ophthalmic composition is stored at a temperature between about 2 ℃ to about 10 ℃ prior to first use. In some embodiments, the ophthalmic composition is stored at a temperature between about 4 ℃ to about 8 ℃ prior to first use. In some embodiments, the ophthalmic composition is stored at room temperature after first use. In some embodiments, the ophthalmic composition is stored at a temperature between about 16 ℃ to about 26 ℃ after first use.

In some embodiments, disclosed herein is an ophthalmic solution comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and deuterated water, at a pD of about 4.2 to about 7.9. In some embodiments, the ophthalmic solution has a pD of one of the following after an extended period of time under storage conditions: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, or less than about 4.8. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the ophthalmic solution comprises one of: less than 5% of H₂O, less than 4% of H₂O, less than 3% of H₂O, less than 2% of H₂O, less than 1% of H₂O, less than 0.5% of H₂O, less than 0.1% of H₂O, or 0% of H₂And O. In some embodiments, the ophthalmic composition comprises a muscarinic antagonist that is one of the following based on initial concentrations after an extended period of time under storage conditions: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%. In some embodiments, the ophthalmic composition further has an efficacy of one of the following after an extended period of time under storage conditions: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99%. In some embodiments, the extended period of time is one of: about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 18 months, about 24 months, about 36 months, about 4 years, or about 5 years. In some embodiments, the muscarinic antagonist is present in the composition at a concentration of one of: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 w%t%, from about 0.001 wt% to about 0.008 wt%, or from about 0.001 wt% to about 0.005 wt%. In some embodiments, the storage conditions have a storage temperature of from about 2 ℃ to about 10 ℃ or from about 16 ℃ to about 26 ℃. In some embodiments, the ophthalmic composition has a change in inter-dose muscarinic antagonist concentration of one of: less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. In some embodiments, the change in the inter-dose muscarinic antagonist concentration is based on one of: 10 consecutive doses, 8 consecutive doses, 5 consecutive doses, 3 consecutive doses, or 2 consecutive doses.

In some embodiments, disclosed herein is an ophthalmic composition comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and water, having a pH of about 3.8 to about 7.5.

In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or atropine sulfate.

In some embodiments, the ophthalmic composition comprises a muscarinic antagonist that is one of the following based on initial concentrations after an extended period of time under storage conditions: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%.

In some embodiments, the ophthalmic composition has a pH of one of the following after an extended period of time under storage conditions: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, less than about 4.8, or less than about 4.2.

In some embodiments, the ophthalmic composition further has an efficacy of one of the following after an extended period of time under storage conditions: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99%.

In some embodiments, the storage conditions have a storage temperature of one of: about 25 ℃, about 40 ℃ or about 60 ℃. In some embodiments, the storage conditions have a storage temperature of from about 2 ℃ to about 10 ℃ or from about 16 ℃ to about 26 ℃.

In some embodiments, the storage conditions have a relative humidity of about 60% or about 75%.

In some embodiments, the ophthalmic composition further comprises an osmolarity adjusting agent. In some embodiments, the osmolality adjusting agent is sodium chloride.

In some embodiments, the ophthalmic composition further comprises a preservative. In some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxy-chloride complex, SofZia, polyquaternium-1, chlorobutanol, edetate disodium, polyhexamethylene biguanide, or combinations thereof.

In some embodiments, the ophthalmic composition is stored in a plastic container. In some embodiments, the material of the plastic container comprises Low Density Polyethylene (LDPE).

In some embodiments, the ophthalmic composition has a change in inter-dose muscarinic antagonist concentration of one of: less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%.

In some embodiments, the change in the inter-dose muscarinic antagonist concentration is based on one of: 10 consecutive doses, 8 consecutive doses, 5 consecutive doses, 3 consecutive doses, or 2 consecutive doses.

In some embodiments, the ophthalmic composition has a pH of one of: about 3.8 to about 7.5, about 4.2 to about 7.5, about 4.8 to about 7.3, about 5.2 to about 7.2, about 5.8 to about 7.1, about 6.0 to about 7.0, or about 6.2 to about 6.8.

In some embodiments, the ophthalmic composition further comprises a pH adjusting agent. In some embodiments, the pH adjusting agent comprises HCl, NaOH, CH₃COOH or C₆H₈O₇。

In some embodiments, the ophthalmic composition comprises one of: less than 60% of D₂O, less than 55% of D₂O, less than 50% of D₂O, less than 45% of D₂O, less than 40% of D₂O, less than 35% of D₂O, less than 30% of D₂O, less than 25% of D₂O, less than 20% of D₂O, less than 15% of D₂O orLess than 10% of D₂O。

In some embodiments, the ophthalmic composition comprises one of: less than 5% of D₂O, less than 4% of D₂O, less than 3% of D₂O, less than 2% of D₂O, less than 1% of D₂O, less than 0.5% of D₂O, less than 0.1% of D₂O, or 0% of D₂And O. In some embodiments, the ophthalmic composition is substantially free of D₂O。

In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

In some embodiments, the ophthalmic composition is formulated as an ophthalmic solution for treating an ophthalmic condition. In some embodiments, the ophthalmic disorder or condition is pre-myopia, or myopia progression.

Other features and technical effects of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only.

In particular, the present invention relates to:

1. an ophthalmic composition comprising from about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and deuterated water, having a pD of from about 4.2 to about 7.9.

2. The ophthalmic composition of paragraph 1, wherein the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof.

3. The ophthalmic composition of paragraph 2, wherein the muscarinic antagonist is atropine or atropine sulfate.

4. The ophthalmic composition of any one of paragraphs 1-3, wherein the ophthalmic composition has a pD of one of the following after an extended period of time under storage conditions: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, or less than about 4.8.

5. The ophthalmic composition of any one of paragraphs 1-4, wherein the ophthalmic composition comprises a muscarinic antagonist that is one of the following, based on initial concentrations, after an extended period of time under storage conditions: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%.

6. The ophthalmic composition of any one of paragraphs 1-5, wherein the ophthalmic composition further has an efficacy of one of the following after an extended period of time under storage conditions: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99%.

7. The ophthalmic composition of any one of paragraphs 1-6, wherein the storage conditions have a storage temperature of from about 2 ℃ to about 10 ℃ or from about 16 ℃ to about 26 ℃.

8. The ophthalmic composition of any one of paragraphs 1-7, wherein the muscarinic antagonist is present in the composition at a concentration of one of: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.008 wt%, or about 0.001 wt% to about 0.005 wt%.

9. The ophthalmic composition of any one of paragraphs 1-8, wherein the ophthalmic composition further comprises an osmolality adjusting agent, a preservative, a buffer, a tonicity adjusting agent, or a combination thereof.

10. The ophthalmic composition of any one of paragraphs 1-9, wherein the ophthalmic composition has a dose-to-dose muscarinic antagonist concentration variation of one of: less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%.

11. The ophthalmic composition of any one of paragraphs 1-10, wherein the ophthalmic composition is substantially free of procaine and benactyzine, or a pharmaceutically acceptable salt thereof.

12. The ophthalmic composition of any one of paragraphs 1-11, wherein the ophthalmic composition further comprises a pD modulator.

13. The ophthalmic composition of paragraph 12, wherein the pD modulator comprises DCl, NaOD, CD₃COOD or C₆D₈O₇。

14. The ophthalmic composition of any one of paragraphs 1-13, wherein the ophthalmic composition comprises one of: less than 5% of H₂O, less than 4% of H₂O, less than 3% of H₂O, less than 2% of H₂O, less than 1% of H₂O, less than 0.5% of H₂O, less than 0.1% of H₂O, or 0% of H₂O。

15. The ophthalmic composition of any one of paragraphs 1-14, wherein the ophthalmic composition is a solution.

16. The ophthalmic composition of any one of paragraphs 1-15, wherein the ophthalmic composition is not formulated as an injectable formulation.

17. The ophthalmic composition of any one of paragraphs 1-16, wherein the ophthalmic composition is formulated as an ophthalmic solution for treating an ophthalmic disorder.

18. The ophthalmic composition of any one of paragraphs 1-17, wherein the ophthalmic disorder or condition is pre-myopia, or myopia progression.

19. A method of preventing myopia progression or preventing myopia progression, the method comprising administering to an eye of an individual in need thereof an effective amount of the ophthalmic composition of paragraphs 1-18.

20. The method of paragraph 19, wherein the ophthalmic composition is stored at a temperature between about 2 ℃ to about 10 ℃ prior to first use.

21. The method of paragraph 19 or 20, wherein after first use, the ophthalmic composition is stored at a temperature between about 16 ℃ to about 26 ℃.

22. An ophthalmic composition comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and water, having a pH of about 3.8 to about 7.5.

23. The ophthalmic composition of paragraph 22, wherein the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof.

24. The ophthalmic composition of paragraph 22 or 23, wherein the ophthalmic composition comprises a muscarinic antagonist that is one of the following based on initial concentrations after an extended period of time under storage conditions: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%.

25. The ophthalmic composition of any one of paragraphs 22-24, wherein the ophthalmic composition has a pH of one of: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, less than about 4.8, or less than about 4.2.

26. The ophthalmic composition of any one of paragraphs 22-25, wherein the ophthalmic composition further has an efficacy of one of the following after an extended period of time under storage conditions: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99%.

27. The ophthalmic composition of any one of paragraphs 22-26, wherein the storage conditions have a storage temperature of from about 2 ℃ to about 10 ℃ or from about 16 ℃ to about 26 ℃.

28. The ophthalmic composition of any one of paragraphs 22-27, wherein the ophthalmic composition further comprises an osmolarity adjusting agent, a preservative, a buffer, a tonicity adjusting agent, optionally a pH adjusting agent, or a combination thereof.

29. The ophthalmic composition of any one of paragraphs 22-28, wherein the ophthalmic composition comprises one of: less than 5% of D₂O, less than 4% of D₂O, less than 3% of D₂O, less than 2% of D₂O, less than 1% of D₂O, less than 0.5% of D₂O, less than 0.1% of D₂O, or 0% of D₂O。

30. The ophthalmic composition of any one of paragraphs 22-29, wherein the ophthalmic composition is formulated as an ophthalmic solution for treating an ophthalmic disorder.

Drawings

The novel features believed characteristic of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

figures 1A-1C show shelf life predictions for 0.01% atropine sulfate solutions based on data obtained from samples stored at 25 ℃ and 40 ℃, where the major degradants are RRT0.87-0.89, and n.m.t. is 0.5% area. The pH range of the atropine sulfate solution is 5.9-6.2.

Figures 2A-2C show shelf life predictions for 0.01% atropine sulfate solutions based on data obtained from samples stored at 25 ℃ and 60 ℃, where the major degradants are RRT0.87-0.89, and n.m.t. is 0.5% area. The pH range of the atropine sulfate solution is 5.9-6.2.

Figure 3 is a graphical representation of the mass balance of the atropine sulfate formulation disclosed in example 9 at 4 weeks and at 60 ℃.

Figure 4 is a graph showing the stability of atropine sulfate (0.010%) formulation in acetic acid. Acetic acid and H for atropine sulfate preparation₂O (upper panel, preparation 3) or D₂O (lower panel, formulation 7). Formulation 3 had a pH of 4.8, while formulation 7 had a pD of 5.2. Both formulations were stored at 60 ℃ for 4 weeks prior to analysis.

Figure 5 illustrates the atropine sulfate (0.01%) formulation stability in citric acid. Citric acid and H for atropine sulfate preparation₂O (upper panel, preparation 5) or D₂O (lower panel, formulation 8). Formulation 5 had a pH of 5.8, while formulation 8 had a pD of 6.2. Prior to the analysis of the sample, the sample is analyzed,both formulations were stored at 60 ℃ for 4 weeks.

FIG. 6 illustrates at H₂Comparison of total RS and tropine acid for atropine sulfate (0.025%) formulation (formulation 4) at pH 4.8 in O.

FIG. 7 illustrates at D₂Comparison of total RS and tropine acid for the atropine sulfate (0.01%) formulation (formulation 7) at pD 5.2 in O.

FIG. 8 is a diagram at H₂Comparison of total RS and tropine acid in O for atropine sulfate (0.01%) formulation (formulation 5) at pH 5.8.

FIG. 9 illustrates at H₂Comparison of total RS and tropine acid for atropine sulfate (0.025%) formulation (formulation 6) at pH 5.8 in O.

FIG. 10 shows graphs of D disclosed in examples 11 and 12₂O and H₂O estimated shelf life of the formulation.

Detailed Description

The present invention recognizes that there is a need for stable ophthalmic compositions having an extended shelf life upon storage. The present invention also recognizes that there is a need for stabilizing ophthalmic compositions by preventing or reducing hydrolysis of at least some of the active agents of the ophthalmic compositions. The present invention further recognizes that there is a need for ophthalmic compositions that provide convenient and effective delivery of muscarinic antagonists, such as atropine, in the eye of a patient.

The present invention recognizes that muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof) prevent or arrest the progression of myopia in humans, for example, as evidenced by a decrease in the rate of increase of myopia in young humans. The present invention also recognizes the effects of muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof) on axial elongation and myopia reduction in vision-impaired chicken eyes, as well as on ocular growth and muscarinic cholinergic receptors in young rhesus monkeys.

In addition, the present invention recognizes that systemic absorption of muscarinic antagonists (e.g., atropine) sometimes results in undesirable side effects, while local delivery of muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof) reduces or prevents such systemic exposure.

Furthermore, the present invention recognizes that some liquid muscarinic antagonist (e.g., atropine) compositions are formulated at a relatively low pH range (e.g., less than 4.5) for stability of the muscarinic antagonist (e.g., atropine or a pharmaceutically acceptable salt thereof). For some individuals, in some cases, lower pH ranges can cause discomfort or other side effects, such as pain or burning sensation to the eye, which is prevented or alleviated by formulating muscarinic antagonist (e.g., atropine) compositions at higher pH ranges. For some individuals, in some cases, a lower pH triggers a lacrimation response, which reduces absorption of the drug in the eye and thus reduces effectiveness.

Furthermore, the present invention recognizes that some muscarinic antagonist (e.g., atropine) liquid compositions formulated at lower concentrations (e.g., 0.001% to 0.05%) exhibit less stability challenges than when formulated at higher concentrations (e.g., 0.1-1%). Without wishing to be bound by any particular theory, it is expected that some muscarinic antagonists (e.g., atropine) contribute to the stability of ophthalmic compositions such as aqueous solutions. For example, in some embodiments, the concentration of the muscarinic antagonist (e.g., atropine) affects the pH or pD of the ophthalmic composition, such as with the muscarinic antagonist as a buffering agent. Furthermore, in some embodiments, the concentration of the muscarinic antagonist (e.g., atropine) affects the interaction between the muscarinic antagonist and the other ingredients of the ophthalmic composition, which in turn affects the stability of the ophthalmic composition.

Finally, the present invention recognizes that deuterated water stabilizes ophthalmic compositions. In some cases, with H₂Deuterated water is a weak acid compared to O, and thus deuterated water contains a lower concentration of a reactive species (e.g., -OD) that in some cases results in base-catalyzed hydrolysis of the active agent in the ophthalmic composition. Thus, in some cases, with H₂The composition comprising deuterated water results in a reduction in base-catalyzed hydrolysis compared to the composition of O. In some cases, deuterated water further reduces the buffering capacity of the ophthalmic composition, thereby resulting in less tear reflex in the eye.

Myopia, i.e. the axial elongation of the eye, affects a large proportion of the population. Myopia usually occurs during primary schools and progresses until eye growth is complete. The present invention recognizes the importance of compositions and treatments for preventing or arresting the development of myopia, particularly compositions and treatments that allow for convenient administration, reduced potential side effects, have adequate stability, and/or provide relatively consistent therapeutic effects.

Ophthalmic muscarinic antagonist compositions

An ophthalmic composition containing a low concentration of an ophthalmic agent is provided herein. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% of an ophthalmic agent for treating an ophthalmic disorder or condition; and an ophthalmically acceptable carrier, wherein the ophthalmic agent is substantially uniformly distributed throughout the ophthalmically acceptable carrier. In some cases, the ophthalmic agent is a muscarinic antagonist.

An ophthalmic composition comprising a low concentration of a muscarinic antagonist is provided. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist for treating an ophthalmic disorder or condition; and an ophthalmically acceptable carrier, wherein the muscarinic antagonist is substantially uniformly distributed throughout the ophthalmically acceptable carrier.

In some cases, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine acid, mephostyline, diphenhydramine, dimenhydrinate, bicyclin, flavoxate, oxybutynin, tiotropium bromide, scopolamine, hyoscyamine (L-scopolamine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine (pirenzapine), homatropine, solifenacin, darifenacin, benztropine, mebeverine, propiconazole, aclidinium, trihexyphenidyl/benzhexol, tolterodine, or a combination thereof. In some cases, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the ophthalmic composition comprises a muscarinic antagonist selected from: atropine, atropine sulfate, nor-atropine, atropine-N-oxide, tropine, tropinic acid, mephostyline, diphenhydramine, dimenhydrinate, bicycloheverine, flavoxate, oxybutynin, tiotropium bromide, scopolamine, hyoscyamine (L-scopolamine), hydroxyzine, ipratropium, tropium, cyclopentolate, pirenzepine, homatropine, homanaxate, solifenacin, darifenacin, benztropine, mebeverine, procyclidine, aclonidinium, trihexyphenidyl/benzhexol, tolterodine, or combinations thereof. In some cases, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, or homatropine.

In some embodiments, the ophthalmic composition comprises two or more muscarinic antagonists, wherein the two or more muscarinic antagonists comprise atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, meperidine, diphenhydramine, dimenhydrinate, bicycloprotein, flavoxapride, oxybutynin, tiotropium bromide, scopolamine, hyoscyamine (L-scopolamine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine, homatropine, soline, solifenacin, darifenacin, benztropine, mebeverine, propiconazole, aclidinium bromide, trihexyphenidyl/benzhexol, tolterodine, or a combination thereof. In some cases, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or any combination thereof.

In some embodiments, the ophthalmic composition comprises a combination of one or more muscarinic antagonists and one or more sympathetic nerve agonists. In some embodiments, the sympathetic agonist is selected from phenylephrine or hydroxylphenylpropylamine. In some embodiments, the ophthalmic composition comprises a combination of one or more muscarinic antagonists that are atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, methamphetamine, diphenhydramine, dimenhydrinate, bivalin, flavoxate, oxybutynin, tiotropium, scopolamine, hyoscyamine (L-scopolamine), hydroxyzine, ipratropium, topiramide, cyclopentolate, pirenzepine, homatropine, solifenacin, darifenacin, benztropine, mebeverine, procyclidine, aclidinium, trihexyphenidyl/diphenhydramine, or tolterodine, and one or more sympathetic agonists; the sympathetic agonist is phenylephrine or hydroxylphenylpropylamine.

Provided herein is an ophthalmic composition comprising a low concentration of atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% of atropine, or a pharmaceutically acceptable salt thereof, for use in treating an ophthalmic disorder or condition; and an ophthalmically acceptable carrier, wherein the ophthalmic agent is substantially uniformly distributed throughout the ophthalmically acceptable carrier.

Provided herein is an ophthalmic composition containing a low concentration of atropine sulfate. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% atropine sulfate for use in treating an ophthalmic disorder or condition; and an ophthalmically acceptable carrier, wherein the ophthalmic agent is substantially uniformly distributed throughout the ophthalmically acceptable carrier.

In some embodiments, the ophthalmic disorder or condition is pre-myopia, or myopia progression.

The present invention further recognizes that clinical use of atropine as a treatment is limited by ocular side effects of atropine, including glare due to pupil dilation and blurred vision due to loss of accommodation. Without wishing to be bound by any particular theory, it is expected that the limitations of the use of atropine to combat myopia progression, including its ocular side effects, are due to the concentration of atropine used in known ophthalmic formulations (e.g., 1 wt% or higher).

The present invention further recognizes that there are challenges in the formulation of compositions containing low, especially very low, concentrations (e.g., about 0.001 wt% to about 0.5 wt%) of ophthalmic agents, such as muscarinic antagonists (e.g., atropine or pharmaceutically acceptable salts thereof). In particular, pharmaceutical compositions having such low concentrations of ophthalmic agents have difficulty maintaining uniformity between doses in terms of ophthalmic agent content and/or distribution.

In some aspects, described herein are formulations or solutions of muscarinic antagonists (e.g., atropine) formulated in deuterated water. In some aspects, a formulation or solution of a muscarinic antagonist (e.g., atropine) formulated in deuterated water is stable at different temperatures, at different relative humidities, and has an acidic pD and a potency of at least 80% relative to the ophthalmic agent. In other aspects, formulations or solutions of muscarinic antagonists (e.g., atropine) formulated in deuterated water have reduced buffering capacity. In such a case, H₂The reduced buffering capacity of the ophthalmic formulation or solution when administered to the eye allows the ophthalmic formulation or solution to reach physiological pH at a faster rate than an equivalent ophthalmic formulation or solution formulated in O.

