~™ llllllllllllllllllllllllllllll (19) J European Patent Office Office europeen des brevets (11) EP 0 673 250 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publicationation and mention (51 ) |nt. CI.6: A61 K 31 /55 of the grant of the patent: 20.10.1999 Bulletin 1999/42 (86) International application number: PCT/US93/11939 (21) Application number: 94903534.9 (87) International publication number: (22) Date of filing: 08.12.1993 WO 94/13299 (23.06.1994 Gazette 1994/14) (54) OPHTHALMIC COMPOSITIONS COMPRISING EMEDASTINE AND THEIR USE FOR TREATING ALLERGIC CONJUNCTIVITIS Ophtalmische Zusammensetzungen enthaltenden Emedastine und ihre Verwendungzur Behandlung von allergischer Konjunktivitis COMPOSITIONS OCULAIRES COMPORTANT DE L'EMEDASTINE ET UTILISATION DESDITES COMPOSITIONS POUR TRAITER LA CONJONCTIVITE ALLERGIQUE (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL EP-A- 0 079 545 EP-A- 0 440 811 PTSE US-A-5 192 780 (30) Priority: 09.12.1992 JP 32921692 ARZNEIM.-FORSCH. vol. 34, no. 7 , 1984 pages 816 - 818 T. FUKUDA ET AL. 'INFLUENCE OF 1- (43) Date of publication of application: (2-ETHOXY ETHYL)-2-(4-METHYL-1 - 27.09.1995 Bulletin 1995/39 HOMOPIPERAZINYL)BENZI MIDAZOLE DIFUMARATE (KB-2413), A NEW (73) Proprietor: ANTIALLERGIC, ON CILIARY MOVEMENT' ALCON LABORATORIES, INC. CHEMICAL & PHARMACEUTICAL BULLETIN Fort Worth Texas 76134-2099 (US) vol. 37, no. 4 , 1989 pages 967 - 972 R. IEMURA ET AL. 'QUANTITATIVE STRUCTURE-ACTIVITY (72) Inventors: RELATIONSHIPS OF H1- ANTIHISTAMINE • YANNI, John, M. BENZIMIDAZOLE DERIVATIVES' Burleson, TX 76028 (US) 'THE MERCK MANUAL' 1 987 MERCK SHARP & • ROBERTSON, Stella, M. , DOHME RESEARCH LABORATORIES , Arlington, TX 76016 (US) RAHWAY, N.J. see page 312 • OKUMURA, Shigetoshi JOURNAL OF OCULAR PHARMACOLOGY vol. 7, Nara-shi, Nara (JP) no. 4 , 1991 pages 313 - 324 G.J. BERDY ET AL. • TANAKA, Hitoshi 'ALLERGIC CONJUNCTIVITIS: A SURVEY OF Nara Kitakatsurigi-gun, (JP) NEW ANTIHISTAMINES' cited in the application • SAITO, Tadayuki J. MED. CHEM. vol. 29 1986 pages 1178-1183 Osaka , Miyakojima-ku, (JP) R. IEMURA ET AL. 'SYNTHESIS OF 2-(4-SUBSTI TUTED-1 -PIPERAZINYL)BENZIMIDAZOLES AS (74) Representative: H1 -ANTIHISTAMINE AGENTS' Lerwill, John et al A.A. Thornton & Co. Northumberland House 303-306 High Holborn London, WC1V7LE(GB) CO o 10 CM CO Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in o a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. Q_ 99(1) European Patent Convention). LU Printed by Xerox (UK) Business Services 2.16.7/3.6 EP 0 673 250 B1 Description Background of the Invention 5 [0001 ] The present invention relates to the field of ophthalmics, particularly the topical treatment of allergic conjunc- tivitis and related ailments. Most particularly, the present invention relates to ophthalmic compositions comprising 1 -(2- ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole, otherwise known as emedastine, and its ophthalmically acceptable acid addition salts and methods for their use. [0002] Allergic conjunctivitis is frequently characterized by ocular pruritus (itching), erythema (inflammatory redness), 10 edema and tearing. This condition is one of the most frequently treated by ophthalmologists, optometrists and allergists. To date, treatment has been primarily through the use of topically applied histamine Hi antagonists in combination with a-agonists. See, for example, the following articles: 1 . Miller, J. and E.H. Wolf, "Antazoline phosphate and naphazoline hydrochloride, singly and in combination for the 15 treatment of allergic conjunctivitis - a controlled, double-blind clinical trial." Ann. Allergy. 35:81-86 (1975). 2. Vandewalker, M.L. et al., "Efficacy of Vasocon-A and its components with conjunctival provocation testing (CPT)." J. Allergy Clin. Immunol.. 83:302 (1989). 3. Abelson, M.B. et al., "Effects of topically applied ocular decongestant and antihistamine." Am. J. Ophthalmol.. 90:254-257(1980). 20 [0003] Recent studies indicate that the antihistamine levocabastine exhibits clinical activity in patients with allergic conjunctivitis without the addition of a vasoconstrictor. See, Dechant, K.L. and K.L. Goa, "Levocabastine. A review of its pharmacological properties and therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis." Drugs. 41:202-224 (1991). In addition, it has recently been demonstrated that Hi antagonists are effective in relieving 25 conjunctival injection (hyperemia) and erythema, as well as pruritus. See, Berdy, G.J. et al., "Allergic conjunctivitis: A survey of new antihistamines." J. Ocular Pharmacol.. 