# US 9,005,596 B2 · Bi-functional co-polymer use for ophthalmic and other topical and local applications

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- Number: US 9,005,596 B2
- Document ID: US9005596B2
- Status: Granted
- Kind: B2
- Application number: 14/328,484
- Filed: 2014-07-10
- Published: 2014-10-30
- Granted: 2015-04-14
- Earliest claimed: 2009-02-18
- Assignees: Eyeon Particle Sciences LLC
- Applicants: Eyeon Particle Sciences LLC
- Inventors: Eugene Rex Cooper; David Maxwell Kleinman; Andrew Loxley; Mark Mitchnick
- Web page: https://patentgrep.com/patent/US9005596B2

## CPC

- A61K 31/785: Polymers containing nitrogen
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0043: {Nose}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0051: {Ocular inserts or implants}
- A61K 9/0073: {Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M)}
- 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 31/045: Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K 31/7036: having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
- A61K 31/74: Synthetic polymeric materials
- A61K 31/765: Polymers containing oxygen
- A61K 35/02: from inanimate materials (carbon A61K33/44)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- G02C 7/04: Contact lenses for the eyes (disinfection or sterilisation of contact lenses A61L12/00)
- 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
- G02C: SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES (trial frames for testing the eyes A61B3/04; goggles or eyeshields not having the same features as spectacles A61F9/00)

## Abstract

The invention contemplates a copolymer which is a graft or block copolymer useful to change wettability and surface characteristics of biological surfaces. Methods for use of these formulations and coatings to change wettability and sterically stabilize, and lubricate biological surfaces in a subject, for example, in the treatment of dry eye syndrome, and to prevent adherence of unwanted proteins, for example in the treatment of contact lens intolerance, are provided.

## Claims

### Claim 1

A method for prolonging the stability of an ocular surface tear film of a subject, comprising contacting said ocular surface of said subject with a composition comprising a graft copolymer having a positively charged backbone and hydrophilic water soluble side chains, wherein said graft copolymer is PLL-g-PEG in an amount and for a duration so as to prolong the stability of said tear film of said subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein said graft copolymer creates a covalent adhesion between said graft copolymer and said ocular surface.

### Claim 3 (depends on 1)

The method of claim 1, wherein said graft copolymer comprises 0.001 to 40% of said composition.

### Claim 4 (depends on 1)

The method of claim 1, wherein said composition further comprises a second polymer.

### Claim 5 (depends on 1)

The method of claim 1, wherein said composition further comprises one or more of a surfactant, a preservative, and a pharmaceutical ingredient selected from the group consisting of: a demulcent, an emollient, sodium chloride and a vasoconstrictor.

### Claim 6 (depends on 1)

The method of claim 1, wherein said composition is contacted topically to an eye of a subject by an eye drop or an eye care solution.

### Claim 7 (depends on 1)

The method of claim 1, wherein said composition is topically administered to an eye of a subject to treat dry eye, ophthalmic irritation, or corneal epithelial disease.

### Claim 8 (depends on 7)

The method of claim 7, further comprising administering to said eye a second, different eye drop.

### Claim 9 (depends on 5)

The method of claim 5, wherein said vasoconstrictor is selected from the group consisting of Ephedrine hydrochloride, Naphazoline hydrochloride, Phenylephrine hydrochloride and Tetrahydrozoline hydrochloride.

### Claim 10 (depends on 5)

The method of claim 5, wherein said emollient is selected from the group consisting of Lanolin, mineral oil, paraffin, petrolatum, white ointment, white petrolatum, white wax and yellow wax.

### Claim 11 (depends on 1)

The method of claim 1, wherein prolonging said stability of an ocular surface tear film of a subject provides prolonged ocular comfort to said subject.

### Claim 12 (depends on 1)

The method of claim 1, wherein said composition is in a volume sufficient for instillation in the eye, and wherein said graft copolymer is at a concentration ranging from 0.1 to 3 wt %.

### Claim 13 (depends on 1)

The method of claim 1, wherein said composition has a viscosity of less than 20 cP.

