Alpha-2 agonist polymeric drug delivery systems

• US 20060233860A1
• Filed: 03/31/2006
• Published: 10/19/2006
• Est. Priority Date: 04/30/2004
• Status: Active Grant

• Current Assignee: Allergan Incorporated (Abbvie Incorporated)
• Original Assignee: Allergan Incorporated (Abbvie Incorporated)
• Inventors: Hughes, Patrick M., Spada, Lon T., Burke, James A., Chang, James N., Blanda, Wendy M., Orilla, Werhner C.
• Granted Patent: US 8,529,927 B2
• Time in Patent Office: Days
• US Class Current: 424/427
• 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 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 2430/16 for reconstruction of eye parts, e.g. intraocular lens, cornea
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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 can be placed in an eye to treat one or more ocular conditions, such as an ocular vasculopathy or glaucoma, including reduction of an elevated intraocular pressure.

Claims

1. A biodegradable intraocular implant comprising an alpha-2 adrenergic receptor agonist and a biodegradable polymer, wherein the biodegradable polymer comprises an ester end-capped biodegradable polymer and an acid end-capped biodegradable polymer.

2. The implant of claim 1, wherein the implant comprises from about 10% to about 91% ester end-capped biodegradable polymer, from about 5 wt % to about 40 wt % acid end-capped biodegradable polymer, and from about 4 wt % to about 50 wt % alpha-2 adrenergic receptor agonist.

3. The implant of claim 2, wherein the implant comprises from about 25% to about 80% ester end-capped biodegradable polymer, from about 10 wt % to about 40 wt % acid end-capped biodegradable polymer, and about 10 wt % to about 35 wt % alpha-2 adrenergic receptor agonist.

4. The implant of claim 2, wherein the implant comprises about 88 wt % ester end-capped biodegradable polymer, about 10 wt % acid end-capped biodegradable polymer, and about 12 wt % alpha-2 adrenergic receptor agonist.

5. The implant of claim 2, wherein the implant comprises from about 53 wt % to about 73% ester end-capped biodegradable polymer, from about 15 wt % to about 35 wt % acid end-capped biodegradable polymer, and from about 9 wt % to about 12 wt % alpha-2 adrenergic receptor agonist.

6. The implant of claim 2, wherein the biodegradable polymer comprises more than one ester end-capped biodegradable polymer.

7. The implant of claim 2, wherein the biodegradable polymer comprises more than one acid end-capped biodegradable polymer.

8. The implant of claim 2, wherein the implant has no or a nominal lag time after ocular implantation or insertion of the implant before release of a therapeutically effective amount of the alpha-2 adrenergic receptor agonist from the implant occurs.

9. The implant of claim 1, wherein the implant comprises greater than or equal to 4 weight percent (wt %) of a biologically active alpha-2 adrenergic receptor agonist.

10. The implant of claim 1 which does not include any pore forming additives, release rate modulators or release rate modifiers.

11. The implant of claim 1, wherein the implant can exhibit a sustained release of the alpha-2 adrenergic receptor agonist from the biodegradable polymeric matrix over a period of at least 115 days.

12. The implant of claim 1, wherein the implant exhibits a substantially linear release of the alpha-2 adrenergic receptor agonist from the biodegradable polymeric matrix of the implant over a period of time of from about 20 days to about 50 days.

13. A biodegradable intraocular implant comprising:

(a) an alpha-2 adrenergic receptor agonist, and;

(b) a biodegradable polymer, wherein the biodegradable polymer comprises an ester end-capped biodegradable polymer and an acid end-capped biodegradable polymer, wherein the implant comprises from about 25% to about 91% of at least two different ester end-capped biodegradable polymers, from about 5 wt % to about 40 wt % acid end-capped biodegradable polymer, and from about 4 wt % to about 35 wt % alpha-2 adrenergic receptor agonist.

14. A process for making a biodegradable intraocular implant comprising:

(a) mixing an alpha-2 adrenergic receptor agonist and a biodegradable polymer, wherein the biodegradable polymer comprises an ester end-capped biodegradable polymer and an acid end-capped biodegradable polymer;

(b) heating the mixture, and;

(c) extruding the heated mixture, to thereby make a biodegradable intraocular implant.

