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,

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- 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. hydrochloric acid. used according to the invention contains acid groups, 20 [0018] The ophthalmologically active agent is advan- and is typically a carboxy vinyl polymer, or hyaluronic tageously an antiglaucoma agent, a sympathomimetic acid. Typical representatives of carboxy vinyl polymers agent, a sympatholytic agent, such as a β-blocker, a car- are the polyacrylic acid polymers, known as carbomers. bonic anhydrase inhibitor, or an antibiotic, antiinflamma- Carbomers are available at different molecular weights, toric, antiallergic agent, etc., or a combination thereof. typically ranging from e.g. 450.000 to 4.000.000, and 25 Preferably an agent active against glaucoma or effective sold under the trade name Carbopol, e.g. Carbopol 907, in the treatment of increased intraocular pressure is 910, 934, 934P, 940, 941, 971, 971P, 974, 974P, 980, used. and 981, preferably Carbopol 941 and 981. [0019] As stated above, especially contemplated [0013] The polymer is preferably used in an amount within the scope of the invention is the use of an amine of 0.01 to 0.8, more preferably 0.01 to 0.4, and advan- 30 group containing pharmaceutically active agent. Thus tageously 0.04 to 0.4 % by weight. according to the invention, the eye drugs contemplated [0014] According to the invention it has been estab- may contain a primary, secondary or tertiary amino lished that it is favourable both from the view point of group or organoammonium or amidine attached to a efficacy of the product in the target site, and of ease of chain or a ring, or a nitrogen atom(s) can be a part in application, to reduce the viscosity of the composition 35 various basic heterocycles, such as imidazole, imidazo- to a level of less than 1000 mPas, suitably less than 500 line, pyridine, piperidine or piperazine. Preferably an mPas, when measured at 25 °C with a Brookfield LVDV- agent active against glaucoma or effective in the treat- III type viscometer at a shear rate D of 1.1 s-1. This ob- ment of increased intraocular pressure is used. A par- ject is achieved by adding to the composition a salt and/ ticularly preferred group of compounds is comprised of or a buffer in the specified amount, preferably in an 40 β -blocking agents having a secondary amine function amount of 0.01 to 1.5 % by weight. As viscosity decreas- such as betaxolol, carteolol, levobunolol, metipranolol, ing salts and buffers, i.a. the following may be men- pindolol, propranolol and timolol, as such or in the form tioned: sodium chloride, potassium chloride, sodium of their acid addition salts. An especially advantageous phosphates (monobasic and dibasic), sodium borate, mode of the invention is such where timolol is used as sodium acetate, and sodium citrate, as well as their 45 its easily crystallizable S-timolol maleate or hemihy- equivalents and mixtures thereof. In case no salts are drate. added, a formulation with an unacceptably high viscos- [0020] Other typical examples of basic drug mole- ity is obtained. - It is to be noted that the composition cules useful in eye therapy in the advantageous mode according to the invention still exhibits favourable non- of the invention include tobramycin and norfloxacin (an- newtonian properties when applied to the eye surface, 50 timicrobial, antibacterial), cyclopentolate, tropicamide, despite the addition of salts. atropine, phenylephrine, metaoxedrine (anticholinergic, [0015] For some purposes, for example for appear- mydriatic), pilocarpine, carbacol, ecothiopate (choliner- ance and storage purposes, the use of a buffering salt gic), adrenaline, dipivefrin, dopamine (adrenergic), nap- is preferred to the use of e.g. sodium or potassium chlo- hazoline, tetryzoline (vasoconstrictor), verapamil, nifed- ride as the viscosity reducing agent. 55 ipine (vasodilator), apraclonidine, clonidine, medetomi- [0016] In case the active agent contains basic groups, dine (α2-agonist), sezolamide (carbonic anhydrase in- such as amine groups, an additional beneficial effect is hibitor), cetirizine (antihistamine), as such or in their acid achieved when using polymers containing acid groups, addition, ester and prodrug forms.

