FR2483778A1 - OPHTHALMIC COMPOSITION CONTAINING 4 '- (1-HYDROXY-2- (ISOPROPYLAMINO) -ETHYL) METHANESULFONANILIDE - Google Patents

Abstract

THE INVENTION IS IN THE FIELD OF OPHTHALMOLOGY. IT CONCERNS OPHTHALMIC COMPOSITIONS WHICH CONTAIN, IN A CARRIER OR VEHICLE, 4-1-HYDROXY-2- (ISOPROPYLAMINO) -ETHYL-METHANESULFONANILIDE OR ONE OF ITS OPHTHALMOLOGICALLY ACCEPTABLE SALTS. APPLICATION TO THE TREATMENT OF GLAUCOMA BY REDUCTION OF INTRAOCULAR PRESSURE.

Description

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  The present invention relates to pharmaceutical-type compositions affecting biological processes and for the treatment of the body. The invention more particularly relates to the treatment of ocular hypertension by ocular instillation of 4 '- (1-hydroxy-2 (isopropylamino) -ethyl) -methanesulfonanilide. Ocular hypertension accompanies glaucoma, an eye disease characterized by a gradual, time-related elevation of intraocular pressure ultimately leading to optic nerve injury. Thus, the main purpose of glaucoma treatment is to prevent the deterioration of optic nerve fibers by lowering high intraocular pressure. Among the medications commonly used for the treatment of glaucoma, there are miotics such as pilocarpine and cholinesterase inhibitors such as physostigmine. Although these drugs are useful, they are known to cause various adverse reactions as a consequence of local effects and sometimes of generalized effects. For example, local side effects such as extreme miosis, myopia of accommodation,

  night blindness and a vision made temporarily confused.

  Other common local effects include blinking of eyelids, eyebrow pain, headache, eye pain, ciliary and conjunctival congestion, tear production, localized allergy manifested by conjunctivitis and contact dermatitis. As a result of their absorption, cholinesterase inhibitors produce undesirable systemic effects such as salivation, sweating, nausea, vomiting, bradycardia and hypotension. Some adrenergic drugs, such as the alpha-agonist epinephrine and the beta-blockers called isoproterenol and salbutamol, have also been used to reduce intraocular pressure. However, when applied topically, these compounds can produce systemic side effects resulting from their absorption, for example tachycardia, hypertension,

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  headache, sweating, tremors, palpitations and tachyphylaxis. A more recent mode of treating glaucoma involves the use of certain beta-adrenergic blocking drugs to lower the production of aqueous humor to reduce intraocular pressure. The

  mechanism on which the beta agents rely

  adrenergic blocking agents to reduce the intra-

  ocular is not known and is considered a paradox, in that * beta-adrenergic agonists (stimulants) also produce hypotension effects

  ocular by reducing the production of aqueous humor.

  According to "AMA Drug Evaluations", page 360, 4th edition (American Medical Association, Chicago), topical preparations of blocking beta-blockers such as propanolol, practolol, atenolol, pindolol, and timolol have been used for the treatment of chronic glaucoma. . The last mentioned agent is described in British Patent No. 1,524,405 and in the US Pat.

  United States of America N 4 195 085.

  The active ingredient of ophthalmic compositions

  of the present invention is the substance called 4 '- (1-

  hydroxy-2- (isopropylamino) ethyl) -méthanesulfonanilide. This compound, described in the patent of the United States of America

  No. 3,341,584, is considered to be a beta agent

  adrenergic blocking and is called sotalol or MJ 1999 in the following publications dealing with the reduction of

intraocular pressure.

  A. Musini and coworkers describe in the American Journal of Ophthalmology, 72 (4), 773-781 (1971) the results of a comparative study of the effect of propanolol, hydrochloride of MJ 1999 (hydrochloride of

  sotalol) and INPEA (nifenolol) on the intra-

  ocular in humans and they conclude from their study that, of the three beta-adrenergic blocking agents, only the

  Propanolol reduces intraocular pressure.

  JW Lamble and colleagues deduce from a study entitled "Effects of catecholamines on the intraocular pressure of conscious monkeys" published in InvestO Ophthalmolo Visual Sci., 16 (7), 628-633 (1977) that sotalol is devoid of activity. intrinsic on pressure

intraocular of Nyctipithecus.

