Celiprolol for the Treatment of Glaucoma

Patentamt 0 1 09 561 JEuropaischesEuropean Patent Office Publication number: B1 Office europeen des brevets

EUROPEAN PATENT SPECIFICATION

Date of publication of patent specification: 23.03.88 3) lnt.CI.4: A 61 K 31/17

Application number: 83110477.3

Date of filing: 20.10.83

Celiprolol for the treatment of glaucoma.

(D Priority: 27.10.82 US 437072 Proprietor: RORER INTERNATIONAL (OVERSEAS) INC. (§) Date of publication of application: 1209 Orange Street 30.05.84 Bulletin 84/22 Wilmington Delaware (US)

Publication of the of the (§) grant patent: Inventor: Peter S. 23.03.88 Bulletin 88/12 Wolf, Richard Somers Road Granite Springs New York (US) (§) Designated Contracting States: Inventor: Kesselman, Morris A. LU NL SE AT BE CH DE FR GB IT LI 21 Autumn Circle YonkersNewYork(US) (58) References cited: DE-A-2458 624 US-A-3 930 016 Representative: Patentanwalte Grunecker, US-A-4 034 009 Kinkeldey, Stockmair & Partner US-A-4038 313 Maximilianstrasse 58 US-A-4120 978 D-8000 Munchen 22 (DE) US-A-4178 374 "Glaucoma Update" Krieglstein et al.. Springer Verlag, N.Y. USA, 1979, pp. 19-23 References cited: CD Pecori-Giraldi et Chem. Abstr. 77: 775w (1972), Werner Blinisch Wochenschrift, 90: 350-354 al. (1978), Borrellietal. 95: 601-604, (1977), Arch. Ophthalmol. Pettner et al.: "Celiprocol A Cardioselective Zimmermann et al Ifl Beta-Receptor Blocking Agent, (UL/2006/1 11, Ophthalmologica, Babel, 184: 198-203 (1982), Chemie Linz AG Drug Division, 1982) Stempel O

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). LU Courier Press, Leamington Spa, England. 0 109 561

Description

This invention relates to an ophthalmic preparation for the treatment of glaucoma and a process of preparing said preparation. 5 Said preparation has been found useful in lowering intraocular pressure. Elevated intraocular pressure is a major risk factor in the onset and development of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optie nerve damage. Attempts have been made to lower intraocular pressure in glaucoma by administering the patients '0 certain beta adrenergic blocking agents, commonly known as beta blockers. In the human body, the beta blockers have several effects. For example, they can reduce the heart rate of an angina patient, which in turn reduces the workload of the heart and thus its need for blood and oxygen. They also tend to decrease the heart's force of concentration, which likewise diminishes the heart's workload. In addition, these drugs reduce the systolic blood pressure which is beneficial to patients with J5 hypertension. In addition to treating heart ailments, some beta blockers were experimented with for treating other ailments, such as migraine, alcohol and drug withdrawal problems, and glaucoma. While the use of beta blockers provides valuable benefits to humankind, it also has some undesirable side effects and reactions. Some beta blockers tend to build up in the central nervous system causing 20 fatigue, lethargy, and confusion. Others may cause bronchial spasm and cannot be used in people with bronchial asthma. Still others, while having minimal side effects, fail to produce acceptable results because of their limited potency. Timolol, a non-selective beta-adrenoceptor antagonist, has been shown to lower intraocular pressure in both patients with normal intraocular pressure and in patients with open angle glaucoma. Sold as 25 TIMOPTIC®, it is the only beta blocker sold in the U.S. for this purpose. Among the adverse reactions reported on the use of timolol is the aggravation or precipitation of certain cardiovascular and pulmonary disorders including bronchospastic disease, sinus bradycardia, cardiogenic shock and cardiac failure. Similarly, atenolol, sotalol, pindolol, oxprenolol, practolol, propranolol, butidrine and metoprolol were reported to have activity in the treatment of glaucoma. However, some of these compounds have been 30 reported to cause pronounced side-effects, for example, metoprolol provokes allergic reactions, oxprenolol may cause corneal epitheliopathy and practolol induces oculomucoculaneous syndrome by immunopathological reactions. Celiprolol hydrochloride has been shown a selective beta-1-adrenoceptor antagonist having intrisnic sympathomimetic, but no local anesthetic activity. DE — A — 24 58 624 discloses 4-ureido-2-acyl 35 phenoxypropylamin derivatives as cardio-selective beta blocking agents. The pharmaceutical composition disclosed having excipients or diluents may be administered orally, rectally or parenterally. The composition may be in the form of tablets, dragees or capsules, or it may be in the form of injectable solutions. It is the object of the present invention to provide an improved ophthalmic preparation for the 40 treatment of glaucoma. Said object is achieved by an opthalmic preparation for the treatment of glaucoma comprising an effective amount of celiprolol salt in a pharmaceutically acceptable ophthalmic carrier with the exception of intravenously injectable solutions. Celiprolol hydrochloride, as well as selected pharmaceutically acceptable salts thereof such as maleate, and succinate when topically applied to the eyes in a pharmaceutically suitable vehicle, such as an 45 ophthalmic solution, is effective in lowering intraocular pressure. Such ophthalmic preparation contain from 0.01% w/v to 5.0% w/v, preferably from 0.03% w/v to 2.0% w/v of the active ingredient along with inactive ingredients used in the art, such as sodium borate-boric acid, sodium hydroxide to adjust pH, benzalkonium chloride as preservative and water as the vehicle of preference. It has also been surprisingly discovered that celiprolol hydrochloride, when used according to the so present invention, produces bronchodilation following each application and as such possesses significant therapeutic advantage to patients suffering from both glaucoma and respiratory disease. The preferred celiprolol salt is coliprolol hydrochloride (3-[3-acetyl-4-[3(tertbutylamino)-2-hydroxy- propoxy]-phenyl]-1, 1-diethylurea hydrochloride) which has the following structure as the free base:

55 CHo I 3 CH3-C-NH-CH2-CH-CH2-O—OH� . HCI CH3 eo CHgCO

It has a molecular weight of 415.95 having C = 57.75%, H = 8.24%, N = 10.10%, O = 15.39% and Cl = 8.52%. 65 Celiprolol can be prepared according to several pathways described- in Austrian Patents 334 465, 0 109 561 as 335 464 and 335 467. The pathways for the preparation of celiprolol according to these patents are illustrated:

5 CH2-CH-CH2-O NH-CO-(C2H5)2 (CH3)2C-NH-CH2-CH-CH2-O OH CH3CO CH3C0 w n*'* (C2H5)2NCOCI is HO NH-CO-(C2H5)2 CHo ,C2H5 CH.CO CHo-C-NH-CH0-CH-CH,-0 NH-CO-N HCI 3 i 2 | d 20 C2H5 OH CH,CO o

