BG60332B2 - Composition and method for treatment of glaucoma by local application of t-butulamino-3-(4-morpholine-1,2,5-thiadiazol-3-iloxy)-2-propanol hydrogenmaleate - Google Patents

Abstract

The composition and method find use in the treatment of elevated intraocular pressure. The antiglaucoma formulation contains t-butylamino-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)-2-propanol hydrogenmaleate. 7 claims

Description

Current drugs such as pilocarpine and its various salts are used to treat glaucoma. Although these drugs are used, they show major side effects such as extreme miosis, spasm of accommodation, night blindness and transistor vision. T-Butylamino-3- (4-morpholino-1,2,5-diaziazol-3-yloxy) 2-propanol hydrogen maleate has been found to be effective in reducing ocular pressure under normal and elevated ocular pressure in the human eye without the side effects of pilocarpine and its derivatives.

Detailed description of the invention

The present invention relates to a method of treating glaucoma and high ocular pressure by administering an effective amount of t-butylamino-3- (4-morpholino-

1.2.5-Thiadiazol-3-yloxy / -2-propanol hydrogen maleate on human or animal eye suffering from glaucoma or ocular hypertension. The invention also includes a method of reducing normal intraocular pressure. The invention also relates to ophthalmic compositions comprising this compound. It is an object of the present invention to test the novel antiglaucoma composition as a method of reducing intraocular pressure with partial or total elimination of one or more of the above-mentioned side effects.

The present invention is based on the finding that t-butylamino-3- (4-morpholino-

1.2.5-Thiadiazol-3-yloxy / -2-propanol hydrogen maleate lowers intraocular pressure when applied topically. The compound of this invention is the known compound used as a beta-adrenergic blocking agent described in US Patent Nos. 3,657,237, US Pat.

Preferably, the compound is administered in the form of an ophthalmic pharmaceutical composition for topical application of the eye as a solution, ointment or as a solid ingredient. This compound may contain from 0.01 to 5%, and in particular from 0.5 to 2% of the drug. Higher doses, for example about 10 or lower, can be used to demonstrate an effective dose to lower intraocular pressure. The most common unit dose of the compound administered to the human eye is between 0.001 and 5.0 mg, preferably 0.005 to 2.0 mg, in particular 0.005 to 1.0 mg. The pharmaceutical composition containing the compound may be mixed with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical pharmaceutical carriers are, for example, water, aqueous mixtures, water-miscible solutions such as weak alkanols or aralkanols, vegetable fats, polyalkylene glycol, basic petroleum gel, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl-methylpyrrolidone and other propylpyrrolidone. The pharmaceutical preparation may also include non-toxic auxiliary substances such as emulsifying, protecting, wetting agents, basic agents and the like, e.g. polyethylene glycol 200, 300, 400 and 600, carbovax 1,000, 1,500, 4,000, 6,000 and 10,000, bacterial components such as quaternary ammonium compound, phenylmercuric salts, known for their cold sterilizing properties and which are harmless in use, thimerosal , methyl and propyl paraben, benzyl alcohol, phenyl ethanol, ingredient buffers such as sodium chloride, sodium borate, sodium acetate, gluconate buffers and other conventional ingredients such as collected monolaurate, triethanolamine monoethylate, polyoxyethylthiobenzyl sorbitan, polyoxyethylthiobenzyl sorbitan oglycerol, thiosorbitol, ethylenediamine tetraacetic acid and the like. For this purpose, ophthalmic vehicles may also be used as carriers including a conventional phosphoric buffer system, isotonic boric acid vehicle, isotonic sodium chloride vehicle, isotonic sodium borate vehicle and the like. The pharmaceutical preparation may also be in the form of a solid ingredient. For example, a solid water-soluble polymer may be used as the drug carrier. The polymer used as an ingredient may be any water-soluble non-toxic polymer, such as cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, (hydroxylveralkyl cellulose), hydroxyethyl cellulose, hydroxypropylmethylcellulose; acrylates, such as polyacrylic acid salts, are itylactylates, polyacrylamides; natural products such as gelatin, alginate, pectin, tragacanth, kara, cartilage, agar, acacia; starch derivatives, such as hydroxypropyl starch, hydroxyethyl starch ethers, and other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthine resin, mixtures of said polymers.

