Sustained Delivery of Therapeutic Agents to an Eye Compartment

• US 20120321719A1
• Filed: 02/25/2011
• Published: 12/20/2012
• Est. Priority Date: 02/25/2010
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Lai, Samuel K., McDonnell, Peter J., Khan, Yasin A., Kashiwabuchi, Renata T., Behrens, Ashley, Hanes, Justin S.
• Granted Patent: US 8,889,193 B2
• Time in Patent Office: Days
• US Class Current: 424/497
• 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 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 disease or disorder in a patient in need thereof, comprising administering into a part of the eye of the patient, a drug delivery system comprising:

a particle comprising a biocompatible core;

a coating of a hydrophilic polymer or hydrophilic-hydrophobic copolymer or block copolymer associated with the particle, wherein the coating is covalently or non-covalently associated with the particle and presents an uncharged or substantially neutrally charged surface to the environment around the particle; and

a therapeutically effective amount of a therapeutic agent to treat an eye disease or.

disorder.

2. The method of claim 1, wherein the coating reduces the inflammation or intraocular pressure (IOP) elicited by the uncoated particle by at least about 10%, 30%, or 50%.

6. The method of claim 1, wherein the coating comprises a molecule having hydrophilic regions and hydrophobic regions.

7. The method of claim 6, wherein at least about 50% of the hydrophobic regions in the coating molecules have a molecular mass of least about 2 kDa or 3 kDa.

9. The method of claim 6, wherein the hydrophobic regions comprise polypropylene oxide (PPO)

10. The method of claim 1, wherein the hydrophilic polymer or regions comprises polyethylene glycol (PEG).

11. The method of claim 6, wherein:

the hydrophobic regions comprise PPO;

the hydrophilic region comprises PEG; and

at least about 50% of the hydrophobic regions in the coating molecules have a molecular mass of least about 3 kDa.

12. The method of claim 1, wherein the particle has a diameter less than about 100,000 nm, 10,000 nm, 5000 nm, 1,000 nm, or 200 nm.

17. The method of claim 1, wherein the particle comprises a biodegradable polymer.

18. The method of claim 1, wherein the particle comprises a polymer selected from the group consisting of polystyrene;

a poly(hydroxy acid);

poly(lactic acid);

poly(glycolic acid);

poly(lactic acid-co-glycolic acid);

poly(lactic-co-glycolic acid);

a polyanhydride;

a polyorthoester;

a polyamide;

a polycarbonate;

a polyalkylene;

polyethylene;

polypropylene;

a polyalkylene glycol;

poly(ethylene glycol);

a polyalkylene oxide;

poly(ethylene oxide);

a polyalkylene terephthalate;

poly(ethylene terephthalate);

a polyvinyl alcohol;

a polyvinyl ether;

a polyvinyl ester;

a polyvinyl halide;

poly(vinyl chloride);

polyvinylpyrrolidone;

a polysiloxane;

a poly(vinyl acetate);

a polyurethane;

a co-polymer of a polyurethane;

a derivativized cellulose;

alkyl cellulose;

a hydroxyalkyl cellulose;

a cellulose ether;

a cellulose ester;

a nitro cellulose;

methyl cellulose;

ethyl cellulose;

hydroxypropyl cellulose;

hydroxy-propyl methyl cellulose;

hydroxybutyl methyl cellulose;

cellulose acetate;

cellulose propionate;

cellulose acetate butyrate;

cellulose acetate phthalate;

carboxylethyl cellulose;

cellulose triacetate;

cellulose sulfate sodium salt;

a polymer of acrylic acid;

methacrylic acid;

a copolymer of methacrylic acid;

a derivative of methacrylic acid;

poly(methyl methacrylate);

poly(ethyl methacrylate);

poly(butylmethacrylate);

poly(isobutyl methacrylate);

poly(hexylmethacrylate);

poly(isodecyl methacrylate);

poly(lauryl methacrylate);

poly(phenyl methacrylate);

poly(methyl acrylate);

poly(isopropyl acrylate);

poly(isobutyl acrylate);

poly(octadecyl acrylate);

poly(butyric acid);

poly(valeric acid);

poly(lactide-co-caprolactone);

a copolymer of poly(lactide-co-caprolactone);

a blend of poly(lactide-co-caprolactone);

polygalactin;

poly-(isobutyl cyanoacrylate);

poly(2-hydroxyethyl-L-glutamine);

poly(caprolactone); and

combinations and copolymers thereof.