25 (CH3)3C-NH-CH2-CH(OH)-CH2-CI (C2H5)2NH2 (C2H5)2NH2 30 (CH3)3C-NH-CH2-CH-CH2-O NH-CO-NH2

OH CH.CO 35 (CH3)3C-NH-CH2-CH-CH2-O— /QV—NH-COOAr

OH CHgCO 40 In accordance with the present invention ophthalmic preparations containing celiprolol hydrochloride incorporated in a suitable carrier is applied to the glaucomatous eyes to relieve intraocular pressure. It is to be understood that both the racemic a levorotatory forms of celiprolol hydrochloride are contemplated for 45 use in the present invention, as well as other pharmaceutically acceptable salts of celiprolol, such as maleate or succinate in the range of 0.01 to 5% w/v. The inactive carriers for the active compounds used in the formulations of the present invention include water and ointment bases, such as mineral oil in the range of 2 to 10% w/v and white petrolatum in the range of 90 to 98% w/v. In preparing the formulations of the present invention, the active compound is 50 solubilized in the carrier. For solubilizing the active compound a co-solvent, in addition to the carrier, may be used. Such co-solvents include glycerin, polyethylene glycol fatty acid esters in the range of 1 to 10% w/v, propylene glycol in the range of 1 to 10% w/v, polyethylene glycol in the range of 1 to 15% w/v, polysorbate 20,60 and 80 in the range of 0.01 to 0.2% w/v and Plun nic F— 68® in the range of 0.01 to 2% w/ v and mixtures thereof. 55 To prevent irritation to the eye the isotonicity of the preparation should be in the range of 270 to 330 milliosmoles. Sodium chloride in the range of 0.9 ± 0.1% w/v may be used, if necessary, to adjust the isotonicity. The ophthalmic preparations of the present invention will have a pH of about 6 to 9, preferably in the range of 7 — 8. Buffers that may be used to obtain said pH range include alkali metal or alkaline metal earth 60 carbonates, bicarbonates, borates, citrates and tris buffers. More specifically such buffers include 0.01 to 0.2 molar concentrations of boric acid-sodium borate, phosphate buffers, boric acid-sodium bicarbonate, boric acid-sodium citrate, citric acid-sodium phosphate, tris(hydroxymethyl) amino methane-maleic acid and tris(hydroxymethyl) amino methane-HCI. Other ingredients which may be desirable to use in the ophthalmic preparations of the present 65 invention include viscosity builder agents, preservatives and stabilizers. Examples of these, which may be 0 109 561 incorporated into the preparations during the process or after the active compound is solubilized, include the following: a. preservatives in the range of 0.001 to 1.0% w/v. b. stabilizers in the range of 0.01 to 5.0% w/v; and viscosity builders or viscosity agents in the range of 5 0.01 to 2.0% w/v. More specific examples include. Preservatives Range % w/v Benzalkonium Chloride 0.004—0.02 w Disodium Ethylenediamine Tetraacetate 0.01—0.20

Thimerosal 0.001—0.01

15 Chlorobutanol 0.5—1.0

Phenylmercuric nitrate 0.002—0.02

Phenylmercuric acetate 0.002—0.02 20 Methyl Paraben 0.03—0.20

Propyl Paraben 0.01—0.05

25 Phenylethyl aleohol 0.25—0.75

Phenyl mercuric borate 0.002—0.02

30 Stabilizers Range % w/v Sodium Bisulfite up to 0.5%

Sodium Thiosulfite up to 0.5% 35 Cysteine up to 3%

Acetyl cysteine up to 3%

40' B-cylcodextrin up to 3% Dextran up to 5%

Thiourea up to 3% 45 Thiosorbitol up to 3%

Monothioglyceryl disodium EDTA up to 3%

50 Dioctyl Sodium Sulfosuccinate up to 3%

65 0 109 561

Visrnsity Aqents Range % w/v Polyvinylpyrrolidone 0.05—2.0% alcohol 0.5—2.0% Polyvinyl . Methyl cellulose 0.1—1.0%

Hydroxypropyl Methylcellulose 0.10—1.0%

10 Hydroxyethyl cellulose 0.10—1.0%

Carboxymethyl cellulose 0.10—1.0%

Sodium Carboxymethyl cellulose 0.01—1.0% 15 Hydroxypropylcellulose 0.01—1 .0%

A preferred preparation comprises in % w/v: °-03 20 boric acid sodium borate 0-01 benzalkonium chloride . disodium ethylenediamine tetraacetate 0.1 25 sodium thiosulfite °-3

polyvinylpyrrolidone 1-5 °-1 30 hydroxyethyl cellulose polysorbate 80 °-01

35 water QS to 100, and having an isotonicity range of 270 to 330 milliosmoles. and manufactured as illustrated In general, the preparations of the present invention may be made in the ointment vehicle ^T, The active drug is dissolved in the aqueous vehicle or thoroughly dispersed bv adequate stirring: such, .. 40 b After dissolution or dispersion of the active drug additional ingredients, as preservatives, further Sodium buffer salts, stabilizers, and/or viscosity agents are added and dissolved by stirring. final volume; chloride is then added, if required, to adjust isotonicity, and the solution is brought to 0.22 membrane or alternatively autoclaved c, The product is then stereilized by filtration through a urn at 121— 123°C, or by a combination of both methods; 45 d., The sterile solution is filled into sterile containers and sealed. The following examples illustrate the present invention. EXAMPLE A 50 Celiprolol

Benzalkonium ChlorideQ.S.�

55 DiSodium EDTA Purified Water,

65 0 109 561

EXAMPLE B % w/v Celiprolol 0.50

Benzalkonium Chloride 0.01

DiSodium EDTA 0.10

Boric Acid 0.215 ro Sodium Borate, Q.S. to pH 7.4

Purified Water, Q.S. 100.00

EXAMPLE C % w/v 20 Celiprolol 0.125

Thimerosal 0.002

Tris (Trihydroxymethyl) amino methane 0.12

Maleic Acid, Q.S. to pH 8.3

Purified Water, Q.S 100-00 30

35 EXAMPLE D % w/v Celiprolol 1.00

Benzalkonium Chloride 0.01 40 Boric Acid 1.115

Sodium Borate, Q.S. to pH 7.4 1.4 45 Polyvinyl Alcohol Purified Water, Q.S. 100.00