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[0021] Especially contemplated in the invention is the solution may be adjusted, if necessary, by adding a base use of a β-blocking agent, such as S-timolol, as the only or an acid. Thereafter the composition is packaged in drug, or as combined with e.g. the base form of pilo- multi- or unit dose form. carpine. [0028] The following examples illustrate the invention [0022] The amount of active agent in the final compo- 5 in more detail, without limiting the same. sition may vary, such as between 0.001 to 5 % by weight, usually however between 0.01 to 0.5 % by weight, and EXAMPLE 1 typically between 0.1 and 0.5 % by weight, especially in the case of S-timolol. [0029] The following composition was made: [0023] According to an advantageous embodiment of 10 the invention, the composition contains in addition, in Composition (g) order to enhance the wetting effect thereof, a wetting S-Timolol hemihydrate 2.56 agent, preferably a polyhydric alcohol, such as glycerol. The amount of wetting agent is generally at the most 3.0 Carbopol 941 0.95 %, such as of the order of 0.5 to 3.0 % by weight. 15 Sodium phosphate monobasic 0.08 [0024] As preservatives, e.g. benzalkonium chloride, Sodium phosphate dibasic 1.80 benzyl alcohol, mercury salts, thiomersal, chlorhexidine Glycerol 23.0 or the like, as such or in combination. The amount of Benzalkonium chloride 0.06 preservative usually lies in the range of 0 to 0.02 % by Water for injection to 1000 mL weight. 20 [0025] A preferred composition according to the in- [0030] Carbopol 941 was dispersed in 300 mL sterile vention in the form of an aqueous solution consists es- water at room temperature. The solution was sterilized sentially of the following components (% being % by in an autoclave. The autoclaved solution was cooled to weight of the total composition): room temperature (solution 1). Benzalkonium chloride, 25 glycerol, sodium phosphate monobasic and dibasic and - timolol in the form of its maleate salt or hemihydrate timolol hemihydrate were dissolved in 700 mL sterile in an amount of 0.1 to 0.5 % by weight, calculated water at room temperature and sterilized by filtration on as the free base, a filter with a pore size of 0.2 µm (solution 2). In the final - polyacrylic acid in an amount of 0.04 to 0.4 % by step the solutions prepared in the two previous steps 30 weight (solution 1 and 2) were combined aseptically and mixed - glycerol in an amount of 0.5 to 2.5 % by weight until they formed a homogenous low viscous solution. - sodium phosphates in an amount of 0.01 to 1.5 % The pH of the solution obtained was 7.4 and its viscosity by weight, was 440 mPas (D = 1.1 s-1). Thereafter the solution was - a preservative in an amount of 0 to 0.02 %, packed in traditional eye drop bottles. 35 - water, and optionally [0031] The viscosity vs. shear rate curve for the com- - a pH-regulating agent to give the composition a pH position is shown in Figure 1. It is to be noted that the of 6.5 to 8.0, and wherein the viscosity of the solu- shape of the curve shows still non-newtonian rheology tion is less than 800 mPas. despite the addition of salts.

40 [0026] According to the invention, the term "consist- EXAMPLE 2 ing essentially of" is intended to mean that the composition contains only or essentially only the components [0032] The following composition was made: listed in connection therewith. The compositions may, however, in addition, contain ophthalmologically accept- Composition (g) able additives and adjuvants of such type and amounts 45 as to have no essential influence on the characteristics S-Timolol maleate 3.42 of the composition. Carbopol 941 2.00 [0027] The composition according to the invention is Sodium chloride 3.5 typically prepared in three stages. In the first step the Glycerol 15.0 polymer is dispersed in sterile water and sterilized by 50 Benzalkonium chloride 0.06 autoclaving. In the second step, the other ingredients, Sodium hydroxide q.s. ad pH 7.5 namely the active ingredient(s), inorganic salt(s), tonic- Water for injection to 1000 mL ity regulating agent(s), preservative(s) and any other additives, are dissolved in sterile water and sterilized by filtration on a filter (pore size e.g. 0.2 µm). In the third 55 [0033] The solution was prepared according to the and last step the solution prepared in the two steps are Example 1 except that the pH of the solution was ad- combined aseptically and mixed until they form a ho- justed to pH 7.5 by adding the sterile filtered sodium hy- mogenous solution with a low viscosity. The pH of the droxide solution. The viscosity of the solution was 430