15. The process of claim 14 , wherein the implant is extruded as a filament with a diameter of about 0.5 mm, a length of about 6 mm and a weight of about 1 mg.

16. A biodegradable intraocular implant made by the process of claim 14, the alpha-2 adrenergic receptor agonist is homogenously distributed throughout the implant.

17. A method for treating an ocular condition selected from the group consisting of:

macular degeneration, age related macular degeneration, non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, retinopathy, diabetic retinopathy, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, cystoid macular edema, and diabetic macular edema, acute multifocal placoid pigment epitheliopathy, Behcet'"'"'s disease, birdshot retinochoroidopathy, syphilis, lyme disease, tuberculosis, toxoplasmosis, uveitis, intermediate uveitis, pars planitis, and anterior uveitis, multifocal choroiditis, multiple evanescent white dot syndrome, ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi-Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat'"'"'s disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease, frosted branch angitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, Eales disease, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, eye trauma, laser induced eye damage, photocoagulation, eye hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy, proliferative vitreal retinopathy, appearance of epiretinal membranes, proliferative diabetic retinopathy, ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome, endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV Infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, myiasis, retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt'"'"'s disease and fundus flavimaculatus, Bests disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby'"'"'s fundus dystrophy, benign concentric maculopathy, Bietti'"'"'s crystalline dystrophy, pseudoxanthoma elasticum, retinal detachment, macular hole, giant retinal tear, retinal disease associated with tumors, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors, punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epithelitis, the method comprising the step of intraocular administration of a biodegradable intraocular implant comprising an alpha-2 adrenergic receptor agonist and a biodegradable polymer, wherein the biodegradable polymer comprises an ester end-capped biodegradable polymer and an acid end-capped biodegradable polymer.

18. The method of claim 17, wherein the alpha-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.

19. A biodegradable intraocular implant comprising a plurality of forms of an alpha-2 adrenergic receptor agonist and a biodegradable polymer.

20. The implant of claim 19, wherein the alpha-2 adrenergic receptor agonist is a brimonidine.

21. The implant of claim 19, wherein the brimonidine is present in two forms in the implant.

22. The implant of claim 21, wherein the two forms of brimonidine present in the implant are brimonidine free base and brimonidine tartrate.

23. The implant of claim 21, wherein the implant comprises from about 50 wt % to about 70% ester end-capped biodegradable polymer, from about 1 wt % to about 49 wt % brimonidine free base and from about 1 wt % to about 49 wt % brimonidine tartrate.

24. The implant of claim 21, wherein the implant comprises from about 50 wt % to about 60% ester end-capped biodegradable polymer, from about 1 wt % to about 49 wt % brimonidine free base and from about 1 wt % to about 49 wt % brimonidine tartrate.

25. The implant of claim 21, wherein the implant comprises from about 50 wt % to about 70% ester end-capped biodegradable polymer, from about 10 wt % to about 30 wt % brimonidine free base and from about 10 wt % to about 30 wt % brimonidine tartrate.

26. The implant of claim 23, wherein the implant comprises from about 55 wt % to about 65% ester end-capped biodegradable polymer, from about 15 wt % to about 20 wt % brimonidine free base and from about 15 wt % to about 20 wt % brimonidine tartrate.

27. The implant of claim 26, wherein the implant comprises about 65 wt % ester end-capped biodegradable polymer, about 18 wt % brimonidine free base and about 18 wt % brimonidine tartrate.

28. The implant of claim 21, wherein the biodegradable polymer comprises more than one ester end-capped biodegradable polymer.

29. The implant of claim 19, wherein the implant has no or a nominal lag time after ocular implantation or insertion of the implant before release of a therapeutically effective amount of the alpha-2 adrenergic receptor agonist from the implant occurs.

30. The implant of claim 19, wherein the implant can exhibit a sustained release of the alpha-2 adrenergic receptor agonist from the biodegradable polymeric matrix over a period of at least 60 days.

