JPS61180723A - Composition for formulating easily absorbable kallidinogenase - Google Patents

Abstract

PURPOSE:The titled composition obtained by incorporating at least one selected from basic amino acids, celluloses and mucopolysaccharides as an absorption promoter with kallidinogenase. CONSTITUTION:A composition for formulating easily absorbable kallidinogenase, obtained by incorporating 0.1-40.0mg, based on 1,000 units kallidinogenase, at least one selected from basic amino acids, e.g. L-arginine, L-lysine or L- histidine, celluloses, e.g. methyl cellulose or carboxymethyl cellulose, and mucopolysaccharides, e.g. mucin, chondroitin sulfate, hyaluronic acid or keratosulfate, as an absorption promoter with the kallidinogenase, and having good absorbability through the intestinal tracts. In producing the above- mentioned composition, albumin, e.g. bovine serum albumin or casein, etc., may be used as a stabilizer together, and the amount to be incorporated is preferably 0.1-200mg based on 1,000 units kallidinogenase as described above.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a composition for a preparation of kallidinogenase, and particularly to a composition for an easily absorbable kallidinogenase preparation that has good absorbability from the intestinal tract.

(Prior art) Callidinogenase is an in vivo enzyme that exists in the urine, serum, saliva, sweat, tears, submandibular line, pancreas, accessory sex glands, kidneys, etc. of animals, and it is extracted from these and used as a medicine for treating cerebrovascular disorders, coronary artery disease, etc. It is an extremely important substance used in the treatment of sexual heart disease, hypertension, limb peripheral blood circulation disorder, Meniere's disease syndrome, etc.

Kallidinogenase is a crosslinkable and unstable substance, and therefore, it is necessary to suppress the decrease in its activity as much as possible not only in its extraction and purification but also in preparation processing. For this reason, the present applicant proposed the use of albumin as a stabilizing agent when formulating kallidinogenase in Japanese Patent Application No. 55-183816 (Japanese Unexamined Patent Publication No. 57-108020), and in Japanese Patent Application No. 59-16119. proposed the use of at least one of basic amino acids, cellulose, casein, casein hydrolyzate, gelatin, and gelatin hydrolyzate in combination with albumin, but it was subsequently found that the combination with albumin was not necessarily necessary. Patent Application No. 8115
No. 9-24961 further proposed the use of at least one of basic amino acids, cellulose, casein, casein hydrolyzate, gelatin, and gelatin hydrolyzate as a stabilizer.

(Problems to be Solved by the Invention) Generally common to enzyme proteins, kallidinogenase also has a problem in that the amount absorbed into the body is extremely small compared to the amount administered, and its utilization efficiency is low. be.

Therefore, an object of the present invention is to increase the chargeability of kallidinogenase from the audience, thereby improving its utilization efficiency and, by extension, its medicinal efficacy.

(Means and effects for solving the problem) Said patent application filed in 1973
As a result of further research related to the stabilized kallidinogenase preparations according to No. 9-16119 and No. 59-24961, basic amino acids and celluloses not only contribute to the stabilization of kallidinogenase formulations, but also contribute to the stabilization of kallidinogenase. was found to be effective as an absorption enhancer. Furthermore, as a result of searching for other kallidinogenase absorption enhancers, it was found that mucopolysaccharides were also effective, leading to the completion of the present invention.

Therefore, the composition for an easily absorbable kallidinogenase preparation according to the present invention is characterized in that at least one selected from basic amino acids, celluloses, and mucopolysaccharides is blended with kallidinogenase as an absorption enhancer.

Basic amino acids that are absorption enhancers in the composition of the present invention include L-fulginine, L-lysine, histidine, etc., and salts thereof, such as sulfates; examples of celluloses include methyl cellulose, Examples of the mucopolysaccharides include mucin, fundroitin sulfate, hyaluronic acid, Examples include keratosulfate and heparan sulfate.

