DE3102593A1 - Pharmaceutical composition for use on the eye - Google Patents

Abstract

The invention relates to a pharmaceutical composition for use on the eye in the form of solution, lyophilisate, suspension, ointment, gel or insert for the treatment of increased intraocular pressure, e.g. associated with aqueous blockage or glaucoma, it containing sotalol as base or salt in a concentration of 0.1 to 2 % at a pH of 7.0 to 10.0.

Description

description

For more than 10 years, the therapeutic principle "BlocRade adrenergic β-receptors "in the field of the treatment of cardiovascular diseases successfully enforced.

About the pharmacological effect and the side effects of the class the so-called beta blockers, which are mainly used perorally in angina pectoris and are used in hypertension, details can be found in a review article in the journal "Der Arzneimittelbrief", 12-, 9 (1978) can be taken.

During one of the first beta blockers, Practolol, because of harmful Side effects, including on the eye, were taken off the market again found that some other beta blockers did not do this when applied locally to the eye glaucoma associated with hypertension (water congestion in the eye that leads to increased pressure in the eye leads) to influence favorably. The principle of action for this is an improvement of the aqueous humor outflow assumed by influencing the ciliary muscle. In a more recent publication (Bonomi c.s., Albrecht von Graefes Arch. klin. exp. Ophthal. 210, 1-8, 1979) the authors report that all nine of them tested Beta blockers when applied locally to rabbits' eyes increased those previously experimentally Were able to lower intraocular pressure.

The most impressive results with regard to the extent and duration of the pressure reduction were achieved with the beta blockers timolol and sotalol 4 '- (1-hydroxy-2-isopropylaminoethyl) methanesulfonanilide (IUP, WHO) sotalolum (NFN) as hydrochloride: sotalol hydrochloride (USAN) C12H20N203S It was already known in 1979 that excessive intraocular pressure can be reduced by the local application of timolol. At this point in time, eye drops containing timolol were already in use in the ophthalmological clinic and practice (in the Federal Republic of Germany on the market under the trademark Chibro-Timoptol eye drops 0.25% and 0.5%).

At the time, some authors spoke of a "turning point in glaucoma therapy", because timolol, thanks to its more highly unknown mechanism of action, the pupil diameter of the human eye and thus the eyesight is not affected. Traditional ones local glaucoma therapeutics such as adrenaline (side effect pupillary dilation) and pilocarpine (Side effect of pupillary constriction) seemed to be out of date. Recently, however Experts are increasingly warning against the local use of timolol, because with the local application a more or less large percentage of the active ingredient passes into the organism and there unpleasant, sometimes even dangerous side effects can trigger.

There is therefore a reasonable medical interest in the replacement of the not harmless timolol with another beta blocker for local glaucoma therapy. When applied locally to the eye, this substance should be the therapeutically desired one Have properties of timolol without negatively affecting the rest of the organism influence. According to the studies by Bonomi cited at the beginning, Sotalol appeared an alternative to timolol has been found to be.

Review of the pharmacological data of Sotalol showed that This medicinal substance only has clear effects in the organism at an eight-fold higher dose (and side effects) unfolded. While timolol in internal medicine in general is used with daily doses of 15 to 45 mg (Mittelwelt 30 mg) is the Usual daily dose for Sotalol 160 to 320 mg (mean value 240 mg) with peroral Supply. Sotalol is used (.150 orally at an eight-fold higher dose than Timolol. Since Bonorr.i c.s. locally on the eye for timolol and sotalol for the same concentrations (Amounts of active ingredient) have established about the same effectiveness, the organism will when using eye drops containing timolol or sotalol via the lacrimal nasal canal loaded with the same amounts of active ingredients in both cases. However, as above stated, Sotalol only works systemically in eight times higher concentrations this substance is the ideal beta blocker for local glaucoma therapy; sche.dliche Side effects on the organism cannot occur.

The subject of the invention is therefore a drug preparation for Use on the eye in the form of a solution, lyophilisate, suspension, ointment, gel or insert for the treatment of the increased intraocular pressure (water congestion, glaucoma) that this causes is characterized in that it sotalol as a base or salt at a pH of 7.0 to 10.0, preferably 7.8 to 9.2, in particular 8.5 to 9.0.

