HK1105170A - Methods for stabilizing ophthalmic compositions - Google Patents

Description

Method for stabilizing ophthalmic compositions

Technical Field

The present invention relates to methods of stabilizing ophthalmic compositions against oxidative degradation during handling, autoclaving, packaging, shipping or storage.

Background

Therapeutic agents for topical application to the eye are typically prepared in liquid or gel form and must be maintained in a sterile state until the time of administration. Thus, ophthalmic treatments require inconvenient and expensive aseptic packaging or heat sterilization. Unfortunately, many therapeutic agents are unstable to oxidation, especially at elevated temperatures.

EDTA is used to improve the stability of certain therapeutic agents during autoclaving. Nevertheless, there is still a need for further compounds which are capable of stabilizing unstable therapeutic drugs which are sensitive to catalytic oxidative degradation reactions.

Disclosure of Invention

The present invention relates to a method comprising stabilizing an oxidatively unstable ophthalmic compound dissolved in an ophthalmic solution during autoclaving by adding to the ophthalmic solution a stabilizing effective amount of at least one electron rich polymer.

The present invention comprises or consists essentially of: at least one oxidatively unstable ophthalmic compound dissolved in an ophthalmic solution is stabilized during autoclaving by adding a stabilizing effective amount of at least one electron-rich polymer to the ophthalmic solution.

As used herein, oxidatively unstable ophthalmic compounds ("OUOC") refer to those therapeutic agents that degrade more than 10% in a solution to which at least one oxidation catalyst is added, and less than 10% in a solution without the at least one oxidation catalyst (otherwise identical) during autoclaving. Oxidative instability can be measured by the following method: a3 ml packaged solution containing 25ppm of the therapeutic agent to be evaluated was prepared and placed in the presence and absence of an oxidation catalyst (100ppm Cu)₂O and 100ppm FeSO₄) Autoclaving was carried out (120 ℃ C., 20 minutes).

Examples of OUOCs include oxidatively unstable pharmaceutical and nutritional compounds. In a specific embodiment, the OUOC includes at least one pharmaceutically active amine. In a specific embodiment, the OUOC comprises at least one tertiary cyclic amine. In another embodiment, the OUOC comprises at least one tertiary cyclohexylamine. In another embodiment, the OUOC includes at least one therapeutic agent selected from the group consisting of: acyclovir, adrenalone, aminocaproic acid, amoxicillin, amitriptyline (amotriptene), amocaine, amodiaquine, antazoline, atrophine, betaxolol, bupivacaine, carbachol, carteolol, chloramphenicol (chlorempenicol), chlortetracycline, coynathine, cromolyn sodium, cyclopentolate, demercunium (demecarbonium), dexamethasone, diclofenac (diclophenamine), dipivefrin, ephedrine, erythromycin, ethambutol, eucalyptol, fluorometholone, gentamicin, brevibacterium peptide, homatropine, indomethacin, ketotifen, levorphanol, levobunolol, levocabastine, lidocaine, linocaine, lomefloxacin, medroxypaine, mepivacaine, acemetacin, naproxen, neomycin, levofloxacin, oxyphenbutazone, oxyphenicol, oxytetracycline, levofloxacin, levocabazine, levofloxacin, Phenylephrine, physostigmine, pirucaine, polymyxin B, prednisolone, proparacaine, mepyramine, scopolamine, sorbinil, sulfacetamide, tamoxifen, tetracaine, tetracycline, tetrahydrodoxoline, timolol, trifluridine, tropicamide, vidarabine, and mixtures thereof. Examples of nutritional compounds include vitamins and supplements such as vitamin A, D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmologically compatible fatty acids such as omega-3 and omega-6 fatty acids, combinations thereof, and combinations with pharmaceutical compounds, and the like. In another embodiment, the OUOC includes at least one therapeutic agent selected from the group consisting of ketotifen fumarate, norketotifen fumarate, 11-dihydro-11- (1-methyl-4-piperidylidene)) -5-H-imidazo [2.1-b ] [3] benzazepine * -3-carboxaldehyde (CAS #147084-10-4), olapatadine, and mixtures thereof. In another embodiment, the OUOC includes at least one therapeutic agent selected from the group consisting of ketotifen fumarate, 11-dihydro-11- (1-methyl-4-piperidinylidene) -5-H-imidazo [2.1-b ] [3] benzazepine * -3-carboxaldehyde (CAS #147084-10-4), and mixtures thereof.

The concentration of OUOC in the oxidation stable ophthalmic compositions of the present invention may be from about 10ppm to about 100,000ppm, in certain embodiments from about 10 to about 10,000ppm, in certain embodiments from about 10 to about 1,000ppm, in certain embodiments from about 10 to about 500 ppm.

