(19) TZZ Z_Z_¥_T (11) EP 2 010 143 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) A61K 47/18 (2006.01) 12.08.2015 Bulletin 2015/33 (86) International application number: (21) Application number: 07758669.1 PCT/US2007/064142 (22) Date of filing: 16.03.2007 (87) International publication number: WO 2007/109523 (27.09.2007 Gazette 2007/39) (54) STABILIZED OPHTHALMIC COMPOSITIONS COMPRISING OXIDATIVELY UNSTABLE COMPONENTS STABILISIERTE OPHTHALMISCHE ZUSAMMENSETZUNG MIT OXIDATIONSUNSTABILEN KOMPONENTEN PROCÉDÉS DE STABILISATION DE COMPOSITIONS INSTABLES DE MANIÈRE OXYDATIVE (84) Designated Contracting States: • MOLOCK, Frank DE FR GB IE IT Orange Park, FL 32003 (US) (30) Priority: 17.03.2006 US 783557 P (74) Representative: Tunstall, Christopher Stephen Carpmaels & Ransford LLP (43) Date of publication of application: One Southampton Row 07.01.2009 Bulletin 2009/02 London WC1B 5HA (GB) (73) Proprietor: Johnson & Johnson Vision Care, Inc. (56) References cited: Jacksonville, FL 32256 (US) EP-A- 1 172 098 EP-A- 1 769 834 WO-A-99/36055 US-A1- 2002 165 254 (72) Inventors: • MAHADEVAN, Shivkumar Orange Park, FL 32003 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 010 143 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 010 143 B1 Description [0001] Therapeutic agents for topical administration to the eye are generally formulated in either a liquid or gel form and must be kept sterile until administration. Accordingly, ophthalmic therapeutic agents are either packaged asceptically, 5 which is cumbersome and expensive or are heat sterilized. Unfortunately, many therapeutic agents are not oxidatively stable, especially at elevated temperatures. [0002] EDTA, Dequest, and Desferal have been used to improve the stability of certain therapeutic agents during autoclaving. However, there remains a need for other compounds capable of stabilizing unstable therapeutic agents that are susceptible to oxidative degradation. This need is met by the following invention. 10 BRIEF DESCRIPTION OF THE DRAWINGS [0003] 15 Fig. 1 Stability Study with Ketotifen and PAA or EDTA Fig. 2. Stability Study with Ketotifen and PAA or EDTA Fig. 3 Stability Study with Ketotifen and PAA or DTPA DETAILED DESCRIPTION OF THE INVENTION 20 [0004] This invention includes a method of stabilizing an ophthalmic composition comprising an oxidatively unstable pharmaceutical ingredient wherein said method comprises adding an effective amount of a stabilizing agent to the ophthalmic composition. [0005] As used herein "oxidatively unstable pharmaceutical ingredient" refers to pharmaceutical compounds used to 25 treat conditions of the eye, and such compounds degrade in the presence of oxygen and certain transition metals. [0006] The pharmaceutical compound are selected from the group consistintg of acrivastine, antazoline, astemizole, azatadine, azelastine, buclizine, bupivacaine, cetirizine, clemastine, cyclizine, cyproheptadine, ebastine, emedastine, ephedrine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotifen, levocabastine, levoceterizine, lomefloxacin, meclizine, mepivacaine, mequitazine, methdilazine, methapyrilene, mianserin, naphazolinepnorastemizole, norebastine, 30 ofloxacin, olopatadine oxymetazoline, pheniramine, phenylephrine, physostigmine, picumast, promethazine, scopo- lamine, terfenadine, tetrahydozoline, thiethylperazine, timolol, trimeprazine, triprolidine, pharmaceutically acceptable salts and mixtures thereof. Preferred pharmaceutical compounds include acrivatine, antazoline, astemizole, azatadine, azelastine, clemastine, cyproheptadine, ebastine, emedastine, eucatropine, fexofenadine, homatropine, hydroxyzine, ketotife, levocabastine, levoceterizine, meclizine, mequitazine, methdialazine, methapyrilene, norastemizole, norebas- 35 tine; oxymetazoline, physootigmine, picumast, promethazine, scopolamine, terfenadine, tetrahyerozoline, fimilol, trime- prazine, triprolidine, and pharmaceutically acceptable salts thereof. Particularly preferred pharmaceutical compounds include phenarimine, ketotifen, ketotifen fumarate nor ketotifen, olopatadine and mixtures thereof. More particularly preferred pharmaceutical compounds include ketotifen, its pharmaceutically acceptable salts, and mixtures thereof. [0007] Preferred pharmaceutical compounds are those that degrade when solutions of these compounds and oxidative 40 catalysts (such as metals and metallic salts) are mixed