4 7 EP 0 752 847 B1 8 mPas (D = 1.1 s-1). Example 1. The pH of the solution was adjusted to pH Viscosity vs. shear rate curve is shown in Figure 1. 7.2 with sodium hydroxide and the viscosity of the solution was 270 mPas (D = 1.1 s-1). EXAMPLE 3 5 EXAMPLE 6 [0034] The following composition was made: [0040] The following composition was made: Composition (g) Composition (g) S-Timolol hemihydrate 2.56 10 Carbopol 981 1.4 Clonidine (base) 1.25 Sodium phosphate monobasic 0.62 Carbopol 981 0.70 Sodium phosphate dibasic 2.85 Sodium phosphate monobasic 0.04 Glycerol 23.0 Sodium phosphate dibasic 0.6 Benzalkonium chloride 0.06 15 Glycerol 23.0 Water for injection to 1000 mL Benzalkonium chloride 0.06 Water for injection to 1000 mL [0035] The solution was prepared according to the Example 1. The pH of the solution obtained was 6.9 and [0041] The solution was prepared according to the 20 the viscosity of the solution was 70 mPas (D = 1.1 s-1). Example 1. The pH of the solution obtained was 7.0 and Viscosity vs. shear rate curve is shown in Figure 1. the viscosity was 540 mPas (D = 1.1 s-1).

EXAMPLE 4 EXAMPLE 7

25 [0036] The following composition was made: [0042] The following composition was made:

Composition (g) Composition (g) S-Timolol hemihydrate 1.02 Pilocarpine (base) 20.0 Carbopol 941 2.28 30 Carbopol 981 3.0 Sodium phosphate monobasic 1.55 Sodium phosphate monobasic 10.6 Sodium phosphate dibasic 7.10 Sodium phosphate dibasic 0.53 Glycerol 20.0 Glycerol 5.0 Sodium hydroxide q.s. ad pH 6.8 Benzalkonium chloride 0.10 35 Water for injection to 1000 mL Water for injection to 1000 mL

[0037] The solution was prepared according to the [0043] The solution was prepared according to the Example 1. The pH of the solution was adjusted to pH Example 1. The pH of the solution obtained was 6.8 and -1 6.8 with a sodium hydroxide solution. The viscosity of 40 the viscosity was 900 mPas (D = 1.1 s ). the solution was 590 mPas (D = 1.1 s-1). [0044] By leaving out from the formulations (Exam- ples 1-3, 5-7) the benzalkonium chloride, corresponding EXAMPLE 5 unit-dose formulations were obtained. [0045] By adding to the formulations (Example 4) ben- [0038] The following composition was made: 45 zalkonium chloride 0.06 mg/ml, a corresponding multi- dose-formulation was obtained. Composition (g) Absorption of timolol into the rabbit eye (Study 1) S-Timolol maleate 6.84 Carbopol 941 3.0 50 [0046] An ophthalmic formulation (Example 1), which Sodium phosphate monobasic 0.59 is a typical example of this invention, was instilled into Sodium phosphate dibasic 8.24 a rabbit eye (n = 6). The concentration of timolol in the Benzalkonium chloride 0.1 aqueous humor was measured after u and 1 hours us- Sodium hydroxide q.s. ad pH 7.2 ing HPLC. The reference product contained the same Water for injection to 1000 mL 55 amount of Carbopol, timolol and preservative, benzalkonium chloride, but did not contain any inorganic salt [0039] The solution was prepared according to the (s). The viscosity of the reference product was much higher (7300 mPas, D = 1.1 s-1).

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[0047] The timolol concentrations in the aqueous hu- the group consisting of antiglaucoma agents, sym- mor in rabbits are shown in Fig. 2. According to Fig. 2, pathomimetic agents, sympatholytic agents, such the absorption of timolol in rabbits eye was equal despite as β-blockers, carbonic anhydrase inhibitors, anti- the different viscosities. biotics, antiinflammatoric, antiallergic agents and 5 combinations thereof.