EXAMPLE E % w/v " 3.00 55 Celiprolol Chlorobutanol 0.50

Boric Acid . 0.05 60 Sodium Thiosulfate 0.30

Sodium Bicarbonate, Q.S. to pH 7.0

Purified Q.S. 100.00 65 Water, 0 109 561

EXAMPLE F % w/v Celiprolol 5-00

Phenyl Mercuric Acetate °-02

Methyl Paraben °-05

Propyl Paraben °-01

10 Polyvinyl Pyrrolidone 2.00

Polysorbate 80 0.05

Purified Water, Q.S. 100.00 15

EXAMPLE G % w/v Celiproioi °-50 25 Benzalkonium Chloride 0-02

DiSodium EDTA 0.10

30 Boric Acid °-05

Sodium Borate, Q.S. to pH 6.0 " Polyvinyl Pyrrolidone 1-50 35 Hydroxyethyl Cellulose 0.20

Purified Water, Q.S. 100.00 40

45 EXAMPLE H % w/v Celiprolol °-50 50 Benzalkonium Chloride 0.005

DiSodium EDTA 0.05

Boric Acid °-215 55 Sodium Borate to adjust pH to 7.4

Polyethylene Glycol 300 5.0

60 Glycerin 1-0

Sodium Thiosulfate 0.5

Purified Water, Q.S 100.00 65 0 109 561

EXAMPLE I %w/v

Methyl Paraben 0.05

Propyl Paraben 0-01

Mineral Oil 5-°

White Petrolatum, Q.S. 100.00 10

EXAMPLE J % w/v 75 Celiprolol 0.5

Chlorobutanol 0.5

Polyethylene Glycol 400 4.0 20 White Petrolatum, Q.S. 100.00

25 Illustrative of the benefits obtained in accorance with the present invention the studies described in the Examples following, were conducted.

Example 1 This example shows that celiprolol decreases intraocular pressure in dogs and that the decrease is 30 dose-dependent.

Animals, Testing Procedure and Apparatus Mongrel dogs of either sex weighing between 9 and 16 kg were anesthetized with sodium pentobarbital, 35 mg/kg, i.v. (Ganes Chemical, Pennsville, N.J.). The animals then were intubated with an 35 endotracheal tube (Rusch, size 8— 9F, Artistic Surgical, New York, N.Y.) and allowed to breathe spontaneously. Pulsatile arterial pressure was monitored using a polyethylene catheter (PE 240, Clay-Adams, Parsippany, N.J.) inserted into the right femoral artery and its tip advanced until a distinct dicrotic notch was observed on the arterial pressure tracing. The catheter was connected to a pressure transducer (P23 ID, 40 Statham, Oxnard, CA) and a D.C. driver amplifier (Model 7D; Grass Instruments, Quincy, MA) via a low level D.C. preamplifier (Model 7P1, Grass Instruments). Mean arterial pressure was determined electronically by damping the pulsatile arterial pressure signal. Heart rate was recorded from the output of a tachometer (Model 7PA, Grass Instruments) triggered by the R wave of a Lead II electrocardiogram (EKG-Tachograph Preamplifier, Model 7P4, Grass Instruments). The outputs of arterial pressure and EKG-Tachometer 45 Preamplifier were recorded continuously on an oscillograph (Model 7D, Grass Instruments). Heart rate was measured manually from the tachometer output or calculated from the EKG preamplifier output. Mean arterial pressure was measured manually from the oscillograph tracings. Intraocular pressure was measured using a pneumatonometer (Model 30R, Digilab, Cambridge, MA). Upon completing of all surgical procedure the animals were allowed to stabilize for 15 — 30 minutes so before pretreatment baseline measurements were taken.

PROTOCOL Eight mongrel dogs were divided into two groups of four dogs each: the control group and the test 55 group. Two pretreatment baseline measurements of intraocular pressure, mean arterial pressure and heart rate were recorded at —15 and 0 minutes. The means values of these two readings were used as the pretreatment (0 times) values. The control group was then administered saline topically in a volume of 5ul instilled into the left eye of each dog at hourly intervals. The test group was administered celiprolol topically in a volume of 50ul instilled into the left eye of each dog, in ascending concentrations (0.03%, 60 0.06%, 0.125%, 0.5%), at hourly intervals. Intraocular pressure, mean arterial pressure and heart rate were recorded at 15 minute intervals for 60 minutes post drug or vehicle (saline) administration for each concentration of celiprolol administered and each administration of saline.

65 0 109 561

Laboratories, mSCeliprolol (RHC 5320— A Lot 2) was dissolved and diluted in normal saline (0.9%, Abbott North Chicago, IL). The control group received normal saline. 5 DataTheaabsolute for intraocular change and the percent change from the pretreatment (0 time) values S.D. The significance of the mean arterial pressure and heart rate were expresed as the mean ± pressure, evaluated t test difference between the vehicle control group and the celiprolol test group were using a Differences data (as described in SAS T TEST Release 79.5, SAS Institute, Gary, NC 1982). were w for qrouped for each considered significant if P < 0.05. In addition, the maximum percent intraocular pressure change concentration of celiprolol administered was expressed as the mean ± 1 S.D.

Result is Test results were shown in Tables I," II & III.

0 109 561 for Table I shows that celiprolol caused an immediate decrease in intraocular pressure which persisted different (P < 0.05) the duration of the experiment. The magnitude of the decrease became significantly dose-dependent from that of the control group at 75 minutes. The data also indicate that celiprolol causes a in intraocular which reaches a maximum at 0.25% concentration. decrease pressure which Table II shows that the celiprolol group exhibited a small decrease in mean arterial pressure 5 this decrease in became significantly different from that of the control at a concentration of 0.06%. Since and not pharmacologically arterial pressure was not dose-dependent, it may be a chance occurrence important. , , .. , Table III shows that celiproloi had no effect on heart rate at any of the concentrations tested. 10 Example II intraocular systemic This example compares the activity of celiprolol and timolol in dogs on pressure, arterial pressure and heart rate. is Animals, Testing Procedure and Apparatus Same as described in Example I.

Drug Preparation 'and 0.5% Merck Sharp and DrU9Celip'rololCeliprolol an saline were used as shown in Example I. Timolol (TIMOPTIC®, 20 Dohme, West Point,Poi PA) was used. PROTOCOL had intraocular Mongrel dogs were screened for intraocular pressure and only dogs that pressures between 3066 Pa(23 mm Hg) and 3732 Pa(28 mm Hg) were chosen in this study. three of Twelve mongrel dogs which met the above-described criterion were subdivided into groups 25 80 Pa(25.3 ± 0.6 mm Hg); the four dogs each. The control group had a mean intraocular pressure of 3373 ± ± 0.6 Hg); and the celiprolol, or test, group had a mean intraocular pressure of 3412 ± 80 Pa(25.6 mm had intraocular pressure of 3359 ± timolol group, with which the celiprolol group was compared, a mean 213 Pa(25.2 ± 1.6 mm Hg). and heart Two pretreatment baseline measurements of intraocular pressure, mean arterial pressure 30 of these two readings were rate were recorded at -15 and 0 minutes for each groups. The mean values then administered into the eft used pretreatment (0 time) values 0.5% celiprolol in a volume of 50ul was as administered into the left of each dog in the test or celiprolol group; 0.5% timolol in a volume of 50ul was left of each in the of each dog in the timolol group; and 50ul of saline was administered into the eye dog eye measurements were made at 35 control group. Intraocular pressure, mean arterial pressure and heart rate various intervals for five hours respectively for post drug or saline administration.

