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Details for Patent: 5,188,826

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Details for Patent: 5,188,826

Title: Topical ophthalmic suspensions
Abstract:A topical, aqueous ophthalmic gel suspension for dry eye is administrable to the eye in drop form, remains as a gel in the eye for a prolonged time, and releases water and one or more ophthalmic demulcents or vasoconstrictors. It comprises water and from 0.1% to 6.5% by weight of lightly cross-linked carboxyl-containing polymer having a particle size of not more than about 50 .mu.m in equivalent spherical diameter. The suspension is at a pH of from 6.6 to 8.0, has an osmolality of from 50 to 400 mOsM, and a viscosity of from about 500 to about 4,000 centipoise (0.5 to 4 Pa.s).
Inventor(s): Chandrasekaran; Santosh K. (Moraga, CA), Reents; Margaret J. (Alameda, CA), Babcock; John C. (Olga, WA), Bowman; Lyle M. (Pleasanton, CA), Archibald; Roy D. (Fremont, CA), Robinson; Joseph R. (Madison, WI)
Assignee: InSite Vision Incorporated (Alameda, CA)
Filing Date:Jul 06, 1990
Application Number:07/549,093
Claims:1. A sustained release topical, aqueous ophthalmic gel suspension for dry eye applications which is administrable to the eye in drop form as a gel and which releases water and one or more ophthalmic demulcents or ophthalmic vasoconstrictors contained therein, comprising water, and from about 0.1% to about 6.5% by weight, based on the total weight of the suspension, of a lightly cross-linked carboxyl-containing polymer having a particle size of not more than about 30 .mu.m in equivalent spherical diameter, at least about 60% by weight of the polymer having been prepared by suspension or emulsion polymerizing at least about 50% by weight of one or more carboxyl-containing monoethylenically unsaturated monomers and from about 0.01% to about 5% by weight of a non-polyalkenyl polyether difunctional cross-linking agent, the weight percentages of monomers being based on the total weight of monomers polymerized, and from about 0.01% to about 4% by weight, based on the total weight of the suspension, of at least one ophthalmic demulcent, or from about 0.01% to about 0.2% by weight, based on the total weight of the suspension, of at least one ophthalmic vasoconstrictor, or a mixture of at least one ophthalmic demulcent and at least one ophthalmic vasoconstrictor from which the above-stated ranges, the suspension being at a pH of from about 6.6 to about 8.0, and an osmolality of from about 50 to about 400 mOsM and having a viscosity of from about 500 to about 4,000 centipoises.

2. A suspension for dry eye applications as in claim 1 in which the pH is from about 6.8 to about 7.6.

3. A suspension for dry eye applications as in claim 1 in which the pH is from about 7.2 to about 7.4.

4. A suspension for dry eye applications as in claim 3 in which the lightly cross-linked carboxyl-containing polymer has a dry particle size of less than about 20 .mu.m.

5. A suspension for dry eye applications as in claim 4 in which the polymer particles are essentially monodisperse.

6. A suspension for dry eye applications as in claim 5 in which the lightly cross-linked carboxyl-containing polymer is one prepared from at least about 90% by weight of one or more carboxyl-containing monoethylenically unsaturated monomers.

7. A suspension for dry eye applications as in claim 6 in which substantially all of the lightly cross-linked carboxyl-containing polymer is prepared by suspension or emulsion polymerizing acrylic acid and a non-polyalkenyl polyether difunctional cross-linking agent.

8. A suspension for dry eye applications as in claim 7 in which the cross-linking agent is 3,4-dihydroxyhexa-1,5-diene.

9. A suspension for dry eye applications as in claim 2 in which the osmolality is achieved using a physiologically and ophthalmologically acceptable salt in an amount of from about 0.01% to about 1% by weight, based on the total weight of the suspension.

10. A suspension for dry eye applications as in claim 9 in which the salt is sodium chloride.

11. A suspension for dry eye applications as in claim 10 in which the ophthalmic demulcent is at least one of sodium carboxymethyl-cellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran 70, gelatin, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, polyvinyl alcohol or polyvinylpyrrolidone.

12. A suspension for dry eye applications as in claim 10 in which the ophthalmic vasoconstrictor is at least one of ephedrine hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride or tetrahydrozoline hydrochloride.

13. A suspension for dry eye applications as in claim 12 wherein at least about 90% of the polymer particles are within a no more than about 10 .mu.m band of major particle size distribution, and no more than about 10% of the total particles are fines.

14. A suspension for dry eye applications as in claim 13 that also contains from about 0.01 to about 0.5% by weight, based on the total weight of the suspension, of a stabilizer.

15. A suspension for dry eye applications as in claim 14 in which the stabilizer is ethylenediaminetetraacetic acid or its sodium salt, present in an amount of from about 0.025 to about 0.3% by weight, based on the total weight of the suspension.

16. A suspension for dry eye applications as in claim 15 in which the ophthalmic demulcent comprises gelatin.

17. A suspension for dry eye applications as in claim 15 in which the ophthalmic demulcent is a mixture of gelatin and hydroxyethylcellulose.

18. A suspension for dry eye applications as in claim 15 in which the ophthalmic demulcent is a mixture of gelatin and dextran.

19. A suspension for dry eye applications as in claim 15 in which the ophthalmic demulcent is a mixture of dextran and polyethylene glycol 400.

