Ophthalmic Composition with Decreased Viscosity Ophtalmische Zubereitung Niedriger Viskosität Composition Ophtalmique a Viscosite Reduite

Europäisches Patentamt *EP000752847B1* (19) European Patent Office Office européen des brevets (11) EP 0 752 847 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61K 9/00, A61K 9/08, of the grant of the patent: A61K 47/34, A61K 47/36 11.07.2001 Bulletin 2001/28 (86) International application number: (21) Application number: 95914362.9 PCT/FI95/00166 (22) Date of filing: 29.03.1995 (87) International publication number: WO 95/26711 (12.10.1995 Gazette 1995/43) (54) OPHTHALMIC COMPOSITION WITH DECREASED VISCOSITY OPHTALMISCHE ZUBEREITUNG NIEDRIGER VISKOSITÄT COMPOSITION OPHTALMIQUE A VISCOSITE REDUITE (84) Designated Contracting States: • ALARANTA, Sakari AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT FIN-21120 Raisio (FI) SE • POHJALA, ESKO FIN-33720 Tampere (FI) (30) Priority: 31.03.1994 SE 9401108 (74) Representative: Grew, Eva Regina et al (43) Date of publication of application: Oy Jalo Ant-Wuorinen Ab 15.01.1997 Bulletin 1997/03 Iso Roobertinkatu 4-6-A 00120 Helsinki (FI) (73) Proprietor: Santen Pharmaceutical Co., Ltd Osaka 533-8651 (JP) (56) References cited: WO-A-91/19481 WO-A-93/00887 (72) Inventors: DE-C- 2 839 752 • REUNAMÄKI, Timo FIN-33820 Tampere (FI) • INTERNATIONAL JOURNAL OF • LEHMUSSAARI, Kari PHARMACEUTICA, Volume 81, 1992, FIN-33560 Tampere (FI) FLORENCE THERMES et al., "Bioadhesion: The • VARTIAINEN, Eija Effect of Polyacrylic Acid on the Ocular FIN-33710 Tmapere (FI) Bioavailability of Timolol", page 59 - page 65. • OKSALA, Olli FIN-33240 Tampere (FI) 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 a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 752 847 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 0 752 847 B1 2 Description sodium chloride from 0.001 to 0.5 % by weight is added in order to prevent the gel from breaking down on the BACKGROUND OF THE INVENTION surface of the eye (see column 4, lines 41 ff). [0001] The present invention relates to an ophthalmic 5 SUMMARY OF THE INVENTION composition in the form of a topical aqueous solution for human and veterinary use, as well as the use of the so- [0007] The present invention is based on the discov- lution, especially for the treatment of glaucoma and oc- ery that the beneficial effect of ophthalmic compositions ular hypertension. of the above type containing viscosity enhancing [0002] It is well known to use polymers alone or in 10 agents, is due to the concentration of the polymer combination with other polymers for the preparation of present in the composition, rather than on the viscosity ophthalmic pharmaceuticals and artificial tear composi- thereof. Thus the aim of the invention is to provide an tions. The inclusion of the polymer aims at increasing ophthalmic composition with a sufficiently high concen- the viscosity of the composition so as to provide for a tration of polymer to control the formation of the polymer longer contact time with the cornea of the eye, and, for 15 film on the cornea of the eye, but which composition is example, in connection with ophthalmic drugs, to pro- still fluid enough for ocular topical application. A further vide for a sustained release of the drug into the eye. object of the invention is to provide an easy-to-use eye [0003] For example, the US-patents 5,075,104 and drop formulation with improved patient compliance. 5,209,927 relate to an ophthalmic gel composition and [0008] According to the invention it has now been an ophthalmic liquid composition, respectively. The first 20 shown that by raising the concentration of the polymer mentioned composition includes 0.25 to 8 % by weight over a value where the composition normally is a gel of a carboxy vinyl polymer (polymer of carbomer type), rather than a liquid and by simultaneously lowering the the latter 0.05 to 0.25 % by weight, resulting in viscosi- viscosity thereof, it is possible to obtain a desired ben- ties of the compositions ranging from 15000 to 300000, eficial effect of the active agent in the eye, while simul- or 10 to 20000, respectively. 