20. The method of claim 1, wherein the coating is bound covalently to the particle.

21. The method of claim 1, wherein the coating is non-covalently associated with the particle.

24. The method of claim 1, wherein the eye disease or disorder is selected from the group consisting of amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs'"'"' endothelial dystrophy, Sjogren'"'"'s syndrome, Stevens-Johnson syndrome, an autoimmune dry eye disease, an environmental dry eye disease, a corneal neovascularization disease, post-corneal transplant rejection prophylaxis, post-corneal transplant rejection treatment, autoimmune uveitis, infectious uveitis, anterior uveitis, posterior uveitis, pan-uveitis, an inflammatory disease of the retina, an inflammatory disease of the vitreious, endophthalmitis prophylaxis, endophthalmitis treatment, macular edema, macular degeneration, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, hypertensive retinopathy, age related macular degeneration, an autoimmune disease of the retina, primary intraocular melanoma, metastatic intraocular melanoma, an intraocular metastatic tumor, open angle glaucoma, closed angle glaucoma, pigmentary glaucoma and combinations thereof.

25. The method of claim 1 comprising injecting the drug delivery system into an eye compartment selected from the group consisting of the vitreous chamber, the sclera, the stroma and the anterior chamber.

27. The method of claim 1, wherein the therapeutic agent is selected from the group consisting of an anti-inflammatory drug, an antimicrobial agent, an anti-angiogenesis agent, an immunosuppressant, an antibody, an antibody fragment, a steroid, a chemotherapeutic agent, an ocular anti-hypertensive drug, and combinations thereof.

29. The method of claim 1, wherein the drug delivery system provides sustained release of the therapeutic agent over a period of time of at least about 1 day, 1 week, or 4 weeks.

61. The method of claim 1 wherein the polymer coating comprises a block copolymer of polyethylene glycol and polypropylene oxide on a core of polylactide-co-glycolide, for delivery of a drug lowering intraocular pressure (IOP), or a steroidal anti-inflammatory.

3-5. -5. (canceled)

8. (canceled)

13-16. -16. (canceled)

19. (canceled)

22-23. -23. (canceled)

26. (canceled)

28. (canceled)

30-32. -32. (canceled)

33. A drug delivery system comprising:

A particle comprising a biocompatible core;

A coating of a hydrophilic polymer or hydrophilic-hydrophobic copolymer or block copolymer associated with the particle, wherein the coating is covalently or non-covalently associated with the particle and presents an uncharged or substantially neutrally charged surface to the environment around the particle; and

A therapeutically effective amount of a therapeutic agent.

62. The drug delivery system of claim 33 wherein the particle compositions are retained within an eye compartment for periods of time greater than those observed with free-standing drugs or uncoated particle compositions.

64. The drug delivery system of claim 33 wherein the polymer comprises hydrophobic segments with molecular weights of at least about 1.8 kDa, at least about 2 kDa, at least about 2.5 kDa, at least about 3 kDa, at least about 3.5 kDa, at least about 4.0 kDa, at least about 4.5 kDa, or at least about 5.0 kDa or more.

65. The drug delivery system of claim 33 wherein at least about 10%,at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99% of the hydrophobic regions in these coatings have molecular weights of at least about 1.8 kDa, at least about 2 kDa, at least about 2.5 kDa, at least about 3 kDa, at least about 3.5 kDa, at least about 4.0 kDa, at least about 4.5 kDa, or at least about 5.0 kDa or more.

34-60. -60. (canceled)

63. A drug delivery system, comprising:

a substrate;

a polymeric coating associated with the substrate, wherein the coating presents a hydrophilic region to the environment around the substrate; and

a therapeutically effective amount of a therapeutic agent;

wherein the drug delivery system elicits less inflammation when administered to a patient than if a drug delivery system comprising an uncoated substrate were administered to the patient.