Bi-functional co-polymer use for ophthalmic and other topical and local applications

• US 9,884,074 B2
• Filed: 03/14/2016
• Issued: 02/06/2018
• Est. Priority Date: 02/18/2009
• Status: Active Grant

• Current Assignee: CALM Water Therapeutics LLC
• Original Assignee: Eyeon Particle Sciences LLC
• Inventors: Cooper, Eugene Rex, Kleinman, David Maxwell, Loxley, Andrew, Mitchnick, Mark A.
• Primary Examiner(s): Basquill, Sean M
• Application Number:
  US15/069,188
• Publication Number:
  US 20160243156A1
• Time in Patent Office: 694 Days
• CPC Class Codes: A61K 31/045 Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61K 35/02 from inanimate materials carbon A61K33/44
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: 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
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/0043 Nose
• 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 9/0073 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
• 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: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: G02C 7/04 Contact lenses for the eyes disinfection or sterilisation of contact lenses A61L12/00

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

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) a positively charged backbone;

wherein the positively charged backbone is selected from the group consisting of poly(aminoethyl methacrylate) homo- and co-polymers containing N,N dimethylaminoethylmethacrylate repeat units, poly(trimethylammonioethyl methacrylate chloride), poly-(2-(dimethylamino) ethyl methacrylate) (pDMAEMA), poly-(2-(dimethylamino) ethyl methacrylateco-methacrylic acid) (pDMAEMA-co-MAA) and poly-(2-methyl-acrylic acid 2-[(2-dimethylamino-ethyl)-methylamino]-ethyl ester) (pDAMA), and cation guar gum, and

b) one or more hydrophilic water soluble side chains selected from the group consisting of polyethylene glycols, polysaccharides, poly(meth)acrylates, polyacrylamides, polyvinyl alcohol (PVA), polyethyloxazoline, poly-N-vinyl pyrrolidone (NVP) and poly boronic-based polymers,

in an amount and for a duration so as to prolong the stability of said tear film of said subject.

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

3. The method of claim 1, wherein said graft copolymer creates an electrolytic interaction between said graft copolymer and said ocular surface.

4. The method of claim 1, where said polyethylene glycols are selected from the group consisting of polyethylene glycol, polypropylene glycol, and mixtures thereof.

5. The method of claim 1, where said polysaccharides are selected from the group consisting of dextran, carboxylated cellulosics, carboxymethyl cellulose, natural gums, carageenan, alginates and hyaluronic acid and mixtures thereof.

6. The method of claim 1, where poly boronic based polymers are selected from polymers having boronic-based functional groups selected from the group consisting of:

a) phenylboronic acid (PBA), 2-carboxyethaneboronic acid, 1, 2-dicarboxyethaneboronic acid, β

β

′

-d carboxyethaneboronate, β

γ

-dicarboxypropaneboronate, 2-nitro- and 4-nitro-3-succinamidobenzene boronic acids, 3-nitro-4-(6-aminohexylamido)phenyl boronic acid, {4-[(hexamethylenetetramine) methyl]phenylboronic acid, 4-(N-methyl)carboxamidobenzene boronic acid, 2-{[(4-boronphenyl)methyl]-ethylammonio} ethyl and 2-{[(4-boronphenyl) methyl]diethylammoniol-ethyl groups, succinyl-3-aminophenylboronic add, 6-aminocaproy 1-3-aminophenylboronic acid, 3-(N succinimidoxycarbonyl) aminophenyl boronate, p-(.omega.-aminoethyl)phenylboronate, p-vinyl benzeneboronate, N-(3-dihydroxyborylphenyl)succinamic acid, N-(4-Mtro-3-dihydroxyborylphenyl)succinamic acid, O-dimethylaminomethylbenzeneboronic acid, 4-carboxybenzeneboronic acid, 4-(N-octyl)carboxamidobenzeneboronic acid, 3-nitro-4-carboxybenzeneboronic acid, 2-nitro-4-carboxybenzene boronic acid, 4-bromophenylboronate, p-vinylbenzene boronate, 4-(.omega.-aminoethyl)phenylboronate, catechol [2-(diethylamino)carbonyl, 4-bromomethyl]phenyl boronate, and 5-vinyl-2-dimethylaminomethylbenzeneboronic acid.

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

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

9. 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.

10. The method of claim 1, further comprising contacting topically to said ocular surface a second, different eye drop.

11. The method of claim 9, wherein said vasoconstrictor is selected from the group consisting of Ephedrine hydrochloride, Naphazoline hydrochloride, Phenylephrine hydrochloride and Tetrahydrozoline hydrochloride.

12. The method of claim 9, wherein said emollient is selected from the group consisting of Lanolin, mineral oil, paraffin, petrolatum, white ointment, white petrolatum, white wax and yellow wax.

13. 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.

14. 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 %.

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

16. The method of claim 1, wherein said composition further comprises an active agent for treating ophthalmic disease.

17. The method of claim 16, 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, ofoxacin, cromalyn, cyclosporine, a cyclosporine pro-drug, a cyclosporine derivative, an immunomodulator, 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, a neuroprotective agent, a nonsteroidal anti-inflammatory agent, 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.

18. The method of claim 17, wherein said antibiotic is selected from the group consisting of fluoroquinolones, vancomycin, cephalosporin, gentamycin, erythromycin, azithromycin, sulfa drugs, bacitracin, gatifloxacin, levofloxin, moxifloxacin and ofloxacin.

19. The method of claim 17, 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 betablocker.