The composition according to the present invention is produced by adding and mixing at least one of the above-mentioned substances as an absorption enhancer to a kallidinogenase solution, and then subjecting this mixture to a conventional operation such as spraying or freeze-drying. can do. In this case, the blending amount of the absorption enhancer is kallidinogenase 1
Approximately 0.1 to 40.011 per 000 units is appropriate. Of course, when producing the composition according to the present invention, albumins such as bovine serum albumin, human serum albumin, and ovalbumin, and casein or casein hydrolyzate can be used in combination as a stabilizing agent. The compounding amount of the agent is 0 per 1000 units of kallidinogenase.
．． Approximately 1 to 20,010 is appropriate.

The composition according to the present invention can be excipientated if necessary.
By adding agents, binders, disintegrants, and lubricants, preparations for oral administration, such as tablets, granules, and capsules, can be prepared by conventional methods, especially those coated with enteric coating. It can be done.

(Manufacturing Examples, etc.) Next, the present invention will be described in more detail with reference to comparative examples, manufacturing examples, and test examples.

Mannitol 1,09 is added to the solution (specific activity 1500 KU/II!7) and dissolved, and then this solution is spray-dried to obtain a composition for a kallidinogenase preparation. I got something.

This powder composition is prepared by adding and mixing appropriate amounts of lactose and crystalline cellulose, and presses the powder composition to 50Kt using a rotary press.
The tablets were compressed into J/ tablets, and an enteric coating was applied to make enteric-coated tablets.

Production example 1 kallidinogenase 400,000 KLJ/10ONI Q solution (
2005 g of each of L-lysine hydrochloride and L-arginine hydrochloride were added and dissolved in a specific activity of 1500 KLI/meal Q), and this solution was then spray-dried to obtain a composition for kallidinogenase preparation.

In addition, this powdered composition is mixed with appropriate amounts of lactose and crystalline cellulose, and is made into 50 KU by a rotary press.
/ It was compressed into tablets, and an enteric coating was applied to make the enteric-coated tablets.

Production Example 2 Same as Production Example 1, except that L-lysine hydrochloride and L-hydrochloride
- A composition for a kallidinogenase preparation was obtained by using 1.2 g of sodium fundroitin sulfate in place of 200 so each of arginine.

This powdered composition was also made into enteric-coated tablets in the same manner as in Production Example 1.

Mouse 1'' LL In the same manner as in Production Example 1, except that L-lysine hydrochloride and L-hydrochloride
- A composition for a kallidinogenase preparation was obtained by using 1.2 g of carboxymethyl cellulose sodium in place of each 200 mg of arginine.

This powder composition was also made into enteric-coated tablets in the same manner as in Production Example 1.

Anonymous kallidinogenase 400,000 KLI/100e Q solution (specific activity 1500 KU/sg) and bovine serum albumin 1.3 g
was added and dissolved, and this solution was then spray-dried to obtain a composition for kallidinogenase preparation.

In addition, this powdered composition is mixed with appropriate amounts of lactose and crystalline cellulose, and is made into 50 KU by a rotary press.
/ Compressed into tablets and coated with enteric coating.
It was made into a molten tablet.

Production example 4 Bovine serum albumin 600,110 in kallidinogenase 400,000 KU/100 μl solution (specific activity 1500 KU/mu)
and 300 weight each of L-lysine hydrochloride and L-arginine hydrochloride were added and dissolved, and this solution was then spray-dried to obtain a composition for kallidinogenase preparation.

In addition, this powdered composition is mixed with appropriate amounts of lactose and crystalline cellulose, and is made into 50 KU by a rotary press.
/ It was compressed into tablets, and an enteric coating was applied to make the enteric-coated tablets.

Production Example 5 Same as Production Example 4, except that bovine serum albumin was added to 1.2
9 and 0 each of L-lysine hydrochloride and L-arginine hydrochloride
．． A composition for kallidinogenase preparation was obtained using 6 g.

This powder composition was prepared in the same manner as in Production Example 4, except that 10
It was made into enteric-coated tablets containing 0KLJ/tablet.

UuL (Effects due to the use of absorption enhancers) (1) Experimental animals Male domestic rabbits weighing 2.0 to 2.5 Ko (Japanese native species, Hibushi Uves Co., Ltd.) ■Test substance and dose A (first control subject) ): kallidinogenase 1000 KU/animal A-1 (second control): kallidinogenase 1000 KU bovine serum albumin 1.0-M animal Composition B according to the present invention: kallidinogenase 1000 KU L-lysine hydrochloride 0.5 ma Shishunshi monofulginine 0. 51aQ/Animal B-1=
Kallidinogenase 1000KLJ L-lysine hydrochloride
1.0-〇L-arginine hydrochloride 1. Oa.