25 taneously reducing any discomfort in the patient's eye, [0004] In the publication WO 93/17664 high viscosity, as compared to the administration of a composition in polymer containing ophthalmic compositions are dis- gel form. The unbroken and even polymer film still being closed containing, in combination, carboxy vinyl poly- formed on the eye facilitates the binding and retaining mers of the carbomer type, and cellulosic polymers. Ac- of water on the surface of the eye, and thus provides for cording to this disclosure lower polymer concentrations 30 an additional wetting effect while providing for a better can be used while still achieving the desired higher vis- contact and thus a controlled absorption of active agent cosity. A wide range for the concentration of polymers into the eye. is given, the broadest range indicated being 0.05 to 3 % [0009] The present invention thus provides an oph- by weight of carbomer, and 0.05 to 5.0 % by weight of thalmological composition in a liquid, easy-to-use form cellulose polymer. A similar two-polymer system is de- 35 which contains a sufficient amount of polymer to provide scribed in the WO-publication WO 91/19481, the system for both an increased and prolonged absorption of active being such which gels when exposed to the pH and tem- agent into the eye. The invention thus makes it possible perature conditions of the eye surface. In the said pub- to treat e.g. glaucoma and ocular hypertension using a lication, an inclusion of up to 0.9 % of salt is contemplat- once-a-day-only or less frequent regimen for adminis- ed for the adjustment of the viscosity. 40 tering the ophthalmological active agent, and to lower [0005] There is also a number of publications relating the dosage clearly below the dosages presently in use. to pharmaceutically active ophthalmic compositions [0010] According to the invention we have shown that containing various polymers, i.a. carboxy vinyl poly- it is the amount of polymer in the composition, rather mers, at various concentrations. As tonicity regulating than the viscosity of the composition as such, which are agents, usually nonionic polyols are suggested so as not 45 improtant from the point of view of obtaining good ab- to interfere with the gel structure (WO 93/00887, WO sorption of drug into the eye. This is especially evident 90/13284). In the publication Int. J. Pharm. 81 (1992) from the tests described below. In the Fig. 2 it is shown, 59-65 aqueous compositions containing timolol maleate for example, that by using the same amount of polymer, and 0.6 % polyacrylic acid (MW 250,000), as well as the in compositions that have different viscosities, the com- salt of timolol base with 0.6 % polyacrylic acid are de- 50 positions provide for substantially the same absorption. scribed, containing mannitol as tonicity regulator. The According to the state of the art one would, however, viscosity measured at low shear rates is indicated as had expected the composition with the higher viscosity being 45 mPas. to provide for the higher absorption. [0006] In the DE-patent specification 28 39 752 oph- [0011] More specifically, the object of the invention is thalmic gel compositions are described containing car- 55 an ophthalmic composition in the form of a topical aque- boxy vinyl polymers in an amount of 0.05 to 5.0 % by ous solution consisting essentially of weight and exhibiting viscosities of 1000 to 100,000 mPas. According to this disclosure, a small amount of - an ophthalmologically active agent, 2 3 EP 0 752 847 B1 4 - an ion sensitive, hydrophilic polymer in an amount such as carboxy groups, due to the ion exchange reac- of 0.004 to 1.5 % by weight, tion or salt formation between the acidic polymer and - at least one salt selected from the group of inorganic the basic active agent. The increased retaining ionic salts and buffers in a total amount of from 0.01 to forces between the polymer and active agent thus pro- 2.0 % by weight, 5 vides for improved delivery of the active agent. Due to - a wetting agent in an amount of 0 to 3.0 % by weight, the fact that the basic drug is well retained by the poly- - a preservative in an amount of 0 to 0.02 % by mer, the dosage can be lowered and/or the daily number weight, of administration of the drug can be reduced, if desired, - water, and optionally without the loss of activity, and consequently the side - a pH regulating agent in an amount sufficient to give 10 effects can be reduced as well. a pH of 4.0 to 8.0 to the composition, [0017] The pH of the composition is suitably from 5.0 to 8, preferably from 6.5 to 8.0. When using a base as the ratio between salt and polymer components being the active agent, the pH of the composition can be reg- such that the solution exhibits a viscosity of less than ulated by the amounts used of acidic polymer and basic 1000 mPas. 15 active agent respectively. However, if necessary, the pH of the composition may be adjusted also by adding an DETAILED DESCRIPTION OF THE INVENTION additional base or an acid, as the case may be, such as an alkali metal hydroxide, especially sodium hydroxide, [0012] The ion-sensitive hydrophilic polymer to be or ammonium hydroxide, or e.g.

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