  L. Bonomi and colleagues compare in Albrecht. Graefes. Arch. rlim. o Exp. Ophthalo, 210 (l) 1-8 (1979) the effects of nine betaadrenergic blocking agents on the intra-ocular pressure of rabbits and found that sotalol instilled in the eye at a concentration of 1% reduced intraocular pressure. in

  rabbits in experimentally induced ocular hypertension

  is lying. Thus, with regard to the use of sotalol as an intraocular pressure lowering agent, the prior art indicates that it is ineffective in humans and

  species belonging to the lower mammals.

  The invention relates to the treatment of human glaucoma by lowering intraocular pressure, by topical application to the glaucomatous eye of a quantity

  effective, ophthalmologically acceptable, 4'-

  (1-hydroxy-2- (isopropylamino) ethyl] methanesulfonanilide.

  This compound is called sotalol herein and is characterized by the formula: -OH

CH 3 SO 2 M CECH 2 N-CH (CH 3) 2

  The invention particularly relates to ophthalmic compositions for use in lowering intraocular pressure, comprising sotalol as the active ingredient or its ophthalmologically acceptable salts such as hydrochloride in combination with a carrier or carrier. ophthalmic material in the form of a buffered isotonic liquid, a solid material or a vegetable oil, which compositions can be administered using

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  a polymeric liner or a soft contact lens. In accordance with the present invention, sotalol is applied topically to the eye in an effective, ophthalmologically acceptable amount to produce an

  therapeutically useful reduction of the intra-

  ocular for a period of 5 to 9 hours. It should be noted that the term "ophthalmologically acceptable effective amount" as used herein means the amount of sotalol required to lower intraocular pressure without causing toxic, injurious or harmful effects such as irritation, pain, allergic reaction, or systemic side effects related to blockage of cardiac and non-cardiac beta-receptors, eg, bradycardia, hypotension and bronchospasm. In the treatment carried out using the compositions of the present invention, sotalol is preferably applied topically in the form of an ophthalmic composition formulated to contain 2 to 4% and especially 4 to 6% of sotalol, in an amount of sufficient to deliver an effective dose of 1 to 8 mg per eye of a pharmaceutically acceptable non-toxic ophthalmic carrier or vehicle. One to four drops of these compositions are sufficient to produce the

  desired reduction in intraocular pressure.

  The ophthalmic preparations of the present invention may be advantageously formulated by mixing sotalol hydrochloride or its ophthalmologically acceptable salts with conventional pharmaceutically acceptable carriers or carriers such as water, water mixtures, and the like. and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum-based gel, methylcellulose, ethylcellulose, oleate

  of ethyl, carboxymethylcellulose, polyvinyl

  pyrrolidone, isopropyl myristate and other acceptable carriers of conventional use. The preparations

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  The ophthalmic agents of the present invention may also contain nontoxic auxiliary substances such as emulsifiers, preservatives, wetting agents, etc., as well as anti-bacterial components such as quaternary ammonium compounds, phenylmercuric salts and the like. known for their properties of

  cold sterilization and that can be used safely.

  Suitable buffering ingredients such as sodium chloride, sodium borate, sodium acetate, gluconate buffers and other conventional ingredients such as sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopalmitate, can also be used. In addition, suitable ophthalmic vehicles may be used as carriers for sotalol (and its salts such as hydrochloride), including conventional phosphate buffered vehicles, isotonic boric acid carriers, isotonic sodium chloride vehicles, isotonic sodium borate vehicles, etc. Water-soluble solid polymeric liners are also used as carriers for sotalol and its salts. The polymer used to form the liner may be any water-soluble, non-toxic polymer

  comprising cellulose derivatives such as methyl

  cellulose, the sodium salt of carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and acrylates such as polyacrylic acid salts, ethyl acrylates, polyacrylamides; natural products such as gelatin, alginates, pectins, gum tragacanth, gum arabic; starch derivatives such as starch acetate,

  hydroxyethyl starch ethers, hydroxylated starch

  propylated, in addition to other synthetic derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, ether

  polyvinyl methyl and the polyethylene oxide.

  The invention is illustrated by the examples

  following particulars, which are given in a non-limitative manner.