Date Analysis Same as in Example I. 40 eSUTest results shown in Tables IV, V and VI Table IV shows that at equal doses both celiprolol and are caused timolol were effective in decreasing intraocular pressure in anesthetized dogs. Celiprolol, however, which for the duration a significant change from control of the one hour post drug administration persisted the control after 180 minutes post 45 of the study, while timolol attained a significant difference from only of the drug administration, which from thereon also persisted for the duration experiment. Table V shows that neither celiprolol nor timolol had any significant effect on means arterial pressure. the first Table VI shows that celiprolol seems to have no effect on heart rate whereas timolol at least for two hours has a tendency to decrease heart rate. 50

0 109 561 In asthmatic patients airway constriction has been reported as the result of the use of certain p- blockers. The present invention, utilizing celiprolol, provides for the treatment of glaucoma without having the deleterious side effects of airway constriction associated with certain 3-blockers, such as atenolol, metoprolol, propanolol, and timolol. Example III describes the comparative study conducted on celiprolol in mechanically ventilated cats 5 with three other beta blocking agents for effects on bronchomotor tone infused with serotonin.

Example III METHOD .. w Male cats (3—5 kg) were anesthetized with pentobarbital sodium, 35 mg/kg i.p. Maintenance anesthetic was administered intravenously as needed. The trachea of each cat was cannulated and a pneumotacho- tracheal graph placed on-line for monitoring airflow. A differential pressure transducer placed between the cannula and a cannula in the pleural cavity was used to monitor transpulmonary pressure. Electronic signals proportional to air flow and transpulmonary pressure were converted by an on-line analog inserted into the 15 computer to values of pulmonary (airway) resistance, RAW, for each breath. Cannulae were blood right femoral artery and both femoral veins. The arterial cannula was used for monitoring pressure and heart rate. In addition, it allowed for withdrawal of arterial blood samples for assessment of PO2, PC02 and pH, as a means of confirming the adequacy of ventilation. The animal was paralyzed with gallamine triethiodide (Flaxedil, 20 mg i.v.) and mechanically ventilated. 20 In order to test for bronchodilator activity, it was necessary to increase the normally low bronchomotor 20 tone of the cat. This increase was induced by a constant i.v. infusion of serotonin (5-HT), approximately ug/kg/min. During this steady state bronchoconstriction, each animal received three or four increasing bolus doses of a single beta blocker, either atenolol (1—10 mg/kg/i.v.), celiprolol hydrochloride (1—10 mg/ kg i.v. or 1—100 mg/kg i.d.), metoprolol tartrate (1—10 mg/kg i.v.) or timolol maleate (0.03—3 mg/kg i.v.). 25 Doses are expressed as the free bases. All drugs were dissolved in 0.9% saline, except timolol, which was used in the form of Timoptic® ophthalmic solution suitably diluted with saline. In experiments in which of celiprolol was given introduodenally, needle-tipped cannulae were surgically inserted into the duodena cats fasted for 16 hours. Drug-induced changes in bronchomotor tone, averaged over 6-second intervals, were calculated as Mean ± standard 30 percent changes in RAW from the steady state values established by serotonin infusion. deviation were calculated for experiments in which n = 3. Data for one celiprolol dose, 10 mg/kg i.d., were calculated using n = 2. Statistical analysis was carried out with the t-test for paired data.

RESULTS • un u " ♦ 35 The results are shown in Table VII wherein RAW = % change in airway resistance; HR = heart rate — breaths/minute; i.v. = intravenous; i.d. = intraduodenal.

40 TABLE VII

Compound mg/kg i.v. HR RAW 45 Atenolol 1 -8 ± 5 23 ± 12 Atenolol 3 -6 ± 3 14 ±5 Atenolol 10 -6 ± 2 48 ± 34

50 Metoprolol 1 -17 ±11 50 ± 23 Metoprolol 3 -25 ± 19 43 ± 21 Metoprolol 10 -94 ± 86 105 ± 37

55 Timolol 0.3 -8 ± 8 11 ±9 Timolol 1 -8 ± 1 18 ± 51

Celiprolol 1 -1 ± 10 -62 ± 10 60 Celiprolol 3 -9 ± 4 -65 + 10 Celiprolol 10 -27 ±7 -70 ± 14

17 0 109 561

As shown in the table, intravenous administration of atenolol, metoprolol and timolol caused dose- dependent bronchoconstriction, i.e., increased RAW. Bronchoconstriction has increased to 48% with atenolol, to 105% with metoprolol and to 49% with timolol. In contrast, celiprolol produced bronchodilation, i.e., RAW decreased to -70%. 5 The duration of the broncodilator effect of celiprolol was about 14 minutes at 1 and 3 mg/kg. The effect of 10 mg/kg lasted for more than 40 minutes.

Example IV The procedure in this example generally follows the procedure used in Example III, except that the test JO compounds of celiprolol and timolol were administered topically as follows. 50 ul of test solution was instilled into the eyes of anesthetized cats whose airway resistance, RAW, had been increased by infusion of serotonin. Three doses of timolol (5 mg/ml) further increased RAW by 20 to 35%. Similar doses of celiprolol decreased RAW by 21 to 23%.

15 Example V This procedure in this sample generally follows the procedure used in Example III, except that celiprolol was administered to cats intraduodenally. Tested in the range_ of 10—100 mg/kg, celiprolol reduced RAW by 29 to 41 %.

