JPH0570368A - Peripheral vascular disease therapeutic agent - Google Patents

Abstract

PURPOSE:To provide a peripheral vascular disease therapeutic agent comprising kallidinogenase as an active ingredient, having reduced adverse actions and excellent use safety, and useful as an external agent. CONSTITUTION:The agent contains a biologically produced enzyme, kallidinogenase. in an amount of 1-1000 kallidinogenase international units (IU)/g as an active ingredient. If necessary, 0.1-10wt.% of a citrate salt is further added as a stabilizer to the agent. The agent is prepared into a preparation shape such as an external cream, external gel ointment, external solution or cataplasm. The external agent different from conventional oral agents and injections permits the effective arrival of the kallidinogenase to a diseased site because of being locally administered. The agent is useful also for hidebound disease, Raynaud's syndrome, venous diseases, etc. The kallidinogenase is extracted from the pancreas of a pig or originated from human urine.

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for peripheral vascular disorders, and more particularly to a therapeutic agent for peripheral vascular disorders containing calidinogenase as an active ingredient. [0002] Calizinogenase is an enzyme produced in the pancreas and excreted in urine. It forms kallidin from kininogen and directly or indirectly affects water electrolyte metabolism in the kidney. Are thought to act on the hypotensive system, and various cardiovascular disorders such as hypertension,
It is useful as a therapeutic drug for peripheral vascular disorders, angina, etc. Conventionally, callizinogenase extracted mainly from the pancreas of pigs has been orally or injected and administered for the purpose of treating the above cardiovascular disorders.However, when kallidinogenase is administered by the oral or injection route for the treatment of peripheral vascular disorders, it is locally administered. Since the amount of calidinogenase reached is extremely small, a large amount and long-term administration are required, and as a result, side effects may occur. From this viewpoint of safety, recently, instead of porcine pancreas, a calidinogenase originating in human urine has attracted attention. However, even if it is a calcinogenase derived from human urine, side effects may occur when a large amount of it is orally or injected and administered over a long period for the purpose of treating peripheral vascular disorders. OBJECTS OF THE INVENTION Therefore, an object of the present invention is to provide a therapeutic agent for peripheral vascular disorders, which is a kalidinogenase preparation and has no or extremely low risk of side effects. Means and Actions for Solving the Problems [0012] The inventors of the present invention have conducted extensive studies on the administration method, therapeutic effect, etc. of calidinogenases of various origins, and found that they have transdermal absorbability. The present invention has been completed by finding out that the above has. Therefore, the therapeutic agent for peripheral vascular disorders according to the present invention is characterized in that it is an external preparation containing calydinogenase as an active ingredient. That is, the therapeutic agent for peripheral vascular disorders according to the present invention has a formulation form externally different from conventional oral preparations and injection preparations, and can be effectively administered with calidinogenase to the affected part because it is locally administered. Therefore, it is possible to significantly reduce the possibility of side effects. Examples of the dosage form of the therapeutic agent for peripheral vascular disease according to the present invention include external creams, external gel ointments, external liquids and poultices. A citrate salt may be added for the purpose of stabilizing the main agent, calidinogenase. The amount of this citrate is sodium citrate
0.1-10% by weight is preferred. The therapeutic agent for peripheral vascular disorders according to the present invention is useful not only for the treatment of pure peripheral vascular disorders but also for the treatment of various skin diseases considered to be caused by quasi-peripheral vascular disorders such as scleroderma, Raynaud's syndrome and venous diseases. Is. Since the therapeutic agent for peripheral vascular disease according to the present invention is an external preparation, the possibility of side effects is extremely low. Therefore, the calidinogenase as the main component may be derived from other animals than humans, and its stabilization is also possible. It can also be a calidinogenase modified with a derivative such as polyethylene glycol. In formulating the therapeutic agent for peripheral vascular disorders according to the present invention, conventional pharmaceutical carriers such as petrolatum, glycerin and cyclodextrin, triethanolamine and tween are used.
A conventional absorption aid such as (mark) can be blended. The amount of calidinogenase to be mixed is determined depending on the type and degree of the disease, but it is generally preferable to be within the range of 1-1000 international units (IU) / g of calidinogenase. , Etc. have been used, but then "IU" or "International Unit