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EXAMPLE 1

  Effects of eye drops with sotalol hydrochloride on intraual pressure in normal surets The aim of the study was to determine the effects and tolerance of eye drops to sotalol hydrochloride on intraocular pressure compared with placebo eye drops in patients with normal test. The study is of the type

  double-blind with statistical distribution in the inter-

  version of the topics. She is driving for two days

  consecutively, followed by a 5-day washing period,

  even followed by a final trial period of 2 consecutive days. Sotalol hydrochloride is administered dropwise into the eye at a concentration of 4.2%, the eye drops placebo consisting of an isotonic salt solution. The drug and the placebo are distributed using coupled containers, using a dropper dispensing

a volume of 28.6 microliters.

  Eight subjects are involved in this study and are divided into two equal groups statistically distributed as follows: First day: no treatment Second day: instillation at 10 o'clock in the morning of 2 drops, in both eyes, of eye drops with sotalol hydrochloride or placebo eye drops

sodium chloride; immediately

after the first group of

tests at 10 o'clock in the morning.

  After a wash period of 5 days, the study groups are inverted, so that the subjects who previously received the eye drops placebo get the eye drops with sotalol hydrochloride and the subjects who have previously received eye drops with sotalol hydrochloride

receive placebo eye drops.

  In the course of the study, tests are performed according to the following program: collected hO 0 vilual luacuity measurement, pupil diameter, pulsations and pressure

blood pressure, the intra-

  The eyepiece (IOP) was measured using a Goldmrann applanation tonometer at 11:30 am PIO0 and pupil diameter.

  13:30 PIO and pupil diameter.

  H30 PIO and pupil diameter 17:00 PIO and pupil diameter,

pulsations and blood pressure.

  The following table reproduces the pre-treatment and post-administration data

TABLE I

  Mean intraocular pressure (kPa), placebo / sotalol hydrochloride Eye n Placebo Fall, Hydrochloride% sotalol Pre-D treatment G

DG 16

1.5 hours later

8 1.65

8 1.60

1.62

D 8 1.50

G 8 1.52

DG 16 1.51

3.5 hours later

D 8 1.48

G 8 1.48

DG 16

5 hours later 1.48

D 8 1.42

G 8 1.40

DG 16 1.41 13.4

7h later

D 8 1.48

G 8 1.45

DG 16

  last D readings G DG D = right eye G = left eye 1.47 1.47 1.46 1, 47 9.8 9.8 1.42 1.35 1.44 1.39 14.6 16.0 L Classical statistical analysis of the above results does not indicate significant differences (P> 0.05) between placebo and sotalol for both the right eye and the left eye at any particular time. However, when the right eye and the left eye are both used as multiple responses by subject, the reduction in time falls,% 1.63 1.68 1.66 1.37 1.48 7.2 1 , 42 14.1 1.25 1.32 8.7 1.28 22.6 1.42 1.48 1.45 12.5 1.37 1.47

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  intraocular pressure is noticeably lower

  (P <0.002) in the case of sotalol hydrochloride compared with

  placebo, 3.5 hours after treatment.

  The combined values analysis for the four observation times after treatment (1.5 hours, 3.5 hours, 5 hours and 7 hours after treatment) gives the following results: the values obtained for sotalol hydrochloride are significantly lower (PO0.007) than for placebo in the right eye. When the values for both eyes are combined as multiple responses by subject, it is again found that the values for sotalol hydrochloride are significantly higher.

low (P <0.02).

  No adverse effects were observed during the study and no significant difference (P> 0.05) occurred between mean pupil diameters, heart rate measurements, and blood pressure measurements.

  sotalol hydrochloride and placebo.

XEM! PLE 2

  Effects of eye drops with sotalol hydrochloride on intraocular pressure in patients with chronic glaucoma or elevated intraocular pressure The aim of this study is to determine the effects and tolerance of eye drops to sotalol hydrochloride on intraocular pressure. -ocular compared to placebo eye drops in a group of patients with chronic glaucoma or high intraocular pressure. Five women and three men take part in this study, with an average age of 73 years ranging from 44 to 80 years. This study is conducted on the double-blind inversion mode with a wash period of 5 days between the two phases of the study. Sotalol hydrochloride is administered dropwise to the eye at a concentration of 4.2%, the eye drops placebo consisting of an isotonic salt solution. The drug and placebo are both dispensed with a pair of containers, using a dropper

  delivering a volume of 28.6 microliters.