20. A sustained release topical, aqueous ophthalmic gel suspension for dry eye applications which is administrable to the eye in drop form as a gel and which releases water and one or more ophthalmic demulcents contained therein, comprising water, from about 0.1% to about 2.0% by weight, based on the total weight of the suspension, of a lightly cross-linked carboxyl-containing essentially monodisperse polymer having a dry particle size of not more than about 30 .mu.m in equivalent spherical diameter, prepared by suspension or emulsion polymerizing acrylic acid and from about 0.01% to about 1% by weight of 3,4-hydroxyhexa-1,5-diene, the weight percentage of monomers being based on the total weight of monomers polymerized, and from about 0.01% to about 4% by weight, based on the total weight of the suspension, of at least one of gelatin, hydroxyethylcellulose, dextran and polyethylene glycol 400 as an ophthalmic demulcent, the suspension being at a pH of from about 7.2 to about 7.4 and an osmolality of from about 100 to about 300 mOsM and having a viscosity of from about 600 to about 3,000 centipoises.

21. A gel suspension for dry eye applications as in claim 20 wherein at least about 80% of the polymer particles are within a no more than about 10 .mu.m band of major particle size distribution and no more than about 20% of the total particles are fines.

22. A gel suspension for dry eye applications as in claim 20 wherein at least about 90% of the polymer particles are within a no more than about 10 .mu.m band of major particle size distribution and no more than about 10% of the total particles are fines.

23. A gel suspension for dry eye applications as in claim 20 wherein at least about 95% of the polymer particles are within a no more than about 10 .mu.m band of major particle size distribution and no more than about 5% of the total particles are fines.

24. The gel suspension for dry eye applications as in claim 21 wherein the band of major particle distribution is from about 1 .mu.m to about 5 .mu.m.

25. A method of treating dry eye which comprises:

preparing a sustained release topical ophthalmic gel suspension, at a pH of from about 7.2 to about 7.4 and an osmolality of from about 100 to aeb out 300 mOsM and a viscosity of from about 600 to about 3,000 cps, containing water, and from about 0.1% to about 2.0% by weight based on the total weight of the suspension, of a lightly cross-linked carboxyl-containing essentially monodisperse polymer having a dry particle size of not more than about 30 .mu.m in equivalent spherical diameter, prepared by suspension or emulsion polymerizing acrylic acid and from about 0.01% to about 1% by weight of 3,4-hydroxyhexa-1,5-diene, the weight percentages of the monomers being based on the total weight of monomers polymerized, and from about 0.01% to about 4% by weight, based on the total weight of the suspension, of an ophthalmic demulcent constituted by at least one of gelatin, hydroxyethylcellulose, dextran and polyethylene glycol 400,

administering the gel to the eye to contact the conjunctival mucosa for a time period sufficient to moisturize that contacted mucosa membrane,

wherein the gel remains in the eye to provide sustained release of both water and the demulcent.

26. The method of claim 25 wherein the gel is applied in an amount sufficient to provide about 0.025 to about 1 mg/cm.sup.2 of the polymer to the mucosa of the eye.

27. A method of preparing a sustained release dry eye formulation comprising:

preparing a topical ophthalmic gel suspension, at a pH of from about 7.2 to about 7.4 and an osmolality of from about 100 to about 300 mOsM, containing water, and from about 0.1% to about 2.0% by weight based on the total weight of the suspension, of a lightly cross-linked carboxyl-containing essentially monodisperse polymer having a dry particle size of not more than about 30 .mu.m in equivalent spherical diameter, prepared by suspension or emulsion polymerizing acrylic acid and from about 0.01% to about 1% by weight of 3,4-hydroxyhexa-1,5-diene, the weight percentages of the monomers being based on the total weight of monomers polymerized, and from about 0.01% to about 4% by weight, based on the total weight of the suspension, of an ophthalmic demulcent constituted by at least one of gelatin, hydroxyethylcellulose, dextran and polyethylene glycol 400, and

packaging the gel at a viscosity of from about 600 to about 3,000 cps, for administration to the eye in drop form.

28. A sustained release topical, aqueous ophthalmic gel suspension for dry eye applications which is administrable to the eye in drop form as a gel and which releases water and one or more ophthalmic demulcents or ophthalmic vasoconstrictors contained therein, comprising water, and from about 0.1% to about 6.5% by weight, based on the total weight of the suspension, of a lightly cross-linked carboxyl-containing polymer having a particle size of not more than about 50 .mu.m in equivalent spherical diameter, at least about 60% by weight of the polymer having been prepared by suspension or emulsion polymerizing at least about 50% by weight of one or more carboyxl-containing monoethylenically unsaturated monomers and from about 0.01% to about 5% by weight of a cross-linking agent, the weight percentages of monomers being based on the total weight of monomers polymerized, and from about 0.01% to about 4% by weight, based on the total weight of the suspension, of at least one ophthalmic demulcent, or from about 0.01% to about 0.2% by weight, based on the total weight of the suspension, of at least one ophthalmic vasoconstrictor, or a mixture of at least one ophthalmic demulcent and at least one ophthalmic vasoconstrictor from which the above-stated ranges, the suspension being at a pH of from about 6.6 to about 8.0, and an osmolality of from about 50 to about 400 mOsM and having a viscosity of from about 500 to about 4,000 centipoise, at least about 80% of the polymer particles being within a no more than 10 .mu.m band of major particle distribution and no more than about 20% of the total particles being fines.

29. The gel suspension for dry eye application as in claim 28 wherein the band of major particle distribution is from about 1 .mu.m to about 6 .mu.m.
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