In some aspects, described herein are formulations of low concentrations of muscarinic antagonists (e.g., atropine) without dose-to-dose variation. In some aspects, described herein are formulations of low concentrations of a muscarinic antagonist (e.g., atropine) that are stable at different temperatures, at different relative humidities, and have an acidic pD and a potency of at least 80% relative to an ophthalmic agent.

In other aspects, described herein includes formulating the ophthalmic composition as an ophthalmic gel or ointment. For example, some ophthalmic gels or ophthalmic ointments described herein allow for desired inter-dose uniformity, reduced or limited systemic exposure, or a combination thereof.

Ophthalmic solution muscarinic antagonist compositions

In certain embodiments, disclosed herein is an ophthalmic composition formulated as an aqueous solution. In some embodiments, the ophthalmic compositions comprise from about 0.001 wt% to about 0.05 wt% of the toxinMuscarinic antagonists and deuterated water. Deuterated water as used herein refers to D₂O, DHO, heavy water and/or deuterium oxide.

In some embodiments, the composition comprises at least about 80% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 81% of an ophthalmic agent (e.g., a muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 82% of an ophthalmic agent (e.g., a muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 83% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 84% of an ophthalmic agent (e.g., a muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 85% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 86% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 87% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 88% of an ophthalmic agent (e.g., a muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 89% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 90% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 91% of an ophthalmic agent (e.g., a muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 92% of an ophthalmic agent (e.g., a muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 93% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 94% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 95% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 96% of an ophthalmic agent (e.g., a muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 97% ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 98% of an ophthalmic agent (e.g., a muscarinic antagonist) over an extended period of time under storage conditions. In some embodiments, the composition comprises at least about 99% of the ophthalmic agent (e.g., muscarinic antagonist) over an extended period of time under storage conditions.

In some embodiments, the composition has at least about 80% efficacy after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 81% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 82% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 83% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 84% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 85% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 86% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 87% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 88% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least about 89% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 90% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 91% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 92% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 93% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 94% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 95% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 96% after an extended period of time under storage conditions. In some embodiments, the composition has at least 97% efficacy after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 98% after an extended period of time under storage conditions. In some embodiments, the composition has an efficacy of at least 99% after an extended period of time under storage conditions.

In some embodiments, the extended period of time is at least 1 week. In some embodiments, the extended period of time is at least 2 weeks. In some embodiments, the extended period of time is at least 3 weeks. In some embodiments, the extended period of time is at least 1 month. In some embodiments, the extended period of time is at least 2 months. In some embodiments, the extended period of time is at least 3 months. In some embodiments, the extended period of time is at least 4 months. In some embodiments, the extended period of time is at least 5 months. In some embodiments, the extended period of time is at least 6 months. In some embodiments, the extended period of time is at least 7 months. In some embodiments, the extended period of time is at least 8 months. In some embodiments, the extended period of time is at least 9 months. In some embodiments, the extended period of time is at least 10 months. In some embodiments, the extended period of time is at least 11 months. In some embodiments, the extended period of time is at least 12 months (i.e., 1 year). In some embodiments, the extended period of time is at least 18 months (i.e., 1.5 years). In some embodiments, the extended period of time is at least 24 months (i.e., 2 years). In some embodiments, the extended period of time is at least 36 months (i.e., 3 years). In some embodiments, the extended period of time is at least 3 years. In some embodiments, the extended period of time is at least 5 years or more.

In some embodiments, the storage conditions are at a temperature between about 20 ℃ and about 70 ℃. In some embodiments, the temperature of the storage conditions is between about 25 ℃ and about 65 ℃, between about 30 ℃ and about 60 ℃, between about 35 ℃ and about 55 ℃, or between about 40 ℃ and about 50 ℃. In some embodiments, the temperature of the storage conditions is about 25 ℃. In some embodiments, the storage conditions are at a temperature of about 40 ℃. In some embodiments, the storage conditions are at a temperature of about 60 ℃.

In some embodiments, the relative humidity of the storage conditions is between about 50% and about 80%, or between about 60% and about 75%. In some embodiments, the relative humidity of the storage conditions is about 60%. In some embodiments, the relative humidity of the storage conditions is about 75%.

In some embodiments, the composition comprises less than 60% H₂And O. In some embodiments, the composition comprises less than 55% H₂And O. In some embodiments, the composition comprises less than 50% H₂And O. In some embodiments, the composition comprises less than 45% H₂And O. In some embodiments, the composition comprises less than 40% of H₂And O. In some embodiments, the composition comprises less than 35% H₂And O. In some embodiments, the composition comprises less than 30% H₂And O. In some embodiments, the composition comprises less than 25% H₂And O. In some embodiments, the composition comprises less than 20% H₂And O. In some embodiments, the composition comprises less than 15% H₂And O. In some embodiments, the composition comprises less than 10% H₂O。

In some embodiments, the composition comprises less than 5% H₂O to 0% of H₂And O. In some embodiments, the composition comprises less than 5% H₂And O. In some embodiments, the composition comprises less than 4.5% H₂And O. In some embodiments, the composition comprises less than 4% H₂And O. In some embodiments, the composition comprises less than 3.5% H₂And O. In some embodiments, the composition comprises less than 3% H₂And O. In some embodiments, the composition comprises less than 2.5% H₂And O. In some embodiments, the composition comprises less than 2% H₂And O. In some embodiments, the composition comprises less than 1.5% H₂And O. In some embodiments, the composition comprises less than 1% H₂And O. In some embodiments, the composition comprises less than 0.5% H₂And O. In some embodiments, the composition comprises less than 0.4% H₂And O. In some embodiments, the composition comprises less than 0.3% H₂And O. In some embodiments, the composition comprises less than 0.2% H₂And O. In some embodiments, the composition comprises less than 0.1% H₂And O. In some embodiments, the composition comprises 0% H₂O。

In some embodiments, the composition has a pD of about 4 to about 8, about 4.5 to about 7.8, about 5 to about 7.5, or about 5.5 to about 7. In some embodiments, the composition has a pD of less than about 7.5. In some embodiments, the composition has a pD of less than about 7.4. In some embodiments, the composition has a pD of less than about 7.3. In some embodiments, the composition has a pD of less than about 7.2. In some embodiments, the composition has a pD of less than about 7.1. In some embodiments, the composition has a pD of less than about 7. In some embodiments, the composition has a pD of less than about 6.9. In some embodiments, the composition has a pD of less than about 6.8. In some embodiments, the composition has a pD of less than about 6.7. In some embodiments, the composition has a pD of less than about 6.6. In some embodiments, the composition has a pD of less than about 6.5. In some embodiments, the composition has a pD of less than about 6.4. In some embodiments, the composition has a pD of less than about 6.3. In some embodiments, the composition has a pD of less than about 6.2. In some embodiments, the composition has a pD of less than about 6.1. In some embodiments, the composition has a pD of less than about 6. In some embodiments, the composition has a pD of less than about 5.9. In some embodiments, the composition has a pD of less than about 5.8. In some embodiments, the composition has a pD of less than about 5.7. In some embodiments, the composition has a pD of less than about 5.6. In some embodiments, the composition has a pD of less than about 5.5. In some embodiments, the composition has a pD of less than about 5.4. In some embodiments, the composition has a pD of less than about 5.3. In some embodiments, the composition has a pD of less than about 5.2. In some embodiments, the composition has a pD of less than about 5.1. In some embodiments, the composition has a pD of less than about 5. In some embodiments, the composition has a pD of less than about 4.9. In some embodiments, the composition has a pD of less than about 4.8. In some embodiments, the composition has a pD of less than about 4.7. In some embodiments, the composition has a pD of less than about 4.6. In some embodiments, the composition has a pD of less than about 4.5. In some embodiments, the composition has a pD of less than about 4.4. In some embodiments, the composition has a pD of less than about 4.3. In some embodiments, the composition has a pD of less than about 4.2. In some embodiments, the composition has a pD of less than about 4.1. In some embodiments, the composition has a pD of less than about 4.

In some embodiments, the composition comprising deuterated water has a phase shift relative to the composition comprising H₂Reduced buffering capacity of equivalent compositions of O. As described elsewhere herein, in some embodiments, the reduced buffering capacity allows compositions comprising deuterated water to be more potent than compositions comprising H₂The faster rate of O normalization to physiological pH. In some embodiments, the reduced buffering capacity allows the composition to induce a phase shift compared to comprising H₂O is less tear reflex than the equivalent composition.

In some cases, compositions comprising deuterated water stabilize muscarinic antagonists (e.g., atropine). In some embodiments, this is due to the equivalent of H₂Concentration of reactive species (e.g., -OH) in O aqueous systems, D₂The concentration of reactive species (e.g., -OD) in the O aqueous system is lower. In some cases, base-catalyzed hydrolysis results in the presence of tropine degradants from atropine. In some cases, the atropine solution is at D when the concentration of reactive species that cause the formation of tropine degradants is low₂O aqueous System to equivalent H₂More stable in aqueous O systems. In some embodiments, with respect to H₂O formulated ophthalmic compositions, ophthalmic compositions formulated with deuterated water allow for more stable ophthalmic compositions.

In some embodiments, the composition comprises less than 20% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 15% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent.

In some embodiments, the composition comprises less than 10% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 5% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 2.0% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 1.5% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 1.0% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 0.5% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 0.4% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 0.3% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 0.2% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition comprises less than 0.1% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the primary degradant is tropine.

In some embodiments, the major degradant is an early elution related material with an RRT of 0.87-0.89 according to the UPLC method described herein (table 10). In some cases, the early elution-related substance is referred to as RRT 0.87-0.89. In some embodiments, the major degradant is RRT 0.87-0.89.

Concentration of ophthalmic muscarinic antagonist

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: from about 0.001% to about 0.050%, from about 0.005% to about 0.050%, from about 0.010% to about 0.050%, from about 0.015% to about 0.050%, from about 0.020% to about 0.050%, from about 0.025% to about 0.050%, from about 0.030% to about 0.050%, from about 0.035% to about 0.050%, from about 0.040% to about 0.050%, or from about 0.045% to about 0.050% of an ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof. In some cases, upon administration of the ophthalmic composition, the prodrug of the ophthalmic agent (e.g., muscarinic antagonist) is chemically converted to the ophthalmic agent (e.g., muscarinic antagonist). In a non-limiting example, the muscarinic antagonist prodrug has a chemical bond that is cleavable by one or more enzymes in the tear fluid. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate. As described herein, the ophthalmic agent includes optically pure stereoisomers, optically enriched stereoisomers, and racemic mixtures of stereoisomers. For example, some ophthalmic compositions disclosed herein comprise atropine or atropine sulfate, wherein the atropine is a racemic mixture of D-and L-isomers; and some ophthalmic compositions disclosed herein comprise atropine or atropine sulfate, wherein the atropine is optically enriched preferentially to the more ophthalmically active L-isomer.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: about 0.001% to about 0.045%, about 0.005% to about 0.045%, about 0.010% to about 0.045%, about 0.015% to about 0.045%, about 0.020% to about 0.045%, about 0.025% to about 0.045%, about 0.030% to about 0.045%, about 0.035% to about 0.045%, or about 0.040% to about 0.045% of an ophthalmic agent or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: about 0.001% to about 0.040%, about 0.005% to about 0.040%, about 0.010% to about 0.040%, about 0.015% to about 0.040%, about 0.020% to about 0.040%, about 0.025% to about 0.040%, about 0.030% to about 0.040%, about 0.035% to about 0.040% of the active ingredient or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: about 0.001% to about 0.035%, about 0.005% to about 0.035%, about 0.010% to about 0.035%, about 0.015% to about 0.035%, about 0.020% to about 0.035%, about 0.025% to about 0.035%, or about 0.030% to about 0.035% of an ophthalmic agent or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: from about 0.001% to about 0.030%, from about 0.005% to about 0.030%, from about 0.010% to about 0.030%, from about 0.015% to about 0.030%, from about 0.020% to about 0.030%, or from about 0.025% to about 0.030% of the active ingredient or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: about 0.001% to about 0.025%, about 0.005% to about 0.025%, about 0.010% to about 0.025%, about 0.015% to about 0.025%, or about 0.020% to about 0.025% of an ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: from about 0.001% to about 0.020%, from about 0.005% to about 0.020%, from about 0.010% to about 0.020%, or from about 0.015% to about 0.020% of the active ingredient or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: about 0.001% to about 0.015%, about 0.005% to about 0.015%, or about 0.010% to about 0.015% of an ophthalmic agent or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: about 0.001% to about 0.010%, about 0.005% to about 0.010%, or about 0.008% to about 0.010% of an ophthalmic agent or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

In some embodiments, the compositions described herein have the following concentrations of ophthalmic agent, by weight of the composition: about 0.001%, 0.005%, 0.010%, 0.015%, 0.020%, 0.025%, 0.030%, 0.035%, 0.040%, 0.045%, or 0.050% of an ophthalmic agent or a pharmaceutically acceptable prodrug or salt thereof. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

Without wishing to be bound by any particular theory, it is contemplated herein that low concentrations of an ophthalmic agent (e.g., a muscarinic antagonist, such as atropine or atropine sulfate) in the disclosed ophthalmic compositions provide sufficient and consistent therapeutic benefit to an individual in need thereof while reducing or avoiding ocular side effects associated with ophthalmic formulations containing higher concentrations of the ophthalmic agent (e.g., a muscarinic antagonist, such as atropine or atropine sulfate), including glare due to pupil dilation and blurred vision due to loss of accommodation.

Stability of aqueous solution

In some embodiments, the compositions described herein comprise a buffer. In some embodiments, the buffer is selected from borate, borate-polyol complex, phosphate buffer, citrate buffer, acetate buffer, carbonate buffer, organic buffer, amino acid buffer, or combinations thereof. In some embodiments, the compositions described herein comprise a buffer comprising deuterated water. In some embodiments, the deuterated buffer is selected from borate, borate-polyol complex, phosphate buffer, citrate buffer, acetate buffer, carbonate buffer, organic buffer, amino acid buffer, or combinations thereof formulated in deuterated water.

In some cases, the borate salt includes boric acid, salts of boric acid, other pharmaceutically acceptable borate salts, and combinations thereof. In some cases, borates include boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and other such borates.

As used herein, the term polyol includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not in a trans configuration relative to each other. In some embodiments, the polyols are chain or cyclic, substituted or unsubstituted, or mixtures thereof, as long as the resulting complex is water soluble and pharmaceutically acceptable. In some cases, examples of polyols include: sugars, sugar alcohols, sugar acids and uronic acids. In some cases, polyols include, but are not limited to: mannitol, glycerol, xylitol and sorbitol.

In some embodiments, the phosphate buffer comprises phosphoric acid; alkali metal phosphates such as disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and tripotassium phosphate; alkaline earth metal phosphates such as calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium dihydrogen phosphate, dimagnesium phosphate (magnesium hydrogen phosphate), and trimagnesium phosphate; ammonium phosphates such as diammonium hydrogen phosphate and ammonium dihydrogen phosphate; or a combination thereof. In some cases, the phosphate buffer is an anhydride. In some cases, the phosphate buffer is a hydrate.

In some embodiments, borate-polyol complexes include those described in U.S. patent No. 6,503,497. In some cases, the borate-polyol complex comprises borate in an amount of about 0.01% w/v to about 2.0% w/v and one or more polyols in an amount of about 0.01% w/v to about 5.0% w/v.

In some cases, the citrate buffer includes citric acid and sodium citrate.

In some cases, the acetate buffer includes acetic acid, potassium acetate, and sodium acetate.

In some cases, the carbonate buffer includes sodium bicarbonate and sodium carbonate.

In some cases, organic buffers include Good buffers such as 2- (N-morpholino) ethanesulfonic acid (MES), N- (2-acetamido) iminodiacetic acid, N- (carbamoylmethyl) iminodiacetic acid (ADA), piperazine-N, N' -bis (2-ethanesulfonic acid) (PIPES), N- (2-acetamido) -2-aminoethanesulfonic Acid (ACES), β -hydroxy-4-morpholinopropanesulfonic acid, 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), cholamine chloride, 3- (N-morpholino) propanesulfonic acid (MOPS), N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (BES), 2- [ (2-hydroxy-1, 1-bis (hydroxymethyl) ethyl) amino ] ethanesulfonic acid (TES), 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 3- (N, N-bis [ 2-hydroxyethyl ] amino) -2-hydroxypropanesulfonic acid (DIPSO), acetamidoglycine, 3- { [1, 3-dihydroxy-2- (hydroxymethyl) -2-propyl ] amino } -2-hydroxy-1-propanesulfonic acid (TAPSO), piperazine-1, 4-bis (2-hydroxypropanesulfonic acid) (POPSO), 4- (2-hydroxyethyl) piperazine-1- (2-hydroxypropanesulfonic acid) Hydrate (HEPSO), 3- [4- (2-hydroxyethyl) -1-piperazinyl ] propanesulfonic acid (HEPPS), Sodium N-tris (hydroxymethyl) methylglycine (tricine), glycinamide, bicine or sodium N-tris (hydroxymethyl) methyl-3-aminopropanesulfonate (TAPS); glycine; and Diethanolamine (DEA).

In some cases, amino acid buffers include taurine, aspartic acid and salts thereof (e.g., potassium salts, etc.), E-aminocaproic acid, and the like.

In some cases, the compositions described herein further comprise a tonicity modifier. Tonicity adjusting agents are agents that are incorporated into formulations such as ophthalmic compositions to reduce local irritation by preventing osmotic shock at the site of application. In some cases, a buffer solution that broadly maintains an ophthalmic solution at a particular ionic concentration and pD and/or a pD modulator is considered a tonicity modifier. In some cases, the tonicity modifier includes various salts, such as halide salts of monovalent cations. In some cases, tonicity adjusting agents include mannitol, sorbitol, dextrose, sucrose, urea, and glycerol. In some cases, suitable tonicity adjusting agents include sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerol, or combinations thereof.

In some cases, the concentration of the tonicity modifier in the compositions described herein is from about 0.5% to about 2.0%. In some cases, the concentration of the tonicity modifier in the compositions described herein is from about 0.7% to about 1.8%, from about 0.8% to about 1.5%, or from about 1% to about 1.3%. In some cases, the concentration of the tonicity modifier is about 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, or 1.9%. In some cases, the percentage is a weight percentage.

In some cases, the compositions described herein further comprise a pD modulator. In some embodiments, the pD modulator used is an acid or a base. In some embodiments, the base is an oxide, hydroxide, carbonate, bicarbonate, or the like. In some cases, the oxide is a metal oxide, such as calcium oxide, magnesium oxide, or the like; hydroxides are hydroxides of alkali metals and alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like or their deuterated equivalents, while carbonates are sodium carbonate, sodium bicarbonate, potassium bicarbonate, and the like. In some cases, the acids are inorganic and organic acids such as hydrochloric acid, nitric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, malic acid, tartaric acid, and the like, or deuterated equivalents thereof. In some cases, the pD modulator includes, but is not limited to, acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof. In some embodiments, the pD modulator includes DCl and NaOD.

In some cases, the composition has a pD of about 4 to about 8, about 4.5 to about 7.8, about 5 to about 7.5, or about 5.5 to about 7. In some embodiments, the composition has a pD of less than about 7.5. In some embodiments, the composition has a pD of less than about 7.4. In some embodiments, the composition has a pD of less than about 7.3. In some embodiments, the composition has a pD of less than about 7.2. In some embodiments, the composition has a pD of less than about 7.1. In some embodiments, the composition has a pD of less than about 7. In some embodiments, the composition has a pD of less than about 6.9. In some embodiments, the composition has a pD of less than about 6.8. In some embodiments, the composition has a pD of less than about 6.7. In some embodiments, the composition has a pD of less than about 6.6. In some embodiments, the composition has a pD of less than about 6.5. In some embodiments, the composition has a pD of less than about 6.4. In some embodiments, the composition has a pD of less than about 6.3. In some embodiments, the composition has a pD of less than about 6.2. In some embodiments, the composition has a pD of less than about 6.1. In some embodiments, the composition has a pD of less than about 6. In some embodiments, the composition has a pD of less than about 5.9. In some embodiments, the composition has a pD of less than about 5.8. In some embodiments, the composition has a pD of less than about 5.7. In some embodiments, the composition has a pD of less than about 5.6. In some embodiments, the composition has a pD of less than about 5.5. In some embodiments, the composition has a pD of less than about 5.4. In some embodiments, the composition has a pD of less than about 5.3. In some embodiments, the composition has a pD of less than about 5.2. In some embodiments, the composition has a pD of less than about 5.1. In some embodiments, the composition has a pD of less than about 5. In some embodiments, the composition has a pD of less than about 4.9. In some embodiments, the composition has a pD of less than about 4.8. In some embodiments, the composition has a pD of less than about 4.7. In some embodiments, the composition has a pD of less than about 4.6. In some embodiments, the composition has a pD of less than about 4.5. In some embodiments, the composition has a pD of less than about 4.4. In some embodiments, the composition has a pD of less than about 4.3. In some embodiments, the composition has a pD of less than about 4.2. In some embodiments, the composition has a pD of less than about 4.1. In some embodiments, the composition has a pD of less than about 4. In some embodiments, the pD is the pD of the composition after an extended period of time under storage conditions.

