JPH0479327B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to kallidinogenase formulations, and more particularly to stable kallidinogenase tablet formulations. Callidinogenase is an enzyme in the body of animals, and is present in urine, serum, saliva, sweat, tears, submandibular gland, pancreas, accessory sex glands, liver, etc., and is used as a drug to treat cerebrovascular disorders, coronary heart disease, and hypertension. It is an extremely important substance used in the treatment of peripheral limb blood circulation disorders, Meniere's syndrome, etc. Kallidinogenase is an extremely unstable substance, and its stability further decreases as the degree of purification increases. Therefore, various proposals have been made to minimize the decrease in activity in its extraction and purification and preparation processing. In other words, for extraction and purification, an adsorption recovery method using an inorganic adsorbent or a combination of this and gel filtration is used, and for pharmaceutical processing, amino acids and glyoxal, which have been known as enzyme stabilizers, are used. , glutaraldehyde, ethylenediamine, etc. have been used. However, even when these general-purpose stabilizers are used in the processing of pharmaceutical preparations, it has not been possible to sufficiently suppress the decrease in activity over time. For this reason, the present applicant previously proposed the use of albumin as a stabilizer in Japanese Patent Application No. 55-183816 (Japanese Unexamined Patent Publication No. 57-108020). Although this known method using albumin as a stabilizing agent is advantageous in increasing the stability of kallidinogenase over time, there are problems in its formulation. For example, when making tablets for oral administration, tableting processing is required, but kallidinogenase activity decreases even when pressurized, so it could not be expected to maintain the pharmacological effect at a high level. Moreover, the fact is that stabilization methods for the formulation of highly purified purified products of kallidinogenase, which have extremely low stability, have not even been studied in the past. In view of this, the present inventors conducted extensive research and found that albumins and at least one member selected from basic amino acids, celluloses, casein, casein hydrolysates, gelatin, and gelatin hydrolysates can be stabilized. By adding a curing agent to the formulation, stability against heat and pressure is improved, and long-term storage at room temperature and tableting are possible.Therefore, we have discovered that even highly purified kallidinogenase can be used as a pharmaceutical raw material. A patent application was filed for the formulation [Japanese Patent Application No. 16119/1983
161925)]. However, after further research, it was unexpectedly discovered that a kallidinogenase preparation with excellent stability against heat and pressure could be obtained without adding albumin, leading to the completion of the present invention. That is, the essential feature of the present invention is the use of gelatin and casein hydrolyzate as stabilizers for kallidinogenase. Therefore, according to the present invention, gelatin and a casein hydrolyzate as a stabilizer are added and mixed to a kallidinogenase solution, and an excipient is added to a kallidinogenase composition obtained by spraying or freeze-drying, and the mixture is formulated by a conventional method. A stable kallidinogenase tablet formulation is provided. The content of the stabilizer in the kallidinogenase composition for the kallidinogenase tablet preparation according to the present invention is 0.005-40.0 mg per unit of kallidinogenase.
is appropriate. As excipients used in formulation, known excipients such as lactose, starch, crystalline cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc. can be used. The preparations according to the invention are treated in a manner customary per se with an aqueous dispersion of hydroxypropyl methylcellulose phthalate dissolved in a non-toxic organic solvent or with other suitable lacquers, such as copolymers of methyl methacrylic acid and methacrylic acid. This is then coated with a gastric juice-resistant coating, thereby making it possible to form an enteric-coated preparation. Next, the present invention will be explained in more detail using production examples and stability test examples. Note that the activity of kallidinogenase was determined by a method of measuring esterase activity using benzoyl arginine ethyl ester. Comparative Example 1 4.0 g of mannitol was added to and dissolved in a 1.2 million KU/400 ml solution of canodinogenase, and then spray-dried. The powder obtained had an activity of 210,000 KU/g, as per the theoretical value. This powder was compressed into tablets using a rotary press to give 50 KU/tablet. The activity of this tablet at the end of tablet compression was 83% of its pre-molding activity. Comparative Example 2 10.0 g of bovine serum albumin was added to a 1.6 million KU/400 ml solution of kallidinogenase (specific activity 1500 KU/mg) and mixed, spray-dried, then lactose was added,
It was compressed into tablets using a rotary press to give 50 KU/tablet. The resulting tablets showed an activity of 42.5 KU/tablet. Comparative Example 3 6.0 g of gelatin was added to and mixed with a 1.2 million KU/400 ml solution of kallidinogenase, spray-dried, lactose was added, and the mixture was compressed into 50 KU tablets using a rotary press. The resulting tablets exhibited 86% activity relative to their pre-molding activity. When this tablet (uncoated tablet) was stored in a constant temperature bath at 50°C for 21 days, the activity was measured, and it was found that the activity decreased to 89% when the activity immediately after tableting was taken as 100%. Production example 2.0 g of gelatin and 4.0 g of casein hydrolyzate were added to and mixed with 1.2 million KU/400 ml solution of kallidinogenase, spray-dried, then lactose was added and tableted using a rotary press to give 50 KU/tablet. Molded. The resulting tablets have 98% of their pre-molding activity.
activity. Stability test In order to examine the stability over time of each tablet (uncoated tablet) obtained by the method described in Production Example and Comparative Examples 1 and 2, these tablets were stored in a thermostat at 40°C and 50°C to determine their activity. When measured, the changes in activity were as shown in the table below.

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Claims (1)

[Scope of Claims] 1 Gelatin and casein hydrolyzate as stabilizers were added to and mixed with a kallidinogenase solution, and an excipient was added to the kallidinogenase composition obtained by spraying or freeze-drying and tableting was performed by a conventional method. , a stable kallidinogenase tablet formulation. 2 The content of the stabilizer in the kallidinogenase composition is 0.005-0.005 per unit of kallidinogenase.
The tablet preparation of kallidinogenase according to claim 1, which is 40.0 mg. 3. The tablet preparation of kallidinogenase according to claim 1, wherein the excipient is at least one of lactose and crystalline cellulose.