HK1228799A1 - Povidone iodine, a novel alternative preservative for ophthalmic compositions - Google Patents

Description

Preservative substitute povidone iodine in ophthalmic compositions

The application is a divisional application of Chinese patent application with application number 200980122263.7 (international application number PCT/US2009/003521), application date of 2009, 6 months and 10 days, and invention name of 'a new preservative substitute povidone iodine in ophthalmic composition'.

RELATED APPLICATIONS

This application claims priority from united states provisional application number 61/129,222 filed on 12.6.2008 and united states provisional application number 61/201,854 filed on 15.12.2008, both of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to preserved ophthalmic compositions, and in particular to preservative replacements in ophthalmic compositions.

Background

Currently, preservatives are an integral part of ophthalmic formulations. Suitable antimicrobial preservatives are typically added to prevent contamination of the multi-dose package. Such materials include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenethyl alcohol, EDTA, sorbic acid, polonium chloride (Onamer M), and other antimicrobial preservatives known to those skilled in the art, or combinations thereof. Benzalkonium chloride (also known as BAK or BAC) is the most commonly used preservative in ophthalmic formulations. Typically, such preservatives are used in amounts of 0.001% to 1.0% by weight. However, recent evidence suggests a potential toxicity of BAK to the cornea and conjunctiva that may lead to serious medical problems such as ocular drug problems (oculopathy), reduced success rates of glaucoma surgery, reduced compliance with ocular medications.

Disclosure of Invention

The present invention includes a preserved ophthalmic formulation comprising povidone-iodine (PVP-I) at a concentration sufficient to preserve the ophthalmic formulation, and at least one component selected from the group consisting of: steroidal anti-inflammatory compounds, non-steroidal anti-inflammatory compounds, antibacterial compounds, antiallergic compounds, and anti-glaucoma compounds.

In one embodiment, PVP-I is present at a concentration selected from the group consisting of: 0.01% to 10%, 0.1% to 2.5%, 0.2 to 1.5%, 0.3% to 1.0%. In another embodiment, PVP-I is present at a concentration of 0.5%.

In one embodiment, the PVP-I concentration is measured on a weight/weight basis based on the entire formulation. In another embodiment, the concentration of PVP-I is measured on a weight/volume basis throughout the formulation.

In one embodiment, the formulation comprises an anti-inflammatory compound selected from the group consisting of: ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, and any combination thereof.

In one embodiment, the formulation further comprises an anti-inflammatory compound selected from the group consisting of: dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluorometholone acetate, fluorometholone alcohol, lotoprenol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone acetate, lodoxylamine tromethamine, and any combination thereof.

In one embodiment, the formulation further comprises an antimicrobial preservative selected from the group consisting of: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, EDTA, sorbic acid, polonium chloride (Onamer M), and any combination thereof.

In one embodiment, the formulation further comprises a viscosity increasing agent. In one embodiment, the viscosity increasing agent is selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, and any combination thereof.

In one embodiment, the formulation further comprises at least one artificial tear-based lubricant.

The invention also includes a method of preserving an ophthalmic agent comprising adding PVP-I to the ophthalmic agent in an amount sufficient to preserve the agent. In one embodiment, the PVP-I concentration added in the method is selected from the group consisting of: 0.01% to 10%, 0.1% to 2.5%, 0.2 to 1.5%, 0.3% to 1.0%. In one embodiment, PVP-I is present at a concentration of 0.5%.

Detailed Description

As used herein, the term "about" means within 10% of the referenced value, inclusive of the recited value.

The ranges recited herein include all values between the two endpoints of the reference value, including both endpoints.

In the present invention, povidone-iodine has been found to be useful as a preservative for a variety of pharmaceutical compositions, and in one aspect of the invention, povidone-iodine is used as a preservative for ophthalmic formulations. Accordingly, in one embodiment, the present invention provides a preserved ophthalmic medicament comprising a povidone-iodine composition.

In one embodiment, povidone-iodine has at least a preservative effect on various pharmaceutical compositions. In one embodiment, povidone-iodine acts as a preservative for ophthalmic agents. The concentration of povidone-iodine as a preservative in the ophthalmic composition may range from 0.01% to 10% (weight/weight or weight/volume), and concentration values within all such ranges. In one embodiment, the povidone-iodine concentration is from 0.1% to 2.5%, in another embodiment from 0.2% to 1.5%, and in yet another embodiment from 0.3% to 1.0%. In one embodiment, the povidone-iodine concentration is about 0.5%.