In some cases, the composition has an initial pD of about 4 to about 8, about 4.5 to about 7.8, about 5 to about 7.5, or about 5.5 to about 7. In some embodiments, the composition has an initial pD of about 7.5. In some embodiments, the composition has an initial pD of about 7.4. In some embodiments, the composition has an initial pD of about 7.3. In some embodiments, the composition has an initial pD of about 7.2. In some embodiments, the composition has an initial pD of about 7.1. In some embodiments, the composition has an initial pD of about 7. In some embodiments, the composition has an initial pD of about 6.9. In some embodiments, the composition has an initial pD of about 6.8. In some embodiments, the composition has an initial pD of about 6.7. In some embodiments, the composition has an initial pD of about 6.6. In some embodiments, the composition has an initial pD of about 6.5. In some embodiments, the composition has an initial pD of about 6.4. In some embodiments, the composition has an initial pD of about 6.3. In some embodiments, the composition has an initial pD of about 6.2. In some embodiments, the composition has an initial pD of about 6.1. In some embodiments, the composition has an initial pD of about 6. In some embodiments, the composition has an initial pD of about 5.9. In some embodiments, the composition has an initial pD of about 5.8. In some embodiments, the composition has an initial pD of about 5.7. In some embodiments, the composition has an initial pD of about 5.6. In some embodiments, the composition has an initial pD of about 5.5. In some embodiments, the composition has an initial pD of about 5.4. In some embodiments, the composition has an initial pD of about 5.3. In some embodiments, the composition has an initial pD of about 5.2. In some embodiments, the composition has an initial pD of about 5.1. In some embodiments, the composition has an initial pD of about 5. In some embodiments, the composition has an initial pD of about 4.9. In some embodiments, the composition has an initial pD of about 4.8. In some embodiments, the composition has an initial pD of about 4.7. In some embodiments, the composition has an initial pD of about 4.6. In some embodiments, the composition has an initial pD of about 4.5. In some embodiments, the composition has an initial pD of about 4.4. In some embodiments, the composition has an initial pD of about 4.3. In some embodiments, the composition has an initial pD of about 4.2. In some embodiments, the composition has an initial pD of about 4.1. In some embodiments, the composition has an initial pD of about 4.

In some embodiments, the pD of a composition described herein is related to the stability of the composition. In some embodiments, the stabilized composition comprises pD of about 4 to about 8, about 4.5 to about 7.8, about 5 to about 7.5, or about 5.5 to about 7. In some embodiments, the stable composition comprises a pD of less than about 7.5. In some embodiments, the stable composition comprises a pD of less than about 7.4. In some embodiments, the stable composition comprises a pD of less than about 7.3. In some embodiments, the stable composition comprises a pD of less than about 7.2. In some embodiments, the stable composition comprises a pD of less than about 7.1. In some embodiments, the stable composition comprises a pD of less than about 7. In some embodiments, the stable composition comprises a pD of less than about 6.9. In some embodiments, the stable composition comprises a pD of less than about 6.8. In some embodiments, the stable composition comprises a pD of less than about 6.7. In some embodiments, the stable composition comprises a pD of less than about 6.6. In some embodiments, the stable composition comprises a pD of less than about 6.5. In some embodiments, the stable composition comprises a pD of less than about 6.4. In some embodiments, the stable composition comprises a pD of less than about 6.3. In some embodiments, the stable composition comprises a pD of less than about 6.2. In some embodiments, the stable composition comprises a pD of less than about 6.1. In some embodiments, the stable composition comprises a pD of less than about 6. In some embodiments, the stable composition comprises a pD of less than about 5.9. In some embodiments, the stable composition comprises a pD of less than about 5.8. In some embodiments, the stable composition comprises a pD of less than about 5.7. In some embodiments, the stable composition comprises a pD of less than about 5.6. In some embodiments, the stable composition comprises a pD of less than about 5.5. In some embodiments, the stable composition comprises a pD of less than about 5.4. In some embodiments, the stable composition comprises a pD of less than about 5.3. In some embodiments, the stable composition comprises a pD of less than about 5.2. In some embodiments, the stable composition comprises a pD of less than about 5.1. In some embodiments, the stable composition comprises a pD of less than about 5. In some embodiments, the stable composition comprises a pD of less than about 4.9. In some embodiments, the stable composition comprises a pD of less than about 4.8. In some embodiments, the stable composition comprises a pD of less than about 4.7. In some embodiments, the stable composition comprises a pD of less than about 4.6. In some embodiments, the stable composition comprises a pD of less than about 4.5. In some embodiments, the stable composition comprises a pD of less than about 4.4. In some embodiments, the stable composition comprises a pD of less than about 4.3. In some embodiments, the stable composition comprises a pD of less than about 4.2. In some embodiments, the stable composition comprises a pD of less than about 4.1. In some embodiments, the stable composition comprises a pD of less than about 4.

As described elsewhere herein, in some cases, D₂Aqueous O systems stabilize muscarinic antagonists (e.g., atropine). In some embodiments, this is due to the equivalent of H₂Concentration of reactive species (e.g., -OH) in O aqueous systems, D₂The concentration of reactive species (e.g., -OD) in the O aqueous system is lower. In some cases, D₂Concentration ratio of reactive species (e.g., -OD) in O aqueous system to equivalent H₂The concentration of reactive species (e.g., -OH) in the aqueous O system is about one third lower. In some cases, this is due to D₂O has a dissociation constant lower than or less than H₂And O. For example, K_a(H₂O) is 1x10^-14And K is_a(D₂O) is 1x10^-15. Thus, D₂O is the ratio H₂O weaker acid. In some cases, base-catalyzed hydrolysis results in the presence of tropine degradants from atropine. In some cases, the atropine solution is at D when the concentration of reactive species that cause the formation of tropine degradants is low₂O aqueous System to equivalent H₂More stable in aqueous O systems. In some embodiments, with respect to H₂O formulated ophthalmic compositions, ophthalmic compositions formulated with deuterated water allow for more stable ophthalmic compositions.

In some embodiments, the presence of deuterated water changes the pKa of the buffer. In some embodiments, the presence of deuterated water allows the ophthalmic composition to mimic the stability of a lower pH system. In some cases, the buffering capacity of the ophthalmic composition is reduced, allowing for a faster change in pH. In some cases, the reduced buffering capacity of an ophthalmic composition when administered into the eye allows the ophthalmic composition to be administered at a ratio of H to H₂Ophthalmic compositions formulated in O reach physiological pH at a faster rate. In some cases, with H₂The ophthalmic composition formulated with deuterated water allows for less tear production or less tear reflex in the eye compared to the ophthalmic composition formulated with deuterated water.

In some cases, the compositions described herein further comprise a disinfectant. In some cases, the disinfecting agent includes a polymeric biguanide, a polymeric quaternary ammonium compound, a chlorite, a biguanide, a chlorite compound (e.g., potassium chlorite, sodium chlorite, calcium chlorite, magnesium chlorite, or mixtures thereof), and combinations thereof.

In some cases, the compositions described herein further comprise a preservative. In some cases, a preservative is added to a composition described herein at a concentration to prevent the growth of or destroy microorganisms introduced into the composition. In some cases, a microorganism refers to a bacterium (e.g., Proteus mirabilis (Proteus mirabilis), Serratia marcescens (Serratia marcescens)), a virus (e.g., herpes simplex virus, herpes zoster virus), a fungus (e.g., a fungus from the genus Fusarium (Fusarium)), a yeast (e.g., Candida albicans)), a parasite (e.g., Plasmodium spp.), a jawborm nematode (Gnathostoma spp.), a protozoan (e.g., Giardia lamblia), a nematode (e.g., Onchocercus volvulus), a helminth (e.g., Dirofilaria immitis), and/or an amoeba (e.g., acanthamoeba (acanthamoba)).

In some cases, the concentration of the preservative is from about 0.0001% to about 1%, from about 0.001% to about 0.8%, from about 0.004% to about 0.5%, from about 0.008% to about 0.1%, and from about 0.01% to about 0.08%. In some cases, the concentration of preservative is about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.008%, 0.009%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0%.

In some embodiments, the preservative is selected from the group consisting of benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxychloro complex, sofzia (alcon), polyquaternium-1, chlorobutanol, disodium edetate, and polyhexamethylene biguanide.

In some embodiments, the compositions described herein are stored in a plastic container. In some embodiments, the material of the plastic container comprises High Density Polyethylene (HDPE), Low Density Polyethylene (LDPE), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polypropylene (PP), Polystyrene (PS), fluorine-treated HDPE, post-consumer recycled (post-consumer) resin (PCR), K-resin (SBC), or bioplastic. In some embodiments, the material of the plastic container comprises LDPE.

In some embodiments, the compositions described herein are stored in a plastic container. In some embodiments, the composition stored in the plastic container has a pD of about 4 to about 8, about 4.5 to about 7.9, or about 4.9 to about 7.5. In some embodiments, the composition stored in the plastic container has a pD of less than about 7.4. In some embodiments, the composition stored in the plastic container has a pD of less than about 7.3. In some embodiments, the composition stored in the plastic container has a pD of less than about 7.2. In some embodiments, the composition stored in the plastic container has a pD of less than about 7.1. In some embodiments, the composition stored in the plastic container has a pD of less than about 7. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.9. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.8. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.7. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.6. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.5. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.4. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.3. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.2. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.1. In some embodiments, the composition stored in the plastic container has a pD of less than about 6. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.9. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.8. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.7. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.6. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.5. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.4. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.3. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.2. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.1. In some embodiments, the composition stored in the plastic container has a pD of less than about 5. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.9. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.8. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.7. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.6. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.5. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.4. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.3. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.2. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.1. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.

In some embodiments, the composition stored in the plastic container has at least 80% efficacy after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container has an efficacy of at least 85% after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container has an efficacy of at least 90% after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container has an efficacy of at least 93% after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container has an efficacy of at least 95% after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container has an efficacy of at least 97% after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container has at least 98% efficacy after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container has an efficacy of at least 99% after an extended period of time under storage conditions. In some cases, the storage conditions include a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some cases, the extended period of time is at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

In some embodiments, the composition stored in the plastic container has at least 80% efficacy at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some embodiments, the composition stored in the plastic container has an efficacy of at least 85% at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some embodiments, the composition stored in the plastic container has at least 90% efficacy at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some embodiments, the composition stored in the plastic container has at least 93% efficacy at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some embodiments, the composition stored in the plastic container has at least 95% efficacy at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some embodiments, the composition stored in the plastic container has at least 97% efficacy at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some embodiments, the composition stored in the plastic container has at least 98% efficacy at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some embodiments, the composition stored in the plastic container has at least 99% efficacy at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃.

In some embodiments, the composition stored in the plastic container has at least 80% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 85% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 90% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 93% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 95% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 97% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 98% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 99% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

In some embodiments, the composition stored in the plastic container comprises less than 20% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 15% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 10% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 5% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions.

In some embodiments, the composition stored in the plastic container comprises less than 2.5% of the major degradant to less than 0.1% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 2.5% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 2.0% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 1.5% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 1.0% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.5% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.4% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.3% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some embodiments, the composition stored in the plastic container comprises less than 0.2% of the major degradant after an extended period of time under storage conditions, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.1% of the major degradants based on the concentration of the ophthalmic agent after an extended period of time under storage conditions. In some cases, the storage conditions include a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some cases, the extended period of time is at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

In some embodiments, the composition stored in the plastic container comprises less than 20% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 15% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 10% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 5% of major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent.

In some embodiments, the composition stored in the plastic container comprises less than 2.5% of the major degradant to less than 0.1% of the major degradant at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 2.5% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 2.0% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 1.5% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 1.0% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.5% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.4% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.3% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.2% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.1% of the major degradants at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃ based on the concentration of the ophthalmic agent.

In some embodiments, the composition stored in the plastic container comprises less than 20% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 15% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 10% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 5% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent.

In some embodiments, the composition stored in the plastic container comprises less than 2.5% of the major degradant to less than 0.1% of the major degradant over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 2.5% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 2.0% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 1.5% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 1.0% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.5% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.4% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.3% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.2% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container comprises less than 0.1% of major degradants over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months, based on the concentration of the ophthalmic agent.

In some embodiments, the compositions described herein are stored in a glass container. In some embodiments, the glass container is a glass vial, such as, for example, a type I, type II, or type III glass vial. In some embodiments, the glass container is a type I glass vial. In some embodiments, the type I glass vial is a borosilicate glass vial.

In some embodiments, the composition stored in the glass container has a pD of greater than about 7. In some embodiments, the composition stored in the glass container has a pD of greater than about 7.5. In some embodiments, the composition stored in the glass container has a pD of greater than about 8. In some embodiments, the composition stored in the glass container has a pD of greater than about 8.5. In some embodiments, the composition stored in the glass container has a pD of greater than about 9.

In some embodiments, the composition stored in the glass container has less than 60% efficacy at a temperature of about 25 ℃, about 40 ℃, or about 60 ℃. In some embodiments, the composition stored in the glass container has less than 60% efficacy over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

In some embodiments, the composition stored in the glass container is less stable than the composition stored in the plastic container.

In some embodiments, the composition is stored in the dark. In some cases, the composition is stored in the presence of light. In some cases, the light is indoor light, or sunlight. In some cases, the composition is stable when stored in the presence of light.

In some embodiments, the compositions described herein are formulated as an aqueous solution. In some embodiments, the aqueous solution is a stable aqueous solution. In some cases, the aqueous solution is stored in a plastic container as described above. In some cases, the aqueous solution is not stored in a glass container. In some cases, the aqueous solution is stored in the dark. In some cases, the aqueous solution is stored in the presence of light. In some cases, the aqueous solution is stable in the presence of light.

In particular embodiments, the ophthalmically acceptable formulation alternatively comprises a cyclodextrin. Cyclodextrins are cyclic oligosaccharides containing 6, 7 or 8 glucopyranose units, and are called α -cyclodextrin, β -cyclodextrin or γ -cyclodextrin, respectively. Cyclodextrins have a hydrophilic exterior that enhances water solubility and a hydrophobic interior that forms a cavity. In an aqueous environment, the hydrophobic portion of other molecules typically enter the hydrophobic cavity of the cyclodextrin to form an inclusion complex. Additionally, cyclodextrins are also capable of other types of non-binding interactions with molecules that are not inside the hydrophobic cavity. The cyclodextrins have three free hydroxyl groups per glucopyranose unit, or 18 hydroxyl groups on α -cyclodextrin, 21 hydroxyl groups on β -cyclodextrin and 24 hydroxyl groups on γ -cyclodextrin. In some embodiments, one or more of these hydroxyl groups are reacted with any of a number of reagents to form a number of cyclodextrin derivatives, including hydroxypropyl ethers, sulfonates, and sulfoalkyl ethers. The structures of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin (HP β CD) are shown below.

In some embodiments, the use of cyclodextrin in the pharmaceutical compositions described herein improves the solubility of the drug. Inclusion compounds are associated with many cases of enhanced solubility; however, other interactions between the cyclodextrin and the insoluble compound also improve solubility. Hydroxypropyl-beta-cyclodextrin (HP β CD) is commercially available as a pyrogen-free product. It is a non-hygroscopic white powder that is readily soluble in water. HP β CD is thermostable and does not degrade at neutral pH. Thus, cyclodextrins improve the solubility of therapeutic agents in the composition or formulation. Thus, in some embodiments, cyclodextrins are included to enhance the solubility of ophthalmically acceptable ophthalmic agents within the formulations described herein. Additionally, in other embodiments, the cyclodextrin serves as a controlled release excipient within the formulations described herein.

By way of example only, cyclodextrin derivatives used include alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfated beta-cyclodextrin, sulfated alpha-cyclodextrin, sulfobutyl ether beta-cyclodextrin.

The concentration of cyclodextrin used in the compositions and methods disclosed herein will vary depending on the physiochemical properties, pharmacokinetic properties, side effects or adverse events, formulation considerations or other factors related to the therapeutic ophthalmic agent or salt or prodrug thereof or to the properties of the other agents in the composition. Thus, in certain instances, the concentration or amount of cyclodextrin used in compositions and methods according to the present disclosure will vary as desired. In use, the principles, examples and teachings described herein are utilized to select the amount of cyclodextrin required to enhance the solubility of an ophthalmic agent and/or to function as a controlled release excipient in any of the formulations described herein.

Other stabilizers useful in the ophthalmically acceptable formulations disclosed herein include, for example, fatty acids, fatty alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ether, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and combinations thereof. In some embodiments, amide analogs of stabilizers are also used. In other embodiments, the stabilizing agent is selected to alter the hydrophobicity of the formulation, improve the mixing of various components in the formulation, control the moisture content of the formulation, or control the fluidity of the phase.

In other embodiments, the stabilizing agent is present in an amount sufficient to inhibit degradation of the ophthalmic agent. Examples of such stabilizers include, but are not limited to: glycerol, methionine, thioglycerol, EDTA, ascorbic acid, polysorbate 80, polysorbate 20, arginine, heparin, dextran sulfate, cyclodextrins, pentosan polysulfate and other heparinoids, divalent cations such as magnesium and zinc, or combinations thereof.

Other stabilizers useful for ophthalmically acceptable formulations include one or more anti-aggregation additives to enhance stability of the ophthalmic formulation by reducing the rate of protein aggregation. The anti-aggregation additive selected will depend on the nature of the condition to which the ophthalmic agent, e.g., a muscarinic antagonist (e.g., atropine or a pharmaceutically acceptable salt thereof), is exposed. For example, certain formulations that undergo agitation and thermal stress require different anti-aggregation additives than formulations that undergo lyophilization and reconstitution. By way of example only, useful anti-aggregation additives include urea, guanidinium chloride, simple amino acids (such as glycine or arginine), sugars, polyols, polysorbates, polymers (such as polyethylene glycol and dextran), alkyl sugars (such as alkyl glycosides), and surfactants.

Other useful formulations optionally include one or more ophthalmically acceptable antioxidants to enhance chemical stability, if desired. By way of example only, suitable antioxidants include ascorbic acid, methionine, sodium thiosulfate, and sodium metabisulfite. In one embodiment, the antioxidant is selected from the group consisting of metal chelators, thiol-containing compounds, and other general stabilizers.

Other useful compositions include one or more ophthalmically acceptable surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, for example, octoxynol 10, octoxynol 40.

In some embodiments, the ophthalmically acceptable pharmaceutical formulations described herein are stable with respect to degradation of the compound (e.g., less than 30% degradation, less than 25% degradation, less than 20% degradation, less than 15% degradation, less than 10% degradation, less than 8% degradation, less than 5% degradation, less than 3% degradation, less than 2% degradation, or less than 5% degradation) under storage conditions (e.g., room temperature) for any period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 5 weeks, at least about 6 weeks. In other embodiments, the formulations described herein are stable with respect to compound degradation over a period of at least about 1 week. Also described herein are formulations that are stable with respect to degradation of the compound over a period of at least about 1 month.

In other embodiments, additional surfactants (co-surfactants) and/or buffers are combined with one or more pharmaceutically acceptable vehicles as described previously herein, such that the surfactants and/or buffers maintain the product at an optimal pD for stability. Suitable co-surfactants include, but are not limited to: a) natural and synthetic lipophilic agents, such as phospholipids, cholesterol and cholesterol fatty acid esters and derivatives thereof; b) nonionic surfactants including, for example, polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Span), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (tween 80), polyoxyethylene (20) sorbitan monostearate (tween 60), polyoxyethylene (20) sorbitan monolaurate (tween 20) and other tweens), sorbitan esters, glycerol esters (e.g., Myrj and triacetin), polyethylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, polysorbate 80, poloxamers (poloxamers), poloxamines (poloxamines), polyoxyethylene castor oil derivatives (e.g., poloxamines)RH40、Cremphor A25、Cremphor A20、EL) and other Cremophor, sulfosuccinates, alkyl sulfates (SLS); PEG glyceryl fatty acid esters, such as PEG-8 glyceryl caprylate/caprate(Labrasol), PEG-4 glyceryl caprylate/caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate (Gelucire 444/14), PEG-6 glyceryl monooleate (Labrafil M1944 CS), PEG-6 glyceryl linoleate (Labrafil M2125 CS); propylene glycol mono-and di-fatty acid esters such as propylene glycol laurate, propylene glycol caprylate/caprate;700. ascorbyl-6-palmitate, octadecylamine, sodium lauryl sulfate, polyoxyethylene glycerol triricinoleate, and any combination or mixture thereof; c) anionic surfactants including, but not limited to, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium sulfosuccinate, dioctyl, sodium alginate, alkyl polyoxyethylene sulfate, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, bile salts, and any combinations or mixtures thereof; and d) cationic surfactants such as cetyltrimethylammonium bromide and dodecyldimethylbenzyl-ammonium chloride.

