Sustained delivery of therapeutic agents to an eye compartment

• US 9,566,242 B2
• Filed: 10/23/2014
• Issued: 02/14/2017
• Est. Priority Date: 02/25/2010
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: McDonnell, Peter J., Khan, Yasin A., Lai, Samuel K., Kashiwabuchi, Renata T., Behrens, Ashley, Hanes, Justin S.
• Primary Examiner(s): Sasan, Aradhana
• Application Number:
  US14/521,904
• Publication Number:
  US 20150044270A1
• Time in Patent Office: 845 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6921 the form being a particulate, a powder, an adsorbate, a bead or a sphere
• CPC Class Codes: A61K 47/6931 the material constituting the nanoparticle being a polymer
• 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 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Compositions and methods for treating eye disorders by administering a drug delivery system into an eye compartment of the patient, wherein the drug delivery system contains a particle containing a core; a coating associated with the particle, wherein the coating is covalently or non-covalently associated with the particle and presents a hydrophilic region to the environment around the particle; and a therapeutic agent are disclosed. The eye compartment can exhibit reduced inflammation or IOP after administration of the drug delivery systems to a patient than if a drug delivery system including an uncoated particle were administered to the patient.

Claims

1. A method for treating an eye disorder in a patient in need thereof, comprising administering by intravitreal injection into the vitreous chamber of the eye of the patient, an effective amount of a drug delivery system comprising:

(i) microparticles comprising a core comprising polylactide or polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticle core, wherein the coating is formed of amphiphilic molecules comprising a polyethylene glycol hydrophilic region and a hydrophobic region; and

(iii) an anti-angiogenic agent encapsulated in or bound to the microparticles,

wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber over a period of time of at least three months; and

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure compared to the vitreous chamber of an eye treated with the same microparticles not coated with the amphiphilic molecules, for at least about 30 days post-administration.

2. The method of claim 1, wherein the microparticle core consists essentially of polylactide-co-glycolide.

3. The method of claim 1, wherein the eye disorder is selected from the group consisting of corneal neovascularization, macular degeneration, diabetic retinopathy, age related macular degeneration, and combinations thereof.

4. The method of claim 1, wherein the anti-angiogenic agent is an anti-vascular endothelial growth factor (VEGF) agent.

5. The method of claim 1, wherein the anti-angiogenic agent is released from the drug delivery system into the vitreous chamber of the patient'"'"'s eye over a period of time of at least six months.

6. The method of claim 1 wherein the coating molecule is a block copolymer.

7. The method of claim 1, wherein the diameter of the microparticles is about 50 microns or less.

8. The method of claim 1, wherein the diameter of the microparticles is about 30 microns or less.

9. The method of claim 1, wherein the patient is a human.

10. The method of claim 1, wherein the drug delivery system is lyophilized and then reconstituted prior to administration by intravitreal injection.

11. The method of claim 1, wherein the drug delivery system is provided in a sterile suspension.

12. The method of claim 11, wherein the sterile suspension includes a suspending agent.

13. A method for treating macular degeneration in a patient in need thereof, comprising administering by intravitreal injection into the vitreous chamber of an eye of the patient an effective amount of a drug delivery system comprising:

(i) microparticles having a diameter of 30 μ

m or less, the microparticles comprising a core consisting essentially of polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles, wherein the coating comprises a molecule having a polyethylene glycol hydrophilic region and a hydrophobic region,

(iii) a therapeutically effective amount of an anti-VEGF agent encapsulated in or bound to the microparticles,

wherein the drug delivery system provides sustained release of the anti-VEGF agent into the vitreous chamber over a period of time of at least three months;

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure compared to the vitreous chamber of an eye treated with the same microparticles not coated with the amphiphilic molecules, for at least about 30 days post-administration; and

wherein the drug delivery system is lyophilized and then reconstituted prior to administration by intravitreal injection in a sterile suspension that includes a suspending agent.

14. The method of claim 13, wherein the anti-VEGF agent is released from the drug delivery system into the vitreous chamber over a period of time of at least six months.

15. The method of claim 13, wherein the patient is a human.

16. A method for treating an eye disorder in a patient in need thereof, comprising administering by intravitreal injection into the vitreous chamber of the eye an effective amount of a drug delivery system comprising:

(i) microparticles comprising a core comprising polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles, wherein the coating comprises a molecule having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-angiogenic agent encapsulated in or bound to the microparticles,

wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber over a period of time of at least three months; and

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure compared to the vitreous chamber of an eye treated with the same microparticles not coated with the amphiphilic molecules.

17. The method of claim 16, wherein the microparticles have a diameter of about 50 microns or less.

18. The method of claim 16, wherein the microparticles have a diameter of about 30 microns or less.

19. The method of claim 16, wherein the coating molecule is a block-copolymer.

20. The method of claim 16, wherein the microparticle core consists essentially of polylactide-co-glycolide.

21. The method of claim 16, wherein the disorder is macular degeneration.

22. The method of claim 16, wherein the disorder is age-related macular degeneration.

23. The method of claim 16, wherein the disorder is diabetic retinopathy.

24. The method of claim 16, wherein the disorder is corneal neovascularization.

25. The method of claim 16, wherein the anti-angiogenic agent is released from the drug delivery system into the vitreous chamber of the patient'"'"'s eye over a period of time of at least six months.

26. The method of claim 16, wherein the anti-angiogenic agent is an anti-VEGF agent.

27. The method of claim 16, wherein the patient is a human.

28. The method of claim 16, wherein the drug delivery system is lyophilized and then reconstituted prior to administration by intravitreal injection.

29. The method of claim 16, wherein the drug delivery system is provided in a sterile suspension.

30. The method of claim 29, wherein the sterile suspension includes a suspending agent.

31. A method for treating macular degeneration in a patient in need thereof, comprising administering by intravitreal injection into the vitreous chamber of an eye of the patient an effective amount of a drug delivery system comprising:

(i) microparticles having a diameter of 30 μ

m or less including a core consisting essentially of polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles, wherein the coating comprises a molecule having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-VEGF agent encapsulated in or bound to the microparticles,

wherein the drug delivery system provides sustained release of the anti-VEGF agent into the vitreous chamber over a period of time of at least three months;

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure compared to the vitreous chamber of an eye treated with the same microparticles not coated with the amphiphilic molecules; and

wherein the drug delivery system is lyophilized and then reconstituted prior to administration by intravitreal injection in a sterile suspension that includes a suspending agent.

32. The method of claim 31, wherein the anti-VEGF agent is released from the drug delivery system into the vitreous chamber over a period of time of at least six months.

33. The method of claim 31, wherein the patient is a human.