# US 10,369,107 B2 · Sustained delivery of therapeutic agents to an eye compartment

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- Number: US 10,369,107 B2
- Document ID: US10369107B2
- Status: Granted
- Kind: B2
- Application number: 15/884,158
- Filed: 2018-01-30
- Published: 2018-06-14
- Granted: 2019-08-06
- Earliest claimed: 2010-02-25
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Peter J. McDonnell; Yasin A. Khan; Samuel K. Lai; Renata T. Kashiwabuchi; Ashley Behrens; Justin S. Hanes
- Web page: https://patentgrep.com/patent/US10369107B2

## CPC

- 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)}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0051: {Ocular inserts or implants}
- A61K 9/1641: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/52: Purines, e.g. adenine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/6921: {the form being a particulate, a powder, an adsorbate, a bead or a sphere}
- A61K 47/6931: {the material constituting the nanoparticle being a polymer}
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 1

A method for treating an eye disease or disorder in a patient in need thereof, comprising administering to a part of the eye of the patient, a drug delivery system comprising:
particles having a diameter between 30 nm and 50 microns, the particles comprising
a biocompatible polymeric core comprising a blend of polymers selected from the group consisting of polylactic acid, poly(lactide-co-glycolide), polyglycolic acid, and copolymers thereof;
a coating of polyalkylene oxide polymer or copolymer,
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 polyalkylene oxide polymer or copolymer are amphiphilic copolymers or block copolymers comprising 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,
covalently or non-covalently associated with the particle,
therapeutic agent to treat an eye disease or disorder;
wherein the drug delivery system provides sustained release of the therapeutic 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 than if the particle were uncoated for at least about 30 days post-administration.

### Claim 2 (depends on 1)

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%, in the vitreous chamber of the eye for at least about 30 days post-administration.

### Claim 3 (depends on 1)

The method of claim 1, wherein at least about 50% of the polymer in the hydrophobic regions of the amphiphilic copolymer in the coating has a molecular mass of least about 2 kDa.

### Claim 4 (depends on 1)

The method of claim 1, wherein the particles have a diameter between about 1 micron and about 30 microns.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

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 vitreous, 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.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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, a steroid, a chemotherapeutic agent, an ocular anti-hypertensive drug, and combinations thereof.

### Claim 10 (depends on 1)

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.

### Claim 11

A drug delivery system comprising:
particles having a diameter between 30 nm and 50 microns, the particles comprising a biocompatible polymeric core comprising a blend of polymers selected from the group consisting of polylactic acid, poly(lactide-co-glycolide), polyglycolic acid, and copolymers thereof;
a coating of polyalkylene oxide polymer or copolymer,
covalently or non-covalently associated with the particle,
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 polyalkylene oxide polymer or copolymer are amphiphilic copolymers or block copolymers comprising 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,
wherein the coating is covalently or non-covalently associated with the surface of the particle; and
a therapeutically effective amount of a therapeutic agent for treatment of an eye disease or disorder,
wherein the drug delivery system provides sustained release of the therapeutic agent into the vitreous chamber of the eye of the patient 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 than if the particle were uncoated for at least about 30 days post-administration.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 11)

The drug delivery system of claim 11, wherein the particles are retained within an eye compartment for periods of time greater than those observed with free-standing drugs or uncoated particle compositions.

### Claim 14 (depends on 11)

The drug delivery system of claim 11, wherein the polymer comprises hydrophobic segments with molecular weights of at least about 4.0 kDa, at least about 4.5 kDa, or at least about 5.0 kDa or more.

### Claim 15 (depends on 11)

The drug delivery system of claim 11, wherein 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.

### Claim 16 (depends on 11)

The drug delivery system of claim 11, wherein the therapeutic agent is an anti-angiogenic agent.

### Claim 17 (depends on 16)

The drug delivery system of claim 16, wherein the anti-angiogenic agent is an anti-vascular epithelial growth factor (VEGF) agent.

### Claim 18 (depends on 11)

The drug delivery system of claim 11, wherein the therapeutic agent is selected from the group consisting of timolol, betaxolol, bromonidine, and dorzolamide.

### Claim 19 (depends on 11)

The drug delivery system of claim 11, wherein the particles are between one and 30 microns in diameter.

### Claim 20 (depends on 11)

The drug delivery system of claim 11, wherein the particles are between one and 50 microns in diameter.

### Claim 21 (depends on 11)

The drug delivery system of claim 11, wherein the particles provide sustained release of the therapeutic agent into the vitreous chamber of the eye of the patient over a period of time of at least six months.

### Claim 22 (depends on 21)

The drug delivery system of claim 21, wherein the patient is a human.

### Claim 23 (depends on 11)

The drug delivery system of claim 11, wherein the particles are suspended in a sterile injectable composition.

### Claim 24 (depends on 23)

The drug delivery system of claim 23, wherein the particles are lyophilized and reconstituted prior to administration.

### Claim 25 (depends on 11)

The drug delivery system of claim 11, wherein the biocompatible core comprises a blend of polylactic acid and poly(lactide-co-glycolide).

### Claim 26 (depends on 25)

The drug delivery system of claim 25, wherein the therapeutic agent is an anti-angiogenic agent.

### Claim 27 (depends on 26)

The drug delivery system of claim 26, wherein the therapeutic agent is an anti-vascular epithelial growth factor (VEGF) agent.

### Claim 28 (depends on 27)

The drug delivery system of claim 27, wherein the particles are between one and 30 microns in diameter.