In one aspect of the invention, povidone-iodine provides antimicrobial properties to ophthalmic formulations. In another aspect, povidone-iodine in ophthalmic formulations provides one or more non-antimicrobial preservative properties (e.g., as an antioxidant).

In one embodiment, the invention also provides povidone-iodine compositions that include one or more components in addition to the povidone-iodine component, as described herein.

In one aspect, the present invention provides a broad spectrum povidone-iodine ophthalmic composition, for example, for use in treating conjunctival or corneal infections of the eye caused by mycobacteria, viruses, fungi and amoebae, with a composition containing the preservative povidone-iodine. On the other hand, the composition of the present invention can be used for infection prevention in patients who are recovering from recent ophthalmic surgery, along with other ophthalmic measures.

In various embodiments, the povidone-iodine ophthalmic compositions of the present invention include, but are not limited to, the following:

1. an artificial tear formulation comprising the preservative povidone-iodine. Artificial tear matrix components include, but are not limited to: ophthalmologically acceptable lubricants, propylene glycol, glycerin, polyethylene glycol, dextran, polyvinyl alcohol blends, polyvinyl alcohol, polyethylene glycol, light mineral oil, hydroxypropyl methylcellulose, hypromellose, carbopol, carbomer 940 (polyacrylic acid), polyvinylpyrrolidone, white petrolatum, soy lecithin, sodium carboxymethylcellulose, and others known to those skilled in the art, or any combination thereof. Typically, such ingredients are used in amounts of from 0.1% to 2% by weight. In one embodiment, the components are propylene glycol 1.0%, glycerin 0.3%, blended polyvinyl alcohol 2.7%, polyvinyl alcohol 1%, polyethylene glycol 1%, light mineral oil, hydroxypropyl methylcellulose 0.3%, soy lecithin 1.0%, sodium carboxymethylcellulose 0.25% or 0.5%. In another embodiment, the total weight of PVP-I and the ingredient based on artificial tear is 0.1% to 4.5% of the total amount of the composition.

2. Anti-inflammatory and steroid formulations comprising the preservative povidone-iodine. Suitable anti-inflammatory agents are not limited to the following examples: ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen or rofecoxib. Suitable steroids are not limited to the following examples: dexamethasone alcohol, dexamethasone sodium phosphate, fluorometholone acetate, fluorometholol, loteprednol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone acetate, and lodoxylamine tromethamine. The anti-inflammatory and steroidal components are generally used in amounts of 0.01% to 2.0% by weight, based on the total weight of the composition. In one aspect, about 0.1% dexamethasone is used in the preserved ophthalmic formulation.

3. BAK-free ophthalmic preparation for the treatment of glaucoma comprising the preservative povidone-iodine. Suitable glaucoma drugs are not limited to the following examples: beta blockers (levobunolol, timolol hemihydrate, betaxolol hydrochloride, timolol maleate, and their related salts); prostaglandin analogs (e.g., bimatoprost, travoprost, latanoprost); alpha receptor agonists (brimonidine, acerbal, alcolonine); carbonic anhydrase inhibitors (pelimine, dorzolamide). These components are used in amounts conventional in the art.

4. An antibacterial/antimicrobial ophthalmic formulation comprising the preservative povidone-iodine. Suitable antibiotic/antimicrobial components are not limited to the following examples: quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, gatifloxacin, etc.); aminoglycosides (tobramycin, gentamicin, neomycin, etc.); polymyxin B combinations (polymyxin B/trimethoprim, polymyxin B/bacitracin neosporine polymyxin B/neomycin/gramicidin, etc.) and other antibiotics (azithromycin, erythromycin (ilomycin), erythromycin (erythromycin), bacitracin, etc.). Typically, such antibiotics and antimicrobial components are used in amounts of 0.001% to 1.0% by weight of the total weight of the composition.

5. An antiallergic preparation comprises the preservative povidone iodine. Suitable antiallergic components are not limited to the following examples: epinastine, emedastine difumarate, azelastine hydrochloride, olopatadine, ketotifen fumarate, pemirolast potassium, nedocromil, lodoxylamine, cromolyn, and cromoglycate. These components are used in amounts conventional in the art.

6. A complex preserved ophthalmic formulation comprising the preservative povidone-iodine. Examples of suitable components are not limited to antimicrobial preservatives. In one embodiment, the antimicrobial preservative is selected from the group consisting of: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, EDTA, sorbic acid, polonium chloride and combinations thereof. These components are used in amounts conventional in the art.

In addition, adjuvants suitable for povidone-iodine compositions of the present invention are not limited to the following examples: co-solvents/surfactants, viscosity modifiers, and/or bioadhesives. These components are used in amounts conventional in the art.