In yet another embodiment, when one or more co-surfactants are used in the ophthalmologically acceptable formulation of the invention, they are combined, e.g., with a pharmaceutically acceptable vehicle, and are present in the final formulation in an amount, e.g., in the range of about 0.1% to about 20%, about 0.5% to about 10%.

In one embodiment, the surfactant has an HLB value of from 0 to 20. In other embodiments, the surfactant has an HLB value of 0 to 3,4 to 6, 7 to 9,8 to 18, 13 to 15, 10 to 18.

pD

In some embodiments, the pds of the compositions described herein are modulated (e.g., by using a buffer and/or a pD modulator) to an ophthalmically compatible pD in the range of about 4 to about 8, about 4.5 to about 7.5, or about 5 to about 7. In some embodiments, the ophthalmic composition has a pD of about 5.0 to about 7.0. In some embodiments, the ophthalmic composition has a pD of about 5.5 to about 7.0. In some embodiments, the ophthalmic composition has a pD of about 6.0 to about 7.0.

In some embodiments, useful formulations comprise one or more pD modulators or buffers. Suitable pD modulators or buffers include, but are not limited to, acetate, bicarbonate, ammonium chloride, citrate, phosphate, deuterated forms of acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof. In some embodiments, the pD modulator or buffer comprises deuterated hydrochloric acid (DCl), deuterated sodium hydroxide (NaOD), deuterated acetic acid (CD)₃COOD) or deuterated citric acid (C)₆D₈O₇)。

In one embodiment, when one or more buffers are used in the formulations of the present invention, they are combined, e.g., with a pharmaceutically acceptable vehicle, and are present in the final formulation in an amount, e.g., in the range of about 0.1% to about 20%, about 0.5% to about 10%. In certain embodiments of the invention, the amount of buffer included in the gel formulation is such that the pds of the gel formulation do not interfere with the body's natural buffer system.

In one embodiment, diluents are also used to stabilize the compounds because they provide a more stable environment. In some cases, salts dissolved in buffer solutions (which also provide pD control or maintenance) are used in the art as diluents, including but not limited to phosphate buffered saline solutions.

In some embodiments, pD is calculated according to the formula disclosed in Glasoe et al, "Use of glass electrodes to measure acids in deuterium oxides," J.physical chem.64(1): 188-. In some embodiments, pD is calculated as pD at pH +0.4, where pH is at a pH that includes deuterated water (e.g., D)₂O) measured or observed pH of the formulated ophthalmic composition in solution.

In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4 to about 8, about 4.5 to about 8, about 4.9 to about 7.9, about 5.4 to about 7.9, about 5.9 to about 7.9, about 6.4 to about 7.9, or about 7.4 to about 7.9. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.5-7.5, about 5.0 to about 7.5, about 5.5 to about 7.5, about 6.0 to about 7.5, or about 7.0 to about 7.5. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.5-7.0, about 5.0 to about 7.0, about 5.5 to about 7.0, about 6.0 to about 7.0, or about 6.5 to about 7.0. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.9-7.4, about 5.4 to about 7.4, about 5.9 to about 7.4, about 6.4 to about 7.4, or about 6.9 to about 7.4. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.5-6.5, about 5.0 to about 6.5, about 5.5 to about 6.5, or about 6.0 to about 6.5. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.9-6.9, about 5.4 to about 6.9, about 5.9 to about 6.9, or about 6.4 to about 6.9. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.5-6.0, about 5.0 to about 6.0, or about 5.5 to about 6.0. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.9-6.4, about 5.4 to about 6.4, or about 5.9 to about 6.4. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.5-5.5, or about 5.0 to about 5.5. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.9-5.9, or about 5.4 to about 5.9. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.5-5.0. In some embodiments, the ophthalmic aqueous, gel, or ointment compositions described herein have a pD of about 4.9-5.4.

In some embodiments, the ophthalmic composition is an ophthalmic aqueous composition. In some cases, the aqueous ophthalmic composition has a pD of about 4 to about 8, about 4.5 to about 7.8, about 5 to about 7.5, or about 5.5 to about 7. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.5. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.4. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.3. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.2. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.1. In some embodiments, the aqueous ophthalmic composition has a pD of about 7. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.9. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.8. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.7. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.6. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.5. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.4. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.3. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.2. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.1. In some embodiments, the aqueous ophthalmic composition has a pD of about 6. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.9. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.8. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.7. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.6. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.5. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.4. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.3. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.2. In some embodiments, the aqueous ophthalmic composition has a pD of about 5.1. In some embodiments, the aqueous ophthalmic composition has a pD of about 5. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.9. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.8. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.7. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.6. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.5. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.4. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.3. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.2. In some embodiments, the aqueous ophthalmic composition has a pD of about 4.1. In some embodiments, the aqueous ophthalmic composition has a pD of about 4. In some embodiments, the pD is an initial pD of the aqueous ophthalmic composition. In some embodiments, the pD is the pD of the aqueous ophthalmic composition after an extended period of time under storage conditions.

In some cases, the aqueous ophthalmic composition has an initial pD of about 4 to about 8, about 4.5 to about 7.8, about 5 to about 7.5, or about 5.5 to about 7. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 7.5. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 7.4. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 7.3. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 7.2. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 7.1. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 7. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.9. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.8. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.7. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.6. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.5. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.4. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.3. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.2. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6.1. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 6. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.9. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.8. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.7. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.6. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.5. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.4. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.3. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.2. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5.1. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 5. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.9. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.8. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.7. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.6. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.5. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.4. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.3. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.2. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.1. In some embodiments, the aqueous ophthalmic composition has an initial pD of about 4.

In some cases, the aqueous ophthalmic composition has a pD of about 4 to about 8, about 4.5 to about 7.8, about 5 to about 7.5, or about 5.5 to about 7. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 7.5. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 7.4. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 7.3. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 7.2. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 7.1. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 7. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.9. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.8. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.7. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.6. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.5. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.4. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.3. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.2. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6.1. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 6. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.9. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.8. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.7. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.6. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.5. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.4. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.3. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.2. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5.1. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 5. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.9. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.8. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.7. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.6. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.5. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.4. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.3. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.2. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4.1. In some embodiments, the aqueous ophthalmic composition has a pD of less than about 4. In some embodiments, the pD is the pD of the aqueous ophthalmic composition after an extended period of time under storage conditions.

In some embodiments, the pD of an aqueous ophthalmic composition described herein correlates with the stability of the aqueous ophthalmic composition. In some embodiments, the stable composition has a pD of about 4 to about 8, about 4.5 to about 7.8, about 5 to about 7.5, or about 5.5 to about 7. In some embodiments, the stable composition has a pD of less than about 7.5. In some embodiments, the stable composition has a pD of less than about 7.4. In some embodiments, the stable composition has a pD of less than about 7.3. In some embodiments, the stable composition has a pD of less than about 7.2. In some embodiments, the stable composition has a pD of less than about 7.1. In some embodiments, the stable composition has a pD of less than about 7. In some embodiments, the stable composition has a pD of less than about 6.9. In some embodiments, the stable composition has a pD of less than about 6.8. In some embodiments, the stable composition has a pD of less than about 6.7. In some embodiments, the stable composition has a pD of less than about 6.6. In some embodiments, the stable composition has a pD of less than about 6.5. In some embodiments, the stable composition has a pD of less than about 6.4. In some embodiments, the stable composition has a pD of less than about 6.3. In some embodiments, the stable composition has a pD of less than about 6.2. In some embodiments, the stable composition has a pD of less than about 6.1. In some embodiments, the stable composition has a pD of less than about 6. In some embodiments, the stable composition has a pD of less than about 5.9. In some embodiments, the stable composition has a pD of less than about 5.8. In some embodiments, the stable composition has a pD of less than about 5.7. In some embodiments, the stable composition has a pD of less than about 5.6. In some embodiments, the stable composition has a pD of less than about 5.5. In some embodiments, the stable composition has a pD of less than about 5.4. In some embodiments, the stable composition has a pD of less than about 5.3. In some embodiments, the stable composition has a pD of less than about 5.2. In some embodiments, the stable composition has a pD of less than about 5.1. In some embodiments, the stable composition has a pD of less than about 5. In some embodiments, the stable composition has a pD of less than about 4.9. In some embodiments, the stable composition has a pD of less than about 4.8. In some embodiments, the stable composition has a pD of less than about 4.7. In some embodiments, the stable composition has a pD of less than about 4.6. In some embodiments, the stable composition has a pD of less than about 4.5. In some embodiments, the stable composition has a pD of less than about 4.4. In some embodiments, the stable composition has a pD of less than about 4.3. In some embodiments, the stable composition has a pD of less than about 4.2. In some embodiments, the stable composition has a pD of less than about 4.1. In some embodiments, the stable composition has a pD of less than about 4.

In some embodiments, D₂Aqueous O systems stabilize muscarinic antagonists (e.g., atropine). In some embodiments, this is due to the equivalent of H₂Concentration of reactive species (e.g., -OH) in O aqueous systems, D₂The concentration of reactive species (e.g., -OD) in the O aqueous system is lower. In some cases, D₂Concentration ratio of reactive species (e.g., -OD) in O aqueous system to equivalent H₂The concentration of reactive species (e.g., -OH) in the aqueous O system is about one third lower. In some cases, this is due to D₂Dissociation constant ratio of O to H₂O is lower or less. For example, K_a(H₂O) is 1x10^-14And K is_a(D₂O) is 1x10^-15. Thus, D₂O is the ratio H₂O weaker acid. In some cases, base-catalyzed hydrolysis results in the presence of tropine degradants from atropine. In some cases, the atropine solution is at D when the concentration of reactive species that cause the formation of tropine degradants is low₂O aqueous System to equivalent H₂More stable in aqueous O systems. In some embodiments, with respect to H₂O formulated ophthalmic composition with deuterated waterThe formulated ophthalmic composition allows for a more stable ophthalmic composition.

In some embodiments, the ophthalmic gel or ointment compositions described herein have a pD of about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, or about 7.9.

In some embodiments, the pds of the ophthalmic aqueous, gel, or ointment compositions described herein are suitable for sterilization (e.g., by filtration or sterile mixing or heat treatment and/or autoclaving (e.g., terminal sterilization)) of the ophthalmic formulations described herein. As used in this disclosure, the term "aqueous composition" includes compositions based on D₂O, or a combination thereof.

In some embodiments, the pharmaceutical formulation described herein is stable with respect to pD for any one of the following periods of time: at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, or longer. In other embodiments, the formulations described herein are stable with respect to pD for a period of at least about 1 week. In other embodiments, the formulations described herein are stable with respect to pD for a period of at least about 2 weeks. In other embodiments, the formulations described herein are stable with respect to pD for a period of at least about 3 weeks. In other embodiments, the formulations described herein are stable with respect to pD for a period of at least about 1 month. Also described herein are formulations that are stable with respect to pD over the following time periods: a period of at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 12 months, at least about 18 months, at least about 2 years, or longer.

Uniformity between aqueous solution doses

Typical aqueous ophthalmic solutions are packaged in eye drops and administered in the form of drops. For example, a single administration (i.e., a single dose) of an ophthalmic aqueous solution includes administering one, two, three, or more drops to the eye of a patient. In some embodiments, one dose of an ophthalmic aqueous solution described herein is one drop of the aqueous solution composition from an eye drop bottle.

In some cases, described herein includes providing an ophthalmic aqueous composition of uniform concentration between doses. In some cases, the inter-dose uniform concentration does not exhibit significant variation in drug content from dose to dose. In some cases, uniform concentration between doses provides consistent drug content between doses.

In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 50%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 40%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 30%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 20%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 10%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than 5%.

In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 10 consecutive doses. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 8 consecutive doses. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 5 consecutive doses. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 3 consecutive doses. In some embodiments, the inter-dose ophthalmic agent concentration variation is based on 2 consecutive doses.

Non-settling formulations should not require shaking to disperse the drug uniformly. A "shake-free" formulation is potentially advantageous over a formulation that requires shaking simply because the patient's shaking behavior is a major source of variability in the amount of drug administered. It has been reported that, although instructions regarding shaking are explicitly noted on the label, patients often do not shake or forget to shake ophthalmic compositions that they need before administering a dose. On the other hand, even for those patients who shake the product, it is often not possible to determine whether the intensity and/or duration of the shaking is sufficient to homogenize the product. In some embodiments, the ophthalmic gel compositions and ophthalmic ointment compositions described herein are "no-shake" formulations that maintain uniformity between doses described herein.

To assess inter-dose uniformity, a dropper bottle or tube containing an ophthalmic aqueous composition, ophthalmic gel composition, or ophthalmic ointment composition is stored upright for a minimum of 12 hours prior to the start of the test. To simulate the recommended administration of these products, a predetermined number of drops or strips are dispensed from each commercially available bottle or tube at predetermined time intervals for an extended period of time or until no product remains in the bottle or tube. All drops and strips were dispensed into tared glass vials, capped, and stored at room temperature until analysis. The concentration of muscarinic antagonists such as atropine at the indicated titration was determined using a reverse phase HPLC method.

Viscosity of aqueous solution

In some embodiments, the composition has a Brookfield RVDV viscosity from about 10cp to about 50,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 100cp to about 40,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 500cp to about 30,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 1000cp to about 20,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 2000cp to about 10,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 4000cp to about 8,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c).

In some embodiments, the aqueous ophthalmic formulation contains a viscosity enhancing agent sufficient to provide a viscosity of about 500 to 50,000 centipoise, about 750 to 50,000 centipoise, about 1000 to 40,000 centipoise, about 2000 to 30,000 centipoise, about 3000 to 20,000 centipoise, about 4000 to 10,000 centipoise, or about 5000 to 8000 centipoise.

In some embodiments, the compositions described herein are low viscosity compositions at body temperature. In some embodiments, the low viscosity composition contains from about 1% to about 10% of a viscosity enhancing agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity composition contains from about 2% to about 10% of a viscosity enhancing agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity composition contains from about 5% to about 10% of a viscosity enhancing agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity composition is substantially free of viscosity enhancing agents (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the low viscosity ophthalmic composition described herein provides an apparent viscosity of from about 100cP to about 10,000 cP. In some embodiments, the low viscosity ophthalmic composition described herein provides an apparent viscosity of from about 500cP to about 10,000 cP. In some embodiments, the low viscosity ophthalmic composition described herein provides an apparent viscosity of from about 1000cP to about 10,000 cP.

Osmolality of volume

In some embodiments, the compositions disclosed herein are formulated so as not to disrupt the ionic balance of the eye. In some embodiments, the compositions disclosed herein have the same or substantially the same ionic balance as the eye. In some embodiments, the compositions disclosed herein do not disrupt the ionic balance of the eye.

As used herein, "actual osmolarity/osmolality" or "deliverable osmolarity/osmolality" means the osmolarity/osmolality of a composition as determined by measuring the osmolarity/osmolality of an ophthalmic agent and all excipients except gelling agents and/or thickening agents (e.g., polyoxyethylene-polyoxypropylene copolymer, carboxymethylcellulose, etc.). The actual osmolarity of the compositions disclosed herein is measured by a suitable method, for example, freezing point depression as described in Viegas et al, int.J.pharm.,1998,160, 157-162. In some cases, the actual osmolarity of a composition disclosed herein is measured by a vapor pressure osmometry (e.g., vapor pressure reduction) that allows the osmolarity of the composition to be determined at higher temperatures. In some cases, the vapor pressure reduction method allows the determination of the osmolality of a composition comprising a gelling agent (e.g., a thermoreversible polymer) at a higher temperature, wherein the gelling agent is in the form of a gel.

In some embodiments, the osmolality at the target site of action (e.g., the eye) is about the same as the delivery osmolality of the compositions described herein. In some embodiments, the compositions described herein have a deliverable volume osmolarity of about 150 to about 500, about 250 to about 350, about 280 to about 370, or about 250 to about 320 mOsm/L.

The ophthalmic composition disclosed herein has an actual osmolality of from about 100 to about 1000mOsm/kg, from about 200 to about 800mOsm/kg, from about 250 to about 500mOsm/kg, or from about 250 to about 320mOsm/kg, or from about 250 to about 350mOsm/kg, or from about 280 to about 320 mOsm/kg. In some embodiments, the compositions described herein have an actual osmolarity of about 100 to about 1000mOsm/L, about 200 to about 800mOsm/L, about 250 to about 500mOsm/L, about 250 to about 350mOsm/L, about 250 to about 320mOsm/L, or about 280 to about 320 mOsm/L.

In some embodiments, suitable tonicity adjusting agents include, but are not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, dextrose, glycerol, mannitol, sorbitol, sodium chloride, and other electrolytes. In some cases, the tonicity modifier is selected from the group consisting of sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

In some embodiments, the ophthalmic compositions described herein comprise one or more salts in an amount necessary to bring the osmolality of the composition within an acceptable range. Such salts include those having a sodium, potassium or ammonium cation and a chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

Sterility of

In some embodiments, the composition is sterilized. Included within the embodiments disclosed herein are means and processes for sterilizing the pharmaceutical compositions disclosed herein for use in humans. The aim is to provide a safe pharmaceutical product, relatively free of infection causing microorganisms. The U.S. food and Drug administration (U.S. food and Drug administration) has provided regulatory guidelines in the publication "guide for Industry: Sterile Drug Products by analytical processing" available at http:// www.fda.gov/cd/guide/5882 fn.

As used herein, sterilization means a process used to destroy or remove microorganisms present in a product or packaging. Any suitable method that can be used for sterilization of the target and composition is used. Methods that may be used for inactivation of microorganisms include, but are not limited to, application of extreme heat, lethal chemicals, or gamma radiation. In some embodiments, the process for preparing an ophthalmic formulation comprises subjecting the formulation to a sterilization method selected from the group consisting of heat sterilization, chemical sterilization, radiation sterilization, or filter sterilization. The method used depends to a large extent on the nature of the device or composition to be sterilized. A detailed description of many sterilization methods is given in chapter 40 of Remington, The Science and Practice of Pharmacy, published by Lippincott, Williams & Wilkins, and The contents of which on this subject are incorporated herein by reference.

Filtration

Sterile filtration is a process used to remove microorganisms from solution without destroying the microorganisms. The heat sensitive solution was filtered using a membrane filter. Such filters are thin, strongly homogeneous polymers of Mixed Cellulose Esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF) or Polytetrafluoroethylene (PTFE) and have pore sizes in the range of 0.1-0.22 μm. Optionally filtering solutions with different characteristics using different filter membranes. For example, PVF and PTFE membranes are well suited for filtering organic solvents, while aqueous solutions are filtered through PVF or MCE membranes. The filter device can be used on many scales ranging from a single-use point disposable filter attached to a syringe to a commercial scale filter for use in a manufacturing plant. The membrane filter is sterilized by autoclaving or chemical sterilization. The validation of the membrane filtration system was carried out following a standardisation protocol (Microbiological Evaluation of filters for SterilizingLiquids, Vol 4, No.3, Washington, D.C.: Health industry manufacturers Association,1981) and involves the use of known quantities (about 10)⁷/cm²) Such as Brevundimonas diminuta (ATCC 19146), attacks the membrane filter.

The pharmaceutical composition is optionally sterilized by passage through a membrane filter. Formulations containing nanoparticles (U.S. Pat. No. 6,139,870) or multilamellar vesicles (Richard et al, International Journal of pharmaceuticals (2006),312(1-2):144-50) are suitable for sterilization by filtration through 0.22 μm filters without destroying their organized structure.

In some embodiments, the methods disclosed herein comprise sterilizing the formulation (or components thereof) by means of filter sterilization. In ophthalmic gel compositions comprising thermosetting polymers, filtration is carried out at a temperature lower than the gel temperature (Tgel) of the formulations described herein (e.g., about 5 ℃) and with a viscosity that allows filtration with a peristaltic pump within a reasonable time (e.g., a theoretical value below 100 cP).

Accordingly, provided herein are methods of sterilizing ophthalmic formulations that prevent degradation of polymeric components (e.g., thermosets and/or other viscosity enhancing agents) and/or ophthalmic agents during the sterilization process. In some embodiments, degradation of an ophthalmic agent (e.g., a muscarinic antagonist such as atropine or atropine sulfate) is reduced or eliminated by using a specific pD range for the buffer components and a specific ratio of viscosity enhancing agents in the formulation. In some embodiments, selection of an appropriate viscosity enhancing agent or thermosetting polymer allows for sterilization of the formulations described herein by filtration. In some embodiments, the use of an appropriate thermosetting polymer or other viscosity enhancing agent in combination with a particular pD range for a formulation allows for high temperature sterilization of the formulation without substantial degradation of the therapeutic agent or polymeric excipient. An advantage of the sterilization process provided herein is that in certain instances, the formulation is subjected to terminal sterilization via autoclaving without any loss of the ophthalmic agent and/or excipient and/or viscosity enhancing agent during the sterilization step and is rendered substantially free of microorganisms and/or pyrogens.

