Sustained release intraocular implants and methods for preventing retinal dysfunction

• US 20050244479A1
• Filed: 04/30/2004
• Published: 11/03/2005
• Est. Priority Date: 04/30/2004
• Status: Active Grant

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: Hughes, Patrick M., Wheeler, Larry A., Donn, Rosy Sheng, Huang, Glenn T., Burke, James, Lin, Ton, Zhang, Kai-Ming
• Granted Patent: US 8,425,929 B2
• Time in Patent Office: Days
• US Class Current: 424/428
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals

Abstract

Biocompatible intraocular implants include an alpha-2 adrenergic receptor agonist and a polymer associated with the alpha-2 adrenergic receptor agonist to facilitate release of the alpha-2 adrenergic receptor agonist into an eye for an extended period of time. The alpha-2 adrenergic receptor agonist may be associated with a biodegradable polymer matrix, such as a matrix of a two biodegradable polymers. The implants may be placed in an eye to prevent the occurrence of one or more ocular conditions, or to reduce one or more symptoms of an ocular condition, such as an ocular neurosensory disorder and the like.

Claims

1. A biodegradable intraocular implant comprising:

an alpha-2 adrenergic receptor agonist associated with a biodegradable polymer matrix that releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant effective to enhance normal retinal neuronal function in an eye in which the implant is placed.

2. The implant of claim 1, wherein the alpha-2 adrenergic agonist is selected from the group consisting of quinoxalines, (2-imidozolin-2-ylamino) quinoxalines, 5-bromo-6-(2-imidozolin-2-ylamino) quinoxalines, derivatives thereof and mixtures thereof.

3. The implant of claim 1, wherein the alpha-2 adrenergic agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.

4. The implant of claim 1, wherein the alpha-2 adrenergic agonist is brimonidine tartrate.

5. The implant of claim 4, further comprising a preservative.

6. The implant of claim 5, wherein the preservative is a purite.

7. The implant of claim 1, further comprising an additional ophthalmically acceptable therapeutic agent.

8. The implant of claim 1, wherein the alpha-2 adrenergic receptor agonist is dispersed within the biodegradable polymer matrix.

9. The implant of claim 1, wherein the matrix comprises a mixture of a first biodegradable polymer of polylactic acid, and a different second biodegradable polymer of polylactic acid.

10. The implant of claim 9, wherein the first biodegradable polymer has an inherent viscosity of about 0.3 dl/g.

11. The implant of claim 10, wherein the second biodegradable polymer has an inherent viscosity of about 1.0 dl/g.

12. The implant of claim 1, wherein the matrix releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant for more than one month from the time the implant is placed in the vitreous of the eye.

13. The implant of claim 1, wherein the matrix releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant for more than forty days from the time the implant is placed in the vitreous of the eye.

14. The implant of claim 1, wherein the matrix releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant for less than 35 days from the time the implant is placed in the vitreous of the eye.

15. The implant of claim 1, wherein the alpha-2 adrenergic receptor agonist is brimonidine, and the matrix releases drug at a rate effective to sustain release of a therapeutically effective amount of brimonidine for about three months.

16. The implant of claim 1, wherein the implant is structured to be placed in the vitreous of the eye.

17. The implant of claim 1, wherein the alpha-2 adrenergic receptor agonist is a brimonidine tartrate provided in an amount of about 20% by weight of the implant, and the biodegradable polymer matrix comprises a combination of two different polylactide polymers.

18. The implant of claim 1, wherein the matrix comprises a mixture of biodegradable polymers, at least one of the biodegradable polymers is a polylactide having a molecular weight of about 64 kD.

19. The implant of claim 18, wherein the mixture comprises a second polymer of a polylactide having a molecular weight of about 14 kD.

20. The implant of claim 1 which is formed by an extrusion process.

21. A method of making a biodegradable intraocular implant, comprising the step of:

extruding a mixture of an alpha-2 adrenergic receptor agonist and a biodegradable polymer component to form a biodegradable material that releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant effective to enhance normal retinal neuronal function in an eye in which the implant is placed.

22. The method of claim 21, wherein the alpha-2 adrenergic agonist is selected from the group consisting of quinoxalines, (2-imidozolin-2-ylamino) quinoxalines, 5-bromo-6-(2-imidozolin-2-ylamino) quinoxalines, derivatives thereof and mixtures thereof.

23. The method of claim 21, wherein the alpha-2 adrenergic agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.

24. The method of claim 21, further comprising a step of mixing the alpha-2 adrenergic receptor agonist with the polymer component before the extrusion step.

25. The method of claim 21, wherein the alpha-2 adrenergic receptor agonist and the polymer component are in a powder form.

26. The method of claim 21, wherein the polymer component comprises a mixture of biodegradable polymers, at least one of the biodegradable polymers is a polylactide having a molecular weight of about 64 kD.

27. The method of claim 21, wherein the polymer component comprises a mixture of two different biodegradable polymers, one biodegradable polymer having an inherent viscosity of about 0.3 dl/g and the other biodegradable polymer having an inherent viscosity of about 1.0 dl/g.

28. A method of treating a retinal dysfunction in an eye of a patient, comprising the step of placing a biodegradable intraocular implant in an eye of the patient, the implant comprising an alpha-2 adrenergic receptor agonist associated with a biodegradable polymer matrix that releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant to provide an amount of the alpha-2 adrenergic receptor agonist effective to prevent or reduce a symptom of a retinal dysfunction.

29. The method of claim 28, wherein the method is effective to treat a retinal neurosensory dysfunction.

30. The method of claim 28, wherein the method is effective to treat an ocular condition selected from the group consisting of:

retinitis pigmentosa, Leber'"'"'s congenital amaurosis, retinal degeration, Usher syndrome, Bardet-Biedl syndrome, rod-cone dystrophy, choroideremia, gyrate-atrophy, and Stargardt'"'"'s disease.

31. The method of claim 28, wherein the implant is placed in the posterior of the eye.

32. The method of claim 28, wherein the implant is placed in the eye with a trocar.

33. The method of claim 28, wherein the implant is placed in the eye with a syringe.

34. The method of claim 28, further comprising a step of administering a therapeutic agent in addition to the alpha-2 adrenergic receptor agonist to the patient.

35. The method of claim 28, wherein the alpha-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.

36. The method of claim 28, wherein the retinal neuronal function includes a measurement of an electroretinogram.

37. The method of claim 36, wherein the placement of the implant in the eye of the patient is effective to increase the amplitude of at least one of a B-wave, an A-wave, or a 30 Hz flicker of the electroretinogram.

38. The method of claim 36, wherein the alpha-2 adrenergic receptor agonist is effective for at least two weeks after placement in the eye.