20 Claims for the Contracting States: BE CH DE FR GB IT LI LU NL SE

1. An ophthalmic preparation for the treatment of glaucoma comprising an effective amount of a celiprolol salt in a pharmaceutically acceptable ophthalmic carrier with the exception of intravenously 25 injectable solutions. 2. The preparation of claim 1 characterised in that from 0.01 to 5.0% w/v of the celiprolol salt is present in said pharmaceutically acceptable carrier. 3. The preparation of claim 1 or 2 characterised in that from 0.03 to 0.5% w/v of the celiprolol salt is present in said pharmaceutically acceptable carrier. 30 4. The preparation of any of claims 1 to 3 characterised in that the celiprolol salt is celiprolol hydrochloride. 5. The preparation of any of claims 1 to 4 characterised in that said pharmaceutically acceptable carrier is a water base or an ointment base. 6. The preparation of any of claims 1 to 5 characterised in that it further comprises a buffer, a tonicity 35 agent, a preservatives a stabilizer, a co-solvent and a viscosity agent. 7. The preparation of any of claims 1 to 6 characterised in that the isotonicity of said preparation is within the range of 270 to 330 milliosmoles. 8. The preparation of any of claims 1 to 7 characterised in that the pH of said preparation is in the range of 6.0 to 9.0. 40 9. The preparation of any of claims 1 to 8 characterised in that jt comprises: a. 0.03 to 2.0 w/v celiprolol hydrochloride; b. a co-solvent selected from glycerin, propylene glycol, polyethylene glycol, polysorbates 20, 60 and 80 or Pluronic F-68; c. a viscosity agent selected from polyvinylpyrrolidone, polyvinyl alcohol, methyl cellulose, 45 hydroxypropyl methylcellulose, hydroxyethyl cellulose and carboxymethylcellulose; sodium carboxymethyl cellulose, or hydroxypropylcellulose; d. a stabilizer selected from sodium bisulfite, sodium thiosulfite, cysteine, acetyl cysteine, p- cyclodextrin, dextran and thiourea, thiosorbitol, morothioglycerol, sodium EDTA, or sodium sulfosuccinate; 50 e. a 0.01 to 0.20 molar buffer selected from boric acid-sodium borate, phosphate buffer, boric acid- sodium bicarbonate, boric acid-sodium citrate, citric acid-sodium phosphate, tris(hydroxymethyl) amino methane-maleic acid and tris(hydroxymethyl) amino methane-HCI; f. a preservative selected from benzalkonium chloride, disodium ethylenediamine tetraacetate, thimerosal, chlorobutanol, phenylmercuric nitrate, phenylmercuric acetate, methyl paraben, propyl 55 paraben, phenyl mercuric borate or phenylethyl alcohol; and g. water Q.S. to 100%. 10. The preparation of any of claims 1 to 8 characterised in that it comprises in % w/v: boric acid-sodium borate 0.03 benzalkonium chloride 0.01 60 disodium ethylenediamine tetraacetate 0.1 sodium thiosulfite 0.3 polyvinylpyrrolidone 1.5 hydroxyethyl cellulose 0.1 polysorbate 80 0.01 65 water QS to 100, and having an isotonicity range of 270 to 330 milliosmoles.

18 0 109 561

11 A of preparing the preparation of claims 1 to 10 characterised by: process acceptable a. dissolving or dispersing an effective amount of the celiprolol salt in a pharmaceutically carrier; b. adding buffer salts, stabilizers, viscosity agents and/or preservatives; chloride to the required isotonicity; 5 c. further optionally adding sodium to adjust d. adjusting to the final volume with purified water. further sterilized by 12. The process according to claim 11 characterised in that the preparation is filtration or autoclaved, or both. 13. Use of a celiprolol salt for the manufacture of a medicament for the treatment ot glaucoma. to Claims for the Contracting State: AT

1. A for preparing an ophthalmic preparation for the treatment of glaucoma comprising process carrier 15 formulating an effective amount of a celiprolol salt with a pharmaceutically acceptable ophthalmic with the exception of intravenously injectable solutions. salt is formulated 2. The process of claim 1 characterised in that from 0.01 to 5.0% w/v of the celiprolol with said pharmaceutically acceptable carrier. of the salt is 3. The process of claim 1 or 2 characterised in that from 0.03 to 0.5% w/v celiprolol 20 formulated with said pharmaceutically acceptable carrier. 4. The process of any of claims 1 to 3 characterised in that celiprolol salt as celiprolol hydrochlonde is used. carrier a 5. The process of any of claims 1 to 4 characterised in that as pharmaceutically acceptable water base or an ointment base is used. buffer, a 25 6. The process of any of claims 1 to 5 characterised in that it further comprises adding a tonicity agent, a preservative, a stabilizer, a co-solvent and a viscosity agent. said is adjusted 7. The process of any of claims 1 to 6 characterised in that the isotonicity of preparation to a range of 270 to 330 milliosmoles. to the 8. The process of any of claims 1 to 7 characterised in that the pH of said preparation is adjusted 30 range of 6.0 to 9.0. 9. The process of any of claims 1 to 8 characterised in that a. 0.03 to 2.0 w/v celiprolol hydrochloride; 60 and b. a co-solvent selected from glycerin, propylene glycol, polyethylene glycol, polysorbates 20, . 80 or Pluronic F-68; 35 c a viscosity agent selected from polyvinylpyrrolidone, polyvinyl alcohol, methyl cellulose, sodium hydroxypropyl methylcellulose, hydroxyethyl cellulose and carboxymethylcellulose; carboxymethyl cellulose, or hydroxypropylcellulose; d. a stabilizer selected from sodium bisulfite, sodium thiosulfite, cysteine, acetyl cysteine, (3- sodium cyclodextrin, dextran and thiourea, thiosorbitol, morothioglycerol, sodium EDTA, or 40 sulfosuccinate; . e. a 0.01 to 0.20 molar buffer selected from boric acid-sodium borate, phosphate buffer, boric acid- sodium bicarbonate, boric acid-sodium citrate, citric acid-sodium phosphate, tris(hydroxymethyl) amino methane-maleic acid and tris(hydroxymethyl) amino methane-HCI; f. a preservative selected from benzalkonium chloride, disodium ethylenediamme tetraacetate, 45 thimerosal, chlorobutanol, phenylmercuric nitrate, phenylmercuric acetate, methyl paraben, propyl paraben, phenyl mercuric borate or phenylethyl alcohol; and g. water Q.S. to 100% are formulated. 10. The process of any of claims 1 to 8 characterised in that in % w/v: boric acid-sodium borate 0.03 so benzalkonium chloride 0.01 disodium ethylenediamine tetraacetate 0.1 sodium thiosulfite 0.3 polyvinylpyrrolidone 1.5 hydroxyethyl cellulose 0.1 55 polysorbate 80 0.01 water QS to 100, and having an isotonicity range of 270 to 330 milliosmoles are formulated. 11. The process of any of claims 1 to 10 characterised by: a. dissolving or dispersing an effective amount of the celiprolol salt in a pharmaceutically acceptable carrier; 60 b. adding buffer salts, stabilizers, viscosity agents and/or preservatives; c. further optionally adding sodium chloride to adjust to the required isotonicity; d. adjusting to the final volume with purified water. is further 12. The process according to any of claims 1 to 11 characterised in that the preparation sterilized by filtration or autoclaved, or both. 65 13. Use of a celiprolol salt for the manufacture of a medicament for the treatment of glaucoma.