Claims 9. The composition of claim 8, wherein the pharmaceutically active agent is selected from the group 1. Ophthalmic composition in the form of a topical consisting of betaxolol, carteolol, levobunolol, meti- aqueous solution consisting essentially of 10 pranolol, pindolol, propranolol and timolol, as well as its mixture with pilocarpine, especially S-timolol, - an ophthalmologically active agent, preferably as its maleate or hemihydrate. - an ion sensitive, hydrophilic polymer in an amount of 0.004 to 1.5 % by weight, 10. The composition of claim 1, consisting essentially of - at least one salt selected from the group of in- 15 organic salts and buffers in a total amount of - timolol, especially S-timolol, in the form of its from 0.01 to 2.0 % by weight, maleate salt or its hemihydrate in an amount of - a wetting agent in an amount of 0 to 3.0 % by 0.1 to 0.5 % by weight, calculated as the free weight, base, - a preservative in an amount of 0 to 0.02 % by 20 - polyacrylic acid in an amount of 0.04 to 0.4 % weight, by weight - water, and optionally - glycerol in an amount of 0.5 to 2.5 % by weight - a pH regulating agent in an amount sufficient to - sodium phosphates in an amount of 0.01 to 1.5 give a pH of 4.0 to 8.0 to the composition, % by weight, 25 - a preservative in an amount of 0 to 0.02 %, the ratio between salt and polymer components be- - water, and ing such that the solution exhibits a viscosity of less - optionally a pH-regulating agent in an amount than 1000 mPas, when measured at 25°C with a sufficient to provide a pH of 6.5 to 8 of the com- Brookfield LVDV-III type viscosimeter at a shear position, and wherein the viscosity of the solu- rate of 1.1 s-1. 30 tion is less than 800 mPas, when measured at 25°C with a Brookfield LVDV-III type viscosim- 2. The composition of claim 1, wherein the polymer is eter at a shear rate of 1.1 s-1. present in an amount of from 0.01 to 0.8, preferably 0.01 to 0.4 and advantageously 0.04 to 0.4 % by 11. The composition of any preceding claim, the pH of weight and is selected from the group of carbomers. 35 the solution having been adjusted by the addition of a pH-regulating agent selected from the group con- 3. The composition of claim 1 or 2, wherein the wetting sisting of organic and inorganic bases and acids, agent is glycerol. especially to a pH of 6.5 to 8.0.

4. The composition of claim 3, wherein the amount of 40 12. The composition of claim 11, wherein the pH-regu- glycerol is 0.5 to 2.5 % by weight. lating agent is sodium hydroxide.

5. The composition of any preceding claim, wherein the salt is selected from the group consisting of so- Patentansprüche dium chloride, potassium chloride, sodium phos- 45 phates, sodium borate, sodium acetate, sodium ci- 1. Ophthalmische Zusammensetzung in der Form ei- trate, equivalents and mixtures thereof, and is ner topischen wäßrigen Lösung, bestehend im we- present preferably in an amount of 0.01 to 1.5 % by sentlichen aus weight. 50 - einem ophthalmisch wirksamen Mittel, 6. The composition of any preceding claim, wherein - einem ionensensitiven, hydrophilen Polymer in the viscosity is less than 800 mPas. einer Menge von 0,004 bis 1,5 Gew.-%, - zumindest einem Salz, ausgewählt aus der 7. The composition of any preceding claim, having a Gruppe anorganischer Salze und Puffern in ei- pH of 5.0 to 8.0, preferably 6.5 to 8.0. 55 ner Gesamtmenge von 0,01 bis 2,0 Gew.-%, - einem Netzmittel in einer Menge von 0 bis 3,0 8. The composition of any preceding claim, wherein Gew.-%, the ophthalmologically active agent is selected from - einem Konservierungsmittel in einer Menge