The solid constituent is preferably made from cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropylmethyl cellulose or other synthetic materials such as polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide or polyvinyl methyl ether. Hydroxypropyl cellulose, one of the preferred polymers for the preparation of the ingredient, is available in various polymeric forms, all of which are suitable for the preparation of this ingredient. Products promoted by Hercules Inc.of Wilmington, Delaware under the Klucel name such as Klucel HF, HWF.MF, GF, JF, LF and EF, which are designed for food or pharmaceutical use, are particularly useful. The molecular weight of these polymers used for the purpose described may be from 30,000 to 1,000,000 or more. An ethylene oxide polymer having a molecular weight of 5,000,000 or more, preferably from 100,000 to 5,000,000, may also be used. For example, Polyox polymer offered by Union Carbide Coa may be used with a molecular weight of 50,000 up to 5,000,000 or more and preferably from 3,000,000 to 4,000,000. Other specific polymers that may be used are polyvinylpyrrolidine having a molecular weight of from 10,000 to 1,000,000 or more, preferably up to 350,000, and in particular from 20,000 to 60,000; polyvinyl alcohol having a molecular weight of from 30,000 to 1,000,000 or more, in particular about 400,000 and in particular from 100,000 to 200,000; hydroxypropylmethyl cellulose having a molecular weight of from 10,000 to 1,000,000 or more, in particular about 200,000 and in particular from 80,000 to 125,000; methyl cellulose having a molecular weight of from 10,000 to 1,000,000 or more, preferably 200,000, and in particular from 50 to 100,000; and CARBOPOL (carboxyvinyl polymer) of B. P. Goodrich and Co., designated grades 934, 940, and 941. It is clear that for the purpose of this invention, the type and molecular weight of the polymer is not critical. Some water-soluble polymers may use an average molecular weight that would allow the polymer and drug to dissolve, respectively, for the desired length of time. The ingredient may be in the form of a square, rectangle, oval, donut circle, semicircle crescent and the like. Ingredients in the form of a stick, donut, oval or crescent are preferred. The ingredient may be in the form of a square, rectangle, oval, circle, donut, semicircle, crescent and the like. Ingredients in the form of a stick, donut, oval and or crescent are preferred. The ingredient can be prepared immediately, for example, by dissolving the drug and polymer in a suitable solution and evaporating the solution respectively into a thin film of polymer, which can then be separated to prepare ingredients of suitable sizes. In another embodiment, the ingredient may be prepared by heating the polymer and drug, molding the resulting mixture in the form of a thin film. The ingredients are preferably prepared by casting or extruding. Cast or extruded products can be divided into ingredients of suitable size for application to the eyes. The ingredient can be of the right size for the eye immediately. For example, molded or injection molded films have a thickness of about 0.25 mm to 15.0 mm and can be separated into suitable ingredients. The rectangular segments of the molded or extruded film having a thickness between 0.5 and 1.5 mm can be cut with a blade in the form of rectangular plates measuring 4 x 5-20 mm or oval of a similar size. Also, extruded rods having a diameter between 0.5 and 1.5 mm can be cut into suitable pieces to test the desired amount of polymer. For example, rods with a diameter of 1.0 to 1.5 mm and a length of about 20 mm are satisfactory. The ingredients can also be formed directly by injection molding. The ophthalmic ingredients contained in the medicament of the present invention are preferably formed in such a way that they are smooth and have no sharp edges and tips that could cause damage to the eye. As the smooth surface, sharp edges and angles are subjectively determined, their use indicates that the intense inflammation of the eye is not the result of the use of the ingredient.

The ophthalmic medical ingredient also contains plastic, buffer and protective agents. Plastic agents suitable for this purpose must, of course, be completely soluble in the lacrimal fluid of the eye. Examples of suitable plastic agents are water, polyethylene glycol, propylene glycol, glycerin, trimethylol propane, di- and tripropylene glycol, hydroxypropyl saccharide and the like. Plastic agents may be present in the ophthalmic component in an amount of 1 to 30% by weight. A preferred plastic agent is water, which is present in an amount of from 5 to 40%. In practice, water is preferably from 10 to 20%, since the softness and plasticity of the ingredient can be more easily achieved. When the plasticity of the solid medical product is carried out with water, the product comes in contact with air having a relative humidity of about 40% and said product captures about 5% of water and becomes softer and more flexible. The relative humidity of the air should preferably be from 60% to 99% and the contact will continue until the product absorbs water from 10 to 20%. Suitable water-soluble fuses that can be used in the ingredient are sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercury, benzobenzyl, benzene, benzyl benzyl, benzene. These agents may be from 0.001 to 5% by weight of the solid constituent, preferably from 0.1 to 2%.

Suitable water-soluble buffering agents are alkali, alkaline earth carbonates, phosphates, bicarbonates, citrates, borates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate and carbonate. These agents may be present in amounts sufficient to maintain the pH of the system between 5.5 to 8.0 and in particular 7-8 and are typically about 2% by weight of the polymer. The composition may contain from 1 mg to 100 mg of the water-soluble polymer, in particular from 5 to 50 mg and in particular from 5 to 20 mg. The drug is 0.1 to 25% by weight of the ingredient.

Hydrogen maleate compound has been carefully studied for its ability to reduce intraocular injection of rabbits with experimental glaucoma induced by intraocular injection of -chymotrypsin. The study shows that the compound is very effective in reducing intraocular pressure when given topically. The pressure decreases in both normal and glaucomatous eyes.

The following examples illustrate the invention.

Example 1.

