JPH0452252B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a kallidinogenase preparation,
In particular, it relates to a method for producing stable kallidinogenase tablet preparations. Callidinogenase is an enzyme in the body of animals and is present in urine, serum, saliva, sweat, tears, submandibular gland, pancreas, accessory gonads, kidneys, etc., and is used as a medicine to treat cerebrovascular disorders, coronary heart disease, and hypertension. It is an extremely important substance used in the treatment of peripheral blood circulation disorders in the extremities, 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 reduction in activity regarding its extraction, purification, and preparation processing. That is, for extraction and purification, an adsorption recovery method using an inorganic adsorbent or a combination of this with a gel filtration method, etc. is used, and for pharmaceutical processing, amino acids, which have been known as enzyme stabilizers, are used. , glyoxal, glutaraldehyde, ethylenediamine, etc. have been added. However, even with the use of these commonly used stabilizers, it has not been possible to sufficiently suppress the decrease in activity over time. The present applicant has also already proposed the use of albumin as a stabilizer (JP-A-57-
108020 Publication). Although the method using albumin as a stabilizer is effective in suppressing the decline in activity of kallidinogenase over time and increasing stability,
There are challenges in its formulation. This is because, for example, when preparing a tablet for oral administration, a tableting process is required, but since kallidinogenase also loses its activity when pressurized, the activity of kallidinogenase is already reduced immediately after being formulated. This is because it has become clear that the pharmacological effect cannot be expected to be maintained at a high level. Moreover, the fact is that stabilization methods for formulating highly purified purified kallidinogenase products with extremely low stability have not even been studied. Therefore, the main object of the present invention is to provide a method for producing a tablet preparation of kallidinogenase that has excellent stability, particularly stability against heat, has a low rate of activity decline over time, and can be stored for a long period of time at room temperature. be. An additional object of the present invention is to prepare a tablet preparation of kallidinogenase which is excellent in stability against pressure and shows only a slight decrease in activity even when it is compressed into tablets, and which can be made into tablets using high-purity kallidinogenase as a raw material. Our goal is to provide a manufacturing method for According to the invention, these objects include a first stabilizer which is albumin and a second stabilizer which is a substance selected from the amino acids L-arginine and L-lysine, methylcellulose and casein hydrolyzate. This is achieved by a process for producing a stable kallidinogenase tablet preparation, which is characterized by adding excipients to a kallidinogenase composition obtained by adding and mixing the kallidinogenase solution to a kallidinogenase solution, and then spray-drying the resulting kallidinogenase composition, and then tableting by a conventional method. That is, according to the method of the present invention, since high-purity kallidinogenase is used as a raw material and spray drying is performed without using the conventional freeze-drying method when preparing a powdered kallidinogenase composition, the processing time is significantly shortened, and moreover, the processing time is significantly reduced. The stability of the resulting tablet formulation is comparable to or even better than that obtained using a lyophilized product. When producing kallidinogenase tablet preparations by the method of the present invention, albumin derived from bovine serum, human serum, or egg white can be used as albumin. The content of the stabilizer in the kallidinogenase composition for kallidinogenase tablet formulation is suitably 0.01-40.0 mg as the first stabilizer, albumin, and 0.005-40.0 mg as the second stabilizer, per unit of kallidinogenase. 20.0mg is appropriate. Lactose or crystalline cellulose can be used as an excipient for formulation. Incidentally, using a solution of hydroxypropyl methylcellulose phthalate dissolved in a non-toxic organic solvent or an aqueous dispersion of a suitable other lacquer, such as a copolymer of methyl methacrylic acid and methacrylic acid, and by a method known per se. Tablet formulations can also be processed to provide gastric juice-resistant coatings, thereby making them enteric-coated formulations. Next, the present invention will be explained in more detail and concretely using production examples and stability test examples. In these examples, kallidinogenase activity was measured by an esterase activity measurement method using benzoyl arginine ethyl ester. Comparative Example 1 10.0 g of bovine serum albumin was added and mixed to a 1.6 million KU/400 ml solution of kallidinogenase (specific activity 1500 KU/mg), 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. Production example 1 0.5 g of L-arginine and L-arginine to 1.2 million KU/400 ml solution of kallidinogenase (specific activity 1500 KU/mg)
0.5 g of lysine was further mixed with 1.0 g of bovine serum albumin, spray-dried, lactose was added, and the mixture was compressed into tablets using a rotary press to give 50 KU/tablet. The resulting tablets are 96% active before molding.
activity. Production Example 2 A composition obtained by adding and mixing 3.0 g of ovalbumin and 1.0 g of methyl cellulose to a 1.2 million KU/400 ml solution of kallidinogenase and then spray drying the solution was 200,000 KU/400 ml.
It showed an activity of KU/g. Lactose was added to this composition, and the composition was compressed into tablets using a rotary press to give 50 KU/tablet. The resulting tablets exhibited 98% activity relative to their pre-molding activity. Production Example 3 2.0 g of bovine serum albumin and 4.0 g of casein hydrolyzate were added to and mixed with 1.2 million KU/400 ml solution of kallidinogenase and spray-dried, then lactose was added,
It was compressed into tablets using a rotary press to give 50 KU/tablet. The resulting tablets exhibited 98% activity relative to their pre-molding activity. Comparative Example 2 4.0 g of albumin was added and dissolved in a 1.2 million KU/400 ml solution of kallidinogenase, and then crystalline cellulose was added to the powder obtained by freeze-drying, and the amount was adjusted to 50 KU/tablet using a rotary press. It was molded into tablets. The resulting tablets exhibited 100% activity relative to their pre-molding activity. Reference Example Each tablet (uncoated tablet) described in Production Examples 1 to 3 and Comparative Examples 1 to 2 was enteric coated using hydroxypropyl methyl cellulose phthalate by a conventional method, and then coated with gelatin, gum arabic powder, granulated sugar, and Sub-coating was performed using precipitated calcium carbonate, and a sugar layer was further formed using granulated sugar to obtain sugar-coated tablets. In this case, the decrease in activity from preparation to completion of sugar-coated tablets was within 6%, except for Comparative Example 1. Comparative Example 1 showed a decrease of 18%. Comparative Example 3 4.0 g of mannitol was added and dissolved in a solution of 1.2 million KU/400 ml of kallidinogenase, and the powder obtained by spray drying had an activity of 210,000 KU/g, as per the theoretical value. This powder was compressed into tablets of 50 KU/tablet using a rotary press. The activity of this tablet at the end of tablet compression was 83% of the activity before molding. Stability test In order to examine the stability over time of each tablet (uncoated tablet) obtained by the method described in Production Examples 1 to 3 and Comparative Examples 1 and 3, these tablets were stored in a thermostat at 40°C and 50°C. When the activity was measured, the changes in activity were as shown in the table below. Compared to Comparative Example 3, a very high stabilizing effect was observed in Production Examples 1 to 3.

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Claims (1)

[Scope of Claims] 1. A first stabilizer, which is albumin, and a second stabilizer, which is a substance selected from amino acids L-arginine and L-lysine, methylcellulose, and casein hydrolyzate, are mixed in a kallidinogenase solution. 1. A method for producing a stable tablet preparation of kallidinogenase, which comprises adding an excipient to a kallidinogenase composition obtained by mixing and spray-drying the kallidinogenase composition, and then tableting by a conventional method. 2. The method for producing a tablet preparation of kallidinogenase according to claim 1, which uses lactose or crystalline cellulose as an excipient.