### Claim 14 (depends on 1)

The method of claim 1, wherein said composition has a viscosity ranging from 1 cP up to and including 100 cP.

### Claim 15 (depends on 1)

The method of claim 1, wherein said composition has a viscosity ranging from 2 cP up to and including 30 cP.

### Claim 16 (depends on 1)

The method of claim 1, wherein said composition further comprises a poly(ethylene oxide)-poly(propylene oxide) block co-polymer surfactant.

### Claim 17

A method for prolonging the stability of an ocular surface tear film of a subject, comprising contacting an ocular surface of said subject with a composition comprising a graft copolymer having a positively charged backbone and hydrophilic water soluble side chains, wherein said graft copolymer is PLL-g-PEG in an amount and for a duration so as to prolong the stability of said tear film of said subject, wherein said prolonging is measured using tear film break up time (TFBUT).

### Claim 18 (depends on 17)

The method of claim 17, wherein the stability of said tear film of said subject is maintained for up to two hours.

### Claim 19 (depends on 17)

The method of claim 17, wherein said tear film break up time (TFBUT) is measured by a methodology selected from the group consisting of:
(a) measuring non-invasive tear film break up time;
(b) using Tearscope™, a non-invasive lighting system and slit lamp biomicroscope observation system comprising a source of diffuse light;
(c) assessing tear film reflectance of light and aberrations;
(d) using wavescan assessments;
(e) using blink rates; and
(f) measuring tear film break up time with fluorescein instilled in the eye.

### Claim 20 (depends on 17)

The method of claim 17, wherein prolonging the stability of said tear film of said subject provides treatment for dry eye.

### Claim 21 (depends on 17)

The method of claim 17, wherein prolonging the stability of said tear film of said subject provides for one or more selected from the group consisting of: treatment of ophthalmic discomfort, prevention of infection, adhesion of bacteria, adhesion of viruses, adhesion of proteins, adhesion of toxins and adhesion of antigens.

### Claim 22 (depends on 17)

The method of claim 17, wherein said composition further comprises an active agent for treating ophthalmic disease.

### Claim 23 (depends on 22)

The method of claim 22, wherein said active agent is selected from the group consisting of an antibiotic, acetazolamide, antazoline, aspirin, atropine, azelastine, bacitracin, betaxolol, bimatoprost, a botanical drug, lutein, lycopene brimonodine, brinzolamide, carbachol, carteolol, ciprofloxacin, ofloxacin, cromalyn, cyclosporine, a cyclosporine pro-drug, a cyclosporine derivative, an immunomodulators, dapiprazole, dexamethasone, diclofenac, dipivifren, dorzolamide, epinephrine, erythromycin, fluoromethalone, flurbiprofen, gentamycin, a glaucoma medication, gramicidin, homatropine, hydrocortisone, hyoscine, keterolac, ibuprofen, ketotifen, latanaprost, levobunolol, levocabastine, levofloxin, lotepprednol, medrysone, methazolamide, metipranolol, naphazoline, natamycin, nedocromil, neomycin, neuroprotective agents, nonsteroidal anti-inflammatory agents, nepafanec, norfloxacin, ofloxacin olopatadine, oxymetazoline, pemirolast, pheniramine, phenylephrine, pilocarpine, povidone, prednisolone, proparacaine, scopolamine, tetracaine, steroids, sulfacetamide, tetrahydrozoline, hypertonic tears, timolal, tobramycin, travaprost, trifluridine, trimethiprim, tropicamide, unoprostone and zinc.

### Claim 24 (depends on 23)

The method of claim 23, wherein said antibiotic is selected from the group consisting of fluoroquinolones, vancomycin, cephalosporin, gentamycin, erythromycin, azithromycin, sulfa drugs, bacitracin, gatifloxacin, levofloxin, moxifloxacin and ofloxacin.

### Claim 25 (depends on 24)

The method of claim 24, wherein said glaucoma medication is selected from the group consisting of a prostaglandin, a carbonic anhydrase inhibitor, an epinephrine agonist, an alpha-agonist, and a beta-blocker.