The preferred salt is sotalol as it is ophthalmologically acceptable Salt, such as sotalol hydrochloride, citrate, maleate, borate, tartrate, pamoate or phosphate is used in a concentration of 0.1 to 2%, in particular 0.25 to 1%.

It is also preferred that the drug adjusted to pH 7-10 in addition to sotalol base or a sotalol salt, it contains pharmaceutical auxiliaries for Shaping, isotonicization, buffering, preservation, film formation and / or for improvement the Drug penetration, such as sodium and potassium phosphates, sodium, potassium and Calcium chloride, citrates, borates and tartrates, fatty and mineral oils, petroleum jelly, Cellulose ethers, polyvinyl alcohols, polyvinylpyrrolidones, polyoxes, thiomersal, sorbic acid, Chlorhexidine salts, quaternary ammonium compounds, sorbitan fatty acid esters and their Ethoxylation products, polyoxyethylene polyoxypropylene polymers and mucosal compatible amphoteric surfactants.

In animal experiments, the observations of Bonomi c.s. confirmed: pressure reduction after 1 drop of timolol or sotalol eye drops, 5 rabbits, increased intraocular pressure due to subunjunctival 4 mg betamethasone, unilateral Use of the two beta blockers (alternative) or 0.9% sodium chloride solution as control, mean values of 5 eyes each time in hours O 1 3 5 7 control 28 + 1.0 28 + 1.7 27 + 1.2 28 + 1.4 28 + 1.9 sotalol 1% 28 + 0.8 20 + 1.4 17 + 0.5 19 + 2.2 27 + 1.7 Control 27 + 1.2 26 + 0.8 27 + 1.5 26 + 1.3 27 + 1.1 Timolol 1% 27 + 1.0 22 + 0.8 22 + 1.5 21 + 1.6 26 + 2.1 control 27 t 0.7 27 + 0.9 27 + 1.3 27 + 1.4 27 + 1.8 Sotalol 0.5% 27 + 0.8 20 + 1.3 18 + 0.9 20% 1.7 27 + 1.0 Control 29 + 0.6 29 + 1.0 28 + 0.5 280.7 29 + 0.5 Timolol 0.5% 29 + 0.9 24 + 1.3 24 + 1.6 24; c 1.9 28 + 1.8 Result: Experimentally increased intraocular pressure is in rabbits by sotalol 1% and sotalol 0.5% in almost the same way, namely decreased by 10 mm Hg after 3 hours and by 8 mm Hg after 5 hours.

There is also no significant difference between timolol 1% and timolol 0.5% Difference: after 3 hours pressure drop by 4.5 mrz Hg and after 5 hours by likewise 4.5 mm Hg.

It is noticeable that the intraocular pressure through the same dosage Sotalol is lowered twice as much as by timolol.

With timolol, the maximum effect lasts longer than with sotalol. the However, pressure reduction after Sotalol is still significant 5 hours after instillation higher, namely almost twice as strong as after timolol.

These excellent results led to trials on 7 volunteers Patients with primary glaucoma who were not yet adjusted and pressure readings around 27 mm Hg. It was used on both sides on consecutive days 1 drop each of the following recipe 1: Sotalol hydrochloride 1.00 g thiomersal (Conservant) 0.01 g sodium chloride (Isotonans) 0.80 g distilled water ad 100.00 ml pH value 4.4 In all patients the pressure was increased i, 3 and 5 hours after the instillation checked, in 6 cases there was no degradation, in one case after 3 hours 2 mm HG decreased. In the latter case, the minimal pressure drop could be achieved but only be found on 2 out of 3 days.

Result: In contrast to rabbits (with artificially created glaucoma) 1% sotalol eye drops work when applied locally to the human eye (Primary glaucoma) not hypotensive. None of the patients (including 2 asthmatics) systemic side effects were noted.

