OCULAR DRUG DELIVERY DEVICES

• US 20110129516A1
• Filed: 10/29/2010
• Published: 06/02/2011
• Est. Priority Date: 10/30/2009
• Status: Abandoned Application

• Current Assignee: Aton Pharma, Inc. (Bausch Health Cos., Inc.), Louisiana State University Agricultural & Mechanical College (Louisiana State University System)
• Original Assignee: Aton Pharma, Inc. (Bausch Health Cos., Inc.), Board of Supervisors of Louisiana State University Agricultural & Mechanical College (Louisiana State University System)
• Inventors: McKee, Yuri, JACOB, Jean Theresa, Halloran, Kevin John
• Application Number:
  US12/916,398
• Publication Number:
  US 20110129516A1
• Time in Patent Office: Days
• US Class Current: 424/427
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/133 having hydroxy groups, e.g. sphingosine
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C08L 1/284 with hydroxylated hydrocarbon radicals

Abstract

A method of forming an ocular delivery device includes exposing a solid, shaped cellulose polymer to a solution including an active pharmaceutical ingredient (API) and a solvent capable of solubilizing the API, wherein the polymer absorbs at least a portion of the solution, including the API and solvent. The method may further include removing at least a portion of the absorbed solvent from the polymer by allowing the absorbed solvent to evaporate from the polymer or by drying the polymer. A variety of cellulose polymers may be used, including hydroxypropyl cellulose. A variety of APIs may be used, including Cyclosporine, Tobramycin and Vancomycin. Ocular delivery devices prepared by the methods may be used to treat a variety of eye disorders.

Claims

1. A method of forming an ocular delivery device comprising:

placing a solid, shaped cellulose polymer in a vessel adapted to restrict the swelling of the polymer in at least one direction;

exposing the polymer, while in said vessel, to a solution comprising an active pharmaceutical ingredient and a solvent capable of solubilizing said active pharmaceutical ingredient, wherein the polymer absorbs at least a portion of the solution, including the active pharmaceutical ingredient and solvent;

allowing the absorbed solvent to evaporate from the polymer or drying the polymer; and

freeing the polymer from the vessel.

2. The method of claim 1, wherein the at least one direction is a radial direction.

3. The method of claim 1, wherein the shape and dimension of an interior surface of the vessel substantially matches the shape and dimension of an exterior surface of the polymer.

4. The method of claim 1, wherein the vessel is a tubular vessel.

5. The method of claim 1, wherein the interior surface of the vessel is coated with a surface-release agent.

6. The method of claim 1, wherein the ocular delivery device is capable of releasing the active pharmaceutical ingredient upon exposure of the ocular delivery device to a medium.

7. The method of claim 6, wherein the medium comprises tear fluid.

8. The method of claim 6, wherein the medium comprises human tear fluid.

9. The method of claim 6, wherein the wherein the ocular delivery device is capable of releasing the active pharmaceutical ingredient over a period of about ½

hour to about 72 hours, about 2 hours to about 60 hours, about 2 hours to about 48 hours, about 2 hours to about 36 hours, about 2 hours to about 24 hours, about 2 hours to about 20 hours, about 2 hours to about 15 hours, about 2 hours to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 2 hours to about 6 hours, and about 2 hours to about 4 hours.

10. The method of claim 6, wherein the release of the active pharmaceutical ingredient from the ocular delivery device is substantially zero-order from about two to about six hours after exposing the ocular delivery device to the medium.

11. The method of claim 1, wherein substantially all of the absorbed solvent is allowed to evaporate from the polymer or wherein the polymer is dried to remove substantially all of the absorbed solvent from the polymer.

12. The method of claim 1, comprising drying the polymer under vacuum.

13. The method of claim 1, wherein the polymer is selected from hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or a mixture of any two or more thereof.

14. The method of claim 1, wherein the polymer is hydroxypropyl cellulose.

15. The method of claim 1, wherein the active pharmaceutical ingredient is thermally unstable above about 80°

C.

16. The method of claim 1, wherein the active pharmaceutical ingredient comprises Acebutolol, Acyclovir, Betaxolol, Bimatoprost, Brimonidine Tartrate, Brinzolamide, Bromfenac Sodium, Cefazolin, Cephalexin, Cephydroxil, Ciprofloxacin, Ciprofloxacin HCl, Cyclosporine, Dexamethasone, Dorzolamide HCl, Epinastine HCl, Erythromycin, Gancicylovir, Gatifloxacin, Gentamicin Sulfate, Ketorolac Tromethamine, Labetalol, Latanoprost, Loteprednol Etabonate, Moxifloxacin HCl, Nepafenac, Ofloxacin, Olopatadine HCl, Penicillin, Pindolol, Prednisolone, Propanolol, Polymyxin B Sulfate/Trimethoprim Sulfate, Sulfacetamide Sodium, Timolol Maleate, Trifluorodine, Tobramycin, Travoprost, Vancomycin, Azelastine HCl, Atropine sulfate, Betamethasone, Carbachol, Pheniramine, Cromolyn sodium, Cyclopentolate, Demecarium bromide, Dexamethasone 21-phosphate, Erythromycin Base, Fluorometholone, Gatifloxacin, Homatropine, Hydroxyamphetamine, Idoxuridine, Medrysone, Methylprednisolone, Naphazoline, Resolvins, Phospholipids, Phenylephrine, Phospholine iodide, Prednisolone Acetate, Prednisolone Sodium Sulfate, Sulfisoxazole, Tetrahydrazoline HCl, Timolol, Tobramycin Sulfate, Tropicamide, 6-hydroxy-2-sulfamoylbenzo[b]thiophene, 6-acetoxy-2-sulfamoylbenzo[b]thiophene, 5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide, or a mixture of any two or more thereof.

