METHOD FOR DISSOLVING ARGININEAMIDES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: A method for dissolving an arginineamide of the invention comprising dissolving N²-arylsulfonyl-L-arginineamide having the general formula (I) wherein R¹ represents a (2R, 4R)-4-alkyl-2-carboxypiperizino group and R² represents a phenyl group or a condensed polycyclic compound residue which may be substituted with one or more substituents selected from lower alkyl groups, lower alkoxy groups and lower alkyl-substituted amino groups, said condensed polycyclic compound residue including a benzene ring which binds to sulfur atom of the sulfonyl group in the general formula (I) and is condensed with one or more other rings which may be heterocyclic and having 7 to 14 carbon atoms as the ring-constituent atoms; and/or its salt in a solvent of alcohol and water is disclosed herein. And, the pharmaceutical composition comprising N²-arylsulfonyl-L-arginineamide having the general formula (I), an alcohol and water is disclosed herein.

Description: The invention relates to a method for dissolving N²-arysulfonyl-L-arginineamides, hereafter referred to as "arginineamides", and more particularly argipidine, and pharmaceutical compositions containing them. Arginineamides are known to have anti-thrombotic activities and are expected to be used as anti-thrombotic agents (please refer to Japanese Patent N° 1382377). However, it is very difficult to obtain a solution containing arginineamides at high concentration due to poor their solubility in water. Therefore these compounds are not suitable for the production of solutions at high concentration suitable for injection. A method for producing arginineamides is disclosed in US patent 4,258,192. It comprises removing the N G -substituent from an N G -substitued-N²-quinolylsufonyl-L-argininamide by means of hydrogenating the quinolyl moiety to the corresponding 1,2,3,4-tetrahydroquinolyl moiety, in the presence of an hydrogen-activing catalyst. The N²-arylsufonyl-L-argininamides are isolated by filtration of the catalyst followed by evaporation of the solvent, and then purified by trituration or recrystallization from a suitable solvent, such as diethyl ethertetrahydrofuran, diethyl ether-methanol and water-methanol, or may be chromographed on silica gel or alumina. US patent 2,854,380 discloses a dosage form of reserpine with a vehicle having a stabilizing effect on the reserpine chemically and which also enhances the physiological activity of reserpine. A vehicle, presented as a most preferred one, is a combination of propylene glycol, sorbitol and ethanol in water. The use of sorbitol in the vehicle increases chemical stability and therapeutic effect. The sorbitol also improves the taste of the preparation in an oral dosage form and eliminates the need for preservatives since it sweetens the preparation without providing a fermentation medium for contaminating organisms. Both propylene glycol and ethanol act as solvents for reserpine which is practically insoluble in aquaeous media and not only contribute to the chemical stability of the reserpine but also bring about a more rapid onset of physiological effect. An article titled: "Einführung in die Verfahrenstechnik der Arzneiformung" (Introduction to the processing techniques in the production of drugs) by Dr. Fritz Gstirner, 1973 edited by the "Wissenschaftliche Verlagsgesellschaft MBH, Stuttgart, pages 271-272 discloses a process for improving the solubility of a drug principles which include both a hydrophobic and hydrophilic parts, by improving the capacity of said hydrophobic parts of being hydrated (hydrotropia) by "hydrotropic" additives, e.g. monohydric or polyhydric alcohols, such as ethanol, benzylic alcohol, glycols (propylenglycol, butylenglycol) glycerin, as well as esters and ethers of glycols and amides. The invention provides a method for dissolving arginineamide comprising dissolving N²-arylsulfonyl-L-arginineamide having the general formula (I) The invention can use the salts of the arginineamide having the general formula (I). The salts may be acid addition salts prepared by reacting with any inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, maleic acid, succinic acid, lactic acid, tartaric acid, gluconic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. Further, the salts may be inorganic or organic salts prepared by reacting organic or inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, N, N′-dibenzylethylenediamine and N-ethylpiperidine. In the method for dissolving an arginineamide according to the invention, the arginineamide and/or its salt is dissolved in a solvent of ethanol and water. A mixture of ethanol and glycerin can be used. Water used in the invention is generally distilled water