The oxidatively stable ophthalmic compositions of the present invention can further comprise at least one electron rich polymer. Suitable electron-rich polymers are water-soluble, contain at least one group with a free electron pair, have a weight average molecular weight, Mw, of greater than about 1000, and in certain embodiments, between about 1000 and about 2,000,000, and are substantially free of transition metal-containing species. As used herein, water-soluble refers to: the temperature and pH ranges and concentrations selected for the selected electron-rich polymers are often used for the preparation, sterile handling and storage of ophthalmic solutions without precipitation or formation of visible gel particles. In certain embodiments, the electron-rich polymer is substantially free of copper and iron-containing species.

For the purposes of the present invention, gel permeation chromatography with a 90 ℃ light scattering and refractive index detector was used to determine the molecular weight. Two columns were PW4000 and PW2500, 75/25wt/wt methanol-water eluents adjusted to 50mM sodium chloride and a mixture of precisely determined polyethylene glycol and polyethylene oxide molecules with molecular weights of 325,000 to 194.

As used herein, "substantially free" means that the amount of transition metal containing material in the electron-rich polymer is insufficient to cause further degradation of the OUOC. Preferably, the transition metal-containing material is present in the electron-rich polymer in an amount less than about 100ppm, in certain embodiments less than about 50ppm, and in certain embodiments less than about 20 ppm.

Suitable electron rich polymers include esters, acids, amines, carbonates, carboxylates, thiols, lactates, amides, carbamates, phosphates, phosphines, nitriles, lactams, and mixtures thereof. Polymers that do not contain at least one free electron pair group, such as polymers that contain only ether groups, alcohol groups, or combinations thereof, are not electron-rich polymers as defined herein. The polymer may contain a large number of electron donating groups, however, the higher the concentration of electron donating groups contained, the less electron rich polymer is used. Specific examples include homopolymers and random or block copolymers of methacrylic acid, acrylic acid, itaconic acid, fumaric acid, maleic acid, vinylpyrrolidone, ethylenemethylacetamide (vinylmethylacetamide), combinations thereof, and the like. More specific examples include poly (acrylic acid), poly (vinylpyrrolidone), and poly (ethylenemethylacetamide), combinations thereof, and the like. In one embodiment, the electron-rich polymer is poly (acrylic acid).

The electron-rich polymer is present in the ophthalmic composition in a stabilizing effective amount. The stabilizing effective amount can vary depending on the OUOC, the concentration of the OUOC in the ophthalmic composition, and the concentration of the other composition, but generally, a stabilizing effective amount refers to an amount sufficient to increase stability by at least about 5%. Suitable amounts of electron-rich polymer include between about 10 to about 5,000ppm, in certain embodiments between about 100 to about 5,000ppm, in certain embodiments between about 500 to about 3,000 ppm.

The OUOC and electron-rich polymer can be combined in any suitable ophthalmically compatible vehicle. Suitable carriers include water, saline, mineral oil, petroleum jelly, water-miscible solvents such as C_15-20Alcohol, C_15-20Amides, C substituted with zwitterions_15-20Alcohols, vegetable or mineral oils containing from 0.5 to 5% by weight of hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone and other ophthalmically compatible, non-toxic, water-soluble polymers such as, for example, cellulose derivatives, alkali metal salts such as methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, hydroxypropylcellulose, chitin and scleroglucan, acrylates or methacrylates, salts such as poly (acrylic acid) or ethyl acrylate, polyacrylamidesNatural products such as gelatin, alginates, pectins, tragacanth, karaya, xanthan, carrageenan, agar and acacia, starch derivatives such as starch acetate and hydroxypropyl starch, and other synthetic products such as poloxamers, e.g. poloxamer F127, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably crosslinked poly (acrylic acid), such as neutral carbomers, or mixtures of the above polymers. Preferred carriers are water, cellulose derivatives such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral carbomers, or mixtures thereof. The concentration of the carrier may be, for example, 0.1 to 100000 times the concentration of the active ingredient composition. When the ophthalmic composition is an ophthalmic solution, preferred carriers include water, pH buffered saline, and mixtures thereof, and the like.

The oxidation stable compositions of the present invention may also be used as packaging or storage solutions for ophthalmic devices such as contact lenses. When the ophthalmic compositions of the present invention are used as a packaging solution for contact lenses, buffered saline is included in the carrier. Any contact lens that can be packaged with the present oxidation-stable ophthalmic compositions include, but are not limited to, commercially available hydrogel formulations such as etafilcon, polymacon, vifilcon, genfilcon A, lenefilcon A, galyficon, senofilcon, balafilcon, lotrafilcon A, lotrafilcon B, and the like.