together at ambient or elevated temperatures, as compared to solutions of these compounds without oxidative catalysts at ambient or elevated temperatures. Particularly preferred pharmaceutical compounds are those that degrade greater than about 10% when heated to about 120°C for about 20 minutes with oxidative catalysts. The concentration of oxidatively unstable pharmaceutical ingredients in the ophthalmic compositions of the invention range from about 2 mg/mL to about 0.5 g/mL, particularly preferred, about 0.1 mg/mL to 45 about 10,000 mg/mL. [0008] The term "ophthalmic composition" refers to liquids, aerosols, or gels that may be topically administered to the eye. The term "stabilizing agent" refers to chelant compositions that inhibit metal catalyzed oxidative degradation of the oxidatively unstable pharmaceutical ingredient. [0009] The stabilizing agent is selected the group consisting of diethylenetriaminepentaacetic acid ("DTPA") and salts 50 of DTPA, such as CaNa3DTPA, ZnNa3DTPA, and Ca2DTPA. The term "effective amount" refers to the amount of stabilizing agent required to inhibit the oxidative degradation of the pharmaceutical ingredient. In most circumstances it is preferred that there is a 1:1 molar ratio of metal present in the ophthalmic composition to chelant, more preferably about 1 of metal to greater than about 1 of chelant compositions, most preferably about 1 of metal to greater than or equal to about 2 of chelant compositions. With respect to concentration limits, it is preferred that the stabilizing agents 55 have a concentration in the ophthalmic composition from about 2.5 mmoles/liter to about, 5000 mmoles/liter more pref- erably from about 20 mmoles/liter to about 1000 mmoles/liter, more preferably from about 100 mmoles/liter to about 1000 mmoles/liter, most preferably from about 100 mmoles/liter to about 500 mmoles/liter. [0010] Aside from the oxidatively unstable pharmaceutical ingredient and the stabilizing agent, the ophthalmic com- 2 EP 2 010 143 B1 position contains suitable ophthalmic carriers. Suitable carriers include antioxidants (radical scavengers), demulcents, antibacterial agents, solubilizers, surfactants, buffer agents, tonicity adjusting agents, chelating agents, preservatives, wetting agents, thickeners, water, saline solution, mineral oil, petroleum jelly, water soluble solvents, such as 15-20C alcohols, C15-20 amides, C15-20 alcohols substituted with zwitterions, vegetable oils or mineral oils comprising from 0.5 5 to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinyl-pyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example cellulose derivatives, such as methylcellulose, alkali metal salts of carboxy-methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropyl-cellulose, hydroxypropylcellulose, chitosan and scleroglucan, acrylates or methacrylates, such as salts of poly(acrylic acid) or ethyl acrylate, polyacrylamides, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, 10 carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products, such as poloxamers, e.g. Poloxamer F127, polyvinyl alcohol, polyvinylpyrrolidone, polyvlnyl methyl ether, polyethylene oxide, preferably cross-linked poly(acrylic acid), such as neutral Carbopol, or mixtures of those polymers. Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymeth- ylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, 15 neutral Carbopol, or mixtures thereof. The concentration of the carrier is, for example, from 0.1 to 100000 times the concentration of the active ingredient combinations thereof and the like. When the ophthalmic composition is an eye drop, preferred carriers include water, pH buffered saline solution and mixtures thereof. The preferred carrier is an aqueous saline solution containing salts including sodium chloride, sodium borate, sodium phosphate, sodium hydro- genphosphate, sodium dihydrogenphosphate, or the corresponding potassium salts of the same. These ingredients are 20 generally combined to form buffered solutions that include an acid and its conjugate base, so that addition of acids and bases cause only a relatively small change in pH. The buffered solutions may additionally include 2-(N-mor- pholino)ethanesulfonic acid (MES), sodium hydroxide, 2,2-bis(hydroxymethyl)-2,2’,2"-nitrilotriethanol, n-tris(hydroxyme- thyl)methyl-2-aminoethanesulfonic acid, citric acid, sodium citrate, sodium carbonate, sodium bicarbonate,