This bad test result cannot be explained plausibly, but coincides with the results of MUSINI c.s., who reported as early as 1971, that with 2% sotalol eye drops the internal pressure of 14 test persons did not (Am. J. Ophthal. 1971; 72,773). A recent publication (Crick c.s., Lancet, October 1980, p. 857) it can be seen that 4.2% sotalol eye drops the intraocular pressure in 8 test persons was significant, but relatively minor decreased, namely after 3.5 hours from 12.5 + 1.2 mmHg to 9.7 + 1.0 mm Hg, so by 2.8 mm Hg (mean values for both eyes).

Timolol eye drops (Chibro-Timoptol TM) are 0.25 to 0.5% strength (Mean value 0.38%) applied. According to the current state of knowledge, Sotalol 4.2% drops in the eyes for local application, i.e. in an 11-fold higher concentration be used as timolol. This means that it is for systemic use Applicable dose-effect ratio sotalol: timolol (8: 1) also for the local Eye therapy (11: 1) applies. The therapeutic one expected after the animal experiments The advantage, namely the lack of side effects with local sotalol therapy, is thus not given in humans for reasons unknown up to now.

In a self-experiment, however, it was found that in the above Test formulation 1 the replacement of 1% sotalol hydrochloride (molecular weight MW 308.8) by 1% sotalol base (MW 272.4) when the intraocular pressure is not pathologically increased leads to a pressure decrease of 3.5 mm Hg. This surprising and unpredictable Effect cannot be explained by MG differences. The CRICK c.s. communicated Results indicate that in sotalol eye drops for human use the active ingredient must be dosed much higher, namely more than four times Amount (4.2 X sotalol base, corresponding to 4.76% sotalol hydrochloride).

Systematic studies have shown that an increase in the pH value to 7.0 to 10.0 in the 0.1 to 2% sotalol preparations used to a clearly noticeable pressure-lowering effect on the glaucoma eye of humans leads. The following test formulations 2 to 11 were used on volunteers Tested pathologically increased intraocular pressure: Formulation 2 sotalol hydrochloride 2.0 g thiomersal 0.01 g Sörensen phosphate buffer isotonic to pH 7.0 sodium chloride 0.6 g distilled water ad 100.00 ml recipe 3 sotalol hydrochloride 1.0 g thiomersal 0.01 g borax buffer pH 8.5 according to Palitzsch / Dolder ad 100.00 ml RezePtur 4 sotalol hydrochloride 0.1 g benzalkonium chloride 0.01 g borax 0.2 g 0.1 N sodium hydroxide solution qu.s. pH 10.0 sodium chloride 0.7 g distilled water to 100.00 ml recipe 5 sotalol base 1.0 g thiomersal 0.01 g potassium chloride 0.1 g sodium chloride 0.1 g borax buffer pH 7.77 1 1?. <I1 / I> (> 1 <1 (r 1 lo (s, 00 Recipe 6 sotalol base 0.1 g thiomersal 0.01 g polysorbate 20 Ph.Eur. III 1.5 g borax 0.3 g 0.1 N sodium hydroxide solution qu.s. pH 10.0 sodium chloride 0.7 g distilled water ad 100.00 ml recipe 7 Sotalol base 0.2 g castor oil Ph.Eur. III 7c, 0 ml ethylenediamine qu. see pH 8.2 medium-chain Triglyceride DAB 8 ad 10.00 ml oil with pH 8.2 (aqueous extraction) formulation 8 sotalol hydrochloride 2.0 g borax qu.s. pH 7.5 paraffin. subliquid. 50.0 g of wool wax alcohol ointment DAB 8 ad 100.0g ointment with pH 7.5 (aqueous shaking), formulation 9 sotalol hydrochloride 0.1 g borax qu.s. pH 9.2 paraffin. subliquidum 5 (), 0 g polysorbate 20 Ph.Eur. III $, 0 g white vaseline ad 100.0 g ointment with pH 9.2 (aqueous extraction) formulation 10 sotalol pamoate, 1.0 g chlorhexidine gluconate 0.01 g sodium chloride 0.6 g borax 0.4 g 0.1 N sodium hydroxide qu.s. pH 9.5 distilled water ad 100.00 ml suspension with pH 9.5 formulation 11 sotalol hydrochloride 1.0 g thiomersal 0.01 g Hydroxyethyl cellulose (Viscontran HEC 30,000) 2.0 g Borax buffer pH 8.5 according to Palitzsch / Dolder ad 100.00 ml gel with pH 8.5 recipe 12 sotalol hydrochloride 0.1 g thiomersal 0.01 g Borax 10.0 g Poloxamer 331 (Pluronic L 101) 5.0 g 0.1 N sodium hydroxide solution or 0.1 N Hydrochloric acid qu. see pH 9.2 polyvinyl alcohol MW 80,000, degree of hydrolysis 86-89% ad 100.00 g According to OS 29 05 033 Manufacture, production of a film with a thickness of 0.4 to 0.5 mm, punching out of sections weighing 20 to 40 mg.

