JPS60161925A - Stable pharmaceutical preparation of kallidinogenase - Google Patents

Abstract

PURPOSE:The titled pharmaceutical preparation, obtained by blending kallidinogenase as a stabilizer with an albumin and a basic amino acid, etc., spray-drying or lyophilizing the blend to give kallidinogenase composition, processing it into oral pharmaceutical preparation. CONSTITUTION:1 unit kallidinogenase as a stabilizer is blended with 0.01-40mg albumin (e.g., bovine serum albumin, globulin, etc.), 0.005-20.0mg basic amino acid (e.g., L-alginine, L-lysine, etc.), and at least one selected from cellulose (e.g., carboxymethyl cellulose, etc.), casein, casein hydrolyzate, gelatin, and gelatin hydrolyzate, the blend is spray-dried or lyophilized to give a kallidinogenase composition, which is optionally mixed with an excipient (e.g., mannitol, etc.), processed into oral pharmaceutical preparation, to give stable pharmaceutical preparation of kallidinogenase. Tablet, granule, capsule, etc. may be used as the dosage form.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to preparations of kallidinogenase, and more particularly to stable kallidinogenase preparations.

Callidinogenase is an enzyme in the body of animals, and is present in urine, self-extinguishing fluids, saliva, sweat, tears, submandibular glands, pancreas, accessory sex glands, kidneys, etc., and is used as a drug to treat cerebrovascular disorders, coronary heart disease, etc. It is an extremely important substance that is used in the treatment of hyperartic pressure, distal limb locomotor disorder, Menier'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 for extraction 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. , geltaraldehyde, ethylenediamine, etc. have been used. However, even when these general-purpose stabilizers are used in pharmaceutical processing, it has not been possible to sufficiently suppress the decline in activity over time. For this reason, the present applicant first proposed the use of albumin as a stabilizing agent in a patent application filed in 1983.
This was proposed in No. 183816 (Japanese Unexamined Patent Publication No. 57-108020). Although this known method of 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 purified products of kallidinogenase, which have extremely low stability, have not even been studied in the past.

Therefore, the main object of the present invention is to provide a kallidinogenase preparation 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.

An additional object of the present invention is to provide a preparation of kallidinogenase which is excellent in stability against compression and can be made into tablets using high-strength kallidinogenase as a raw material, since its activity is only slightly reduced even when it is compressed into tablets. There is a particular thing.

According to the present invention, these objects are achieved by adding albumin as a stabilizer to kallidinogenase and at least one member selected from basic amino acids, celluloses, casein, casein hydrolyzate, gelatin, and gelatin hydrolyzate. This is achieved by forming a stable kallidinogenase preparation by adding excipients, if desired, to a kallidinogenase composition obtained by adding, mixing, spraying or freeze-drying, and preparing an oral preparation by a conventional method.

When producing the preparation according to the present invention, bovine serum albumin, human self-consuming albumin, ovalbumin, etc. and globulins can be used as albumins, and L-arginine, L-lysine, etc. can be used as basic amino acids. can be used.

The content of albumin or globulins in the kallidinogenase composition is 0.0 per unit of kallidinogenase.
1 to 40 vaa is suitable, and the content of stabilizers such as basic amino acids is suitably 0.005 to 20.0+a, and salts thereof such as hydrochlorides can also be used. As celluloses, salts such as carboxymethylcellulose and methylcellulose, such as sodium salts, can be used.

Excipients used in formulation may include, for example, mannitol, lactose, sucrose, etc. In particular, in tabletting, known excipients such as lactose, starch, crystalline cellulose, polyvinylvinylvinylidene may be used. , hydroxypropyl cellulose, etc. can be used.

The preparations according to the invention are prepared in a manner customary per se using solutions of hydroxypropyl methylcellulose phthalate in non-toxic a-solvents or aqueous dispersions of suitable other lacquers, such as copolymers of methyl methacrylic acid and methacrylic acid. It can be processed to provide a gastric juice-resistant coating, thereby making it an enteric-coated preparation.