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von 0 bis 0,02 Gew.-%, wesentlichen aus - Wasser, und gegebenenfalls - einem den pH-Wert einstellenden Stoff in einer - Timolol, insbesondere S-Timolol, in der Form Menge, die ausreicht, der Zusammensetzung seines Maleatsalzes oder seines Hemihydrats einen pH-Wert von 4 bis 8 zu geben, 5 in einer Menge von 0,1 bis 0,5 Gew.-%, berech- wobei das Verhältnis zwischen Salz- und Poly- net als die freie Base, merkomponenten derart ist, dass die Lösung - einer Polyacrylsäure in einer Menge von 0,04 eine Viskosität von weniger als 1000 mPas, ge- bis 0,4 Gew.-%, messen bei 25°C mit einem Viskosimeter vom - Glycerin in einer Menge von 0,5 bis 2,5 Gew.- Typ Brookfield LVDV-III bei einer Scherge- 10 %, schwindigkeit von 1,1 s-1, aufweist. - Natriumphosphaten in einer Menge von 0,01 bis 1,5 Gew.-%, 2. Zusammensetzung nach Anspruch 1, in der das Po- - einem Konservierungsmittel in einer Menge lymer in einer Menge von 0,01 bis 0,8, vorzugswei- von 0 bis 0,02 %, se von 0,01 bis 0,4 and vorteilhaft von 0,04 bis 0,4 15 - Wasser, und Gew.-% vorliegt ist und aus der Gruppe von Carbo- - gegebenenfalls einem den pH-Wert regulieren- meren gewält ist. den Stoff in einer Menge, die ausreicht, der Zu- sammensetzung einen pH-Wert von 6,5 bis 8 3. Zusammensetzung nach Anspruch 1 oder 2, in der zu geben, das Netzmittel Glycerin ist. 20 und in der die Viskosität der Lösung weniger als 800 mPas, gemessen bei 25°C mit einem 4. Zusammensetzung nach Anspruch 3, in der die Viskosimeter vom Typ Brookfield LVDV-III bei Menge von Glycerin bei 0,5 bis 2,5 Gew.-% liegt. einer Schergeschwindigkeit von 1,1 s-1, be- trägt. 5. Zusammensetzung nach einem der vorherigen An- 25 sprüche, in der das Salz aus der Gruppe bestehend 11. Zusammensetzung nach einem der vorherigen An- aus Natriumchlorid, Kaliumchlorid, Natriumphos- sprüche, wobei der pH-Wert der Lösung durch Zu- phaten, Natriumborat, Natriumacetat, Natriumci- gabe eines den pH-Wert regulierenden Stoffes, der trat, deren Äquivalenten und Mischungen gewält aus der Gruppe bestehend aus organischen und ist, und vorzugsweise in einer Menge von 0,01 bis 30 anorganischen Basen und Säuren bewählt ist, ins- 1,5 Gew.-% vorliegt. besondere auf einen pH-Wert von 6,5 bis 8 einge- stellt worden ist. 6. Zusammensetzung nach einem der vorherigen An- sprüche, in der die Viskosität weniger als 800 mPas 12. Zusammensetzung nach Anspruch 11, in der der beträgt. 35 den pH-Wert regulierende Stoff Natriumhydroxid ist. 7. Zusammensetzung nach einem der vorherigen An- sprüche, die einen pH-Wert von 5 bis 8, vorzugsweise 6,5 bis 8, aufweist. Revendications 40 8. Zusammensetzung nach einem der vorherigen An- 1. Composition ophtalmique sous forme de solution sprüche, in der das ophthalmisch wirksame Mittel aqueuse à usage local comprenant essentiellement aus der Gruppe bestehend aus Mitteln gegen Glau- kom, sympathomimetischen Mitteln, sympatholyti- - un agent ophtalmologiquement actif, schen Mitteln wie β-Blockern, Carboanhydrase-In- 45 - un polymère hydrophile à sensibilité ionique en hibitoren, antibiotischen Mitteln, antiinflammatori- une quantité comprise entre 0,004 et 1,5 % en schen Mitteln, antiallergischen Mitteln und deren poids, Kombinationen gewählt ist. - au moins un sel sélectionné dans le groupe comprenant les sels et les tampons inorgani- 9. Zusammensetzung nach Anspruch 8, in der das 50 ques en une quantité totale comprise entre 0,01 pharmazeutisch wirksame Mittel aus der Gruppe et 2,0 % en poids, bestehend aus Betaxolol, Carteolol, Levobunolol, - un agent mouillant en une quantité comprise Metipranolol, Pindolol, Propranolol und Timolol, so- entre 0 et 3,0 % en poids, wie deren Mischungen mit Pilocarpin, insbesonde- - un conservateur en une quantité comprise en- re S-Timolol, vorzugsweise als dessen Maleat oder 55 tre 0 et 0,02 % en poids, Hemihydrat, gewählt ist. - de l'eau et, en option - un agent de contrôle du pH en une quantité suf- 10. Zusammensetzung nach Anspruch 1, bestehend im fisante pour donner un pH compris entre pH =