19 0 109 561 Patentanspruche fur die Vertragsstaaten: BE CH DE FR GB IT LI LU NL SE

1. Ophthalmologische Zubereitung zur Behandlung von Glaukom, umfassend eine wirksame Menge eines Celiprololsalzes in einem pharmazeutisch annehmbaren ophthalmoiogischen Trager mit Ausnahme 5 von intravenos injizierbaren Losungen. 2. Zubereitung nach Anspruch 1, dadurch gekennzeichnet, daft 0,01 bis 5,0% (Gewicht/Volumen) Celiprololsalz in dem pharmazeutisch annehmbaren Trager vorliegen. 3. Zubereitung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dalS 0,03 bis 0,5% (Gewicht/ Volumen) Celiprololsalz in dem pharmazeutisch annehmbaren Trager vorliegen. w 4. Zubereitung nach einem der Anspruche 1 bis 3, dadurch gekennzeichnet, dalS das Celiprololsalz Celiprololhydrochlorid ist. 5. Zubereitung nach einem der Anspruche 1 bis 4, dadurch gekennzeichnet, daft der pharmazeutisch annehmbare Trager eine Wassergrundlage oder eine Saibengrundlage ist. 6. Zubereitung nach einem der Anspruche 1 bis 5, dadurch gekennzeichnet, dafc sie weiterhin einen 15 Puffer, ein Tonizitatsmittel, ein Konservierungsmittel, einen Stabilisator, ein Colosungsmittel und ein Viskositatsmittel umfalSt. 7. Zubereitung nach einem der Anspruche 1 bis 6, dadurch gekennzeichnet, dalS die Isotonizitat der Zubereitung innerhalb des Bereichs von 270 bis 330 Milliosmol liegt. 8. Zubereitung nach einem der Anspruche 1 bis 7, dadurch gekennzeichnet, dalS der pH der 20 Zubereitung im Bereich von 6,0 bis 9,0 liegt. 9. Zubereitung nach einem der Anspruche 1 bis 8, dadurch gekennzeichnet, dalS sie umfalSt: a. 0,03 bis 2,0% (Gewicht/Volumen) Celiprololhydrochlorid; b. ein Colosungsmittel, gewahlt aus Glycerin, Propylenglykol, Polyethylenglykol, Polysorbat 20, 60 und 80 oder Pluronic F-68; 25 c. ein Viskositatsmittel, gewahlt aus Polyvinylpyrrolidon, Polyvinylalkohol, Methylcellulose, Hydroxypropylmethylcellulose, Hydroxyethylcellujose und Carboxymethylcellulose, Natriumcarboxymethylcellulose oder Hydroxypropylcellulose; d. einen Stabilisator, gewahlt aus Natriumbisulfit, Natriumthiosulfit, Cystein, Acetylcystein, (3- Cyclodextrin, Dextran und Thioharnstoff, Thiosorbitol, Morothioglycerol, Natrium EDTA oder Natrium- 30 sulfosuccinat; e. einen 0,01 bis 0,20 molaren Puffer, gewahlt aus Borsaure-Natriumborat, Phosphatpuffer, Borsaure- Natriumbicarbonate, Borsaure-Natriumcitrat, Citronensaure-Nastriumphosphat, Tris(hydroxymethyl)- aminomethan-Maleinsaure und Tris(hydroxymethyl)aminomethan-HCI; f. ein Konservierungsmittel, gewahlt aus Benzalkoniumchlorid, Dinatriumethylendiamintetraacetat, 35 Thimerosal, Chlorbutanol, Phenylquecksilber(ll)nitrat, Phenylquecksilber(ll)acetat, Methylparaben, Propylparaben, Phenylquecksilber(ll)borat oder Phenylethylalkohol, und g. Wasser Q.S. bis 100%. 10. Zubereitung nach einem. der Anspruche 1 bis 8, dadurch gekennzeichnet, daB sie in % (Gewicht/ Volumen) umfaSt: 40 Borsaure-Natriumborat 0,03 Benzalkoniumchlorid 0,01 Dinatriumethylendiamintetraacetat0,1 Natriumthiosulfit 0,3 Polyvinylpyrrolidon 1,5 45 Hydroxyethylcellulose 0,1 Polysorbat 80 0,01 Wasser QS bis 100, und einen Isotonizitats-Bereich von 270 bis 330 Milliosmol besitzt. 11. Verfahren zur Herstellung der Zubereitung nach den Anspriichen 1 bis 10, dadurch gekennzeichnet, daft so a. eine wirksame Menge des Celiprololsalzes in einem pharmazeutisch annehmbaren Trager gelost oder dispergiert wird, b. Puffersalze, Stabilisatoren, Viskositatsmittel und/oder Konservierungsmittel zugegeben werden, c. gegebenenfalls Natriumchlorid zur Einstellung der erforderlichen Isotonizitat zugegeben wird, d. mit gereinigtem Wasser auf das Endvolumen eingestellt wird. 55 12. Verfahren nach Anspruch 11, dadurch gekennzeichnet, dalS die Zubereitung weiterhin durch Filtration und/oder Autoklavenbehandlung sterilisiert wird. 13. Verwendung eines Celiprololsalzes zur Herstellung eines Medikaments zur Behandlung von Glaukom.

60 Patentanspruche fur den Vertragsstaat: AT

1. Verfahren zur Herstellung einer ophthalmoiogischen Zubereitung zur Behandlung von Glaukom, bei dem eine wirksame Menge eines Celiprololsalzes mit einem pharmazeutisch annehmbaren 65 ophthalmoiogischen Trager mit Ausnahme von intravenos injizierbaren Losungen formuliert wird.