In one aspect, the compositions of the present invention optionally may comprise a co-solvent or surfactant. In one embodiment, the co-solvent may be the same or different from the surfactant. In one embodiment, the solubility of the components in the composition may be increased by the addition of a surfactant or suitable co-solvent to the composition. Such co-solvents/surfactants include, but are not limited to: polysorbate-20, polysorbate-60, polysorbate-80, polyoxyethylene/polyoxypropylene surfactants (such as pluronic F-68 and F-84 and P-103), cyclodextrin, tyloxapol (tyloxapol), polyethylene glycol 35 castor oil (Cremophor EL), polyethylene glycol 40 stearic acid (Myrj 52), and others known to those skilled in the art, or any combination thereof. Typically, these co-solvents are used in amounts of 0.01% to 2% by weight.

In another aspect, the compositions of the present invention optionally may comprise an optional viscosity increasing or decreasing agent. A viscosity higher than a single aqueous solution may promote ocular absorption of the active ingredient, reduce variability in the formulated dosage form, reduce physical separation of components in the dosage form in suspension or microemulsion, and/or otherwise improve the ophthalmic dosage form. Such tackifiers include, but are not limited to: polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, and others known to those skilled in the art, and/or any combination thereof. These co-solvents are generally used in amounts of 0.01% to 2% by weight.

In another aspect, bioadhesives may be included in the composition to increase the retention time of the drug gradient on the biological matrix. Bioadhesives include, but are not limited to: polyvinylpyrrolidone (PVP), xanthan gum, locust bean gum, acacia gum, Hydroxypropylmethylcellulose (HPMC), sodium alginate, pectin, gelatin, carbomer, polyvinyl alcohol, gellan gum, tragacanth gum, acacia gum and sodium carboxymethylcellulose, as well as other agents known to those skilled in the art, or any combination thereof.

In addition, the composition can be combined with an effective amount of a chemical agent to produce a cooling sensation, which can relieve irritation to the eyes, enhance eye comfort, produce a refreshing effect, and improve the sensation when povidone-iodine solution is instilled into the eyes. Such chemical agents include a variety of chemicals and classes of compounds, including, but not limited to, cooling agents such as mint, menthol derivatives including menthone glycerol acetals and menthyl esters, carboxamides, menthane glycerol ketals, alkyl substituted ureas, sulfonamides, terpene analogues, furanones, and phosphorus oxide; or camphor and borneol.

The formulation form of the povidone-iodine containing composition may be a solution, a suspension, an emulsion, an ointment, a cream, a gel, or a controlled/sustained release preparation. For example, the composition may be in the form of a contact lens care solution, an eye wash, eye drops, and the like.

Any of the compositions disclosed herein for topical administration, e.g., topical administration to the eye, the mixture can be formulated as an aqueous solution having a pH in the range of 3.5 to 6.5. It should be understood that the ranges recited herein are meant to encompass the upper and lower limits of the range. In one embodiment, the pH range is 4 to 5. This pH range can be achieved by adding acid/base dropwise to the solution. In another embodiment, the pH range is 3 to 7.

The present invention also provides a method of using a composition comprising povidone-iodine, in one embodiment in a volume of between about 10 microliters to about 200 microliters, in another embodiment in a volume of between about 20 microliters to about 100 microliters, in another embodiment in a volume of between about 50 microliters to about 80 microliters, and in another embodiment in a volume of about one drop per eye. In one aspect, each drop of solution is between about 50 microliters to about 80 microliters.

In one embodiment, the frequency of administration may range from any one value in the range of 1 to 100 times per day. In another embodiment, the frequency of administration may be 2 to 24 times per day. In another embodiment, the frequency of administration may be 2 to 4 times per day. One skilled in the art can screen to identify the precise dosage regimen, and the composition can be applied topically, one drop per eye, about 1 to 24 times per day. For example, the liquid medicine is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 48 or 96 times per day.

Examples

The following examples are described herein for reference. These examples are provided solely for the purpose of illustrating the invention and should not be construed as limiting the invention to only these examples but rather as encompassing any and all variations which may be derived from the teachings herein.

