Drug delivery systems and use thereof

• US 20050175708A1
• Filed: 11/02/2004
• Published: 08/11/2005
• Est. Priority Date: 05/02/2002
• Status: Abandoned Application

• Current Assignee: Massachusetts Eye And Ear Infirmary (Foundation of The Massachusetts Eye and EAR Infirmary Incorporated)
• Original Assignee: Massachusetts Eye And Ear Infirmary (Foundation of The Massachusetts Eye and EAR Infirmary Incorporated)
• Inventors: Miller, Joan W., Gragoudas, Evangelos S., Adamis, Anthony P., Carrasquillo, Karen G.
• Application Number:
  US10/979,785
• Publication Number:
  US 20050175708A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B01J 14/00 Chemical processes in general for reacting liquids with liquids; Apparatus specially adapted therefor B01J8/00, B01J19/08 take precedence

Abstract

The invention provides a microsphere formulation for the sustained delivery of an aptamer, for example, an anti-Vascular Endothelial Growth Factor aptamer, to a preselected locus in a mammal, such as the eye. In addition, the invention provides methods for making such formulations, and methods of using such formulations to deliver an aptamer to a preselected locus in a mammal. In particular, the invention provides a method for delivering the aptamer to an eye for the treatment of an ocular disorder, for example, age-related macular degeneration.

Claims

1. A microsphere for sustained aptamer delivery, the microsphere comprising an anti-vascular endothelial growth factor aptamer and a biocompatible polymer.

2. The microsphere of claim 1, wherein the aptamer comprises from 0.1% (w/w) to 30% (w/w) of the microsphere.

3. The microsphere of claim 2, wherein the aptamer comprises from 0.1% (w/w) to 10% (w/w) of the microsphere.

4. The microsphere of claim 3, wherein the aptamer comprises from 0.5% (w/w) to 5% (w/w) of the microsphere.

5. The microsphere of claim 1, further comprising trehalose.

6. The microsphere of claim 5, wherein the mass ratio of aptamer to trehalose is at least 1:

3.

7. The microsphere of claim 1, wherein the biocompatible polymer is a degradable polymer.

8. The microsphere of claim 7, wherein the degradable polymer is selected from the group consisting of polycarbonate, polyanhydride, polyamide, polyester, polyorthoester, and copolymers or mixtures thereof.

9. The microsphere of claim 8, wherein the polyester is selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), polycaprolactone, and mixtures thereof or copolymers thereof.

10. The microsphere of claim 9, wherein the polymer comprises poly(lactic acid-co-glycolic acid).

11. The microsphere of claim 7, wherein the polymer has a half-life of degradation under physiological conditions of at least 1 month.

12. The microsphere of claim 1, wherein the biocompatible polymer is a non-degradable polymer.

13. The microsphere of claim 12, wherein the non-degradable polymer is selected from the group consisting of polyether, vinyl polymer, polyurethane, cellulose-based polymer, and polysiloxane.

14. The microsphere of claim 13, wherein the polyether is selected from the group consisting of poly(ethylene oxide), poly(ethylene glycol), and poly(tetramethylene oxide).

15. The microsphere of claim 13, wherein the vinyl polymer is selected from the group consisting of polyacrylate, acrylic acid, poly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate).

16. The microsphere of claim 13, wherein the cellulose-based polymer is selected from the group consisting of cellulose, alkyl cellulose, hydroxyalkyl cellulose, cellulose ether, cellulose ester, nitrocellulose, and cellulose acetate.

17. The microsphere of claim 1, 10 or 11, wherein the microsphere has a diameter of about 15 μ

m.

18. A method of preventing, treating, or inhibiting an ocular disease in a mammal in need thereof, the method comprising administering to the mammal the microsphere of claim 1 in an amount sufficient to prevent, treat or inhibit an ocular disease.

19. The method of claim 18, wherein the administering step comprises contacting a scleral surface of the eye of the mammal with the microspheres.

20. The method of claim 18, wherein the administering step comprises administering the microspheres by intravitreal injection.

21. The method of claim 18, wherein the disease is optic disc neovascularization, iris neovascularization, retinal neovascularization, choroidal neovascularization, corneal neovascularization, vitreal neovascularization, glaucoma, pannus, pterygium, macular edema, vascular retinopathy, retinal degeneration, uveitis, inflammatory diseases of the retina, or proliferative vitreoretinopathy.

22. The method of claim 21, wherein the corneal neovascularization is associated with trauma, chemical burns, or corneal transplantation.

23. The method of claim 21, wherein the iris neovascularization is associated with diabetic retinopathy, vein occlusion, ocular tumor or retinal detachment.

24. The method of claim 21, wherein the retinal neovascularization is associated with diabetic retinopathy, vein occlusion, sickle cell retinopathy, retinopathy of prematurity, retinal detachment, ocular ischemia or trauma.

25. The method of claim 21, wherein the intravitreal neovascularization is associated with diabetic retinopathy, vein occlusion, sickle cell retinopathy, retinopathy of prematurity, retinal detachment, ocular ischemia or trauma.

26. The method of claim 21, wherein the choroidal neovascularization is associated with a retinal or subretinal disorder of age-related macular degeneration, presumed ocular histoplasmosis syndrome, myopic degeneration, angioid streaks or ocular trauma.

32. A method of preparing the microsphere of claim 1, the method comprising the steps of:

(a) dissolving a biocompatible polymer in a solvent to form a solution;

(b) combining the solution with an aptamer to produce a mixture; and

(c) combining the mixture of step (b) with a coacervating agent under conditions such that the biocompatible polymer forms microspheres containing the aptamer.

33. The method of claim 32, wherein step (b) further comprises the step of adding trehalose.

34. The method of claim 33, wherein the mass ratio of aptamer to the trehalose is at least 1:

3.

27. A method of treating age-related macular degeneration in a human, wherein the method comprises administering to a human in need thereof a microsphere formulation comprising an anti-VEGF aptamer.

28. The method of claim 27, wherein the microsphere formulation is administered locally.

29. The method of claim 28, wherein the microsphere formulation is administered by transcleral delivery.

30. The method of claim 28, wherein the microsphere formulation is administered by intravitreal injection.

31. The method of claim 27, wherein the aptamer is EYE001.