The compositions of the present invention may further contain additional components such as antioxidants, demulcents, antimicrobials, solubilizers, surfactants, buffers, tonicity adjusting agents, chelating agents, preservatives, humectants, thickeners, combinations thereof, and the like. The oxidation stable compositions of the present invention must be ophthalmically compatible. If the addition of the electron-rich polymer lowers the pH of the ophthalmic composition to an undesirable level, a stoichiometric amount of a base, such as sodium hydroxide, or a buffering agent, such as sodium borate, may be added. Generally, a desired pH of between about 5 and about 9, and in certain embodiments, a pH of between about 6 and about 8 is desirable. In certain embodiments, the stabilizing effect of the electron-rich polymer is most effective between about pH 6.5 and about 7.5.

The oxidation stable compositions of the present invention can be prepared by combining the OUOC and the electron rich polymer with a selected carrier. When a liquid composition such as an eye drop or a contact lens package, the OUOC and the electron-rich polymer are dissolved in a carrier. When the oxidation-stable composition is a gel or ointment, the OUOC and electron-rich polymer can be incorporated in any suitable manner, such as by dissolving, mixing, or compounding into the selected carrier.

Generally, it is desirable that the oxidation stabilizing compositions of the present invention have a useful life of greater than about 6 months, and in some instances, greater than about 1 year, or even greater than about 2 years. The original concentration of OUOC needs to be retained for at least about 80%, and in certain embodiments, greater than about 90%, over the life of the oxidatively stable composition.

The following examples are not intended to limit the invention. They are merely intended to suggest a method of practicing the invention. Those skilled in the art of contact lenses and other specialties may find other ways of practicing the invention. Also, those other methods should fall within the scope of the present invention.

Examples 1 to 3

The solutions of table 1 were prepared by combining the listed components with reverse osmosis purified water to a volume of 1 liter. The pH of the solution was adjusted to 7.5, 7.3 and 6.9 by addition of HCl. To each solution was added 80ppm ketotifen fumarate. 3.0ml of each was taken out of the solution and placed in a vial. Each vial was autoclaved, heated to 121 ℃ and held at this temperature for 30 minutes, and subjected to cycles as listed in table 2, using 3 vials per identical condition. The concentration of ketotifen was determined by HPLC using Agilent Zorbax eclipse XDB-C18 and HP1100 from Rapid Resolution HT 50X 4.6mm X1.8. mu. column under the following conditions:

detection wavelength 299nm

Flow rate 1.0 mL/min

Injection volume 3 μ L

Mobile phase

Eluent A17% acetonitrile is dissolved in 0.025M potassium dihydrogen phosphate buffer solution,

0.2% of triethylamine, 0.13% of orthophosphoric acid

Eluent B50% acetonitrile is dissolved in 0.025M potassium dihydrogen phosphate buffer solution,

0.2% of triethylamine, 0.13% of orthophosphoric acid

Time (minutes)	Eluent A (%)	Eluent B (%)
			0	100	0
5	100	0
			20	0	100
21	100	0
			25	100	0

Table 2 shows the average of three measurements of the ketotifen concentration remaining in the vial as a percentage of the original concentration.

TABLE 1

Compound (g/100ml)	Example 1	Example 2	Example 3	Comparative example 1	Comparative example 2	Comparative example 3
							NaCl	0.83	0.83	0.83	0.83	0.83	0.83
Boric acid	0.91	0.91	0.91	0.91	0.91	0.91
							Sodium borate	0.1	0.1	0.1	0.1	0.1	0.1
PAA(MW＝225000)	0.1	0.1	0.1	0	0	0

TABLE 2 ketotifen concentrations after autoclaving

	Example 1	Example 2	Example 3	Comparative example 1	Comparative example 2	Comparative example 3
							PH	7.5	7.3	6.9	7.5	7.3	6.9
0 cycle	100	100	100	100	100	100
							1 cycle	64	96	96	0	0	0
2 cycles of	55	86	84	-	-	-
							3 cycles of	22	64	62	-	-	-

Examples 4 to 6

The solution of example 1 was prepared with the amount of PAA shown in table 3 below. The pH of each solution was adjusted to 7.22 using 0.1N HCl. As in example 1, 80ppm by weight of ketotifen fumarate was added to each solution. The stability of the solution was determined as described in example 1. The results obtained are shown in table 3.

TABLE 3

	Example 4	Example 5	Example 6
				[PAA]ppm	500	2000	5000
0 cycle	100	100	100
				1 cycle	88	94	94
2 cycles of	64	81	83
				3 cycles of	36	66	70

Example 7

Ketotifen fumarate solutions can be obtained by mixing the components listed in table 4 with reverse osmosis purified water to a volume of 1 liter. The pH of the solution was about 7.2. Each of the three vials was filled with 3.0ml of the solution. The initial concentration of ketotifen was determined using HPLC. The vials were autoclaved, heated to 121 ℃ and held at this temperature for 30 minutes. The concentration of ketotifen remaining after one heat sterilization cycle was determined using HPLC as described above.