or purified water, but a physiological saline or Ringer's solution may be used. The mixed ratio (by weight) of alcohol to water in the above solvent is generally 0.1 to 10, preferably 0.2 to 5 and more preferably 0.3 to 3. Saccharides can be admixed with the solvent of alcohol and water in the invention. As saccharides used in the invention, monosaccharides, oligosaccharides, polysaccharides and their reduced derivatives (for example sugaralcohol) which are soluble in water are mentioned. Among them, glucose, fructose, maltose, saccharose and D-sorbitol each of which has a high solubility in water are preferable. D-sorbitol is particularly preferable. A mixture of these saccharides may be used. The mixed ratio (by weight) of saccharide (if present) to water is generally 0.1 to 10, preferably 0.4 to 4 and more preferably 0.5 to 2. The manner how to dissolve the arginineamide having the general formula (I) in the solvent of alcohol and water and optionally saccharide is not particularly limited. Generally, the saccharide is dissolved in water and then the alcohol is added thereto followed by mixing. Next, the arginineamide is slowly added while stirring until complete dissolution. The temperature on dissolution is not particularly limited. When the saccharide is dissolved in water, however, it is preferable to warm water at 40 to 70°C for accelerating the dissolution rate. It is necessary to take care for preventing the evaporation of ethanol, for example by cooling the solution to room temperature before the dissolution, or dissolving in a closed container. The concentration of arginineamide in the solution can be selected within the wide range depending on the intended uses. According to the invention, the solution in which the arginineamide is dissolved at high concentration, for example from several times to several thousands times the solubility of arginineamide in water can be obtained. The solution containing the arginineamide having the general formula (I) in the solvent of ethanol water and glycerin or saccharide thus obtained can constitute the pharmaceutical composition of the invention. The pharmaceutical compositions of the invention are useful for treating thrombosis. Accordingly, the pharmaceutical compositions can be used as the anti-thrombotic agents. The pharmaceutical composition of the invention may contain antiseptics, anti-oxidants, soothing agents and pH-controlling agents. And, if necessary any pharmaceutical ingredient(S) other than the arginineamide may be added to form a combined preparation. The pharmaceutical composition of the invention can be as an injection. This injectable composition may prepared contain stabilisers, buffers preservatives and which are acceptable for the injection and may be added in addition to the above-mentioned ingredients. If desired, the injectable composition according to the invention is prepared containing the arginineamide at very high concentration, and is used by diluting with water, electrolyte, carbohydrate solution or Ringer's solution on application such as by infusion or dialysis. Alternatively, the pharmaceutical composition of the invention is topically applicable as a solution for topical application, or is useful for the production of an ointment or a suppository. When the pharmaceutical composition is used as a solution for topical application, the solution prepared above can be used as it is. And, the ointment or the suppository of the invention may be prepared by dissolving the solution prepared above in a base. EXAMPLES The invention will now be further described by the following, non-limiting examples. Example 1 (2R, 4R)-1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid (argipidine) was dissolved in a solvent of ethanol and water while varying the mixed ratio of ethanol to water at 20°C () or 5°C (○ ). This results are shown in Fig. 1. In Fig. 1, the ordinate is the solubility of argipidine in the solvent (mg/ml) and the abscissa is the weight percentages of ethanol and water (w/w %). As shown in Fig. 1, the solubility of argipidine in the solvent comprising 70% by weight of ethanol and 30% by weight of water at 20°C was 33.23 mg/ml ant that at 5°C was 10.73 mg/ml. Comparative example 1 Argipidine was dissolved in the aqueous sorbitol solution while varying the sorbitol concentration at 20°C. The result was shown in Fig. 2. In Fig. 2, the ordinate is the solubility of argipidine in the aqueous sorbitol solution (mg/ml) and the abscissa is the concentration of sorbitol in the aqueous solution (w/w %). As shown in Fig. 2, the solubility of argipidine in the aqueous sorbitol solution was low and it was the substantially same as the solubility of argipidine in water. Example 2 Argipidine was dissolved in a solvent comprising