Example 1: antibacterial and antiseptic effectiveness test of PVP-I antiseptic artificial tear

Compositions comprising at least one artificial tear component as described herein, further comprising PVP-I useful as a preservative, testing of preservative performance of compositions of the invention, e.g., ophthalmic agents containing PVP-I, using methods described in the United States Pharmacopeia (USP) <51>, for example, or using methods known in the art for determining the effectiveness of antimicrobial preservatives. A PVP-I solution was prepared according to the methods described herein at a concentration of about 0.36% by weight. According to one non-limiting example, a solution containing PVP-I is prepared using a formulation containing about 0.36% by weight PVP-I as desired for the final product and PVP-I is mixed with 0.01% edetate disodium, 1.2% sodium sulfate, 0.25% hydroxyethyl cellulose, 0.5% tyloxapol, 0.35% sodium chloride to adjust osmolality (osmolality) to 300-350mOsm/kg, pH is adjusted to about 4.0 using sodium hydroxide and/or sulfuric acid, and sufficient purified water is added to bring the total volume to 100%.

The test solutions were tested using a selected series of standard laboratory strains. The week period was 0, 7, 14, 28 days apart, samples were removed and analyzed for viability.

Example 2: antibacterial and preservative Performance test of 0.1% dexamethasone suspensions preserved with PVP-I

The preservative performance of the compositions of the present invention, such as ophthalmic agents containing PVP-I, are tested, for example, using the United States Pharmacopeia (USP) <51> method, or using methods well known in the art for determining the effectiveness of antimicrobial preservatives. PVP-I solutions were prepared according to the methods described herein at concentrations of about 0.18% and about 0.36% by weight. According to one non-limiting example, a PVP-I containing solution is prepared using PVP-I containing about 0.18% or about 0.36% by weight, depending on the desired end product, and PVP-I is mixed with 0.1% dexamethasone, 0.01% edetate disodium, 1.2% sodium sulfate, 0.25% hydroxyethyl cellulose, 0.5% tyloxapol, 0.35% sodium chloride to adjust osmolality (osmolality) to 300-350mOsm/kg, sodium hydroxide and/or sulfuric acid to adjust the pH to 4.0, and sufficient purified water is added to make the total volume 100%. The test solutions were tested using a selected series of standard test strains. The week period was 0, 7, 14, 28 days apart, samples were removed and analyzed for viability.

Example 3: antimicrobial activity of solutions preserved with PVP-I

According to one non-limiting example, a PVP-I solution having a concentration of about 0.36% by weight is prepared according to the method described herein. According to one non-limiting example, a PVP-I containing solution is prepared using 0.36% by weight PVP-I depending on the requirements of the final product. And PVP-I was mixed with 0.1% dexamethasone, 0.01% edetate disodium, 1.2% sodium sulfate, 0.25% hydroxyethyl cellulose, 0.5% tyloxapol, 0.35% sodium chloride to adjust osmolality (osmomolality) to 350mOsm/kg, pH to 4.0 using sodium hydroxide and/or sulfuric acid, and sufficient purified water was added to make the total volume 100%. These solutions were then tested for in vitro microbial activity. Antimicrobial activity can be tested by antimicrobial-e.g. inhibition of bacteria found in the oral cavity (p. As another example, the bactericidal time test is performed by a series of log phase cultures of gram negative and gram positive bacteria including gentamicin-resistant Pseudomonas aeruginosa (Pseudomonas aeruginosa), methicillin-resistant Staphylococcus aureus (staph aureus), Escherichia coli, Chlamydia trachomatis (Chlamydiathromyces) and selected viruses. The control used may include commercially available antimicrobial ophthalmic agents. Samples of bacteria were withdrawn at 30 seconds, 1, 2, 5, 10 and 15 minutes and transferred to medium containing iodine inactivator. Similarly, in the virucidal time test, samples were withdrawn at one minute and transferred to inactivation medium. The results of the test samples were compared to control samples to evaluate the level of antimicrobial activity of the compositions of the present invention.

Example 4: preparation of a PVP-I preserved suspension of 0.3% tobramycin and 0.1% dexamethasone

BAK-free preserved with PVP-I at a concentration of from about 0.36% to about 0.6% by weight prepared according to the methods described hereinOphthalmic suspensions. According to one non-limiting example, the composition is prepared using 0.36%, 0.48%, or 0.6% by weight PVP-I, depending on the desired end product, and mixed with 0.3% tobramycin, 0.1% dexamethasone, 0.01% edetate disodium, 1.2% sodium sulfate, 0.25% hydroxyethyl cellulose, 0.5% tyloxapol, 0.35% sodium chloride to adjust osmolality (osmolality) to 300-350mOsm/kg, pH to about 4.0 using sodium hydroxide and/or sulfuric acid, and sufficient purified water is added to make the total volume 100%.