Bovine serum albumin 1. Osa/Animal B-2: Kallidinogenase 1000KLI L-lysine hydrochloride
0.75■9 Fundamental L-Arginine 0.751
+1 bovine serum albumin 1.5g+g/nasal 8-
3 Nicalidinogenase 1000KU L-lysine hydrochloride
0.519 L-arginine hydrochloride 0.5 mg Bovine serum albumin 2.0-g/Animal C: Kallidinogenase 1000 KU Sodium chondroitin sulfate 1.0 IQ/Animal D: Callidinogenase 1000 KLJ Carboxymethyl cellulose major thorium 1.0 IQ/Animal E: Kallidinogenase 1000 KU Gastric mucin 1.0IQ/animal (3) Obtaining kallidinogenase specimen (by rabbit mesenteric vascular perfusion method) After fasting healthy laboratory animals for 2 days, subcutaneously injected with urethane 1.5o/KQ. Under anesthesia by injection, the abdomen is opened and the lower ileum is controlled by 30 to 40 cm! Cannulae were placed in the arteries and veins and both ends were ligated, and the test substance described in section %02-saturated with 5% CO2));
The perfusate that has reached the venous side is collected at regular intervals and used as a sample.

(4) P is a substrate for measuring the kallidinogenase activity of the specimen
ro -P re -A rg-M CA (prolyl-
7-enylalanyl-arginine-4-methylcoumaryl-
7-amide) (0,046μm0Q>50μm and sample 1
00+Q, 105M phosphate buffer 750μ and 5B
The reaction was carried out at 37°C for 15 minutes in the presence of TI (1000 μa/we) 100+42, then cooled on ice and treated with 10% acetic acid 2.
The reaction was stopped by adding 0 μQ, and its fluorescence intensity (1:xcit: 380 nl
, ElSS, : 460 nm), and based on a separately prepared calibration curve, this measured value is converted into kallikrein units and used as the kallidinogenase activity.

■Results The results are shown in the table below, and it was found that the absorption of kallidinogenase was improved by using basic amino acids, cellulose, or mucopolysaccharide together with kallidinogenase, and it was also stabilized as a third component. It can be seen that the combined use of a curing agent (albumin) does not adversely affect the absorbability of kallidinogenase.

Table ■ (Effects of the Invention) The same problem has arisen in that kallidinogenase has low absorbability and therefore its utilization efficiency is low even when administered as a kallidinogenase preparation.However, according to the composition for kallidinogenase preparation of the present invention, the absorption of kallidinogenase is low. Absorption properties, particularly from the intestinal tract, are improved. Even if albumin or the like is present as a stabilizer in the composition of the present invention, this does not adversely affect the absorbability of kallidinogenase.

Therefore, when the composition according to the present invention is further formulated, a stabilizer can be added thereto if necessary, and therefore, a decrease in the activity of kallidinogenase can be prevented as much as possible.

Claims (6)

[Claims] (1) A composition for an easily absorbable kallidinogenase preparation, characterized in that at least one selected from basic amino acids, celluloses, and mucopolysaccharides is blended with kallidinogenase as an absorption enhancer. (2) The amount of absorption enhancer is kallidinogenase 1000
Composition according to claim 1, characterized in that the amount is 0.1 to 40.0 mg per unit. (3) The composition according to claim 1 or 2, wherein the basic amino acids are selected from L-arginine, L-lysine, L-histidine, and salts thereof. . (4) Celluloses include methylcellulose, carboxymethylcellulose, carboxymethylethylcellulose,
Claim 1, characterized in that the cellulose is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose and salts thereof.
Or the composition according to item 2. (5) The composition according to claim 1 or 2, wherein the mucopolysaccharide is selected from mucin, sodium chondroitin sulfate, hyaluronic acid, keratosulfate, and heparan sulfate. (6) Any one of claims 1 to 3, wherein the absorption enhancer is selected from basic amino acids and contains equal amounts of L-lysine hydrochloride and L-arginine hydrochloride. A composition according to one.