Ophthalmic formulation of a selective cyclooxygenase-2 inhibitory drug

• US 20020035264A1
• Filed: 07/12/2001
• Published: 03/21/2002
• Est. Priority Date: 07/13/2000
• Status: Abandoned Application

• Current Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Pharmacia & Upjohn Company (Pfizer Inc.)
• Inventors: Singh, Satish K., Kararli, Tugrul T., Bandyopadhyay, Rebanta, Hawley, Leslie C.
• Application Number:
  US09/904,098
• Publication Number:
  US 20020035264A1
• Time in Patent Office: Days
• US Class Current: 546/300
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/465 Nicotine; Derivatives thereof
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 : Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/26 : Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/32 : Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/38 : Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0048 : Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/145 : with organic compounds
• CPC Class Codes: A61K 9/5138 : obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5161 : Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/12 : for cataracts
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents

Abstract

There is provided a pharmaceutical composition suitable for topical administration to an eye which contains a selective COX-2 inhibitory drug or nanoparticles of a drug of low water solubility, in a concentration effective for treatment and/or prophylaxis of a disorder in the eye, and one or more ophthalmically acceptable excipients that reduce rate of removal from the eye such that the composition has an effective residence time of about 2 to about 24 hours. Also provided is a method of treating and/or preventing a disorder in an eye, the method comprising administering to the eye a composition of the invention.

Claims

1. A pharmaceutical composition suitable for topical administration to an eye, the composition comprising a selective COX-2 inhibitory drug or a salt or prodrug thereof in a concentration effective for treatment and/or prophylaxis of a COX-2 mediated disorder in the eye, and at least one ophthalmically acceptable excipient ingredient that reduce rate of removal of the composition from the eye by lacrimation such that the composition has an effective residence time in the eye of about 2 to about 24 hours.

2. The composition of claim 1 wherein the selective COX-2 inhibitory drug is of low water solubility.

3. The composition of claim 1 wherein the selective COX-2 inhibitory drug is a compound having the formula:

4. The composition of claim 3 wherein the five- to six-membered ring is a ring selected from the group consisting of:

cyclopentenone, furanone, methylpyrazole, isoxazole, and a pyridine ring substituted at no more than one position.

5. The composition of claim 1 wherein the selective COX-2 inhibitory drug is selected from the group consisting of:

celecoxib;

deracoxib;

valdecoxib;

rofecoxib;

etoricoxib;

2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one;

(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid; and

2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinone.

6. The composition of claim 1 that is in a form selected from the group consisting of:

solutions;

suspensions and solution/suspensions that are gellable in situ upon placement in the eye;

ointments; and

solid articles suitable for ocular implant.

7. The composition of claim 1 that is an in situ gellable solution, suspension or solution/suspension having ophthalmically compatible pH and osmolality.

8. The composition of claim 7 that comprises about 0.01% to about 50% weight/volume of the selective COX-2 inhibitory drug.

9. The composition of claim 7 that comprises about 0.1% to about 20% weight/volume of the selective COX-2 inhibitory drug.

10. The composition of claim 7 that is a suspension or solution/suspension wherein the selective COX-2 inhibitory drug is present predominantly as nanoparticles.

11. The composition of claim 10 wherein average particle size of the drug is about 500 to about 900 nm.

12. The composition of claim 7 that (a) comprises about 0.1% to about 6.5% by weight of one or more lightly cross-linked carboxyl-containing polymers, (b) has a pH of about 3 to about 6.5 and an initial viscosity, when administered to the eye, of about 1000 to about 30,000 cPs, and (c) gels on contact with tear fluid having a pH of about 7.2 to about 7.4.

13. The composition of claim 12 wherein the carboxyl-containing polymer is polycarbophil.

14. The composition of claim 7 that comprises about 0.1% to about 2% by weight of a polysaccharide that gels when it contacts an aqueous medium having the ionic strength of tear fluid.

15. The composition of claim 14 wherein the polysaccharide is gellan gum.

16. The composition of claim 7 that comprises about 0.2% to about 3% by weight of a polysaccharide that gels on contact with calcium ions, and about 1% to about 50% of a water-soluble film-forming polymer.

17. The composition of claim 16 wherein the polysaccharide is selected from gellan gum, alginate gum, xanthan gum and chitosan.

18. The composition of claim 7 that comprises an ophthalmically acceptable mucoadhesive polymer.

19. The composition of claim 7 that is a solution or solution/suspension wherein the selective COX-2 inhibitory drug is solubilized at least in part by an ophthalmically acceptable solubilizing agent.

20. The composition of claim 19 wherein the solubilizing agent is a cyclodextrin.

21. The composition of claim 19 wherein the solubilizing agent is polyethylene glycol.

22. The composition of claim 10 comprising from about 0.01% to about 50% by weight of valdecoxib, from about 0.05% to about 10% by weight of carrageenan, and from about 0.5% to about 20% by weight of hydroxypropyl β

-cyclodextrin.

24. The method of claim 23 wherein the mammalian subject is a human subject.

25. The method of claim 24 wherein the selective COX-2 inhibitory drug is a compound having the formula:

26. The method of claim 25 wherein the five- to six-membered ring is selected from the group consisting of:

cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at no more than one position.

27. The method of claim 24 wherein the selective COX-2 inhibitory drug is selected from the group consisting of:

celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib, 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid and 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinone.

28. The method of claim 24 that further comprises topical administration to the eye, in co-therapy, co-administration and/or co-formulation with the selective COX-2 inhibitory drug, a second drug.