Example 5: preparation of 0.3% tobramycin solution preserved with PVP-I

An ophthalmic solution of BAK-free tobramycin preserved with PVP-I at a concentration of from about 0.36% to about 0.6% by weight is prepared according to the method described herein. According to one non-limiting example, the composition is prepared using 0.36%, 0.48%, or 0.6% by weight PVP-I, depending on the requirements of the final product, and mixed with 0.3% tobramycin, boric acid, sodium sulfate, sodium chloride, tyloxapol, sodium hydroxide and/or sulfuric acid (for pH adjustment) and a pure water phase.

Example 6: preparation of 0.5% moxifloxacin hydrochloride ophthalmic solution preserved with PVP-I

An ophthalmic solution of moxifloxacin hydrochloride free of BAK preserved with PVP-I was prepared at a concentration of from about 0.36% to about 0.6% by weight according to the method described herein. According to one non-limiting example, the composition is prepared using 0.36%, 0.48%, or 0.6% by weight PVP-I, depending on the requirements of the final product, and mixed with 0.5% moxifloxacin hydrochloride, boric acid, sodium chloride, and purified water. In one embodiment, the preserved eye drops contain hydrochloric acid and/or sodium hydroxide to adjust the pH.

Example 7: preparation of 1.0% prednisolone acetate suspension preserved with PVP-I

A BAK-free prednisolone acetate suspension preserved with PVP-I was prepared at a concentration of from about 0.36% to about 0.6% by weight according to the methods described herein. According to one non-limiting example, the composition is prepared using PVP-I at 0.36%, 0.48%, or 0.6% by weight, depending on the requirements of the final product, and mixed with 1.0% prednisolone acetate, boric acid, disodium edetate, hypromellose, tween 80, sodium bisulfite, sodium citrate, sodium chloride and purified water.

The invention has been described herein by reference to specific embodiments. However, since modifications thereof will readily occur to those skilled in the art, the invention should not be considered limited to the embodiments set forth herein in view of the disclosure herein. All patents, patent applications, and cited references are incorporated herein by reference in their entirety.

Claims (16)

1. A preserved ophthalmic formulation comprising:

a. povidone-iodine (PVP-I) at a concentration sufficient to preserve said ophthalmic formulation, and

b. at least one component selected from the group consisting of steroidal anti-inflammatory compounds, non-steroidal anti-inflammatory compounds, antibacterial compounds, anti-allergic compounds, and anti-glaucoma compounds.

2. The ophthalmic preparation of claim 1, wherein the PVP-I is present at a concentration selected from the group consisting of 0.01% to 10%, 0.1% to 2.5%, 0.2 to 1.5%, 0.3% to 1.0%.

3. The ophthalmic preparation of claim 1, wherein the PVP-I is present at a concentration of 0.5%.

4. The ophthalmic preparation of claim 2, wherein the PVP-I concentration is measured on a weight/weight basis relative to the entire preparation.

5. The ophthalmic preparation of claim 2, wherein the PVP-I concentration is measured on a weight/volume basis relative to the entire preparation.

6. The ophthalmic formulation of claim 1, wherein the anti-inflammatory compound is selected from the group consisting of ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, and any combination thereof.

7. The ophthalmic formulation of claim 1, wherein the anti-inflammatory compound is selected from the group consisting of dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluoromethalone acetate, fluoromethalone alcohol, loteprednol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone acetate, lodoxylamine tromethamine, and any combination thereof.

8. The ophthalmic formulation of claim 1, wherein the formulation further comprises an antimicrobial preservative selected from the group consisting of: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, EDTA, sorbic acid, poloxammonium chloride, and any combination thereof.

9. The ophthalmic formulation of claim 1, wherein the formulation further comprises a viscosity increasing agent.

10. The ophthalmic formulation of claim 9, wherein the viscosity increasing agent is selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, and any combination thereof.

11. The ophthalmic preparation according to claim 1, wherein the preparation comprises at least one artificial tear-based lubricant.

12. A method of preserving an ophthalmic formulation comprising adding PVP-I to the ophthalmic formulation in an amount sufficient to preserve the ophthalmic formulation.

13. The method of claim 12, wherein the PVP-I is present at a concentration selected from the group consisting of 0.01% to 10%, 0.1% to 2.5%, 0.2 to 1.5%, 0.3% to 1.0%.

14. The method of claim 12, wherein the PVP-I is present at a concentration of 0.5%.

15. The method of claim 12, wherein the PVP-I concentration is measured on a weight/weight basis relative to the entire formulation.

16. The method of claim 12, wherein the PVP-I concentration is measured on a weight/volume basis relative to the entire formulation.