19. The ocular delivery device prepared according to the method of claim 1.

17. A method of forming an ocular delivery device comprising:

exposing a solid, shaped cellulose polymer to a solution comprising an active pharmaceutical ingredient and a solvent capable of solubilizing said active pharmaceutical ingredient, wherein the polymer absorbs at least a portion of the solution, including the active pharmaceutical ingredient and solvent; and

allowing substantially all of the absorbed solvent to evaporate from the polymer or drying the polymer to remove substantially all of the absorbed solvent from the polymer.

18. A method of forming an ocular delivery device comprising:

exposing a solid, shaped hydroxypropyl cellulose polymer to a solution comprising an active pharmaceutical ingredient and a solvent capable of solubilizing said active pharmaceutical ingredient, wherein the polymer absorbs at least a portion of the solution, including the active pharmaceutical ingredient and solvent; and

allowing the absorbed solvent to evaporate from the polymer or drying the polymer.

20. An ocular delivery device comprising:

a solid, shaped, cellulose polymer, and

a therapeutically effective amount of an active pharmaceutical ingredient dispersed in the polymer,

wherein the active pharmaceutical ingredient is selected from Acebutolol, Acyclovir, Betaxolol, Bimatoprost, Brimonidine Tartrate, Brinzolamide, Bromfenac Sodium, Cefazolin, Cephalexin, Cephydroxil, Ciprofloxacin, Ciprofloxacin HCl, Cyclosporine, Dexamethasone, Dorzolamide HCl, Epinastine HCl, Erythromycin, Gancicylovir, Gatifloxacin, Gentamicin Sulfate, Ketorolac Tromethamine, Labetalol, Latanoprost, Loteprednol Etabonate, Moxifloxacin HCl, Nepafenac, Ofloxacin, Olopatadine HCl, Penicillin, Pindolol, Prednisolone, Propanolol, Polymyxin B Sulfate/Trimethoprim Sulfate, Sulfacetamide Sodium, Timolol Maleate, Trifluorodine, Tobramycin, Travoprost, Vancomycin, Azelastine HCl, Atropine sulfate, Betamethasone, Carbachol, Pheniramine, Cromolyn sodium, Cyclopentolate, Demecarium bromide, Dexamethasone 21-phosphate, Erythromycin Base, Fluorometholone, Gatifloxacin, Homatropine, Hydroxyamphetamine, Idoxuridine, Medrysone, Methylprednisolone, Naphazoline, Resolvins, Phospholipids, Phenylephrine, Phospholine iodide, Prednisolone Acetate, Prednisolone Sodium Sulfate, Sulfisoxazole, Tetrahydrazoline HCl, Timolol, Tobramycin Sulfate, Tropicamide, 6-hydroxy-2-sulfamoylbenzo[b]thiophene, 6-acetoxy-2-sulfamoylbenzo[b]thiophene, 5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide, or a mixture of any two or more thereof.

21. The ocular delivery device of claim 20, wherein the active pharmaceutical ingredient is Vancomycin.

22. The ocular delivery device of claim 20, wherein the polymer comprises more than 30 wt % hydroxypropyl cellulose.

23. The ocular delivery device of claim 20, wherein the polymer consists essentially of hydroxypropyl cellulose.

24. The ocular delivery device of claim 20, wherein the ocular delivery device is not suspended in an ointment or a liquid.

25. An ocular delivery device comprising:

a solid, shaped, cellulose polymer, and

a therapeutically effective amount of an active pharmaceutical ingredient dispersed in the polymer.

26. The ocular delivery device of claim 25, wherein the solid, shaped, cellulose polymer has a length from about 1 mm to 7 mm and a width from about 1 mm to 4 mm.

27. The ocular delivery device of claim 25, wherein the active pharmaceutical ingredient is a mixture of Vancomycin and Tobramycin.

28. The method of treating an eye disorder, the method comprising:

depositing one or more of the ocular delivery device of claim 25 into an eye of a subject in need thereof.