an aqueous 25% sorbitol solution (○ ), an aqueous 50% sorbitol solution (□ ) or a 70% sorbitol solution (▵ ) and ethanol while varying the mixed ratio of ethanol to the aqueous sorbitol solution at 30°C. The results are shown in Fig. 3. In Fig. 3, the ordinate is the solubility of argipidine in the solvent (mg/ml) and the abscissa is the weight percentages of the aqueous sorbitol solution and ethanol (w/w %). Example 3 Argipidine was dissolved in a solvent comprising an aqueous 33% glucose solution (○ ), an aqueous 50% glycerine solution (▵ ), a 50% sorbitol solution () or an aqueous 50% sucrose solution (□ ) and ethanol while varying the mixed ratio of ethanol to the aqueous solution at 30°C. The results are shown in Fig. 4. In Fig. 4, the ordinate is the solubility of argipidine in the solvent (mg/ml) and the abscissa is the weight percentages of the aqueous solution and ethanol (w/w %). Example 4 The distilled water for injection (200 g) was placed in a one-litre beaker, to which D-sorbitol (300 g) was added with stirring and dissolved. At this time, if necessary the solution may be heated. Then, ethanol (400 g) was added and mixed with stirring followed by adding argipidine (100 g) with stirring until complete dissolution. The thus-obtained solution can be used for dialysis after diluting it with the weak acidic solution containing D-sorbitol. Example 5 The distilled water for injection (200 g) was placed in a one-litre beaker, to which glucose (200 g) was added with stirring and dissolved. Then, ethanol (400 g) was added and mixed with stirring followed by adding argipidine (100 g) with stirring. Further, the distilled water for injection was added till the total volume of the solution became 1 litre. The thus-obtained solution can be used for drip infusion after diluting it with the aqueous sorbitol solution, the aqueous D-sorbitol solution or Ringer's solution on use. Example 6 The distilled water for injection (200 g) was placed in a one-litre beaker, to which -sorbitol (300 g) was added with stirring and dissolved. At this time, if necessary the solution may be heated. Then, glycerine (200 g) and ethanol (200 g) were added and mixed with stirring followed by adding argipidine (100 g) with stirring. Further, the distilled water for injection was added till the total volume of the solution became 1 litre. The thus-obtained solution can be used for dialyses after diluting the weak acidic solution containing D-sorbitol. EFFECT OF THE INVENTION According to the method for dissolving the arginineamide of the invention, the injection containing an arginineamide having the general formula (I) and/or their salts, particularly at high concentration can be obtained.

Claims: 1. A method for dissolving an arginineamide comprising dissolving N²-arylsulfonyl-L-arginineamide represented by the formula (I): or a salt thereof or both in a solvent containing ethanol, water and a third component consisting of glycerin and or a saccharide. 2. The method according to claim 1, wherein the third component is a saccharide and the saccharide is at least one selected from sorbitol, glucose, maltose, fructose and sucrose. 3. The method according to claim 2, wherein the saccharide is D-sorbitol. 4. The method according to claim 1, wherein the mixed ratio of ethanol to water in the solvent is 0.1 to 10. 5. The method according to claim 4, wherein the mixed ratio of ethanol to water in the solvent is 0.2 to 5. 6. The method according to claim 5, wherein the mixed ratio of ethanol to water in the solvent is 0.3 to 3. 7. The method according to claim 1 alone or in combination with any of claims 2 to 6, wherein the mixed ratio of saccharide to water is 0.1 to 10. 8. The method according to claim 7, wherein the mixed ratio of saccharide to water is 0.4 to 4. 9. The method according to claim 8, wherein the mixed ratio of saccharide to water is 0.5 to 2. 10. A pharmaceutical composition for injection comprising N²-arylsulfonyl-L-arginineamide represented by the formula (I): or a salt thereof or both in solubilized form in a mixture of ethanol, water and a third component consisting of glycerin and or a saccharide, as defined. 11. The composition according to claim 10, wherein the third component is saccharide and said saccharide is sorbitol, glucose, maltose, fructose or sucrose. 12. The composition according to claim 11, wherein the third component is a saccharide and said saccharide is D-sorbitol. 13. The composition of claim 10, wherein said third component is glycerin.

Inventors: NOMURA, TATSUO 1-303 MITSUBISHI-KASEI-DAIICHI, OFUCHI, KUNIHIKO 1-204 MITSUBISHI-KASEI-DAINI
Applicants: MITSUBISHI KASEI CORPORATION
Application year: 1988
Main classification: A61K47
IPC codes: A61K31, C07K5, A61P7, A61K38, A61K9, A61K47, C07K1