7:313-324 (1991). [0004] Although there are many different antihistamines available for systemic treatment of allergies and related ail- ments, many such antihistamines are not suitable for topical ophthalmic use because of limited ocular bioavailability. For example, terfenadine (Seldane®, made by Marion Merrell Dow), astemizole (Hismanal®, made by Janssen Phar- 30 maceutica) and loratadine (Claritin®, made by Schering) all have good systemic activity; however, terfenadine has little or no local ocular activity, and astemizole and loratadine each have greatly reduced local ocular activity (as compared to its systemic activity). A need therefore exists for an antihistamine having good local ocular activity and having minimal side effects. 35 Summary of the Invention [0005] It has now been unexpectedly discovered that topical ophthalmic compositions comprising 1 -(2-ethoxyethyl)- 2-(4-methyl-1-homopiperazinyl)-benzimidazole and its ophthalmically acceptable add addition salts are useful in treat- ing allergic conjunctivitis and related ailments. In particular, the components of the present invention have good local 40 activity, with quick onset of action and fairly long duration of action. Detailed Description of the Invention [0006] 45 50 55 [0007] 1 -(2-Ethoxyethyl)-2-(4-methyl-1 -homopiperazinyl)-benzimidazole, otherwise known as emedastine, is pictured above and is disclosed and claimed in US Patent No. 4,430,343 (lemura et al.), along with numerous other benzimida- zole derivatives, lemura et al. disclose the use of this class of compounds as anti-allergics and antihistamines, but do 2 EP 0 673 250 B1 not disclose the ophthalmic use of these types of compounds. US Patent No. 5,192,780 (York et al.) discloses the use of combinations of antiallergics and antihistamines to prevent and treat ophthalmic allergic responses. Arzneim.-For- sch./Drug Res. 34 (II), No 7 (1984), 816-818 (Fukuda et al.) discloses a test in which a solution of emedastine is admin- istered into the conjunctival sac of guinea pigs; the solutions are, however, not described as compositions for 5 Therapeutical treatment. [0008] The compounds useful in the present invention include emedastine and its ophthalmically acceptable acid addition salts. Ophthalmically acceptable acid addition salts include salts of organic or inorganic adds, such as maleic acid, fumaric acid, hydrochloric acid or sulfuric acid. These salts may be formed conventionally. It is preferred to use the difumarate salt of emedastine. 10 [0009] In forming compositions for topical administration, the compounds of the present invention are generally for- mulated as between about 0.0001 and about 1 .0 percent by weight (wt%) solutions in water at a pH between about 6 and about 8. The compounds are preferably formulated as between about 0.005 and about 0.2 wt% and, most prefer- ably, between about 0.05 and about 0.2 wt%. While the precise regimen is left to the discretion of the clinician, it is rec- ommended that the resulting compositions be topically applied by placing one or more drops in each eye one or more 15 times a day. [0010] The compositions of the present invention may be prepared by combining one or more of the compounds of the present invention with a suitable vehicle to form a solution, dispersion or gel. The compositions of the present inven- tion may also include one or more ingredients conventionally found in ophthalmic formulations, such as preservatives (e.g., benzalkonium chloride orthimerosal), viscosity-imparting agents (e.g., polyvinyl alcohol or hydroxypropyl methyl- 20 cellulose) and tonicity agents (e.g., sodium chloride or mannitol). The compositions will typically also include buffering agents to maintain the pH within physiological pH (between 6 and 8); however, it has been found that citrate, acetate and phosphate buffers are not compatible with the compounds of the present invention, as these buffering agents, par- ticularly phosphate buffers, compromise the stability and solubility of the compounds. It is therefore preferred to use Tris (tri(hydroxymethyl)aminomethane) as a buffering agent in the compositions of the present invention. Hydrochloric add 25 or sodium hydroxide will normally be used to adjust the pH of the resultant compositions. EXAMPLE 1 [001 1 ] The following examples are typical compositions of the present invention. These formulations may be prepared 30 in accordance with procedures known to those skilled in the art. INGREDIENT FORMULATION A FORMULATION B FORMULATION C 35 (wt%) (wt%) (wt%) Emedastine Difumarate 0.177 0.0884 0.884 Benzalkonium Chloride 0.01 0.01 0.01 Disodium EDTA 0.01 0.01 0.01 40 Tris(hydroxymethyl)aminomethane