Next, the present invention will be explained in more detail using reporting examples and stability test examples. These pupil sides are all related to tablets, and were selected as examples to show that the reduction rate of kallidinogenase activity is low even when the preparation according to the present invention is compressed into tablets. It should be noted that the formulation according to the invention can be made into various oral dosage forms other than tablets, such as granules, powder, capsules, etc., by conventional methods. Note that the activity of kallidinogenase was determined by a method of measuring esterase activity using benzoyl arginine ethyl ester.

Stop ttr kallidinogenase 1.6 million KU/400+e Q, WI
To the liquid (specific activity 1500 KU/a+o) was added and mixed 10.00 Ushimukai albumin and spray-dried, then lactose was added and the mixture was compressed into tablets using a rotary press to give 50 KU/tablet. The resulting tablets exhibited an activity of 42.5 KU/tablet.

m kallidinogenase 1.2 million Ill/400+a (L solution (specific activity 1500 KU/10) with L-arginine 0.
5a and 0.50 of lysine were further mixed with 1.0 g of bovine serum albumin, spray-dried, then lactose was added, and the mixture was compressed into tablets using a rotary press to give a concentration of 50 KLJ/l. The resulting tablets had an activity of 96% before molding.
% activity.

Gai 1" Shishi kallidinogenase 1.2 million KU/400++ Q solution with ovalbumin 3.0 g and methyl cellulose 1. Og
The composition obtained by adding and mixing and then spray drying showed an activity of 200,000 KU10. Adding lactose to this composition,
It was compressed into tablets using a rotary press to give a weight of 50 KLJ/tablet. The resulting tablets have an activity of 98% for their pre-molding activity.
% activity.

4. Mouse 1.2 million KU of kallidinogenase/400 dilution solution with 2.0 g of bovine serum albumin and casein hydrolyzate. Oa
were added and mixed and spray-dried, then lactose was added and the mixture 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.

11L kallidinogenase 1.2 million KU/400m Q solution with albumin 4. Og was added and dissolved, and crystalline cellulose was added to the powder obtained by freeze-drying, and the mixture was compressed into tablets using a rotary press to give 50 KU/tablet.

The resulting tablets exhibited 100% activity relative to their pre-molding activity.

11 Each tablet (uncoated tablet) described in Production Examples 1 to 3 and Comparative Examples 1 to 2
Then, enteric coating was applied using hydroxypropyl methylcellulose phthalate by a conventional method.
Next, sub-coating was performed using gelatin, gum arabic powder, granulated sugar, and precipitated calcium carbonate, and a sugar layer of granulated sugar was further formed to form a sugar-coated tablet.

In this case, the decrease in activity from preparation to completion of sugar-coated tablets was within 6%, except for Comparative Example 1. 1 for comparative example 1
It showed a decrease of 8%.

The activity of the powder obtained by adding and dissolving 4.0 g of mannitol into the solution of lateral 11 branch kallidinogenase was 210,000 KU10, as per the theoretical value.
Met. 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 its pre-molding activity.

E L911 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 placed in a thermostat at 40°C and 50°C. When the product was stored and its activity was measured, the activity curve was as shown in the table below. Compared with Comparative Example 3, a very strong stabilizing effect was observed in Examples 1 to 3.

Table 1 (stored at 40℃) Table 2 (Stored at 50℃)

Claims (1)

[Claims] (1) Adding and mixing albumin as a stabilizer to kallidinogenase and at least one selected from basic amino acids, celluloses, casein, casein hydrolyzate, gelatin and gelatin hydrolyzate, A stable kallidinogenase preparation prepared by adding excipients, if desired, to a kallidinogenase composition obtained by spraying or freeze-drying to form an oral preparation by a conventional method. (2) The kallidinogenase preparation according to claim 1, wherein the amount of the stabilizer per unit of kallidinogenase in the kallidinogenase composition is 0.005 to 40.0 wo. (2) The kallidinogenase preparation according to claim 1, wherein the excipient is at least one of lactose and crystalline cellulose. (4) The kallidinogenase preparation according to claim 1, which is a compressed tablet. ■ Claim 1, which is a compressed tablet and is coated with an m-soluble coating. The kallidinogenase preparation described in section.