29. The method of claim 28, wherein the eye disorder comprises a corneal infection.

30. The method of claim 29, wherein the corneal infection comprises bacterial keratitis.

31. An ocular delivery device comprising:

a half-cylinder having a proximal end, a distal end, and a length;

the half-cylinder comprising a solid cellulose polymer;

a therapeutically effective amount of an active pharmaceutical ingredient dispersed in the half-cylinder;

wherein the active pharmaceutical ingredient is selected from Acebutolol, Acyclovir, Betaxolol, Bimatoprost, Brimonidine Tartrate, Brinzolamide, Bromfenac Sodium, Cefazolin, Cephalexin, Cephydroxil, Ciprofloxacin, Ciprofloxacin HCl, Cyclosporine, Dexamethasone, Dorzolamide HCl, Epinastine HCl, Erythromycin, Gancicylovir, Gatifloxacin, Gentamicin Sulfate, Ketorolac Tromethamine, Labetalol, Latanoprost, Loteprednol Etabonate, Moxifloxacin HCl, Nepafenac, Ofloxacin, Olopatadine HCl, Penicillin, Pindolol, Prednisolone, Propanolol, Polymyxin B Sulfate/Trimethoprim Sulfate, Sulfacetamide Sodium, Timolol Maleate, Trifluorodine, Tobramycin, Travoprost, Vancomycin, Azelastine HCl, Atropine sulfate, Betamethasone, Carbachol, Pheniramine, Cromolyn sodium, Cyclopentolate, Demecarium bromide, Dexamethasone 21-phosphate, Erythromycin Base, Fluorometholone, Gatifloxacin, Homatropine, Hydroxyamphetamine, Idoxuridine, Medrysone, Methylprednisolone, Naphazoline, Resolvins, Phospholipids, Phenylephrine, Phospholine iodide, Prednisolone Acetate, Prednisolone Sodium Sulfate, Sulfisoxazole, Tetrahydrazoline HCl, Timolol, Tobramycin Sulfate, Tropicamide, 6-hydroxy-2-sulfamoylbenzo[b]thiophene, 6-acetoxy-2-sulfamoylbenzo[b]thiophene, 5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide, or a mixture of any two or more thereof.

32. The ocular delivery device of claim 31, wherein the active pharmaceutical ingredient is Cyclosporine.

33. A method of forming an ocular delivery device comprising an active pharmaceutical ingredient, the method comprising:

placing a half-cylinder comprising a solid, cellulose polymer, in a trough; and

exposing the half-cylinder, to a solution comprising the active pharmaceutical ingredient and a solvent capable of solubilizing said active pharmaceutical ingredient, wherein the half-cyclinder absorbs at least a portion of the solution, including the active pharmaceutical ingredient and the solvent.

34. The method of claim 33, wherein the trough maintains the shape of the half-cylinder during the exposing.

35. The method of claim 34, further comprising allowing the absorbed solvent to evaporate from the half-cylinder, or drying the half-cylinder.

36. The method of claim 35, further comprising freeing the ocular delivery device, from the trough.

37. The method of claim 33, wherein the active pharmaceutical ingredient is selected from Acebutolol, Acyclovir, Betaxolol, Bimatoprost, Brimonidine Tartrate, Brinzolamide, Bromfenac Sodium, Cefazolin, Cephalexin, Cephydroxil, Ciprofloxacin, Ciprofloxacin HCl, Cyclosporine, Dexamethasone, Dorzolamide HCl, Epinastine HCl, Erythromycin, Gancicylovir, Gatifloxacin, Gentamicin Sulfate, Ketorolac Tromethamine, Labetalol, Latanoprost, Loteprednol Etabonate, Moxifloxacin HCl, Nepafenac, Ofloxacin, Olopatadine HCl, Penicillin, Pindolol, Prednisolone, Propanolol, Polymyxin B Sulfate/Trimethoprim Sulfate, Sulfacetamide Sodium, Timolol Maleate, Trifluorodine, Tobramycin, Travoprost, Vancomycin, Azelastine HCl, Atropine sulfate, Betamethasone, Carbachol, Pheniramine, Cromolyn sodium, Cyclopentolate, Demecarium bromide, Dexamethasone 21-phosphate, Erythromycin Base, Fluorometholone, Gatifloxacin, Homatropine, Hydroxyamphetamine, Idoxuridine, Medrysone, Methylprednisolone, Naphazoline, Resolvins, Phospholipids, Phenylephrine, Phospholine iodide, Prednisolone Acetate, Prednisolone Sodium Sulfate, Sulfisoxazole, Tetrahydrazoline HCl, Timolol, Tobramycin Sulfate, Tropicamide, 6-hydroxy-2-sulfamoylbenzo[b]thiophene, 6-acetoxy-2-sulfamoylbenzo[b]thiophene, 5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide, or a mixture of any two or more thereof.

38. The ocular delivery device of claim 37, wherein the active pharmaceutical ingredient is Cyclosporine.

39. The method of claim 33, wherein the solvent comprises ethanol.

40. The ocular delivery device prepared by the method of claim 33.

41. The method of treating an eye disorder, the method comprising:

administering one or more of the ocular delivery device of claim 33 into an eye of a subject in need thereof.

42. The method of claim 41, wherein the eye disorder comprises a dry eye syndrome.

43. The method of claim 42, wherein the dry eye syndrome comprises meibumium gland dysfunction and aqueous deficient dry eye.

44. The method of claim 41, wherein the active pharmaceutical ingredient is administered to the eye in an amount more, similar to, or less than that administered by an eye drop.