  O The eight patients are divided into two groups

  equals statistically distributed as follows -

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  Day 1: No treatment Day 2: 9.00 am. Instillation in both eyes of eye drops with sotalol hydrochloride or eye drops placebo with sodium chloride; immediately after the first set

tests at 9.00 am.

  After a wash period of 5 days, the groups are switched, so that patients who have previously received the eye drops placebo receive sotalol hydrochloride eye drops and patients who have previously received eye drops with sotalol hydrochloride receive the eye drops. placebo. During the study, tests are conducted according to the following schedule: Time of day, 09.00: visual acuity, pupil diameter, pulsations and blood pressure with measurement of intraocular pressure (IOP)

  using a Goldman aplanation tonometer.

  , 30: IOP and pupil diameter 12.30: IOP and pupil diameter 14.30: IOP and pupil diameter 16.30: IOP and pupil diameter,

pulsations and blood pressure.

  The following Table II reproduces the results

  collected in pre-treatment and post-administration.

TABLE II

  Mean Intraocular Pressure (kPa), Placebo / Sotalol Hydrochloride Time Placebo Falls,% Chlorhydrate Fall,% sotalol

9:00 3.01 - 2.93 -

: 30 2.87 4.7 2.64 10.0

12:30 2.65 11.9 2.47 15.6

14:30 2.82 6.3 2.62 10.8

16:30 2.87 4.7 2.75 6.2

  The classical statistical analysis of the above results does not indicate any significant differences (P> 0.05) between placebo and sotalol for both the right eye and the left eye at any particular time. However, when the right eye and the left eye are both used as multiple responses per patient, the intraocular pressure is lower in the case of sotalol than in the placebo at 1.5 hours, 3, 5 hours, 5.5 hours and 7.5 hours with the following P values - 0.07 - 0.29

0.03 and 0.27.

  Mean pupil diameter, pulse and blood pressure values are reproduced in the following Table III with the differences observed without

  statistical significance according to the calculation.

  1 5 TABL1U iII Mean Pupil Diameter - Quasi-systolic and diastolic zoonous localization of placebo and sotalol hydrochloride Mean pupil diameter (ai) Hour Placebo Sotalol HCl

09.00 3.11 3.08

3.04 3.49

12.30 3.03 3.42

14.30 2.99 3.21

16.30 3.14 3.23

  Pulsations (batteoents per minute) Time Placebo Sotalol.HCl

09.00 75.25 76.88

16.30 76.25 76.88

  Blood pressure kPa) Systol e / distolie Time Placebo Sotalol.HCl

09.00 18.80 / 10.33 18.00 / 10.33

16.30 19.10 / 11.06 19.05 / 11.54

  No adverse effects were observed during the study.

EXAMPLE 3

  Ophthalmic compositions containing sotalol Ophthalmic compositions comprising medicinal solutions, ointments and eye fillings, consisting of sotalol hydrochloride and a pharmaceutically acceptable non-toxic ophthalmic carrier or carrier, suitable for ocular instillation, are appreciated for the implementation of the invention. Ophthalmic solutions of sotalol used in the process of the invention may be formulated in accordance with the correct pharmaceutical practice as set forth in Chapter 83 of Remington's Pharmaceutical Sciences, 14th Edition, Mack Publishing Company. Such solutions are preferably sterile, their sterility being maintained during use by conventional bacteriostatic agents such as a quaternary ammonium salt such as benzalkonium chloride. Since sotalol or its ophthalmologically acceptable salts such as hydrochloride are not appreciably susceptible to oxidative decomposition, an antioxidant is not essential, but may be used on the basis of oxidation. optionally. Suitable antioxidants include, for example, sodium bisulfite, N-acetylcystine salts, sodium ascorbate, and other water soluble acceptable antioxidants.

  ophthalmological view known in the field of pharmacy.

  Ophthalmic solutions of sotalol hydrochloride can be adjusted with inert ingredients such as sodium chloride or boric acid to form a

  solution whose application to the eye is not unpleasant.

  For example, a composition containing about 4.2% sotalol hydrochloride (equivalent to 3.7% sotalol base) with 0.9% sodium chloride or a tonicity vehicle

  such as 1.9% boric acid is satisfactory.

  tory. Ointments are prepared with conventional petrolatum vehicles, using liquid petrolatum and petrolatum in proportions chosen to

  form a suitable fluidity ointment.