Radiation sterilization

One advantage of radiation sterilization is the ability to sterilize various types of products without thermal degradation or other damage. The radiation commonly used is beta radiation or alternatively from⁶⁰Gamma irradiation from a Co source. The penetration ability of gamma radiation allows its use in sterilization of many product types including solutions, compositions and heterogeneous mixtures. The germicidal action of radiation results from the interaction of gamma radiation with biological macromolecules. This interaction generates a charged species and a free radical. Subsequent chemical reactions, such as rearrangement and cross-linking processes, result in the loss of the normal function of these biological macromolecules. The formulations described herein are also optionally sterilized using beta radiation.

Heat sterilization

Many methods are available for sterilization by application of high heat. One method is by using a saturated steam autoclave. In the method, saturated steam at a temperature of at least 121 ℃ is brought into contact with the object to be sterilized. Heat is transferred directly to the microorganisms in the case of the objects to be sterilized or indirectly by heating the body of aqueous solution to be sterilized. This method is widely used because it allows flexibility, safety and economy of the sterilization process.

Microorganisms

In some embodiments, the composition is substantially free of microorganisms. Acceptable levels of bioburden or sterility are based on applicable criteria defining therapeutically acceptable compositions, including but not limited to United states Pharmacopeia (United states Pharmacopeia) Chapter <1111> and below, and the like. For example, an acceptable level of sterility (e.g., bioburden) includes about 10 colony forming units (cfu) per gram of formulation, about 50cfu per gram of formulation, about 100cfu per gram of formulation, about 500cfu per gram of formulation, or about 1000cfu per gram of formulation. In some embodiments, an acceptable level of bioburden or sterility for a formulation includes less than 10cfu/mL microbial agent, less than 50cfu/mL microbial agent, less than 500cfu/mL microbial agent, or less than 1000cfu/mL microbial agent. In addition, acceptable bioburden levels or sterility include exclusion of specified undesirable microbial agents. By way of example, specified undesirable microbial agents include, but are not limited to, escherichia coli (e.coli), Salmonella sp, Pseudomonas aeruginosa (p.aeruginosa), and/or other specific microbial agents.

Sterility assurance an important part of the quality control, quality assurance and verification process is the method of sterility testing. By way of example only, sterility testing is performed by two methods. The first is direct inoculation, in which a sample of the composition to be tested is added to the growth medium and incubated for a period of up to 21 days. Turbidity of the growth medium indicates contamination. Disadvantages of this method include the small sample size of the host material (which reduces sensitivity), and detection of microbial growth based on visual inspection. An alternative method is membrane filtration sterility testing. In this method, a volume of product is passed through a small membrane filter. The filter paper is then placed in a culture medium to promote microbial growth. This method has the advantage of greater sensitivity because the entire host product is sampled. A commercially available Millipore Steritest system is optionally used for the determination by the membrane filtration sterility test. For the filtration test of creams or ointments, the Steritest filter system No. TLHVSL210 was used. For filtration testing of emulsions or viscous products, the Steritest filter system No. TLAREM210 or TDAREM210 was used. For the filtration test of the pre-filled syringe, the Steritest filter system No. tthasy210 was used. For filtration testing of materials dispensed as aerosols or foams, the Steritest filter system No. tthva210 was used. For filtration testing of soluble powders in ampoules or vials, the Steritest filter system No. tthadad 210 or TTHADV210 was used.

The tests for E.coli and Salmonella included the use of lactose broth incubated at 30-35 ℃ for 24-72 hours, MacConkey and/or EMB agar for 18-24 hours, and/or Rappaport medium. The test for detecting pseudomonas aeruginosa involves the use of NAC agar. Chapter <62> of the united states pharmacopeia further lists testing procedures for specified undesirable microorganisms.

In certain embodiments, the ophthalmic formulations described herein have less than about 60 Colony Forming Units (CFU), less than about 50 colony forming units, less than about 40 colony forming units, or less than about 30 colony forming units of microbial agent per gram of formulation. In certain embodiments, the ophthalmic formulations described herein are formulated to be isotonic with the eye.

Endotoxin

Another aspect of the sterilization process is the removal of by-products (hereinafter "products") produced by killing the microorganisms. Depyrogenation removes pyrogens from the sample. Pyrogens are endotoxins or exotoxins that induce an immune response. An example of an endotoxin is the Lipopolysaccharide (LPS) molecule found in the cell wall of gram-negative bacteria. Although sterilization procedures such as autoclaving or ethylene oxide treatment kill the bacteria, LPS residues induce proinflammatory immune responses such as septic shock. Since the molecular size of endotoxin varies widely, the presence of endotoxin is expressed as "endotoxin unit" (EU). One EU is equivalent to 100 picograms of E.coli LPS. In some cases, humans respond as low as 5EU/kg body weight. Bioburden (e.g., microbial limit) and/or sterility (e.g., endotoxin levels) are expressed in any units recognized in the art. In certain embodiments, the ophthalmic compositions described herein contain a lower endotoxin level (e.g., <4EU/kg subject body weight) as compared to a conventionally acceptable endotoxin level (e.g., 5EU/kg subject body weight). In some embodiments, the ophthalmic formulation has less than about 5EU/kg of subject body weight. In other embodiments, the ophthalmic formulation has less than about 4EU/kg of subject body weight. In other embodiments, the ophthalmic formulation has less than about 3EU/kg of subject body weight. In other embodiments, the ophthalmic formulation has less than about 2EU/kg of subject body weight.

In some embodiments, the ophthalmic formulation has less than about 5EU/kg of formulation. In other embodiments, the ophthalmic formulation has less than about 4EU/kg of formulation. In other embodiments, the ophthalmic formulation has less than about 3EU/kg of formulation. In some embodiments, the ophthalmic formulation has less than about 5EU/kg of product. In other embodiments, the ophthalmic formulation has less than about 1EU/kg of product. In other embodiments, the ophthalmic formulation has less than about 0.2EU/kg of product. In some embodiments, the ophthalmic formulation has less than about 5EU/g units or products. In other embodiments, the ophthalmic formulation has less than about 4EU/g unit or product. In other embodiments, the ophthalmic formulation has less than about 3EU/g units or products. In some embodiments, the ophthalmic formulation has less than about 5EU/mg units or products. In other embodiments, the ophthalmic formulation has less than about 4EU/mg unit or product. In other embodiments, the ophthalmic formulation has less than about 3EU/mg units or products. In certain embodiments, the ophthalmic formulations described herein contain from about 1 to about 5EU/mL of the formulation. In certain embodiments, the ophthalmic formulations described herein contain from about 2 to about 5EU/mL of the formulation, from about 3 to about 5EU/mL of the formulation, or from about 4 to about 5EU/mL of the formulation.

In certain embodiments, the ophthalmic compositions described herein contain lower endotoxin levels (e.g., <0.5EU/mL formulation) as compared to conventionally acceptable endotoxin levels (e.g., 0.5EU/mL formulation). In some embodiments, the ophthalmic formulation has less than about 0.5EU/mL of formulation. In other embodiments, the ophthalmic formulation has less than about 0.4EU/mL of formulation. In other embodiments, the ophthalmic formulation has less than about 0.2EU/mL of formulation.

By way of example only, pyrogen detection is performed by several methods. Suitable Tests for Sterility include those described in the United States Pharmacopeia (USP) <71> sterilite Tests (23 rd edition, 1995). Both The rabbit pyrogen test and The limulus amebocyte lysate test are described in detail in The United States pharmacopoeia Chapter <85> and Chapter <151> (USP23/NF 18, Biological Tests, The United States pharmaceutical Convention, Rockville, Md., 1995). Alternative pyrogen assays have been developed based on the monocyte activation-cytokine assay. Homogeneous cell lines suitable for quality control applications have been developed and have demonstrated the ability to detect pyrogenicity in samples passed the rabbit pyrogen test and the limulus amoebocyte lysate test (Taktak et al, J.Pharm.Pharmacol. (1990),43: 578-82). In another embodiment, the ophthalmic formulation is depyrogenated. In yet another embodiment, the process of preparing the ophthalmic formulation comprises testing the pyrogenicity of the formulation. In certain embodiments, the formulations described herein are substantially free of pyrogens.

Ophthalmic muscarinic antagonist-Mucus Penetrating Particle (MPP) compositions

Mucus Penetrating Particles (MPPs) are particles that rapidly penetrate mucus, such as human mucus. In some cases, the MPP includes nanoparticles having a particle size of about 200nm to 500 nm. In some cases, the nanoparticles are further coated with a mucus penetrating agent. In some cases, the compositions described herein are formulated with MPP for mucus penetration. In some cases, the ophthalmic composition described herein is formulated with MPP for mucus penetration. In some cases, the ophthalmic agent is a muscarinic antagonist. In some cases, a muscarinic antagonist composition described herein is formulated with MPP for mucus penetration. In some cases, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine acid, metronidazole, diphenhydramine, dimenhydrinate, bicyclofolin, flavoxate, oxybutynin, tiotropium bromide, scopolamine, hyoscyamine (L-scopolamine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine, homatropine, solifenacin, darifenacin, benztropine, mebeverine, propidin, aclidinium, trihexyphenidyl/diphenhydrasol, or tolterodine. In some cases, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some cases, the muscarinic antagonist is atropine sulfate. In some cases, the atropine compositions described herein are formulated with MPP for mucus penetration. In some cases, the atropine sulfate compositions described herein are formulated with MPP for mucus penetration. In a non-limiting example, MMPs for use in the disclosed compositions are obtained from Kala Pharmaceuticals, Inc (100Beaver Street #201, Waltham, MA 02453).

In some embodiments, the nanoparticles comprise any suitable material, such as an organic material, an inorganic material, a polymer, or a combination thereof. In some cases, the nanoparticles include inorganic materials, such as, for example, metals (e.g., Ag, Au, Pt, Fe, Cr, Co, Ni, Cu, Zn, and other transition metals), semiconductors (e.g., silicon compounds and alloys, cadmium selenide, cadmium sulfide, indium arsenide, and indium phosphide), or insulators (e.g., ceramics, such as silicon oxide). In some cases, the nanoparticles include organic materials, such as synthetic polymers and/or natural polymers. Examples of synthetic polymers include non-degradable polymers such as polymethacrylates and degradable polymers such as polylactic acid, polyglycolic acid and copolymers thereof. Examples of natural polymers include hyaluronic acid, chitosan, and collagen.

In some embodiments, the nanoparticles are coated with a mucus penetrating agent. In some cases, the mucus penetrating agent includes any suitable material, such as a hydrophobic material, a hydrophilic material, and/or an amphiphilic material. In some cases, the mucus penetrating agent is a polymer. In some cases, the polymer is a synthetic polymer (i.e., not a naturally occurring polymer). In other embodiments, the polymer is a natural polymer (e.g., protein, polysaccharide, rubber). In certain embodiments, the polymer is a surface active polymer. In certain embodiments, the polymer is a nonionic polymer. In certain embodiments, the polymer is a nonionic block copolymer. In some embodiments, the polymer is a diblock copolymer, a triblock copolymer, for example, where one block is a hydrophobic polymer and the other block is a hydrophilic polymer. In some embodiments, the polymer is charged or uncharged.

Other examples of suitable polymers include, but are not limited to, polyamines, polyethers, polyamides, polyesters, polyurethanes, polyureas, polycarbonates, polystyrenes, polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyleneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates. Non-limiting examples of specific polymers include poly (caprolactone) (PCL), ethylene vinyl acetate polymer (EVA), poly (lactic acid) (PLA), poly (L-lactic acid) (PLLA), poly (glycolic acid) (PGA), poly (lactic-co-glycolic acid) (PLGA), poly (L-lactic-co-glycolic acid) (PLLGA), poly (D, L-lactide) (PDLA), poly (L-lactide) (PLLA), poly (D, L-lactide-co-caprolactone-co-glycolide), poly (D, L-lactide-co-PEO-co-D, L-lactide), poly (D, L-lactide-co-PPO-co-D, l-lactide), polyalkyl cyanoacrylates, polyurethanes, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA), poly (ethylene glycol), poly-L-glutamic acid, poly (hydroxy acid), polyanhydride, polyorthoester, poly (ester amide), polyamide, poly (ester ether), polycarbonate, polyalkylene (such as polyethylene and polypropylene), polyalkylene glycol (such as poly (ethylene glycol) (PEG)), polyalkylene oxide (PEO), polyalkylene terephthalate (such as poly (ethylene terephthalate)), polyvinyl alcohol (PVA), polyvinyl ether, polyvinyl ester (such as poly (vinyl acetate)), polyvinyl halide (such as poly (vinyl chloride) (PVC)), polyvinylpyrrolidone, polysiloxane, Polystyrene (PS), polyurethane, derivatized cellulose (such as alkylcellulose), poly (ethylene glycol) (PEO), poly (ethylene glycol) (PVA), poly (ethylene glycol) (PEO), hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocellulose, hydroxypropyl celluloses, carboxymethyl celluloses), polymers of acrylic acid (such as poly (methyl (meth) acrylate) (PMMA), poly (ethyl (meth) acrylate), poly (butyl (meth) acrylate), poly (isobutyl (meth) acrylate), poly (hexyl (meth) acrylate), poly (isodecyl (meth) acrylate), poly (lauryl (meth) acrylate), poly (phenyl (meth) acrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (stearyl acrylate) (collectively referred to herein as "polyacrylic acid")) and copolymers and mixtures thereof, polydioxanones and copolymers thereof, polyhydroxyfatty acid esters, poly (fumaric acrylate), polyoxymethylene, poloxamers, poly (meth) acrylates), poly (, Poly (ortho) esters, poly (butyric acid), poly (valeric acid), poly (lactide-co-caprolactone) and trimethylene carbonate, polyvinylpyrrolidone.

In some cases, an ophthalmic agent (e.g., a muscarinic antagonist such as atropine or atropine sulfate) is present in the MPP formulation at the following concentrations, by weight of the composition: from about 0.001 wt% to about 0.05 wt%, from about 0.005% to about 0.050%, from about 0.010% to about 0.050%, from about 0.015% to about 0.050%, from about 0.020% to about 0.050%, from about 0.025% to about 0.050%, from about 0.030% to about 0.050%, from about 0.035% to about 0.050%, from about 0.040% to about 0.050%, or from about 0.045% to about 0.050% of an ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof. In some cases, additional agents such as buffers, pD modulators, and/or preservatives are formulated in the MPP formulation.

In some cases, the ophthalmic-MPP compositions are formulated using any suitable method. In some embodiments, the size of the solid material is reduced using a milling process to form particles in the micron to nanometer size range. In some cases, dry and wet milling methods (such as jet milling, freeze milling, ball milling, media milling, and homogenization) are known and used in the methods described herein. Typically, in wet milling, a suspension of the material to be used as nanoparticles is mixed with a milling media, with or without excipients, to reduce the particle size. Dry milling is a process in which the material to be used as nanoparticles is mixed with grinding media with or without excipients to reduce the particle size. In the freeze-milling process, a suspension of the material to be used as nanoparticles is mixed with a milling medium with or without excipients at a cooling temperature.

In some embodiments, any suitable grinding media is used for milling. In some embodiments, ceramic and/or polymeric materials and/or metals are used. Examples of suitable materials include zirconia, silicon carbide, silicon oxide, silicon nitride, zirconium silicate, yttria, glass, alumina (alumina), alpha-alumina (alpha-alumina), alumina (alumina), polystyrene, poly (methyl methacrylate), titanium, steel. In some cases, the grinding media are of any suitable size. For example, the grinding media have an average diameter of at least about 0.1mm, at least about 0.2mm, at least about 0.5mm, at least about 0.8mm, at least about 1mm, at least about 2mm, or at least about 5 mm. In some cases, the grinding media have an average diameter of less than or equal to about 5mm, less than or equal to about 2mm, less than or equal to about 1mm, less than or equal to about 0.8, less than or equal to about 0.5mm, or less than or equal to about 0.2 mm. Combinations of the above ranges are also possible (e.g., at least about 0.5 millimeters and an average diameter of less than or equal to about 1 mm). Other ranges are also possible.

In some embodiments, any suitable solvent is used for milling. In some cases, the choice of solvent depends on the following factors: such as the solid material being milled (e.g., a muscarinic antagonist, such as atropine), the particular type of stabilizing/mucopenetrant used (e.g., a mucopenetrant that allows penetration of particulate mucus), the abrasive material used, and other factors. In some cases, suitable solvents are solvents that do not substantially dissolve the solid material or the milled material, but dissolve the stabilizing/mucopenetrant to an appropriate degree. Non-limiting examples of solvents include, but are not limited to, water, buffered solutions, other aqueous solutions, alcohols (e.g., ethanol, methanol, butanol), and mixtures thereof, optionally including other components such as pharmaceutical excipients, polymers, pharmaceutical agents, salts, preservatives, viscosity modifiers, tonicity modifiers, taste masking agents, antioxidants, pD modifiers, and other pharmaceutical excipients. In other embodiments, an organic solvent is used. In some cases, the pharmaceutical agent (e.g., a muscarinic antagonist, such as atropine) has any suitable solubility in these or other solvents, such as a solubility in one or more of the above-described ranges for water solubility or for solubility in the coating solution.

In some cases, the MPP is an MPP as described in WO 2013/166385. In some cases, the MPP is an MPP as described in Lai et al, "Rapid transport of large polymeric nanoparticles in fresh undiluted dhumum multicus," PNAS 104(5):1482-1487 (2007). In some cases, the ophthalmic-MPP compositions are formulated using a method as described in WO 2013/166385. In some cases, ophthalmic-MPP compositions are formulated using methods such as those described in Lai et al, "Rapid transport of large polymeric nanoparticles in fresh undiluted human serum," PNAS 104(5):1482-1487 (2007). In some cases, the ophthalmic agent is a muscarinic antagonist, such as atropine or atropine sulfate.

Ophthalmic gel muscarinic antagonist compositions

Gels are defined in a number of ways. For example, the united states pharmacopoeia defines gels as suspensions composed of small inorganic particles or semi-solid systems composed of liquid interpenetrating organic macromolecules. Gels include single phase or two phase systems. Single phase gels consist of organic macromolecules uniformly distributed throughout a liquid in such a way that there is no distinct boundary between the dispersed macromolecules and the liquid. Some single phase gels are prepared from synthetic macromolecules (e.g., carbomer) or from natural gums (e.g., tragacanth). In some embodiments, the single phase gel is generally aqueous, but will also be made using alcohols and oils. Two-phase gels consist of a network of small discrete particles.

In some embodiments, gels are also classified as hydrophobic or hydrophilic. In certain embodiments, the base of non-limiting examples of hydrophobic gels include liquid paraffin with polyethylene or fatty oil gelled with silica gel or aluminum or zinc soap. In contrast, the matrix of non-limiting examples of hydrophilic gels includes water, glycerol or propylene glycol gelled with a suitable gelling agent (e.g., tragacanth, starch, cellulose derivatives, carboxyvinyl polymers and magnesium-aluminosilicate). In certain embodiments, the rheology of the compositions disclosed herein is pseudoplastic, plastic, thixotropic, or dilatant.

In some embodiments, the ophthalmic composition is an ophthalmic gel, and wherein the ophthalmically acceptable carrier comprises water and at least one viscosity enhancing agent. In some embodiments, the viscosity enhancing agent is selected from a cellulose-based polymer, a polyoxyethylene-polyoxypropylene triblock copolymer, a dextran-based polymer, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycol, chitosan, collagen, gelatin, hyaluronic acid, or a combination thereof.

In some embodiments, the ophthalmic gel compositions described herein are semi-solid or in a gelled state prior to topical application (e.g., at room temperature). For example, suitable viscosity enhancing agents for such gels include, by way of example only, gelling agents and suspending agents. In one embodiment, the viscosity-enhancing formulation does not comprise a buffer. In other embodiments, the viscosity-enhancing formulation comprises a pharmaceutically acceptable buffer. Sodium chloride or other tonicity agents are optionally used to adjust tonicity if necessary.