The average concentration of the remaining ketotifen fumarate was 80. mu.g/ml. Thus, only about 17% of the ketotifen fumarate salt is lost during one heat sterilization cycle. A control solution having the composition as listed in table 4, but no 400ppm PVP, lost more than 50% of the ketotifen fumarate salt after one heat sterilization cycle.

TABLE 4

Components
		NaCl	0.83gm/ml
Boric acid	0.91gm/ml
		Sodium borate	0.1gm/ml
PVP(MW＝90,000)	400ppm
		Ketotifen fumarate	97μg/ml

Thus, the foregoing examples clearly show that the stability of oxidatively unstable ophthalmic compositions, such as ketotifen fumarate, is significantly improved upon the addition of at least one electron rich polymer, such as poly (acrylic acid).

Claims (23)

1. A method of stabilizing an oxidatively unstable ophthalmic compound dissolved in an ophthalmic solution during autoclaving, comprising incorporating into said ophthalmic solution a stabilizing effective amount of at least one electron-rich polymer.

2. A method of autoclaving an ophthalmic solution comprising at least one oxidatively unstable ophthalmic compound and a stabilizing effective amount of at least one electron rich polymer.

3. The method of claim 2 wherein said oxidatively unstable ophthalmic compound is at least one pharmaceutically active amine.

4. The method of claim 3, wherein the pharmaceutically active amine is a tertiary cyclic amine.

5. The method of claim 3, wherein the pharmaceutically active amine is tert-cyclohexylamine.

6. The method of claim 2 wherein said oxidatively unstable ophthalmic compound is selected from the group consisting of ketotifen fumarate, norketotifen fumarate, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-imidazo [2, 1-b ] [3] benzazepine * -3-carboxaldehyde, olapatadine, and mixtures thereof.

7. The method of claim 2 wherein the oxidatively unstable ophthalmic compound is selected from the group consisting of ketotifen fumarate, 11-dihydro-11- (1-methyl-4-piperidinylidene) -5H-imidazo [2, 1-b ] [3] benzazepine * -3-carboxaldehyde, and mixtures thereof.

8. The method of claim 2, wherein said oxidatively unstable ophthalmic compound comprises ketotifen fumarate.

9. The method of claim 2, wherein the electron-rich polymer is selected from the group consisting of polyethers, polyesters, polyacids, polyamines, polycarbonates, polycarboxylates, polythiols, polylactates, polyamides, polyurethanes, polyphosphates, polynitriles, polylactams, and copolymers and mixtures thereof.

10. The method of claim 2, wherein the electron rich polymer is selected from the group consisting of poly (acrylic acid), poly (vinylpyrrolidone), and poly (vinylmethylacetamide), and mixtures thereof.

11. The method of claim 2, wherein the amount of electron-rich polymer is between about 10 to about 5000 ppm.

12. The method of claim 2, wherein the amount of electron-rich polymer is between about 100 to about 5000 ppm.

13. An autoclaved solution comprising an ophthalmic solution comprising at least one oxidatively unstable ophthalmic compound and a stabilizing effective amount of at least one electron rich polymer.

14. The autoclaved solution of claim 13 wherein the oxidatively unstable ophthalmic compound is at least one pharmaceutically active amine.

15. The autoclaved solution of claim 13 wherein the pharmaceutically active amine is a tertiary cyclic amine.

16. The autoclaved solution of claim 13 wherein the pharmaceutically active amine is tertiary cyclohexylamine.

17. The autoclaved solution of claim 13 wherein the oxidatively unstable ophthalmic compound is selected from the group consisting of ketotifen fumarate, nor-ketotifen fumarate, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-imidazo [2, 1-b ] [3] benzazepine * -3-carboxaldehyde, olapatadine and mixtures thereof.

18. The autoclaved solution of claim 13 wherein the oxidatively unstable ophthalmic compound is selected from the group consisting of ketotifen fumarate, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-imidazo [2, 1-b ] [3] benzazepine * -3-carboxaldehyde, and mixtures thereof.

19. The autoclaved solution of claim 13 wherein the oxidatively unstable ophthalmic compound comprises ketotifen fumarate.

20. The autoclave solution of claim 13, wherein the electron rich polymer is selected from the group consisting of polyethers, polyesters, polyacids, polyamines, polycarbonates, polycarboxylates, polythiols, polylactates, polyamides, polyurethanes, polyphosphates, polynitriles, polylactams, and copolymers and mixtures thereof.

21. The autoclaved solution of claim 13 wherein the electron rich polymer is selected from the group consisting of poly (acrylic acid), poly (vinyl pyrrolidone), and poly (ethylene methyl acetamide), and mixtures thereof.

22. The autoclaved solution of claim 13 wherein the amount of the electron rich polymer is between about 10 and about 5000 ppm.

23. The autoclaved solution of claim 13 wherein the amount of the electron rich polymer is between about 100 to about 5000 ppm.