INJECTION OF NICARDIPINE HYDROCHLORIDE AND PRODUCTION THEREOF

Abstract: This invention provides an injection of nicardipine hy­ drochloride comprising an aqueous nicardipine hydrochlo­ ride solution containing 2 to 7 w/v % of polyhydric alcohol and having a pH of 2.5 to 5.5.

Description: This invention relates to an injection of nicardipine hydrochloride having cerebral vascular dilator activity, coronary dilator activity, and anti-hypertension activity; and to a process of producing the injection. Hitherto, oral administration formulations containing nicardipine hydrochloride have been available, but no satisfactory injection containing nicardipine hydrochloride has been developed. This is because the compound has reduced solubility in known isotonic aqueous injection media; thus in the presence of sodium chloride, which is usually used as an isotonizing agent for injections, it is only possible to obtain an aqueous nicardipine hydrochloride solution which is of too low concentration and/or of insufficient stability for satisfactory use as an injection. We have now found that when nicardipine hydrochloride is dissolved in water together with 2 to 7 w/v% of polyhydric alcohol, a stable isotonic aqueous solution of the nicardipine hydrochloride is unexpectedly obtained. According to this invention there is provided an injection of nicardipine hydrochloride containing 2 to 7 w/v% of polyhydric alcohol and preferably having a pH of 2.5 to 5.5. This invention also provides a process of producing an injection of nicardipine hydrochloride which comprises dissolving in water nicardipine hydrochloride and 2 to 7 w/v% of polyhydric alcohol based on the total injection, and if necessary adjusting the pH of the solution to 2.5 to 5.5, preferably 2.5 to 5.0. Even when the pH of the solution as initially formed is from 2.5 to 5.0 or 5.5, it may be preferred to adjust the pH to a specific desired value, e.g. 3.0,3.5 or 5.0. As polyhydric alcohols for use in this invention, there are e.g. sorbitol, mannitol, xylitol, propylene glycol, glycerol, inositol. They may be used alone or in admixture of any two or more. The polyhydric alcohol constitutes about 2 to 7, preferably about 5, w/v% of the whole amount of the injection. If the polyhydric alcohol should give insufficient isotonization when used at about 2 w/v%, the isotonization of the injection may be controlled by using other isotonizing agent. Also, if the pH of the injection is lower than 2, the stability of nicardipine hydrochloride is reduced, while if the pH is higher than 6, the solubility of nicardipine hydrochloride is reduced. The concentration of nicardipine hydrochloride in the injection of this invention is dependent upon the polyhydric alcohol concentration and the pH. By selecting appropriate conditions, a solubility of about 0.6 w/v% can be obtained. The injection of this invention can be prepared by dissolving predetermined amounts of nicardipine hydrochloride and polyhydric alcohol in water, e.g. at 50°C to 60°C, adjusting the pH(if necessary or desired), preferably to about 3.5, and then adjusting the volume of the solution to a predetermined volume by the addition of water. The pH of the solution can be controlled by mineral acid such as hydrochloric acid or, as the case may be, by base such as sodium hydroxide or sodium hydrogencarbonate. The injection of nicardipine hydrochloride thus obtained can maintain its desired concentration (higher than 0.1 w/v%) and can be stably stored for a long time without change in quality. In addition, it is preferred to use light-resistant ampoules for the injection. Tests on the solubility if nicardipine hydrochloride and the stability of nicardipine hydrochloride solutions are set out below : A. Effect of polyhydric alcohol (a) Storing at 60°C (i) Sample: The injection of Example 1: Sorbitol (5 w/v%) The injection of Example 2: Mannitol (5 w/v%) The injection of Example 3: Xylitol (5 w/v%) The injection of Example 4: Propylene glycol (5 w/v%) Control : An aqueous solution of nicardipine hydrochloride (0.1 w/v%, pH 3.5) containing no polyhydric alcohol. (ii) Storage conditions: Each sample was stored in a bath maintained at 60°C and sampled after the same definite periods. (iii)Quantitative determination: The quantitative determination was performed by high performance liquid chromatography (HPLC). Conditions of HPLC : Column: Nucleosil C₁₈ (150 x 4 mm ) Column temperature: 40°C Eluent: Methanol-0.01 M potassium hydrogenphosphate solution (18 : 7) Detection: Ultraviolet absorption detector Wave length 254 n. m. (iv) Result: The remaining percentage of nicardipine hydrochloride in each sampled solution is shown in the following table. (b) Storing at 100°C (i) Sample: The injection of Example 7: Sorbitol (2 w/v%) The injection of Example 8: Sorbitol (4 w/v%) The injection of Example 9: Mannitol (2 w/v%) The injection of Example 10: Mannitol (4 w/v%) The injection of Example 11: Xylitol (2 w/v%) The injection of Example 12: Xylitol (4 w/v%) The injection of Example 13: Propylene glycol (2 w/v%) The injection of Example 14: Propylene glycol (4 w/v%) Control : as for test A (a) above. (ii) Storage conditions: Each sample was stored in a chamber at 100°C and sampled after the same definite periods. (iii)Quantitative determination: as for test A (a) above. (iv) Result: The remaining percentage of nicardipine hydrochloride in each sampled solution is shown in the following table. B. Influence of pH (i) Sample: The injection of the Comparison example: pH 2.0 The injection of Example 15: pH 3.0 The injection of Example 16: pH 4.0 The injection of Example 17: pH 5.0 (ii) Test conditions: Each sample was stored in a chamber maintained at 100°C and sampled after the same definite periods. (iii)Quantitative determination: as for test A (a) above. (iv) Result: The remaining percentage of nicardipine hydrochloride in each sampled solution is shown in the following table. C. Comparative test of stability of sodium chloride/nicardipine hydrochloride solution and polyhydric alcohol/nicardipine hydrochloride solution. (i) Sample: (ii) Storage conditions: Each sample was stored in a chamber at 121°C for 6 hours. (iii) Results: D. Comparative test of the effects of sodium chloride and polyhydric alcohol on nicardipine hydrochloride solubility. (i) Solubility of nicardipine hydrochloride in 0.6w/v% sodium chloride solution. (ii) Solubility of nicardipine hydrochloride in 5w/v% sorbitol solution: The following Examples are intended to illustrate this invention Example 1 About 2 litres of distilled water was heated to 50 to 60°C and 2.5 g of nicardipine hdyrochloride and 125 g of sorbitol were dissolved therein with stirring. After cooling the solution (pH about 4.5) thus obtained to room temperature, the pH thereof was adjusted to 3.5 using 0.1 N hydrochloric acid. Then, the whole volume thereof was adjusted to 2.5 litres by the addition of distilled water and after filtering the solution, 5 ml. aliquots of the solution were filled into respective light-resistant brown ampoules. Example 2 By following the same procedure as Example 1 using the same amount of mannitol in place of sorbitol, an injection was obtained. Example 3 By following the same procedure as Example 1 using the same amount of xylitol in place of sorbitol, an injection was obtained. Example 4 By following the same procedure as Example 1 using the same amount of propylene glycol in place of sorbitol, an injection was obtained. Example 5 By following the same procedure as Example 1 using the same amount of glycerol in place of sorbitol, an injection was obtained. Example 6 By following the same procedure as Example 1 using the same amount of inositol in place of sorbitol, an injection was obtained. Example 7 By following the same procedure as Example 1 using 50 g of sorbitol, an injection was obtained. Example 8 By following the same procedure as Example 1 using 100 g of sorbitol, an injection was obtained. Example 9 By following the same procedure as Example 2 using 50 g of mannitol, an injection was obtained. Example 10 By following the same procedure as Example 2 using 100 g of mannitol, an injection was obtained. Example 11 By following the same procedure as Example 3 using 50 g of xylitol, an injection was obtained. Example 12 By following the same procedure as Example 3 using 100 g of xylitol, an injection was obtained. Example 13 By following the same procedure as Example 4 using 50 g of propylene glycol, an injection was obtained. Example 14 By following the same procedure as Example 4 using 100 g of propylene glycol, an injection was obtained. Example 15 About 2 litres of distilled water was heated to 50 to 60°C and 1.0 g of nicardipine hydrochloride and 125 g of sorbitol were dissolved therein with stirring. After cooling the solution (pH about 5.0) to room temperature, the pH of the solution was adjusted to 3.0 using 0.1 N hydrochloric acid. Then, the whole volume of the solution was adjusted to 2.5 litres by the addition of distilled water and after filtering the solution, 5 ml. aliquots of the solution were filled into respective light-resistant brown ampoules. Example 16 By following the same procedure as Example 15, but adjusting the pH of the solution to 4.0, an injection was obtained. Example 17 By following the same procedure as Example 15, but adjusting the pH of the solution to precisely 5.0 using 0.1 N sodium hydroxide in place of 0.1 N hydrochloric acid, an injection was obtained. Example 18 By following the same procedure as Example 1 using 62.5 g of sorbitol and 62.5 g of mannitol in place of 125 g of sorbitol, an injection was obtained. Comparison example By following the same procedure as Example 15 but adjusting the pH of the solution to 2.0, an injection was obtained.