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4,0 et pH = 8,0 à la composition, la pilocarpine, notamment le S-timolol, de préféren- ce sous la forme de son maléate ou de son semi- la proportion entre les composants sel et po- hydrate. lymère étant telle que la solution présente une vis- cosité inférieure à 1000 mPas, lorsqu'elle est me- 5 10. Composition selon la revendication 1, comprenant surée à 25°C avec un viscosimètre de type Brook- essentiellement : field LVDV-III à un gradient de cisaillement de 1,1 s-1. - le timolol, notamment le S-timolol, sous la forme de son sel de maléate ou de son semi-hy- 2. Composition selon la revendication 1, dans laquelle 10 drate, en une quantité comprise entre 0,1 et 0,5 le polymère est présent en une quantité comprise % en poids, calculée comme la cocaïne épu- entre 0,01 et 0,8, de préférence entre 0,01 et 0,4 et rée, de manière profitable entre 0,04 et 0,4 % en poids, - l'acide polyacrylique, en une quantité comprise et est sélectionné dans le groupe des carboxypoly- entre 0,04 et 0,4 % en poids, méthylènes. 15 - le glycérol, en une quantité comprise entre 0,5 et 2,5 % en poids, 3. Composition selon la revendication 1 ou la reven- - les phosphates de sodium, en une quantité dication 2, dans laquelle l'agent mouillant est le gly- comprise entre 0,01 et 1,5 % en poids, cérol. - un conservateur, en une quantité comprise en- 20 tre 0 et 0,02 %, 4. Composition selon la revendication 3, dans laquelle - de l'eau, et la quantité de glycérol est comprise entre 0,5 et 2,5 - en option, un agent de contrôle du pH en une % en poids. quantité suffisante pour donner un pH compris entre pH = 6,5 et pH = 8,0 à la composition, et 5. Composition selon l'une quelconque des revendi- 25 cations précédentes, dans laquelle le sel est sélec- dans laquelle la viscosité de la solution est in- tionné dans le groupe comprenant le chlorure de férieure à 800 mPas, lorsqu'elle est mesurée à sodium, le chlorure de potassium, les phosphates 25°C avec un viscosimètre de type Brookfield de sodium, le borate de sodium, l'acétate de so- LVDV-III à un gradient de cisaillement de 1,1 s-1. dium, le citrate de sodium, des équivalents et des 30 mélanges de ceux-ci, et est de préférence présent 11. Composition selon l'une quelconque des revendi- en une quantité comprise entre 0,01 et 1,5 % en cations précédentes, le pH de la solution ayant été poids. ajusté, par addition d'un agent de contrôle du pH sélectionné dans le groupe comprenant les bases 6. Composition selon l'une quelconque des revendi- 35 et les acides organiques et inorganiques, en parti- cations précédentes, dans laquelle la viscosité est culier à un pH compris entre pH = 6,5 et pH = 8,0. inférieure à 800 mPas. 12. Composition selon la revendication 11, dans laquel- 7. Composition selon l'une quelconque des revendi- le l'agent de contrôle du pH est l'hydroxyde de so- cations précédentes, ayant un pH compris entre pH 40 dium. = 5,0 et pH = 8,0, de préférence entre pH = 6,5 et pH = 8,0.

8. Composition selon l'une quelconque des revendications précédentes, dans laquelle l'agent ophtal- 45 mologiquement actif est sélectionné dans le groupe comprenant les agents anti-glaucome, les agents sympathomimétiques, les agents sympatholyti- ques, par exemple des β-bloquants, des inhibiteurs de l'anhydrase carbonique, les antibiotiques, les 50 anti-inflammatoires, les agents antiallergiques et des combinaisons de ceux-Ci.

9. Composition selon la revendication 8, dans laquelle l'agent pharmaceutiquement actif est sélectionné 55 dans le groupe comprenant le bêtaxolol, le cartéo- lol, le lévobunolol, le métipranolol, le pindolol, le propanolol et le timolol, ainsi que son mélange avec

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