29. The method of claim 28 wherein the second drug is selected from acebutolol, aceclidine, acetylsalicylic acid, N4 acetylsulfisoxazole, alclofenac, alprenolol, amfenac, amiloride, aminocaproic acid, p-aminoclonidine, aminozolamide, anisindione, apafant, atenolol, bacitracin, benoxaprofen, benoxinate, benzofenac, bepafant, betamethasone, betaxolol, bethanechol, bimatoprost, brimonidine, bromfenac, bromhexine, bucloxic acid, bupivacaine, butibufen, carbachol, carprofen, cephalexin, chloramphenicol, chlordiazepoxide, chlorprocaine, chlorpropamide, chlortetracycline, cicloprofen, cinmetacin, ciprofloxacin, clidanac, clindamycin, clonidine, clonixin, clopirac, cocaine, cromolyn, cyclopentolate, cyproheptadine, demecarium, dexamethasone, dibucaine, diclofenac, diflusinal, dipivefrin, dorzolamide, enoxacin, eperezolid, epinephrine, erythromycin, eserine, estradiol, ethacrynic acid, etidocaine, etodolac, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flufenamic acid, flufenisal, flunoxaprofen, fluorocinolone, fluorometholone, flurbiprofen and esters thereof, fluticasone propionate, furaprofen, furobufen, furofenac, furosemide, gancyclovir, gentamycin, gramicidin, hexylcaine, homatropine, hydrocortisone, ibufenac, ibuprofen and esters thereof, idoxuridine, indomethacin, indoprofen, interferons, isobutylmethylxanthine, isofluorophate, isoproterenol, isoxepac, ketoprofen, ketorolac, labetolol, lactorolac, latanoprost, levobunolol, lidocaine, linezolid, lonazolac, loteprednol, meclofenamate, medrysone, mefenamic acid, mepivacaine, metaproterenol, methanamine, methylprednisolone, metiazinic, metoprolol, metronidazole, minopafant, miroprofen, modipafant, nabumetome, nadolol, namoxyrate, naphazoline, naproxen and esters thereof, neomycin, nepafenac, nitroglycerin, norepinephrine, norfloxacin, nupafant, olfloxacin, olopatadine, oxaprozin, oxepinac, oxyphenbutazone, oxyprenolol, oxytetracycline, penicillins, perfloxacin, phenacetin, phenazopyridine, pheniramine, phenylbutazone, phenylephrine, phenylpropanolamine, phospholine, pilocarpine, pindolol, pirazolac, piroxicam, pirprofen, polymyxin, polymyxin B, prednisolone, prilocaine, probenecid, procaine, proparacaine, protizinic acid, rimexolone, salbutamol, scopolamine, sotalol, sulfacetamide, sulfanilic acid, sulindac, suprofen, tenoxicam, terbutaline, tetracaine, tetracycline, theophyllamine, timolol, tobramycin, tolmetin, travoprost, triamcinolone, trimethoprim, trospectomycin, isopropyl unoprostone, vancomycin, vidarabine, vitamin A, warfarin, zomepirac and pharmaceutically acceptable salts thereof.

30. The method of claim 28 wherein the second drug is a prostaglandin.

31. The method of claim 30 where iridial pigmentation after administration to an eye is reduced by comparison with treatment with the prostaglandin alone.

32. The method of claim 30 where the drugs are administrated as surgical adjunct therapy in connection with eye surgery.

33. The method of claim 30 wherein the prostaglandin is selected from latanoprost, bimatoprost travoprost and isopropyl unoprostone.

34. The method of claim 24 wherein the composition is an in situ gellable solution, suspension or solution/suspension having ophthalmically compatible pH and osmolality.

35. The method of claim 24 wherein the selective COX-2 inhibitory drug is present predominantly as nanoparticles.

36. The method of claim 35 wherein average particle size of the drug is about 500 to 900 nm.

38. The method of claim 23 wherein the drug is administered by electroosmosis, electroporation or by iontophoresis.

23. A method of treating and/or preventing a COX-2 mediated disorder in an eye of a mammalian subject, the method comprising administering in each of one or more topical applications to the eye a therapeutically or prophylactically effective amount of a composition comprising a selective COX-2 inhibitory drug or a salt or prodrug thereof and one or more ophthalmically acceptable excipient ingredients that reduce rate of removal of the composition from the eye by lacrimation such that the composition has an effective residence time in the eye of about 2 to about 24 hours.

37. A method of manufacturing a medicament for topically treating or preventing a COX-2 mediated disorder in an eye, comprising a step of utilizing a composition comprising a selective COX-2 inhibitory drug or a salt or prodrug thereof and one or more ophthalmically acceptable excipient ingredients that reduce rate of removal of the composition from the eye by lacrimation such that the composition has an effective residence time in the eye of about 2 to about 24 hours in the medicament.

39. A pharmaceutical composition suitable for topical administration to an eye, the composition comprising nanoparticles of a drug of low water solubility in a concentration effective for treatment and/or prophylaxis of a disorder in the eye, and one or more ophthalmically acceptable excipients that reduce rate of removal of the composition from the eye by lacrimation such that the composition has an effective residence time in the eye of about 2 to about 24 hours.

40. A method of treating and/or preventing a disorder in an eye of a mammalian subject, the method comprising administering in each of one or more topical applications to the eye a therapeutically or prophylactically effective amount of a composition comprising nanoparticles of a drug of low water solubility and one or more ophthalmically acceptable excipients that reduce rate of removal of the composition from the eye by lacrimation such that the composition has an effective residence time in the eye of about 2 to about 24 hours.