Inserts with pH 9.2 (aqueous solution) Result: With the recipes 2 to 12, the previously pathologically increased intraocular pressure was found in all glaucoma patients significantly below the tolerable value of 20 mm Hg, depending on from the initial pressure the pressure reduction for the 0.1% days aqueous sotalol preparations 1 to 4 mm Hg, for the 1% days aqueous sotalol preparations (including suspension) 3 to 8 mm Hg and for the 2% aqueous sotalol preparations 7 until 10 mm Hg (1 drop in each eye 2 to 3 times a day).

The oily sotalol preparation (recipe 7) and the ointment-shaped Preparations (recipes 8, 9 and 11) showed in comparison with recipes 2 up to 6 have a somewhat stronger and significantly longer effect.

The best retardation (prolongation of effect) was found with the formulation 12th

A patient who no longer responded to 0.5% timolol eye drops, showed a drop in pressure just 2 hours after instillation after using formulation 2 to 15 mm Hg.

4 more timolol patients (each 0.5%) who had atf pressure values of 20 mm Hg and did not decrease any further, showed according to the recipe 3 or 5 or 7 or 11 a significant reduction in pressure to about 15 mm Hg.

This not only shows the effect of recipes 2 to 12, but also their therapeutic advantage over those already in therapy well-known timolol eye drops.

A total of 25 patients, each patient partially with different Formulations, treated, including 3 hypertensive and 3 asthmatic. In no patient side effects have been observed. This results in the - compared it timolol eye drops - better tolerability (eye drops containing otalol.

Claims (6)

MEDICINAL PREPARATION FOR USE ON THE EYE Patent claims 1. Medicinal preparation for use on the eye in the form of a solution, lyophilisate, suspension, Ointment, gel or insert for the treatment of excessive intraocular pressure (water congestion, Glaucoma), d u r c h e k e n n z e 1 c h n e t that they use sotalol as a base or Contains salt in a concentration of 0.1 to 2% at a pH of 7.0 to 10.0. 2. Medicinal preparation according to claim 1, d a d u r c h g e k e It is noted that the pH is in the range of 7.8 to 9.2. 3. Medicinal preparation according to claim 2, d a d u r c h g e k e It should be noted that the pH is in the range of 8.5 to 9.0. 4. Medicinal preparation according to claim 1 or 2, d a -d u r c h it is not noted that they use sotalol as ophthalmologically acceptable Salt, such as sotalol hydrochloride, citrate, maleate, borate, tartrate, pamoate or - contains phosphate. 5. Medicinal preparation according to one of claims 1 to 4, d a d It is not stated that they use sotalol as a base or in the ophthalmological form contains compatible salts in a concentration of 0.25 to 1%. 6. Medicinal preparation according to one of claims 1 to 5, d a d u r c h e k e n n n n z e i n e t that they are used for shaping, isotonicization, buffering, Preservation, film formation and / or to improve drug penetration contains suitable pharmaceutical excipients, such as sodium and potassium phosphates, Sodium, potassium and calcium chloride, citrates, borates and tartrates, fats and minerals Oils, vaseline, cellulose ethers, polyvinyl alcohols, polyvinylpyrrolidones, polyoxes, Thimerosal, sorbic acid, chlorhexidine salts, quaternary ammonium compounds, sorbitan fatty acid esters and their ethoxylation products, polyoxyethylene polyoxypropylene polymers and mucosal compatible amphoteric surfactants.