31. The implant of claim 19, wherein the implant exhibits a substantially linear release of the alpha-2 adrenergic receptor agonist from the biodegradable polymeric matrix of the implant over a period of time of from about 20 days to about 50 days.

45. The implant of claim 2 or claim 19, wherein the implant has no or a nominal lag time in vitro before release of a therapeutically effective amount of the alpha-2 adrenergic receptor agonist from the implant occurs.

32. A biodegradable intraocular implant comprising:

(a) brimonidine free base;

(b) brimonidine tartrate;

(c) an ester end-capped biodegradable polymer, wherein the implant comprises from about 50 wt % to about 70% of the ester end-capped biodegradable polymer, from about 1 wt % to about 49 wt % of the brimonidine free base and from about 1 wt % to about 49 wt % of the brimonidine tartrate.

33. A process for making a biodegradable intraocular implant comprising:

(a) mixing a plurality of forms of alpha-2 adrenergic receptor agonist and a biodegradable polymer;

(b) heating the mixture, and;

(c) extruding the heated mixture, to thereby make a biodegradable intraocular implant.

34. The process of claim 33, wherein the implant is extruded as a filament with a diameter of about 0.5 mm, a length of about 6 mm and a weight of about 1 mg.

35. A biodegradable intraocular implant made by the process of claim 33, wherein the plurality of forms of the alpha-2 adrenergic receptor agonist are homogenously distributed throughout the implant.

36. A method for treating an ocular condition selected from the group consisting of:

macular degeneration, age related macular degeneration, non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, retinopathy, diabetic retinopathy, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, cystoid macular edema, and diabetic macular edema, acute multifocal placoid pigment epitheliopathy, Behcet'"'"'s disease, birdshot retinochoroidopathy, syphilis, lyme disease, tuberculosis, toxoplasmosis, uveitis, intermediate uveitis, pars planitis, and anterior uveitis, multifocal choroiditis, multiple evanescent white dot syndrome, ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi-Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat'"'"'s disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease, frosted branch angitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, Eales disease, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, eye trauma, laser induced eye damage, photocoagulation, eye hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy, proliferative vitreal retinopathy, appearance of epiretinal membranes, proliferative diabetic retinopathy, ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome, endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV Infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, myiasis, retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt'"'"'s disease and fundus flavimaculatus, Bests disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby'"'"'s fundus dystrophy, benign concentric maculopathy, Bietti'"'"'s crystalline dystrophy, pseudoxanthoma elasticum, retinal detachment, macular hole, giant retinal tear, retinal disease associated with tumors, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors, punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epithelitis, the method comprising the step of intraocular administration of a biodegradable intraocular implant comprising a plurality of forms of an alpha-2 adrenergic receptor agonist and a biodegradable polymer.

37. The method of claim 36, wherein the plurality of forms of the alpha-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.

38. A method of treating a symptom of glaucoma, the method comprising the step of placing a biodegradable intraocular implant comprising an alpha-2 adrenergic receptor agonist associated with a biodegradable polymer into the vitreous of an eye, thereby treating a symptom of the glaucoma.

39. The method of claim 38, wherein the symptom of the glaucoma is reduced for at least about 35 days after intravitreal placement of the implant.

40. The method of claim 38, wherein the symptom of the glaucoma is elevated intraocular pressure.

41. The method of claim 38, wherein the alpha-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.

42. A biodegradable intraocular implant comprising about 12% brimonidine tartrate, about 78 wt % PLA, and about 10 wt % PLGA, wherein the PLA is made using two different molecular weight polymers.

43. A process for making a biodegradable intraocular implant comprising:

(a) mixing an alpha-2 adrenergic receptor agonist and a biodegradable polymer, wherein the biodegradable polymer comprises an ester end-capped biodegradable polymer and an acid end-capped biodegradable polymer, and;

(b) compressing the mixture into a pellet.

44. A non-biodegradable intraocular implant comprising a plurality of forms of an alpha-2 adrenergic receptor agonist and a non-biodegradable polymer.