Solution Composition t-Butylamino-3/4-morpholino

1,2,5-Thiadiazol-3-yloxy / -2-propanol

hydrogen maleate (I) 1 mg 15 mg Monobasic sodium phosphate. 2H ₂ 0 9.38 mg 6.10 mg Dual base sodium phosphate .12H ₂ O 28.48 mg 16.80 mg Banzalkonium chloride 0.10 mg 0.10 mg Sodium hydroxide q.s. pH 6.8 pH 6.8 Water for injection q.s. ad 1.0 ml 1.0 ml

(I) -phosphate buffer salts and benzalkonium chloride are added and dissolved in water; The pH of the solution is fixed to

6.8 with sodium hydroxide and the final solution diluted to volume. The solution is sterilized by filtration through a sterilization filter.

Example 2 t-Butylamino-3- / 4-morpholino-

1,2,5-Thiadiazol-3-yloxy / -2-propanol hydrogen maleate (I) 5 mg

Petrolate q.s. ad 1 y

Compound (I) and petroleum are aseptically combined until plastic. Suitable ingredient sizes are achieved by cutting the film.

Example 5.

t-Butylamino-3- (4-morpholino-1,2,5-thiadiazol-3-yloxy) -2-propanol hydrogen maleate (I) 1 mg

Hydroxypropyl methyl cellulose

q.s.ad. 12 mg

Example 3.

t-.butylamino-3- / morpholino-

1,2,5-Thiadiazol-3-yloxy / -2 propanol hydrogen maleate (I) 1 mg

Hydroxypropyl cellulose q.s. 12 mg

The ophthalmic ingredients are produced by compression molding films, which are prepared on a cutting press by subjecting the powder mixture of the above ingredients to a pressure of 12,000 lbs (measure) and 350 ° F for one to four minutes. The film is cooled under pressure by cold water circulating in the roller. The ophthalmic ingredients are individually cut from the film by a rod punch. Each ingredient was placed in an ampoule and then in a humidified room / 88% R.H. at 30 ° C / for two to four days. After removal from the humid room, the tubes are blocked. The hydrated ingredient vials were autoclaved at 250 ° F for 1/2 hour.

Example 4.

t-Butylamino-3- / 4-morpholino

1,2,5-Thiadiazol-3-yloxy / -2-propanol hydrogen maleate (1) 1 mg

Hydroxypropyl cellulose

q.S. ad 12 mg

The ophthalmic ingredients are made from a soluble cast film prepared by the production of a viscous powder solution using methanol as a solvent. The solution was placed in a Teflon container to dry under ambient conditions. After drying, the film is placed in a room with 88% R.H.,

The ophthalmic ingredients are made from a soluble cast film, which is prepared by the production of a viscous powder solution using a methanol-verd soluble system (10 ml of methanol is added to 2.5 g of the powder mixture, to which 11 ml of water are added in three separate portions). The solution was placed in a Teflon container, allowing it to dry under ambient conditions. After drying, the film is placed in a room with 88% R.H. until plastic. Suitable ingredient sizes are achieved by cutting the film.

Example 6

t-Butylamino-3- / 4-morpholino-

1,2,5-Thiadiazol-3-yloxy / -2-propanol hydrogen maleate (I) 1 mg

Hydroxypropylmethyl cellulose q.s.ad. 12 mg

The ophthalmic ingredients, which are made from compression-modulated films, are prepared on a cutting press using a powder mixture of the respective ingredients under a pressure of 12,000 lbds at 350 ° F for one minute. The film is cooled under pressure by cold water circulating in the roller. The ophthalmic ingredients are individually cut from the punch film. Each ingredient was placed in an ampoule and then in a damp room / 88% RN. at 30 ° C / for two to four days. After removal from the humid room, the ampoules are blocked. The hydrated ingredient vials were autoclaved at 250 ° F for 1/2 hour.

Claims (7)

Claims 1. A method for treating glaucoma and reducing blood pressure, characterized in that it involves topical administration of the glaucomatous eye to the effective compound t-butylamino-3- (4-morpholino-1,2,5-thiadiazole). -3-yloxy / -2-propanol hydrogen maleate. A method according to claim 1, characterized in that morpholino-1,2,5-thiadiazol-3-yloxy / -2-propanol is applied in a water-soluble polymer. The process according to claim 2, wherein the polymer is 15 hydroxypropylcellulose. 4. The method of claim 1, wherein the t-butylamino-3 (4-morpholino-1,2,5-thiadiazol-3-yloxy) -2-propanol is administered as a 0.01 to 5% solution of m-bu-20 thylamino-3- (4-morpholino-1,2,5-thiadiazol-3yloxy) -2-propanol in an ophthalmologically acceptable carrier. 5. Ophthalmic composition for topical treatment of glaucoma, characterized in that it comprises reducing the eye pressure in an effective amount of a solution of t-butylamino-3- (4-morpholino-1,2,5-thiadiazole-Zyloxy) -2- propanol hydrogen maleate and liquid ophthalmic carrier. Composition according to claim 5, characterized in that the solution is from 0.01 to 5% m-butylamino-3- (4-morpholino-1,2,5-thiadiazol-3-yloxy) -2-propanol hydrogen maleate . 7. A composition according to claim 5, wherein the solution is from 0.5 to 2% m-butylamino-3- (4-morpholino-1,2,5-thiadiazol-3-yloxy) 2- propanol hydrogen maleate.