20 0 109 561

2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daft 0,01 bis 5,0% (Gewicht/Volumen) des Celiprololsalzes mit dem pharmazeutisch annehmbaren Trager formuliert werden. 3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dafc 0,03 bis 0,5% (Gewicht/Volumen) des Celiprololsalzes mit dem pharmazeutisch annehmbaren Trager formuliert werden. daB als 5 4. Verfahren nach einem der Anspruche 1 bis 3, dadurch gekennzeichnet, Cehprololsalz Celiprololhydrochlorid verwendet wird. 5. Verfahren nach einem der Anspruche 1 bis 4, dadurch gekennzeichnet, dafc als pharmazeutisch annehmbarer Trager eine Wassergrundlage oder eine Salbengrundlage verwendet werden. 6. Verfahren nach einem der Anspruche 1 bis 5, dadurch gekennzeichnet, dalS es weiterhin die Zugabe Stabiiisators, eines jo eines Puffers, eines Tonizitatsmittels, eines Konservierungsmittels, eines Colosungsmittels und eines Viskositatsmittels umfaftt. 7. Verfahren nach einem der Anspruche 1 bis 6, dadurch gekennzeichnet, daS die Isotonizitat der Zubereitung auf einen Bereich von 270 bis 330 Milliosmol eingestellt wird. 8. Verfahren nach einem der Anspruche 1 bis 7, dadurch gekennzeichnet, dalS der pH der Zubereitung 15 auf einen Bereich von 6,0 bis 9,0 eingestellt wird. 9. Verfahren nach einem der Anspruche 1 bis 8, dadurch gekennzeichnet, daS a. 0,03 bis 2,0% (Gewicht/Volumen) Celiprololhydrochlorid; b. ein Colosungsmittel, gewahlt aus Glycerin, Propylenglykol, Polyethylenglykol, Polysorbat 20, 60 und 80 oder Pluronic F-68; 20 c. ein Viskositatsmittel, gewahlt aus Polyvinylpyrrolidon, Polyvinylalkohol, Methylcellulose, Hydroxypropylmethylcellulose, Hydroxyethylcellulose und Carboxymethylcellulose, Natriumcarboxymethylcellulose oder Hydroxypropylcellulose; d. ein Stabilisator, gewahlt aus Natriumbisulfit, Natriumthiosulfit, Cystein, Acetylcystein, (3- EDTA oder Natrium- Cyclodextrin, Dextran und Thiohamstoff, Thiosorbitol, Morothioglycerol, Natrium 25 sulfosuccinat; e. ein 0,01 bis 0,20 moiaren Puffer, gewahlt aus Borsaure-Natriumborat, Phosphatpuffer, Borsaure- Natriumbicarbonat, Borsaure-Natriumcitrat, Citronensaure-Natriumphosphat, Tris(hydroxymethyl)- aminomethan-Maleinsaure und Tris(hydroxymethyl)aminomethan-HCI; f. ein Konservierungsmittel, gewahlt aus Benzalkoniumchlorid, Dinatriumethylendiammtetraacetat, 30 Thimerosal, Chlorbutanol, Phenylquecksilber(ll)nitrat, Phenylquecksilber(ll)acetat, Methylparaben, Propylparaben, Phenylquecksilber(ll)borat oder Phenylethylalkohol, und g. Wasser Q.S. auf 100% formuliert werden. 10. Verfahren nach einem der Anspruche 1 bis 8, dadurch gekennzeichnet, dalS in % (Gewicht/ Volumen): 35 Borsaure-Natriumborat 0,03 Benzalkoniumchlorid 0,01 Dinatriumethylendiamintetraacetat0,1 Natriumthiosulfit 0,3 Polyvinylpyrrolidon 1,5 40 Hydroxyethylcellulose 0,1 Polysorbat 80 0,01 Wasser QS bis 100, mit einem Isotonizitats-Bereich von 270 bis 330 Milliosmol formuliert werden. 45 11. Verfahren nach einem der Anspruche 1 bis 10, dadurch gekennzeichnet, daS a. eine wirksame Menge des Celiprololsalzes in einem pharmazeutisch annehmbaren Trager gelost oder dispergiert werden; b. Puffersalze, Stabilisatoren, Viskositatsmittel und/oder Konservierungsmittel zugegeben werden, c. gegebenenfalis Natriumchlorid zugegeben wird, urn die benotigte Isotonizitat einzustellen; so d. mit gereinigtem Wasser auf das Endvolumen eingestellt wird. 12. Verfahren nach einem der Anspruche 1 bis 11, dadurch gekennzeichnet, dalS die Zubereitung weiterhin durch Filtration und/oder Autoklavenbehandlung sterilisiert wird. 13. Verwendung eines Celiprololsalzes zur Herstellung eines Medikaments zur Behandlung von Glaukom. ' 55

Revendications pour Ies Etats contractants: BE CH DE FR GB IT LI LU NL SE

1. Composition ophtalmique pour le traitement du glaucome, caracterisee par le fait qu'elle comprend acceptable, 6o une quantite efficace d'un sel de celiprolol dans un vehicule ophtalmique pharmaceutiquement a I'exception des solutions injectables par voie intraveineuse. 2. Composition selon la revendication 1, caracterisee par le fait que de 0,01 a 5,0% en poids/volume du sel de celiprolol est present dans le vehicule pharmaceutiquement acceptable. 3. Composition selon I'une des revendications 1 et 2, caracterisee par la fait que de 0,03 a 0,5% en acceptable. 6S55 poids/volumepoias/voiume duau selsei deae celiprololceuproiui estesi pieseiupresent uanodans le vehicule pharmaceutiquement

21 0 109 561

4. Composition selon I'une quelconque des revendications 1 a 3, caracterisee par le fait que le sel de celiprolol est le chlorhydrate de celipropol. 5. Composition selon I'une quelconque des revendications 1 a 4, caracterisee par le fait que le vehicule pharmaceutiquement acceptable est une base aqueuse ou une base d'onguent. 5 6. Composition selon I'une quelconque des revendications 1 a 5, caracterisee par le fait qu'elle comprend en outre un tampon, un agent de tonicite, un conservateur, un stabilisant, un cosolvant et un agent de viscosite. 7. Composition selon i'une quelconque des revendications 1 a 6, caracterisee par le fait que I'isotonie de cette composition est de la gamme de 270 a 330 milliosmoles. w 8. Composition selon I'une quelconque des revendications 1 a 7, caracterisee par le fait que le pH de cette composition est de la gamme de 6,0 a 9,0. 9. Composition seion I'une quelconque des revendications 1 a 8, caracterisee par le fait quelle comprend: a) 0,03 a 2,0% en poids/volume de chlorhydrate de celiprolol; is b) un cosolvant choisi entre le glycerol, le propyleneglycol, le polyethyleneglycol, les polysorbates 20, 60 et 80 ou le Pluronic F-68; c) un agent de viscosite choisi entre la polyvinylpyrrolidone, I'alcool polyvinylique, la methylcellulose, I'hydroxypropylmethylcellulose, I'hydroxyethylcellulose et la carboxymethylcellulose; la sodiumcarboxy- methylcellulose ou I'hydroxopropylceliulose; 20 d) un stabilisant choisi entreale bisulfite de sodium, le thiosulfite de sodium, la cysteine, I'acetylcysteine, la p-cyclodextrine, le dextrane et la thiouree, le thiosorbitol, le monothioglycerol, I'EDTA- sodium ou le sulfosuccinate de sodium; e) un tampon 0,01 a 0,20 M choisi entre I'acide borique-borate de sodium, le tampon phosphate, I'acide borique-bicarbonate de sodium, I'acide borique-citrate de sodium, I'acide citrique-phosphate de sodium, le 25 tris-(hydroxymethyl)-aminomethane-acide maleique et le tris-(hydroxymethyl)-aminomethane-HCI; f) un conservateur choisi entre le chlorure de benzalkonium, I'ethylenediaminetetracetate disodique, le thimerosal, le chlorobutanol, le nitrate phenylmercurique, I'acetate phenylmercurique, le methylparaben, le propylparaben, le borate phenylmercurique ou I'alcool phenylethyulique; et g) de I'eau, Q.S. pour 100%. 30 10. Composition selon I'une quelconque des revendications 1 a 8, caracterisee par le fait qu'elle comprend, en % en poids/volume: acide borique-borate de sodium 0,03 chlorure de benzalkonium 0,01 ethylenediaminetetraacetate disodique 0,1 _, 35 thiosulfite de sodium 0,3 polyvinylpyrrolidone 1,5 hydroxyethylcellulose 0,1 polysorbate 80 0,01 eau Q.S. pour 100 40 et qu'elle a une gamme d'isotonie de 270 a 330 milliosmoles. 11. Procede de preparation de la composition des revendications 1 a 10, caracterise par le fait: a) que I'on dissout ou que Ton disperse une quantite efficace du sel de celiprolol dans un vehicule pharmaceutiquement acceptable; 45 b) que I'on ajoute des sels tampons, des stabilisants, des agents de viscosite et/ou des conservateurs; c) qu'en outre, facultativement, on ajoute du chlorure de sodium pour ajuster a I'isotonie voulue; d) que I'on ajuste au volume final avec de I'eau purifiee. 1 2. Procede selon la revendication 1 1 , caracterise par le fait qu'en outre on sterilise la composition par filtration ou qu'on la passe a I'autoclave, ou les deux. so 13. Utilisation d'un sei de celiprolol pour la fabrication d'un medicament pour le traitement du glaucome.