By way of example only, ophthalmically acceptable viscosity agents include hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, sodium hyaluronate. Other viscosity enhancing agents compatible with the target eye site include, but are not limited to, acacia (gum arabic), agar, magnesium aluminum silicate, sodium alginate, sodium stearate, fucus, bentonite, carbomer (carbomer), carrageenan, Carbopol (Carbopol), xanthan gum, cellulose, microcrystalline cellulose (MCC), carob bean gum (ceratonia), chitin, carboxymethyl chitosan, carrageenan (chondrus), dextrose, furcellaran, gelatin, gum Ghatti (Ghatti gum), guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, karaya gum, xanthan gum, tragacanth gum, ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, sodium alginate, sodium stearate, carrageenan, bentonite, carrageenan, xanthan gum, carrageenan, xanthan gum, guar gum, lactose, sucrose, maltodextrin, sodium alginate, poly (hydroxyethyl methacrylate), oxidized poly (gelatin), pectin, polygeline, povidone, propylene carbonate, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), poly (methoxyethyl methacrylate), poly (methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropyl methyl-cellulose (HPMC), sodium carboxymethyl-cellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl,(dextrose, maltodextrin, and sucralose), or a combination thereof. In particular embodiments, the viscosity enhancing excipient is a combination of MCC and CMC. In another embodiment, the viscosity enhancing agent is carboxymethyl chitosan or a combination of chitin and alginate. Combinations of chitin and alginate with ophthalmic agents disclosed herein act as controlled release formulationsDiffusion of the ophthalmic agent from the formulation is limited. In addition, a combination of carboxymethyl chitosan and alginate is optionally used to help increase the osmolarity of the ophthalmic agent in the eye.

In some embodiments is a viscosity-enhancing formulation comprising from about 0.1mM to about 100mM of an ophthalmic agent, a pharmaceutically acceptable viscosity agent, and water for injection, the viscosity agent being present in the water at a concentration sufficient to provide a viscosity-enhancing formulation having a final viscosity of from about 100cP to about 100,000 cP. In certain embodiments, the viscosity of the gel is in the range of about 100cP to about 50,000cP, about 100cP to about 1,000cP, about 500cP to about 1500cP, about 1000cP to about 3000cP, about 2000cP to about 8,000cP, about 4,000cP to about 50,000cP, about 10,000cP to about 500,000cP, about 15,000cP to about 1,000,000 cP. In other embodiments, where an even more viscous medium is desired, the biocompatible gel comprises at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 70%, at least about 75%, or even at least about 80% by weight of the ophthalmic agent. In a highly concentrated sample, the biocompatible enhanced viscosity formulation comprises at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75%, at least about 85%, at least about 90%, or at least about 95% by weight or more of an ophthalmic agent.

In one embodiment, a pharmaceutically acceptable viscosity-enhancing ophthalmically acceptable formulation comprises at least one ophthalmic agent and at least one gelling agent. Suitable gelling agents for preparing gel formulations include, but are not limited to, cellulose derivatives, cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose), guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid), silicates, starch, tragacanth, carboxyvinyl polymers, carrageenan, paraffin, petrolatum, and any combination or mixture thereof. In some other embodiments, hydroxypropyl methylcellulose is usedAs a gelling agent. In certain embodiments, the viscosity enhancing agents described herein are also used as gelling agents for the gel formulations set forth herein.

In some embodiments, the ophthalmic gel compositions described herein are in situ gel formulations. In some cases, in situ gel formation is based on increased pre-corneal residence time of the ophthalmic composition, which improves ocular bioavailability, corneal mucoadhesion, lysosomal interactions and ionic gelation, improved corneal absorption, thermal gelation, or a combination thereof. In some cases, the in situ gel formulation is activated by pH, temperature, ion, UV, or solvent exchange.

In some cases, the ophthalmic gel composition comprises a muscarinic antagonist and one or more gelling agents. In some cases, the gelling agent includes, but is not limited to, poloxamers (e.g., poloxamer 407), tetronics, ethyl (hydroxyethyl) cellulose, Cellulose Acetate Phthalate (CAP), carbopols (e.g., carbopol 1342P NF, carbopol 980NF), alginates (e.g., low acetyl gellan gum)) Gellan gum, hyaluronic acid, Pluronic (e.g., Pluronic F-127), chitosan, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), dextran, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), Methyl Cellulose (MC), thiolated xyloglucan, polymethacrylic acid (PMMA), polyethylene glycol (PEG), pseudolatex (pseudolatex), xyloglucan, or a combination thereof.

In some cases, the in situ gel formation further comprises a permeation enhancer. In some cases, the penetration enhancer includes surfactants (e.g., nonionic surfactants), benzalkonium chloride, EDTA, surface active heterosides (heteroglycosides), calcium chelators, hydroxypropyl beta cyclodextrin (HP beta CD), bile salts, and the like.

In some embodiments, other gel formulations are useful depending on the particular ophthalmic agent, other pharmaceutical agent or excipient/additive used, and are therefore considered to fall within the scope of the present invention. For example, other commercially available groups are contemplatedGels in glycerol, glycerol-derived compounds, bound or crosslinked gels, matrices, hydrogels and polymers as well as gelatin and its derivatives, alginates and alginate-based gels, and even various natural and synthetic hydrogels and hydrogel-derived compounds, can be used in the ophthalmic formulation described herein. In some embodiments, ophthalmically acceptable gels include, but are not limited to, alginate hydrogels-Gel(ConvaTec,Princeton,N.J.)、Hydroactive Gel(ConvaTec)、Nu-(Johnson&Johnson Medical,Arlington,Tex.)；(V) Acemannan Hydrogel (Carrington Laboratories, Inc., Irving, Tex.); glycerol gelHydrogel (Swiss-American Products, Inc., Dallas, Tex.) and K-Sterile(Johnson&Johnson). In other embodiments, the biodegradable biocompatible gel also represents a compound present in an ophthalmically acceptable formulation as described and disclosed herein.

In some embodiments, the viscosity enhancing agent is a cellulose-based polymer selected from cellulose gum, alkyl cellulose, hydroxy-alkyl cellulose, carboxy-alkyl cellulose, or a combination thereof. In some embodiments, the viscosity enhancing agent is a hydroxy-alkyl alkylcellulose. In some embodiments, the viscosity enhancing agent is hydroxypropyl methylcellulose.

In certain embodiments, the enhanced viscosity formulation is characterized by a phase transition between room temperature and body temperature (including severely febrile individuals, e.g., up to about 42 ℃). In some embodiments, the phase transition occurs at a temperature of 1 ℃ below body temperature, 2 ℃ below body temperature, 3 ℃ below body temperature, 4 ℃ below body temperature, 6 ℃ below body temperature, 8 ℃ below body temperature, or 10 ℃ below body temperature. In some embodiments, the phase transition occurs at a temperature of about 15 ℃ below body temperature, about 20 ℃ below body temperature, or about 25 ℃ below body temperature. In particular embodiments, the formulation described herein has a gelling temperature (Tgel) of about 20 ℃, about 25 ℃, or about 30 ℃. In certain embodiments, the formulation described herein has a gelling temperature (Tgel) of about 35 ℃ or about 40 ℃. Included within the definition of body temperature are body temperatures of healthy or unhealthy individuals, including those of febrile (up to about 42 ℃). In some embodiments, the pharmaceutical compositions described herein are liquid at about room temperature and are administered at or about room temperature.

Polyoxypropylene and polyoxyethylene copolymers (e.g., polyoxyethylene-polyoxypropylene triblock copolymers) form thermoset gels when incorporated into aqueous solutions. These polymers have the ability to change from a liquid to a gel state at temperatures near body temperature, thus allowing for a useful formulation to be applied to the target ocular site. The phase change from liquid to gel depends on the polymer concentration and composition in the solution.

In some embodiments, the amount of thermosetting polymer in any of the formulations described herein is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer in any of the formulations described herein is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 7.5% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 10% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 11% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 12% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 13% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 14% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 15% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 16% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 17% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 18% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 19% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 20% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 21% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 23% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., poloxamer 407) in any of the formulations described herein is about 25% of the total weight of the formulation. In some embodiments, the amount of thickener (e.g., gelling agent) in any of the formulations described herein is about 1%, about 5%, about 10%, or about 15% of the total weight of the formulation. In some embodiments, the amount of thickening agent (e.g., gelling agent) in any of the formulations described herein is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of the total weight of the formulation.

In an alternative embodiment, the thermogel is a PEG-PLGA-PEG triblock copolymer (Jeong et al, Nature (1997),388: 860-2; Jeong et al, J.Control.Release (2000),63: 155-63; Jeong et al, adv.drug Delivery Rev. (2002),54: 37-51). The polymer exhibits sol-gel behavior at a concentration of about 5% w/w to about 40% w/w. Depending on the desired properties, the molar ratio of lactide/glycolide in the PLGA copolymer is in the range of about 1: 1 to about 20: 1, in the above range. The resulting copolymer is soluble in water and forms a free-flowing liquid at room temperature, but forms a hydrogel at body temperature. A commercially available PEG-PLGA-PEG triblock copolymer is RESOMER RGP t50106 produced by Boehringer Ingelheim. The material consisted of a 50:50 poly (DL-lactide-co-glycolide) PLGA copolymer and 10% w/w PEG and had a molecular weight of about 6000.

Other biodegradable thermoplastic polyesters include(provided by Atrix Laboratories, inc.) and/or those disclosed in, for example, U.S. patent nos. 5,324,519, 4,938,763, 5,702,716, 5,744,153, and 5,990,194; wherein suitable biodegradable thermoplastic polyesters are disclosed as thermoplastic polymers. Examples of suitable biodegradable thermoplastic polyesters include polylactide, polyglycolide, polycaprolactone, copolymers thereof, terpolymers thereof, and any combination thereof. In some such embodiments, suitable biodegradable thermoplastic polyesters are polylactides, polyglycolides, copolymers thereof, terpolymers thereof, or combinations thereof. In one embodiment, the biodegradable thermoplastic polyester is 50/50 poly (DL-lactide-co-glycolide) having carboxyl end groups; present in about 30 wt.% to about 40 wt.% of the composition; and has an average molecular weight of about 23,000 to about 45,000. Alternatively, in another embodiment, the biodegradable thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide) without carboxyl end groups; about 40 wt.% of the composition%To about 50 wt.%; and has an average molecular weight of about 15,000 to about 24,000. In further or alternative embodiments, the end group of the poly (DL-lactide-co-glycolide) is a hydroxyl, carboxyl or ester, depending on the polymerization method. Polycondensation of lactic acid or glycolic acid provides a polymer with terminal hydroxyl and carboxyl groups. The ring-opening polymerization of cyclic lactide or glycolide monomers with water, lactic acid or glycolic acid provides polymers with the same end groups. However, ring opening of cyclic monomers with monofunctional alcohols such as methanol, ethanol or 1-dodecanol provides a polymer having one hydroxyl group and one ester end group. Ring-opening polymerization of cyclic monomers with diols such as 1, 6-hexanediol or polyethylene glycol provides polymers with only hydroxyl end groups.

Since the polymer system of the thermosetting gel dissolves more completely at reduced temperatures, the solubilization method comprises adding the desired amount of polymer at reduced temperatures to a quantity of water to be used. Typically, after wetting the polymer by shaking, the mixture is capped and placed in a cooling chamber or thermostatic vessel at about 0-10 ℃ to dissolve the polymer. The mixture is stirred or shaken to dissolve the thermosetting gel polymer more quickly. The ophthalmic agent and various additives, such as buffers, salts and preservatives, are then added and dissolved. In some cases, the pharmaceutical agent is suspended if it is not soluble in water. The pD is adjusted by the addition of a suitable buffer.

Ophthalmic ointment muscarinic antagonist compositions

Ointments are uniformly viscous semisolid preparations intended for external application to the skin or mucous membranes, most commonly fatty thickened oils (e.g. 80% oil-20% water) with high viscosity. The ointment has a water number (water number) that defines the maximum amount of water it contains. They are used as emollients or for applying active ingredients to the skin for protective, therapeutic or prophylactic purposes, and where the degree of occlusion (oclusion) is desired. The ointment is topically applied to a variety of body surfaces. These include the skin and mucous membranes of the eyes (eye ointment), vulva, anus and nose.

The vehicle for the ointment is referred to as the ointment base. The choice of matrix depends on the clinical indication of the ointment. The different types of ointment bases are: hydrocarbon bases such as hard paraffin, soft paraffin, microcrystalline wax and ozokerite; absorbent bases such as lanolin, beeswax; water soluble bases such as polyethylene glycol 200, 300, 400; emulsifying bases, such as emulsifying wax, cetrimide; vegetable oils, such as olive oil, coconut oil, sesame oil, almond oil and peanut oil.

Ointments are formulated to provide immiscible, miscible or emulsifiable formulations with skin secretions using hydrophobic, hydrophilic or water-emulsifying bases. In some embodiments, the ointment is also derived from a hydrocarbon (fat), absorbent, water removable, or water soluble base. The active agent is dispersed in the matrix and subsequently separated after the drug has penetrated to the target site (e.g., membrane, skin, etc.).

The present invention recognizes that it is sometimes difficult to incorporate low concentrations of drugs into ointments with sufficient dose-to-dose uniformity for effective treatment of a disorder or disease. In some embodiments, poly (ethylene glycol), polyethoxylated castor oil (c), (d), (EL), alcohols having 12 to 20 carbon atoms or mixtures of two or more of said components are effective excipients for dispersing and/or dissolving an effective amount of an ophthalmic drug, in particular ascomycin (ascomycin) and staurosporine (staurosporine) derivatives, in an ointment base, in particular in an ointment base essentially comprising oily and hydrocarbon components, and the skin and eye tissue are well tolerated by the resulting ointment.

The present invention further recognizes that ophthalmic drugs such as muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof) incorporated in the ointment compositions described herein target the choroid and/or retina of a patient when the composition is topically applied to the ocular surface, particularly the sclera of the patient. In some embodiments, an ophthalmic ointment composition comprises an ophthalmic drug, an ointment base, and an agent for dispersing and/or dissolving the drug in the ointment base selected from the group consisting of poly (ethylene glycol), polyethoxylated castor oil, an alcohol having from 12 to 20 carbon atoms, and a mixture of two or more of the components.

In some embodiments, the ointment base includes ophthalmically acceptable oil and fat bases such as natural waxes, e.g., white and yellow beeswax, carnauba wax, wool wax (lanolin), purified lanolin, anhydrous lanolin; petroleum waxes, such as hard paraffin wax, microcrystalline wax; hydrocarbons such as liquid paraffin, white and yellow soft paraffin, white vaseline, yellow vaseline; or a combination thereof.

The above mentioned oil and fat bases are described in more detail in, for example, the British Pharmacopoeia (British Pharmacopoeia) 2001 th edition or the European Pharmacopoeia (European Pharmacopoeia) 3 rd edition.

In some embodiments, the ointment base is present in an amount of about 50% to about 95%, preferably 70% to 90%, by weight, based on the total weight of the composition.

Preferred ointment bases comprise one or more combinations of one or more natural waxes (such as the waxes shown above), preferably wool wax (lanolin), with one or more hydrocarbons (such as the hydrocarbons shown above), preferably soft paraffin or petrolatum, more preferably with liquid paraffin.

A specific embodiment of the above ointment base comprises, for example, 5-17 parts by weight of lanolin and 50-65 parts by weight of white petrolatum and 20-30 parts by weight of liquid paraffin.

In some embodiments, the agent for dispersing and/or dissolving the ophthalmic drug in the ointment base is selected from the group consisting of poly (ethylene glycol), polyethoxylated castor oil, alcohols having 12-20 carbon atoms, and mixtures of two or more of said components. The agent is preferably used in an amount of 1-20 percent, more preferably 1-10 percent, by weight of the entire semi-solid ophthalmic composition.

The alcohols having 12 to 20 carbon atoms specifically include stearyl alcohol (C18H37OH), cetyl alcohol (C16H33OH), and mixtures thereof. Preferably so-called cetostearyl alcohol, mixtures of solid alcohols consisting essentially of stearyl alcohol and cetyl alcohol and preferably containing not less than 40% by weight of stearyl alcohol and the total amount of stearyl and cetyl alcohol amounting to at least 90% by weight, and compositions containing not less than 80% by weight of cetostearyl alcohol and emulsifiers, in particular sodium cetostearyl sulphate and/or sodium lauryl sulphate, preferably in an amount of not less than 7% by weight of emulsifiers.

Polyethoxylated castor oil is the reaction product of natural or hydrogenated castor oil with ethylene glycol. In some cases, such products are obtained in a known manner, for example by reacting natural or hydrogenated castor oil or fractions thereof with ethylene oxide in a molar ratio of, for example, about 1: 30 to about 1: 60 and optionally removing free polyethylene glycol components from the product according to methods disclosed in, for example, German Auslegeschriften 1,182,388 and 1,518,819. Particularly suitable and preferred are those under the trade name EL is a commercially available product having a molecular weight (by vapor osmometry) of about 1630, a saponification number of about 65-70, an acid number of about 2, an iodine number of about 28-32 and nD25 of about 1.471. Also suitable for this category are, for example,HCO-60, which is the reaction product of hydrogenated castor oil and ethylene oxide, exhibits the following characteristics: acid number about 0.3; a saponification number of about 47.4; hydroxyl number about 42.5; pH (5%) -about 4.6; color APHA of about 40; m.p. about 36.0 ℃; freezing point about 32.4 ℃; the H2O content (%, KF) is about 0.03.

According to the present invention, poly (ethylene glycol) is used in some embodiments as an agent for dispersing and/or dissolving an ophthalmic drug in an ointment base. Suitable poly (ethylene glycols) are generally of the formula H- (OCH)₂-CH₂)_nA mixture of OH polymeric compounds wherein subscript n is typically in the range of 4-230 and has an average molecular weight of about 200 to about 10000. Preferably, n is a number from about 6 to about 22 and has an average molecular weight between about 300 and about 1000, more preferably, n is in the range from about 6 to about 13 and has an average molecular weight of about 300 to about 600, most preferably, n has a value from about 8.5 to about 9 and a relative molecular weight of about 400. Suitable poly (ethylene glycols) are readily available commercially, for example, poly (ethylene glycols) having an average molecular weight of about 200, 300, 400, 600, 1000, 1500, 2000, 3000, 4000, 6000, 8000 and 10000.

The poly (ethylene glycol), particularly of the preferred type described in the preceding paragraph, is preferably used in an amount of 1 to 10% by weight, more preferably 1 to 5% by weight, of the total semi-solid ophthalmic composition.

A particularly preferred embodiment of the composition according to the present disclosure comprises an agent for dispersing and/or dissolving the drug in the ointment base, which agent is selected from poly (ethylene glycol), polyethoxylated castor oil and preferably a mixture of said components.

Gel/ointment viscosity

In some embodiments, the composition has a Brookfield RVDV viscosity from about 10,000cp to about 300,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 15,000cp to about 200,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 50,000cp to about 150,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 70,000cp to about 130,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c). In some embodiments, the composition has a Brookfield RVDV viscosity from about 90,000cp to about 110,000cp at about 20 ℃ and has a viscosity of 1s^-1The shear rate of (c).

In some embodiments, the ophthalmic gel formulation contains a viscosity enhancing agent sufficient to provide the following viscosities: about 500 to 1,000,000 centipoise, about 750 to 1,000,000 centipoise, about 1000 to 400,000 centipoise, about 2000 to 100,000 centipoise, about 3000 to 50,000 centipoise, about 4000 to 25,000 centipoise, about 5000 to 20,000 centipoise, or about 6000 to 15,000 centipoise. In some embodiments, the ophthalmic gel formulation contains a viscosity enhancing agent sufficient to provide a viscosity of about 50,0000 to 1,000,000 centipoise.

In some embodiments, the compositions described herein are low viscosity compositions at body temperature. In some embodiments, the low viscosity composition contains from about 1% to about 10% of a viscosity enhancing agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity composition contains from about 2% to about 10% of a viscosity enhancing agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity composition contains from about 5% to about 10% of a viscosity enhancing agent (e.g., a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity composition is substantially free of viscosity enhancing agents (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the low viscosity ophthalmic composition described herein provides an apparent viscosity of from about 100cP to about 10,000 cP. In some embodiments, the low viscosity ophthalmic composition described herein provides an apparent viscosity of from about 500cP to about 10,000 cP. In some embodiments, the low viscosity ophthalmic composition described herein provides an apparent viscosity of about 1000cP to about 10,000 cP.

In some embodiments, the compositions described herein are viscous compositions at body temperature. In some embodiments, the adhesive composition contains from about 10% to about 25% of a viscosity enhancing agent (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the adhesive composition contains from about 14% to about 22% of a viscosity enhancing agent (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the adhesive composition contains from about 15% to about 21% of a viscosity enhancing agent (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the tacky ophthalmic compositions described herein provide an apparent viscosity of from about 100,000cP to about 1,000,000 cP. In some embodiments, the tacky ophthalmic compositions described herein provide an apparent viscosity of from about 150,000cP to about 500,000 cP. In some embodiments, the tacky ophthalmic compositions described herein provide an apparent viscosity of from about 250,000cP to about 500,000 cP. In some such embodiments, the viscous ophthalmic composition is a liquid at room temperature and gels at temperatures between about room temperature and body temperature (including individuals with severe fever, e.g., up to about 42 ℃). In some embodiments, the viscous ophthalmic composition is administered as a monotherapy to treat an ophthalmic disease or condition described herein.