Claims: An injection of nicardipine hydrochloride comprising an aqueous nicardipine hydrochloride solution containing 2 to 7 w/v % of polyhydric alcohol and having a pH of 2.5 to 5.5. An injection according to claim 1 wherein the polyhydric alcohol is selected from sorbitol, mannitol, xylitol, propylene glycol, glycerol, and inositol. An injection according to claim 1 or 2 having a pH of 2.5 to 5. A process of producing a nicardipine hydrochloride injection which comprises forming a solution of nicardipine hydrochloride and 2 to 7 w/v% of polyhydric alcohol (based on the whole amount of the injection) in water, the pH of the solution being 2.5 to 5.5. A process according to claim 4 wherein the polyhydric alcohol is selected from sorbitol, mannitol, xylitol, propylene glycol, glycerol, and inositol. A process according to claim 4 or 5 wherein the solution pH is 2.5 to 5, e.g. 3.5. A process according to any of claims 4 to 6 which comprises dissolving the nicardipine hydrochloride and polyhydric alcohol in water, adjusting the solution pH, and then adding water to adjust the solution to a predetermined volume.

Inventors: ARUGA, MASAYOSHI, KATAYASU, OGAWA, OHTANI, GO, YOKOTA, SHOJI
Applicants: YAMANOUCHI PHARMACEUTICAL CO. LTD.
Application year: 1985
Main classification: A61K9
IPC codes: C07D211, A61K9, A61K47, A61P9, A61K31