Revendications pour I'Etat contractant: AT

55 1. Procede pour preparer une composition ophtalmique pour le traitement du glaucome, caracterise en ce qu'il consiste a associer une quantite efficace d'un sel de celiprolol a un vehicule ophtalmique pharmaceutiquement acceptable a I'exception des solutions injectables par voie intraveineuse. 2. Procede selon la revendication 1, caracterise par le fait que I'on associe de 0,01 a 5,0% en poids/ volume du sel de celiprolol au vehicule pharmaceutiquement acceptable. 60 3. Procede selon i'une des revendications 1 et 2, caracterise par le fait que I'on associe de 0,03 a 0,5% en poids/volume du sel de celiprolol au vehicule pharmaceutiquement acceptable. 4. Procede selon I'une quelconque des revendications 1 a 3, caracterise par le fait que comme sel de celiprolol, on utilise le chlorhydrate de celiprolol. 5. Procede selon I'une quelconque des revendications 1 ea 4, caracterise par le fait que comme 65 vehicule pharmaceutiquement acceptable on utilise une base aqueuse ou une base d'onguent.

22 0 109 561 consiste outre a 6 Procede selon I'une quelconque des revendications 1 a 5, caracterise en ce qu'il en cosolvant et un agent de ajouter un tampon, un agent de tonicite, un conservateur, un stabilisant, un VISC°SI I'on procede selon I'une quelconque des revendications 1 a 6, caracterise par le fait que ajuste I'isotonie de la composition a une gamme de 270 a 330 milliosmoles. 5 le fait I le pH 8. Procede selon I'une des quelconque revendications 1 a 7, caracterise par que on ajuste de la composition a la de 6,0 a 9,0. gamme fait I associe: 9. Procede selon I'une des quelconque revendications 1 a 8, caracterise par le que on a) 0,03 a 2,0% en poids/volume de chlorhydrate de celiprolol; les polysorbates 20, w b) un cosolvant choisi entre le glycerol, le propyleneglycol, le polyethyleneglycol, 60 80 le Pluronic F-68; et ou la methylcellulose,... c) de viscosite choisi entre la polyvinylpyrrolidone, I'alcool polyvmyhque, un agent la sodiumcarboxy- I'hydroxypropylmethylcellulose, I'hydroxyethylcellulose et la carboxymethylcellulose; methylcellulose ou I'hydroxopropylcellulose; th.osulfite de sodium, la cysteme, 15 d) un stabilisant choisi entre le bisulfite de sodium, le le monthioglycerol, I EDTA- I'acetylcysteine, la p-cyclodextrine, le dextrane et la thiouree, le thiosorbitol, le sulfosuccinate de sodium; sodium ou I acide 0,01 a 0,20 M choisi entre I'acide borique-borate de sodium, le tampon phosphate, e) un tampon de sodium, borique-bicarbonate de sodium, I'acide borique-citrate de sodium, I'acide citrique-phosphate 20 tris-(hydroxymethyl)-aminomethane-l'acide maleique et le tris-(hydroxymethyl)-aminomethane-HCI; choisi entre le chlorure de benzalkonium, I'ethylenediaminetetraacetate d.sodique, f) un conservateur le le thimerosal, le chlorobutanol, le nitrate phenylmercurique, I'acetate phenylmercunque, I'alcool et methylparaben, le propylparaben, le borate phenylmercurique ou phenylethyhque; q) de I'eau, Q.S. pour 100%. le fait, . I„ on associe, 25 10. Procede selon I'une quelconque des revendications 1 a 8, caractensee par que en % en poids/volume: acide borique-borate de sodium 0,03 chlorure de benzalkonium 0,01 ethylenediaminetetraacetate disodique 0,1 30 thiosulfite de sodium °-3 polyvinylpyrrolidone 1f5 hydroxyethylcellulose - 0*1 polysorbate 80 °-01 eau Q.S. pour 100%, d'isotonie de 270 a 330 milliosmoles. 35 et ayant une gamme le fait: 11 Procede selon I'une quelconque des revendications 1 a 10, caracterise par efficace du sel de celiprolol dans un vehicule a) que I'on dissout ou que Ton disperse une quantite pharmaceutiquement acceptable; viscosite.. , et/ou conservateurs,+QIiro- b) que I'on ajoute des sels tampons, stabilisants, agents de sodium ajuster a I isotonie voulue; 40 c) qu'en outre, on ajoute facultativement du chlorure de pour d) I'on ajuste au volume final avec de I'eau purifiee. que le fait en outre on 12 Procede selon I'une quelconque des revendications 1 a 11, caracterise par qu la filtration ou qu'on la passe a I'autoclave, ou les deux. sterilise composition par le traitement du 13. Utilisation d'un sel de celiprolol pour la fabrication d'un medicament pour 45 glaucome.