In some embodiments, the viscosity of the gel formulations set forth herein is measured by any of the means described. For example, in some embodiments, LVDV-II + CP Cone Plate Viscometer and Cone Spindle CPE-40 are used to calculate the viscosity of the gel formulations described herein. In other embodiments, the viscosity of the gel formulations described herein is calculated using a Brookfield (spindle and cup) viscometer. In some embodiments, the viscosity ranges mentioned herein are measured at room temperature. In other embodiments, the viscosity ranges mentioned herein are measured at body temperature (e.g., at the average body temperature of a healthy person).

Gel/ointment dose-to-dose uniformity

Typical ophthalmic gels are packaged in eye drops and administered in the form of drops. For example, a single administration (i.e., a single dose) of an ophthalmic gel includes administering one, two, three, or more drops into the eye of a patient. In addition, typical ophthalmic ointments are packaged in tubes or other squeezable containers having a dispensing nozzle through which the strip of ointment is delivered. For example, a single administration (i.e., a single dose) of an ophthalmic ointment includes administering one or more strips into the eye of a patient. In some embodiments, one dose of an ophthalmic gel described herein is one drop of the gel composition from an eye drop bottle. In some embodiments, one dose of ophthalmic ointment is one strip of ointment composition dispensed through the nozzle of the dispensing tube.

In some cases, described herein includes providing an ophthalmic gel composition that is uniformly concentrated between doses. In some cases, the inter-dose uniform concentration does not exhibit significant variation in drug content from dose to dose. In some cases, uniform concentration between doses provides consistent drug content between doses.

In some cases, described herein includes providing an ophthalmic ointment composition that is uniform concentration between doses. In some cases, the inter-dose uniform concentration does not exhibit significant variation in drug content from dose to dose. In some cases, uniform concentration between doses provides consistent drug content between doses.

Non-settling formulations should not require shaking to disperse the drug uniformly. A "shake-free" formulation is potentially advantageous over a formulation that requires shaking simply because the patient's shaking behavior is a major source of variability in the amount of drug administered. It has been reported that, although instructions for shaking are explicitly noted on the label, patients often do not shake or forget to shake ophthalmic compositions that they need before administering a dose. On the other hand, even for those patients who shake the product, it is often not possible to determine whether the intensity and/or duration of the shaking is sufficient to homogenize the product. In some embodiments, the ophthalmic gel compositions and ophthalmic ointment compositions described herein are "no-shake" formulations that maintain uniformity between doses described herein.

To assess inter-dose uniformity, a dropper bottle or tube containing an ophthalmic aqueous composition, ophthalmic gel composition, or ophthalmic ointment composition is stored upright for a minimum of 12 hours prior to the start of the test. To simulate the recommended administration of these products, a predetermined number of drops or strips are dispensed from each commercially available bottle or tube at predetermined time intervals for an extended period of time, or until no product remains in the bottle or tube. All drops and strips were dispensed into tared glass vials, capped, and stored at room temperature until analysis. The concentration of muscarinic antagonists such as atropine at the indicated titration was determined using a reverse phase HPLC method.

Method of treatment

Disclosed herein are methods of preventing myopia progression by administering to the eye of an individual in need thereof an effective amount of an ophthalmic composition as described above. Also disclosed herein are methods of preventing myopia progression by administering to the eye of an individual in need thereof an effective amount of an ophthalmic composition as described above.

In some embodiments, the ophthalmic aqueous formulations described herein are packaged in eye drops and administered in the form of droplets. For example, a single administration (i.e., a single dose) of an ophthalmic aqueous formulation includes administering one, two, three, or more drops into the eye of a patient. In some embodiments, the ophthalmic gel formulations described herein are packaged in eye drops and administered in the form of droplets. For example, a single administration (i.e., a single dose) of an ophthalmic gel includes administering one, two, three, or more drops into the eye of a patient. In some embodiments, the ophthalmic ointment formulations described herein are packaged in a tube or other squeezable container having a dispensing nozzle through which the strip of ointment is delivered. For example, a single administration (i.e., a single dose) of an ophthalmic ointment includes administering one or more strips into the eye of a patient. In some embodiments, one dose of an ophthalmic aqueous formulation described herein is one drop of an aqueous composition from an eye drop bottle. In some embodiments, one dose of an ophthalmic gel described herein is one drop of the gel composition from an eye drop bottle. In some embodiments, one dose of ophthalmic ointment is one strip of ointment composition dispensed through the nozzle of the dispensing tube.

In some embodiments of the disclosed methods, the ophthalmic composition is stored at a temperature below room temperature prior to first use. In some embodiments of the disclosed methods, the ophthalmic composition is stored at a temperature between about 2 ℃ to about 10 ℃ prior to first use. In some embodiments of the disclosed methods, the ophthalmic composition is stored at about 2 ℃, about 3 ℃, about 4 ℃, about 5 ℃, about 6 ℃, about 7 ℃, about 8 ℃, about 9 ℃, or about 10 ℃ prior to first use. In some embodiments of the disclosed methods, the ophthalmic composition is stored at a temperature between about 4 ℃ to about 8 ℃ prior to first use.

In some embodiments of the disclosed methods, the ophthalmic composition is stored at room temperature after first use. In some embodiments of the disclosed methods, the ophthalmic composition is stored at a temperature between about 16 ℃ to about 26 ℃ after first use. In some embodiments of the disclosed methods, the ophthalmic composition is stored at about 16 ℃, about 17 ℃, about 18 ℃, about 19 ℃, about 20 ℃, about 21 ℃, about 22 ℃, about 23 ℃, about 24 ℃, about 25 ℃, or about 26 ℃ after first use.

In some embodiments, the ophthalmic aqueous formulation is administered as follows: the lower eyelid to which it is to be applied is pulled down and a predetermined amount of aqueous formulation (e.g., 1-3 drops) is applied to the inside of the eyelid. The ophthalmic tip of the dispensing mechanism does not contact any surface to avoid contamination and/or damage.

In some embodiments, the ophthalmic gel formulation is administered as follows: the lower eyelid to be applied is pulled down and a predetermined amount of gel (e.g., 1-3 drops) is applied to the inside of the eyelid. The ophthalmic tip of the dispensing mechanism does not contact any surface to avoid contamination and/or damage.

In some embodiments, the ophthalmic ointment formulation is administered as follows: the lower eyelid to which the application is to be made is pulled down and a small amount of ointment (about 0.25 inch) is applied to the inside of the eyelid. The ophthalmic tip of the dispensing mechanism does not contact any surface to avoid contamination and/or damage.

In some embodiments, the ophthalmic composition is administered at predetermined time intervals over an extended period of time. In some embodiments, the ophthalmic composition is administered once daily. In some embodiments, the ophthalmic composition is administered once every other day. In some embodiments, the ophthalmic composition is administered within 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, or 12-15 years.

In some embodiments, the ophthalmic composition is administered at a dose at which the concentration of the ophthalmic agent varies by less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5% between doses.

The number of times the composition is administered to an individual in need thereof will depend on the judgment of the medical professional, the condition, the severity of the condition, and the individual's response to the formulation. In some embodiments, the compositions disclosed herein are administered once to an individual in need thereof who has a mild acute condition. In some embodiments, a composition disclosed herein is administered more than once to an individual in need thereof with a moderate or severe acute condition. In the event that the patient's condition does not improve, the ophthalmic agent is administered chronically (i.e., over an extended period of time, including the entire duration of the patient's life) to alleviate or otherwise control or limit the symptoms of the disease or condition in the patient, at the discretion of the physician.

In the event that the patient's condition does not improve, the ophthalmic agent is administered chronically (i.e., over an extended period of time, including the entire duration of the patient's life) to alleviate or otherwise control or limit the symptoms of the disease or condition in the patient, at the discretion of the physician.

Continuing administration of the ophthalmic agent according to the judgment of the doctor, if the condition of the patient is indeed improved; alternatively, the dose of drug administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., the "drug holiday"). The length of the drug holiday varies between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. Dose reduction during the drug holiday is 10% -100%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once the patient's ocular condition is improved, a maintenance dose of the ophthalmic agent is administered, if necessary. Subsequently, the dose or frequency of administration, or both, is optionally reduced to a level that maintains improvement in the disease, disorder, or condition, depending on the symptoms. In certain embodiments, once any symptoms have recurred, the patient requires chronic intermittent treatment.

The amount of ophthalmic agent corresponding to such amount will depend on factors such as the particular compound, disease condition and its severity, and will vary according to the particular circumstances concerning the case, including, for example, the particular ophthalmic agent administered, the route of administration, the condition being treated, the target area being treated, and the subject or host being treated. The required dose is provided in a single dose or as separate doses administered simultaneously (or over a short period of time) or at appropriate intervals.

In some embodiments, the initial administration is of a particular ophthalmic agent, while the subsequent administration is of a different formulation or ophthalmic agent.

Kit/article of manufacture

The invention also provides a kit for preventing or arresting the development of myopia. Such kits will generally comprise one or more ophthalmic compositions disclosed herein and instructions for using the kit. The invention also relates to the use of one or more ophthalmic compositions in the manufacture of a medicament for treating, alleviating, reducing or ameliorating the symptoms of a disease, dysfunction or disorder in a mammal, such as a human, that has, is suspected of having, or is at risk of developing myopia.

In some embodiments, the kit comprises a carrier, package, or container that is compartmentalized to receive one or more containers, e.g., vials, tubes, and the like, each container comprising a separate element to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the container is formed from a variety of materials, such as glass or plastic.

The articles provided herein contain packaging materials. Packaging materials for packaging pharmaceutical products are also provided herein. See, for example, U.S. patent nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, dropper bottles, tubes, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the chosen formulation and the intended mode of administration and treatment. To a wide range of ophthalmic compositions provided herein for use in a variety of treatments for any disease, disorder or condition that would benefit from controlled release administration of an ophthalmic agent to the eye.

In some embodiments, the kit includes one or more additional containers, each having one or more different materials (such as rinses, wipes, and/or devices) desirable from a commercial and user perspective for use with the formulations described herein. Such materials also include labels and/or instructions for listing the contents and package inserts with instructions for use. Optionally including a set of instructions. In another embodiment, the label is on or associated with the container. In yet another embodiment, the label is on the container when the letters, numbers or other characters comprising the label are attached, molded or etched onto the container itself; a label is associated with a container when the label is present in a receptacle or carrier that also holds the container (e.g., as a package insert). In other embodiments, a label is used to indicate that the contents are to be used for a particular therapeutic application. In yet another embodiment, the label also indicates instructions regarding the use of the contents, e.g., in the methods described herein.

In certain embodiments, the ophthalmic compositions are provided in a dispenser device containing one or more unit dosage forms containing a compound provided herein. In another embodiment, the dispenser device is accompanied by instructions for administration. In yet another embodiment, the dispenser is also accompanied by a notice associated with the container in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency of the form of the pharmaceutical for human or veterinary administration. In another embodiment, the notice is, for example, a label or approved product insert approved by the U.S. food and drug administration for prescription drugs. In yet another embodiment, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in an appropriate container, and labeled for treatment of the condition shown.

Examples

EXAMPLE 1 ophthalmic preparation

Exemplary compositions for preparing ophthalmic formulations are described in tables 1-8.

TABLE 1 aqueous solution preparation (atropine)

TABLE 2 aqueous solution formulation (atropine sulfate)

TABLE 3 aqueous solution formulation (atropine sulfate)

TABLE 4 mucus penetrating particle preparation (atropine)

TABLE 5 mucus penetrating particle preparation (atropine sulfate)

TABLE 6 cellulose gel preparation (atropine sulfate)

TABLE 7 thermosetting gel formulations (atropine sulfate)

TABLE 8 ointment preparations (atropine sulfate)

Example 2-in D₂Preparation of an aqueous solution formulation containing 0.01% atropine in O

1% stock solution

For 100mL of solution, 1 gram of atropine and 0.77g of NaCl (and other ingredients/components, preferably in their dry state) are added, as well as an amount of sterile deuterated water for injection sufficient to equal 100 mL. The solution was mixed in a beaker of appropriate size with a stir bar on a hot plate until all solid powder had dissolved and the solution had become clear with no visible particles. Next, the stir bar was removed and the solution was poured into a filter flask and vacuum filtered through a 0.22 micron polyethersulfone membrane filter into a sterile flask. The filter top is removed from the sterile storage bottle and the storage bottle is capped with a sterile bottle cap for storage.

Diluted 0.01% solution

0.3mL of the 1% solution was combined with sterile 0.9% sodium chloride for injection (USP) in an amount sufficient to achieve a total volume of 30 mL. The solution was thoroughly mixed. The pH of the solution was recorded. A 0.22 micron filter was placed on the tip of the syringe and the solution aliquoted into separate sterile containers.

EXAMPLE 3 preparation of an aqueous solution formulation containing 0.01% atropine sulfate

1% stock solution

For 100mL of solution, 1 gram of atropine sulphate and 0.77g of NaCl (as well as other ingredients/components, preferably in their dry state) are added, together with an amount of sterile water for injection sufficient to equal 100 mL. The solution was mixed in a beaker of appropriate size with a stir bar on a hot plate until all solid powder had dissolved and the solution had become clear with no visible particles. Next, the stir bar was removed and the solution was poured into a filter flask and vacuum filtered through a 0.22 micron polyethersulfone membrane filter into a sterile flask. The filter top is removed from the sterile storage bottle and the storage bottle is capped with a sterile bottle cap for storage.

Diluted 0.01% solution

Example 4 stability analysis

Five 0.01% atropine sulfate solutions (prepared as described in example 2) were prepared from a stock solution of 1% atropine sulfate. For solutions 1-5, the pH of the five solutions were 5.87, 5.97, 5.90, 6.24, and 6.16, respectively. Each solution was mixed thoroughly. A 0.22 micron filter was placed on the tip of the syringe and the solution was aliquoted into individual sterile containers according to table 9.

TABLE 9 Container filling summary

The samples were then stored under different conditions for stability analysis. Samples were analyzed at different time points up to 2 months. The storage conditions included: 40 ℃ and 75% Relative Humidity (RH) (samples were transferred at 2-8 ℃ after 3 days), 25 ℃ and 60% RH, and 60 ℃. Time points were 1 week, 2 weeks, 1 month and 2 months. At each time point, one plastic eye dropper (LDPE plastic) and one glass vial from each storage condition were removed and allowed to equilibrate to ambient conditions. Once equilibrated, both the plastic dropper and the glass vial were inverted 3 times. The solution in the eye dropper was transferred drop wise via a dropper to an HPLC vial. The solution in the glass vial was aliquoted into the HPLC vial using a glass Pasteur pipette. The samples were then tested for purity and potency using the UPLC method listed in table 10.

TABLE 10 UPLC method parameters

Modified from the original method to maintain sensitivity at 100 μ g/mL nominal (nominal).

Table 11 shows the stability data for the 0.01% atropine sulfate solution.

TABLE 11.0.01 stability data for atropine sulfate solution

¹Samples at 25 ℃ and 60 ℃ were taken at 15 days and samples at 40 ℃ were taken at 11 days.

²Samples at 25 ℃ and 60 ℃ were taken at 28 days and samples at 40 ℃ were taken at 24 days.

²Samples at 25 ℃ and 60 ℃ were taken at 46 days.

A change in pH of the 0.01% atropine sulfate solution was observed during the stability study. Plastic (LDPE) eye dropper tubes maintain pH around 6.2 when stored for 2 months at 25 ℃. However, at the same time point, the pH of 0.01% atropine increased to 7.2 when stored in glass vials. In addition, the pH in plastic (LDPE) eye dropper tubes drops to about 4-5 when stored at elevated temperatures (e.g., 40 ℃ and 60 ℃), while the pH is maintained at around 7.2 when stored in glass vials.

There was also a significant difference in the degradation rate of atropine sulfate (0.01%) when stored in plastic (LDPE) eye dropper tubes versus type I glass vials. However, in both containers, the early elution-related substances with a Relative Retention Time (RRT) of 0.87-0.89 were increased. In some cases, such early elution-related substances are referred to as primary degradants. In some cases, this major degradant is referred to as RRT 0.87-0.89. The relevant substance is likely to be the first parameter out of specification regardless of the container. The amount of the relevant substance was tracked at each time point and is listed in table 12.

TABLE 12.0.01 area (%)% of major degradants of atropine sulfate (RRT 0.87-0.89)

Shelf-life predictions based on Arrhenius were calculated using the relevant material data from table 12. These predictions are based on the assumption that degradation is first order (linear). These predictions are shown in fig. 1 and 2. Figure 1 shows shelf life predictions for 0.01% atropine sulfate solutions based on data obtained from samples stored at 25 ℃ and 40 ℃, where the major degradants are RRT0.87-0.89 and n.m.t. is 0.5% area. The pH range of the atropine sulfate solution is 5.9-6.2. Figure 2 shows shelf life predictions for 0.01% atropine sulfate solutions based on data obtained from samples stored at 25 ℃ and 60 ℃, where the major degradants are RRT0.87-0.89 and n.m.t. is 0.5% area. The pH range of the atropine sulfate solution is 5.9-6.2.

EXAMPLE 5-1% atropine sulfate (Bausch + Lomb) sample analysis

A1% atropine sulfate sample was obtained from Bausch + Lomb (batch No. 198421). For comparison, the pH of a 1% atropine sulfate drug product was determined in pure solution as well as samples diluted to the current nominal concentration (0.01% atropine sulfate) using vehicle. In addition, the sample was diluted to nominal concentration with the process diluent. Two samples diluted to nominal concentration were analyzed using the RP-UPLC method (table 10). The results are listed in table 13.

TABLE 13 pH and purity of Bausch + Lomb atropine sulfate samples

Not determined ND

EXAMPLE 6 dose uniformity (10 doses)

To assess the inter-dose uniformity, the dropper bottles containing the ophthalmic aqueous compositions were stored upright for a predetermined period of time (e.g., 12 hours) before the test began. To simulate the recommended administration of the product, 10 drops of the aqueous composition are dispensed from each bottle at predetermined time intervals (e.g., continuously, every 1 minute, every 10 minutes, every hour, or every 24 hours). All drops were dispensed into tared glass vials, capped, and stored at room temperature until analysis. The concentration of atropine in the indicated drops was determined using a reverse phase HPLC method.

EXAMPLE 7 dose uniformity (5 doses)

To assess the inter-dose uniformity, the dropper bottles containing the ophthalmic aqueous compositions were stored upright for a predetermined period of time (e.g., 12 hours) before the test began. To simulate the recommended administration of the product, 5 drops of the aqueous composition are dispensed from each bottle at predetermined time intervals (e.g., continuously, every 1 minute, every 10 minutes, every hour, or every 24 hours). All drops were dispensed into tared glass vials, capped, and stored at room temperature until analysis. The concentration of atropine in the indicated drops was determined using a reverse phase HPLC method.

EXAMPLE 8 dose uniformity (2 doses)

To assess the inter-dose uniformity, the dropper bottles containing the ophthalmic aqueous compositions were stored upright for a predetermined period of time (e.g., 12 hours) before the test began. To simulate the recommended administration of the product, 2 drops of the aqueous composition are dispensed from each bottle at predetermined time intervals (e.g., continuously, every 1 minute, every 10 minutes, every hour, or every 24 hours). All drops were dispensed into tared glass vials, capped, and stored at room temperature until analysis. The concentration of atropine in the indicated drops was determined using a reverse phase HPLC method.

Example 9 comparison of formulation stability

The experiment was performed using atropine sulfate monohydrate (MP Bio; batch No. 7825K) and tropine acid (Sigma Aldrich; batch No. STBD 6457V). Eight formulations shown in table 14A were analyzed at t ═ 0, 2 weeks, and 4 weeks. The analysis was performed using the RP-HPLC method.

TABLE 14A atropine sulfate formulations

Values are expressed in% w/v. Formulations were prepared in a volumetric glassware on a 100mL scale. Formulations 7 and 8 had pds of 5.2 and 6.2, respectively. In some cases, pD is calculated as pD-0.4 + pH, where pH is the measured or observed pH of a solution formulated in a solution containing deuterated water.

Table 14B shows the time points of analysis for the formulations listed in table 14A.

TABLE 14B atropine sulfate formulation test schedules

Table 15 shows atropine sulfate purity data associated with each of the eight formulations. Purity is expressed as a percentage of the area under the curve.

TABLE 15 purity of atropine sulfate (in area%)

¹For many of the t-4 week stability samples, some chromatographic disturbances were observed late in the run (approximately 27-32 minutes) and were considered to be system related in some cases.

After storage at 60 ℃ for four weeks, in some cases, the atropine sulfate concentration affected the stability of the acetic acid containing formulation at pH 4.2. For example, atropine sulfate at a concentration of 0.025% w/v (formulation 2) showed a 2.8% increase in% purity at pH 4.2, as compared to atropine sulfate at a concentration of 0.010% w/v (formulation 1). This trend was not observed for the acetic acid formulations at pH 4.8 (formulations 3 and 4); in contrast, a 0.6% reduction in purity was observed for the higher dose.