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  Ophthalmic solution Sotalol hydrochloride 4.2 g Excipient, sufficient for 100.0 g Excipient composition: Benzalkonium chloride 0.02 g Sodium dihydrogenphosphate dihydrate 0.00586 g Disodium hydrogenphosphate anhydrous 0.0536 g Water, amount sufficient for 100.00 g. If necessary, the water can be replaced by 0.9% by weight aqueous sodium chloride as a solvent. The solution is sterilized by filtration and packaged in

aseptic conditions.

  Ophthalmic Ointment Sotalol Micronized Hydrochloride 4.76 g Vaseline, amount sufficient for) 100.0 g Liquid Petrolatum, amount) sufficient) The product is prepared and packaged in

  aseptic conditions to form a sterile ointment.

  Sotalol hydrochloride may also be applied to the eye by the vehicle with a polymeric liner or a soft contact lens. For the latter purpose, polymeric hydrophilic hydrogels prepared from polymers of acrylic and methacrylic esters, modified collagens, crosslinked polyether gels, crosslinked polyvinyl alcohol or partially hydrolyzed crosslinked polyvinyl acetate, as described in US Pat. United States of America Nos. 2,976,576, 3,220,960 and 3,419,006 may be used and are hereby incorporated by reference. Ocular seals prepared from these polymeric materials as well as others which are insoluble in tear fluid, but which can absorb this fluid to form an inflated hydrogel, as described in U.S. Patent Nos. 3,416 530 and No. 3,618,604, may also be used and are hereby incorporated by reference. All these modes of application of hydrochloride

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  sotalol to the eye are within the scope of the present invention as well as compositions suitable for such use. In carrying out the method of the present invention for the lowering of intraocular pressure by topical administration of sotalol hydrochloride, an ophthalmologically acceptable polymeric ocular seal placed and maintained in contact with an eyeball is preferred, the compound then diffusing from the liner at a rate sufficient to produce an effective dose, lowering the intraocular pressure, of

  1.0 g to 5.5 mg over a period of 5 to 9 hours.

  Ophthalmic fillings particularly preferred in the practice of the process of the present invention are prepared conventionally, for example by immersion of a polymeric liner or soft lens in a 1-5% sotalol hydrochloride solution until a balance has been established, which usually takes place

in a period of 1 to 5 minutes.

  Ocular seal Sotalol hydrochloride 1 mg Hydroxypropylcellulose, sufficient for 12 mg Ophthalmic fillings are also made from compression-molded films, which are prepared by subjecting the above powder mixture to an effective compressive strength of 50 mg. , 4 kN at 148.90C for a period of 1 to 4 minutes on a suitable press. The film is cooled under pressure by circulation of cold water in the tray. Ophthalmic glands are cut individually in the film by means of a cylindrical punch. Each liner is placed in a vial which is then installed in a chamber with 88% humidity and maintained at 300C for 2 to 4 days. When the vials have been removed from the humid chamber, they are plugged and capped. Vials containing hydrated lining

  are then autoclaved for half an hour at 93-121 ° C.

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  Ophthalic fillings in the form of a solvent-cast fill can be made by preparing a

  viscous solution of sotalol hydrochloride and hydroxy

  propyl methylcellulose in the above proportions using methanol as the solvent. The solution is placed on a Teflon plate and allowed to dry under ambient conditions. After drying, the film is placed in an 88% humidity chamber until it is flexible.

movie.

Claims (4)

  1. Ophthalmic composition for the topical treatment of glaucoma, characterized in that it comprises in solution an amount, effective for lowering the intraocular pressure, of 4 '- [1-hydroxy-2- (isopropylamino) -ethyl] methanesulfonanilide or ophthalmologically acceptable salts thereof, preferably the hydrochloride, with an ophthalmic carrier or carrier in the form of a solid material, a vegetable oil or a buffered isotonic liquid.   2. Composition according to claim 1, characterized in that the support is a filling water-soluble polymer.   Ophthalmic composition according to claim 1, characterized in that it consists of a   4.2% by weight aqueous solution of hydrochloride of 4 '- (1-   hydroxy-2- (isopropylamino) -ethyl J-methanesulfonanilide   intended to be applied topically.   4. Composition according to claim 1, characterized in that the buffered isotonic liquid   contains 4.2% by weight of 4 '- (1-hydroxy-2- hydrochloride)   (Isopropylamino) -ethyl-methanesulfonanilide.