The dose-dependent stability trend observed at pH 4.2 was also observed in formulations containing citric acid at pH 5.8 (formulations 5 and 6). After storage at 60 ℃ for four weeks, the degradation in the higher dose was about 14% less than that observed in the lower dose.

At high and low doses, more degradation was observed in formulations starting at higher pH. This degradation is mainly a growth of tropine acid. In some cases, the buffer substance plays a role in the degradation observed between different pH values.

The percentage of tropine acid observed for each formulation at t-4 weeks and at 60 ℃ was as follows:

formulation 1-tropine acid was observed to be 0.54%.

Formulation 2-0.93% tropine acid was observed.

Formulation 3-tropine acid 1.58% was observed.

Formulation 4-tropine acid was observed to be 3.03%.

Formulation 5-tropine acid was observed to be 29.13%.

Formulation 6-16.84% tropine acid was observed.

Formulation 7-tropine acid 1.07% was observed.

Formulation 8-tropine acid was observed to be 4.03%.

In some embodiments, the water source is switched to deuterated water (D)₂O) had an effect on the increase of the tropine peak of the formulation containing acetic acid (formulation 7) stabilizing the pD at 5.2, see fig. 4. Furthermore, in the formulation containing citric acid at pD 6.2 (formulation 8), deuterated water also stabilized atropine sulfate, see fig. 5.

Table 16 shows tropine for each of the eight formulations as the area under the curve. Tropine acid is a degradation product of atropine sulfate. In some cases, the LOQ was previously found to be 0.05% using the RP-HPLC method.

TABLE 16 tropine acid (in area%)

Table 17 shows the percent efficacy of atropine in the eight formulations.

TABLE 17 efficacy%

After 4 weeks of storage, the efficacy values observed increased from the t0 and 2 week time points, except for formulations 5 and 6 at 60 ℃, which decreased in efficacy due to degradation. In some cases, these potency values are within the error of the HPLC method, but appear to tend upwards. The mass balance of the 60 ℃ data was calculated and the results were consistent between each formulation and degradation level, although skewed downward at 4 weeks due to higher than expected efficacy values, see figure 3.

Table 18 shows the pH or pD stability of the eight formulations.

TABLE 18 pH/pD stability

Italics are the pD values of the deuterated samples. In some embodiments, the deuterated sample has a pD at pD-pH_{Reading number}+0.4(Glasoe et al, "Use of glass electrodes to means acids in a material oxide" J.physical chem.64(1): 188-.

At two lower temperatures, the pH at t-4 weeks increased slightly from the t-2 week time point. These data were generated using a new glass pH probe. In some cases, the observed differences are due to probe differences or other variables, such as, for example, the age of standard buffers or temperature gradients within the laboratory environment. The trend of pH decrease with increasing temperature for each formulation at t-4 weeks is consistent with previous data and with an increase in the amount of tropine present in the stability samples.

EXAMPLE 10 determination of shelf-Life and activation energy

The activation energies of the eight formulations disclosed in example 9 were calculated and compared to reference standards using formulations 4-7.

Table 19 shows the activation energy (Ea) calculations. Ea minimum of 17.8Kcal/mol, Ea maximum of 21.3Kcal/mol, and Ea average of 19.5 Kcal/mol. Mean values are +/-3 standard deviations. Fig. 6 and 7 show the poor correlation between RS and tropine for formulations 4 and 7, respectively. Fig. 8 and 9 show the improved correlation between RS and tropine for formulations 5 and 6, respectively. At lower pH (e.g. pH 4.8 or lower), a poor correlation was observed (formulation 4 and formulation 7). This is due to slow hydrolysis and increased alternative degradation pathways. At higher pH (e.g. pH 5.8 or higher), improved or better correlation was observed (formulation 5 and formulation 6). This is due to the hydrolysis of atropine as the major degradant. It should be noted that the activation energy is for the catalytic degradation of a particular acid to tropine acid (the major degradation products and degradation mechanisms operating at pH 5.8 or higher).

TABLE 19 activation energies of Total Related Substances (RS) and tropine

Table 20 shows the rate of RS or tropine formation per week at 40 ℃.

Watch 20

Table 21 shows the activation energy and predicted shelf life at 30 ℃ calculated based on table 20. For this calculation, it is assumed that the tropine acid and total RS are 5% (shelf life).

TABLE 21A

TABLE 21B

At pD 6.2, the deuterated formulation (formulation 8) had a predicted shelf life of approximately 2 years at 30 ℃.

Table 22 shows the predicted shelf life of formulations 4-8 at 40 ℃, 30 ℃,25 ℃ and 2-8 ℃ temperatures for total RS and tropine acid, respectively.

TABLE 22

EXAMPLE 11 comparison of stability of other formulations

The experiment was performed using atropine sulfate monohydrate (MP Bio; batch No. 7825K) and tropine acid (Sigma Aldrich; batch No. STBD 6457V). Thirteen formulations shown in table 23A were analyzed. Formulations 1-8 were analyzed at t ═ 0, 2 weeks, 4 weeks, and 8 weeks. Formulations 9-13 were analyzed at t ═ 0, 2 weeks, and 4 weeks. The pH values reported herein were measured using a Thermoscientific, Orion Dual Star pH/ISE bench-top pH meter and using a H-base₂O standard calibrated Orion Double Junction Micro pH Probe S/N S01-18520.

TABLE 23A atropine sulfate formulations

Values are expressed in% w/v. Formulations were prepared in volumetric glassware on a 100mL scale and filled into LDPE eye-dropper tubes. In some cases, pD is calculated as pD-0.4 + pH, where pH is the measured or observed pH of a solution formulated in a solution containing deuterated water.

Table 23B shows the time points of analysis for the formulations listed in table 23A.

TABLE 23B atropine sulfate formulation test schedules

Table 24A and table 24B show atropine sulfate purity data relating to the atropine sulfate formulations. Purity is expressed as a percentage of the area under the curve. ↓ and ↓ represent high or low concentrations of atropine sulfate monohydrate (0.01% and 0.025%). A and C represent the buffer substances used, acetic acid and citric acid, respectively.

TABLE 24A.H₂Atropine sulfate purity of O preparation (expressed as area%)

TABLE 24B.D₂Atropine sulfate purity of O preparation (expressed as area%)

Tables 25A and 25B show tropine acid formation in relation to the atropine sulfate formulations. Tropine acid is a degradant of atropine sulfate and is expressed as a percentage of the area under the curve. LOQ was found to be 0.05% by RP-HPLC method. ↓ and ↓ represent high or low concentrations of atropine sulfate monohydrate (0.01% and 0.025%). A and C represent the buffer substances used, acetic acid and citric acid, respectively.

TABLE 25A.H₂Tropine acid of O formulation (in area%)

TABLE 25B.D₂Tropine acid of O formulation (in area%)

Table 26A and table 26B show the percent efficacy of atropine in the formulations. ↓ and ↓ represent high or low concentrations of atropine sulfate monohydrate (0.01% and 0.025%). A and C represent the buffer substances used, acetic acid and citric acid, respectively.

TABLE 26A.H₂Percentage of efficacy of O formulation

TABLE 26B.D₂Percentage of efficacy of O formulation

Tables 27A and 27B show the pH or pD stability of the atropine sulfate formulations. ↓ and ↓ represent high or low concentrations of atropine sulfate monohydrate (0.01% and 0.025%). A and C represent the buffer substances used, acetic acid and citric acid, respectively.

TABLE 27A.H₂pH stability of O formulations

TABLE 27B.D₂pD stability of O formulations

Example 12 determination of shelf-life and activation energy of the atropine sulfate formulations of example 11

The activation energy of the atropine sulfate formulation disclosed in example 11 was calculated. Specifically, the activation energy was calculated from the total% (2 points) of the Related Substances (RS) at 40 ℃ and 60 ℃ and from the formation of tropine acid (2 points) at 40 ℃ and 60 ℃. These values are then averaged. Table 28 shows the activation energy calculations. Table 29 shows the shelf life estimated from the 40 ℃ formation rates of% RS and tropine acid, respectively. FIG. 10 shows D₂O and H₂O estimated shelf life of the formulation.

TABLE 28 activation energy

TABLE 29 estimated shelf life

Table 30 shows the predicted shelf life of formulations 2-8 at 40 ℃, 30 ℃,25 ℃ and 2-8 ℃ temperatures for total RS and tropine acid, respectively.

Watch 30

Example 13 Effect of pH on acceptability of the eyes in guinea pigs

One group of guinea pigs was administered 50 μ L of the ophthalmic formulations described herein with different pH values. For example, administering to an animal a composition comprising H₂O or deuterated water (e.g. D)₂O) ophthalmic formulation. Animal behavior was recorded at predetermined time intervals to assess the acceptability of the ophthalmic formulations.

EXAMPLE 14 in vivo eye irritation test in rabbits

Exemplary compositions disclosed herein were subjected to a rabbit eye irritation test to evaluate their safety profile. The test compositions were tested in New Zealand rabbits using the eye irritation test (see, e.g., Abraham M H et al, Draizrabit eye test compliance with eye irritation thresholds in humans: acquisition structure-activity relationship, Toxicol Sci.2003, 12 months; 76(2) 384-91.Epub2003, 26 months; see also Gettings S D et al, A composition of volume, Draize and in a video eye irritation test data. III. Surfactant-base formulations, food chemistry Toxicol.1998, 3; 36(3): 209-31). The study involved monocular administration in the right eye of each of three rabbits, and the same volume of placebo in their left eye. Rabbits were examined immediately after instillation of the composition and at 4 hours, 24 hours, 48 hours, and 72 hours after instillation to record signs/symptoms of ocular irritation (if present). The test compositions showed no signs of irritation in the cornea, iris and conjunctiva of rabbit eyes.

Example 15 in vivo testing of aqueous ophthalmic formulations in guinea pigs

Focus Deprivation Myopia (FDM) is achieved by covering one eye with a latex mask. For defocus-induced myopia, a latex-made mask was held in place by a rubber band around the animal's head, leaving both eyes, nose, mouth and ears freely exposed. the-4.00D lenses were glued to the plastic frame. The frame is then attached to the mask around one eye with a fabric hook and loop fastener after aligning the optical center of the lens with the center of the pupil. The lenses were detached and cleaned on both sides with water-wetted gauze at least once a day and then reattached to the mask. All animals were maintained in a 12h cycle of illumination (500 lux) and 12h of darkness during the experiment.

A group of 3-week-old guinea pigs were randomly assigned to FDM group (mask worn on one eye) or defocus-induced myopia group (4.00D lens worn on one eye) and control group. FDM groups are treated with an ophthalmic aqueous formulation, an ophthalmic vehicle (no ophthalmic agent) or FDM only. Defocus-induced myopic groups were treated with aqueous ophthalmic formulations, ophthalmic vehicle (no ophthalmic agent) or defocus only. The control group was treated with an aqueous ophthalmic formulation, an ophthalmic vehicle (no ophthalmic agent) or not. Ocular biometric parameters of both eyes of a single animal were measured before treatment and on day 11 of treatment.

After the mask or lens is removed, biometric parameters (e.g., refractive, corneal curvature, and axial component of the eye) are measured by an optometrist, visual axis orthotist, or ophthalmologist with the aid of an animal care assistant during the light period (daytime). The treatment conditions for each animal were concealed from the optometrist, visual axis correctionist or ophthalmologist.

Refraction was measured by retinoscopy after complete dilation of the pupil by topical application of 1% cyclopentolate hydrochloride. The results of the retinoscopy were recorded as the mean of the horizontal and vertical meridians (meridian).

Keratometer modified by attaching a +8D lens to the anterior surface of the keratometer was used to measure corneal curvature. A set of stainless steel balls with a diameter of 5.5 to 11.0mm was measured with a modified keratometer. Three readings were recorded for each measurement to provide an average result. The radius of curvature of the cornea is then inferred from the reading of a sphere of known radius.

The axial components of the eye (lens thickness and vitreous length and axial length) were measured using an a-scan ultrasonic plotter (a-scan ultrasonic plotter). As previously mentioned, for the measurement of the lens thickness a speed of 1,723.3m/s was performed, whereas for the measurement of the vitreous length a speed of 1,540m/s was performed. Each axial component was calculated as the average of 10 repeated measurements.

EXAMPLE 16 safety and efficacy Studies of aqueous ophthalmic formulations

Clinical trials were conducted to investigate the efficacy and safety of the ophthalmic aqueous formulations described herein in myopes. In some cases, the study is an open label, single-blind, or double-blind study. Patient selection criteria include myopic refraction of at least 1.0D in both eyes and other factors such as astigmatism, documented myopic progression, age, sex, and/or health condition.

Patients were randomly assigned to receive in both eyes once a night at H₂O or deuterated water (e.g. D)₂O) 0.05%, 0.01% or 0.001% atropine aqueous formulation. In some cases, the distribution ratio is defined based on a patient population.

Patients were evaluated on day 0 (baseline), 14 days, 30 days, followed by 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months, 18 months, 20 months, 24 months, and 36 months. The best corrected distance logMar visual acuity (BCVA) was evaluated at each visit by an optometrist, visual axis correctionist or ophthalmologist using an early treatment diabetic retinopathy study chart. Near visual acuity was assessed using distance visual correction (distance variable correction) with the scaled down logMar reading chart placed at 40cm under well-lighted conditions. The adjusted Near Point (NPA) is measured with the RAF ruler using the best corrected distance visual correction. The patient is instructed to move the target inward until the N5 footprint becomes slightly blurred, and then outward until the N5 footprint just becomes clear. The adjustment amplitude is calculated as the inverse of NPA. The intermediate vision pupil size was measured using a Procyon 3000 pupillometer. Neuroptics pupillometers were used to measure photopic pupil size.

Autorefractometry for cycloplegic was performed using a Canon RK-F1 autorefractometer 30 minutes after 3 drops of 1% cyclopentolate administered 5 minutes apart. The eye axis length was measured using a non-contact partial coherence interferometry Zeiss IOL Master.

The primary result is myopia progression over the study period. Safety is assessed by adverse events including allergies, irritation, or development of blurred vision in one or both eyes.

EXAMPLE 17 preparation of an ointment formulation containing atropine sulfate

Atropine sulfate is mixed with a dispersant (e.g., polyethylene glycol) under heat and sonication, and the mixture is further thoroughly mixed with a molten ointment base (e.g., a mixture of wool wax, white petrolatum, and liquid paraffin). The mixture was placed in a pressure vessel and sterilized at 125 ℃ for 30-45 minutes and cooled to room temperature. In another embodiment, autoclaving is performed under nitrogen. The resulting ophthalmic ointment is aseptically filled into a previously sterilized container (e.g., tube).

EXAMPLE 18 atropine-mucus penetrating particle composition

A 0.01% atropine-mucus penetrating particle composition was prepared using a milling procedure. An aqueous dispersion containing atropine particles and an MPP-enabling mucus penetration agent is milled with milling media until the particle size is reduced to about 200nm, with a polydispersity index of less than 0.15 as measured by dynamic light scattering. Other agents, such as preservatives, are also added during the milling procedure. Subsequently, the atropine-MPP composition is stored at a temperature between about 15 ℃ and about 25 ℃.

EXAMPLE 19 atropine sulfate-mucus penetrating particle composition

A 0.01% atropine sulfate-mucus penetrating particle composition was prepared using a milling procedure. An aqueous dispersion containing atropine particles and an MPP-enabling mucus penetration agent is milled with milling media until the particle size is reduced to about 200nm, with a polydispersity index of less than 0.15 as measured by dynamic light scattering. Other agents, such as preservatives, are also added during the milling procedure. Subsequently, the atropine-MPP composition is stored at a temperature between about 15 ℃ and about 25 ℃.

According to another aspect of the invention, described herein is an ophthalmic composition comprising from about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and water, having a pH of from about 3.8 to about 7.5.

In some cases, the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some cases, the muscarinic antagonist is atropine. In some cases, the muscarinic antagonist is atropine sulfate.

In some cases, the ophthalmic composition comprises a muscarinic antagonist at one of the following based on initial concentrations after an extended period of time under storage conditions: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%.

In some cases, the ophthalmic composition has a pH of one of the following after an extended period of time under storage conditions: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, less than about 4.8, or less than about 4.2.

In some cases, the ophthalmic composition further has an efficacy of one of the following after an extended period of time under storage conditions: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99%.

In some cases, the extended period of time is one of: about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 18 months, about 24 months, about 36 months, about 4 years, or about 5 years.

In some cases, the storage condition has a storage temperature of one of: about 25 ℃, about 40 ℃ or about 60 ℃. In some cases, the storage conditions have a storage temperature of about 2 ℃ to about 10 ℃ or about 16 ℃ to about 26 ℃. In some cases, the storage condition has a relative humidity of about 60% or about 75%.

In some cases, the ophthalmic composition is in the form of an aqueous solution. In some cases, the muscarinic antagonist is present in the composition at a concentration of one of: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.008 wt%, or about 0.001 wt% to about 0.005 wt%.

In some cases, the ophthalmic composition further comprises an osmolality adjusting agent. In some cases, the osmolality adjusting agent is sodium chloride.

In some cases, the ophthalmic composition further comprises a preservative. In some cases, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxy-chloride complex, SofZia, polyquaternium-1, chlorobutanol, edetate disodium, polyhexamethylene biguanide, or a combination thereof.

In some cases, the ophthalmic composition further comprises a buffering agent. In some cases, the buffer is selected from borate, borate-polyol complex, phosphate buffer, citrate buffer, acetate buffer, carbonate buffer, organic buffer, amino acid buffer, or combinations thereof.

In some cases, the ophthalmic composition further comprises a tonicity adjusting agent. In some cases, the tonicity modifier is selected from the group consisting of sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

In some cases, the ophthalmic composition is stored in a plastic container. In some cases, the material of the plastic container includes Low Density Polyethylene (LDPE).

In some cases, the ophthalmic composition has a change in concentration of the muscarinic antagonist between doses of one of: less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. In some cases, the change in muscarinic antagonist concentration between doses is based on one of: 10 consecutive doses, 8 consecutive doses, 5 consecutive doses, 3 consecutive doses, or 2 consecutive doses.

In some cases, the ophthalmic composition has a pH of one of: about 3.8 to about 7.5, about 4.2 to about 7.5, about 4.8 to about 7.3, about 5.2 to about 7.2, about 5.8 to about 7.1, about 6.0 to about 7.0, or about 6.2 to about 6.8.

In some cases, the ophthalmic composition further comprises a pH adjusting agent. In some cases, the pH adjuster comprises HCl, NaOH, CH₃COOH or C₆H₈O₇。

In some cases, the ophthalmic composition comprises one of: less than 5% of D₂O, less than 4% of D₂O, less than 3% of D₂O, less than 2% of D₂O, less than 1% of D₂O, less than 0.5% of D₂O, less than 0.1% of D₂O, or 0% D₂And O. In some cases, the ophthalmic composition is substantially free of D₂O。

In some cases, the ophthalmic composition further comprises a pharmaceutically acceptable carrier.

In some cases, the ophthalmic composition is formulated as an ophthalmic solution for treating an ophthalmic condition. In some cases, the ophthalmic disorder or condition is pre-myopia, or myopia progression.

In some cases, the ophthalmic composition is not formulated as an injectable formulation.

While preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only. Various alternatives to the embodiments described herein are optionally used in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

2. The ophthalmic composition of claim 1, wherein the muscarinic antagonist comprises atropine, atropine sulfate, noratropine, atropine-N-oxide, atropine, tropinic acid, scopolamine, hyoscyamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof.

3. The ophthalmic composition of claim 2, wherein the muscarinic antagonist is atropine or atropine sulfate.

4. The ophthalmic composition of any one of claims 1-3, wherein the ophthalmic composition has a pD of one of the following after an extended period of time under storage conditions: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, or less than about 4.8.

5. The ophthalmic composition of any one of claims 1-4, wherein the ophthalmic composition comprises a muscarinic antagonist that is one of the following based on initial concentrations after an extended period of time under storage conditions: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%.

6. The ophthalmic composition of any one of claims 1-5, wherein the ophthalmic composition further has an efficacy of one of the following after an extended period of time under storage conditions: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99%.

7. The ophthalmic composition of any one of claims 1-6, wherein the storage conditions have a storage temperature of about 2 ℃ to about 10 ℃ or about 16 ℃ to about 26 ℃.

8. The ophthalmic composition of any one of claims 1-7, wherein the muscarinic antagonist is present in the composition at a concentration of one of: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.008 wt%, or about 0.001 wt% to about 0.005 wt%.

9. The ophthalmic composition of any one of claims 1-8, wherein the ophthalmic composition further comprises an osmolality adjusting agent, a preservative, a buffer, a tonicity adjusting agent, or a combination thereof.

10. An ophthalmic composition comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and water, having a pH of about 3.8 to about 7.5.