it "IU") unified]. [Manufacturing Examples, etc.] Next, the present invention will be described in more detail and specifically by reference examples, manufacturing examples and test examples. Reference Example 1 (Production Method of Modified Calizinogenase) 2-o-Methoxypolyethylene glycol-4,6-dichloro-S-
200 mg of triazine and 25 mg of calidinogenase were added to 0.1M.
After reacting for 2 hours in a borate buffer solution under low temperature conditions, ultrafiltration and lyophilization were performed to obtain polyethylene glycol-modified calidinogenase. Production Example 1 (cream for external use) The following ingredients were mixed to prepare an external cream. Porcine pancreatic Karijinogenaze 0.5 (g) (110 million in the biological unit) of diethyl Sodium benzoate 0.5 sebacic acid 10.0 Polyoxyethylene oil ether sodium phosphate 6.0 Petrolatum remaining part Total 100.0 [0011] Production Example 2 (topical gel ointment) following various The ingredients were mixed to prepare a gel ointment for external use by a conventional method. Production Example 3 (External Solution) The following ingredients were mixed to prepare an external solution by a conventional method. Production Example 4 (External Hap Agent) 1.5 g of sodium polyacrylate and Carbopol 90
(Mark) 0.6 g was mixed, the following components were added thereto, purified water was added to make the total amount 100 g, and then the mixture was further mixed to prepare a haptic substrate. Gelatin 6 (g) Tween 80 (mark) 3 Glycerin 30 Calizinogenase 1 (2.2 million biological units) The above-mentioned suppository substrate is coated on a suppository carrier to a thickness of 3 mm or less To
A poultice containing 500,000 biological units was obtained. Test Example 1 (Transdermal Absorption Test) The present applicant has developed a urinary calidinogenase assay reagent, which is commercially available as “Naftest-UK (mark)”. Accordingly, the transdermal absorbability of the preparation according to the present invention was investigated. a) Cut off the abdominal skin of the test male rat, apply the suppository according to Formulation Example 4, and after 60 minutes, 1 cm ² of this skin with physiological saline.
The sample was immersed in 10 ml and stirred for 120 minutes to give a sample. b) Reagent i) Prepared using 0.03% sodium laurate buffer solution 1
00 mM phosphate buffer (pH 7.0). ii) Substrate prolyl phenylalanyl arginine naphthyl ester
Prepared by adding purified water to (PPANE) 5.56mg to make the total volume 3ml. iii) Prepared by adding purified water to 60 mg of the color-developing agent Fast Red ITR salt to make the total volume 6 ml. iv) Antitropin agent 4-methyl-1- [N- (3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid (MD-805) Was prepared so as to contain 10 ^-4 g per 1 ml of the above buffer. v) Using pure glacial acetic acid as a reaction terminator. c) Calizinogenase assay test method 0.1 ml each of the above sample, buffer solution, substrate, and anti-tropin agent was collected, mixed with stirring, and then at 37 ° C.
Shake for 30 minutes. Next, 0.1 ml of the above color-developing agent was added, and the mixture was stirred and allowed to stand at 37 ° C for 5 minutes.
The azo dye forming reaction is stopped by adding 0 ml. The absorbance of the obtained solution was measured at a wavelength of 475 nm within 1 hour after the addition of glacial acetic acid. On the other hand, using a pure calidinogenase instead of the above sample, set the calidinogenase concentration to various values and carry out the same method as above to prepare a standard calibration curve plotting the relationship between the absorbance and the calidinogenase concentration. Oita. The absorbance value measured on the above-mentioned sample is collated with the absorbance value on this standard calibration curve to obtain the calidinogenase concentration for the sample. d) Test result The measured concentration of calidinogenase in the sample is 0.035 NU / ml.
(NU: α-naphthol unit), which revealed that the calidinogenase is transdermally absorbable. Test Example 2 (Acute toxicity) Calizinogenase is an enzyme (glycoprotein) produced by a living body, and its toxicity varies depending on the species of the source animal, and physicochemically varies depending on the source animal. Therefore, it is difficult to ascertain the safety in clinical use from the results of animal experiments, but the acute toxicity when orally or intravenously administering to humans the calidinogenase of human urine origin is as follows:
Considering that the therapeutic agent for peripheral vascular disorders according to the present invention is an external preparation, it can be said that the toxicity of the preparation according to the present invention is extremely low. [0016] Test Example 3 (Transdermal Absorption Test) It is the action of the calidinogenase to confirm peripheral vascular disorder therapeutic activity of the calidinogenase in animal experiments because it is difficult to prepare a diseased animal and test the inhalation and discharge. The percutaneous absorption of nitroglycerin, which is considered to be caused by the action, was examined. a) Test method Male Wistar rats weighing 245-410 g were shaved on the back, and 50 mg of nitroglycerin ointment (1 mg / animal as nitroglycerin) on a lint cloth and 50 mg of gel ointment according to Preparation Example 2 (11 IU / calydinogenase as 11). Was applied to conduct a percutaneous absorption test of nitroglycerin. On the other hand, as a control test, a lint cloth coated only with nitroglycerin ointment was applied to the shaved back of the rat to conduct a percutaneous absorption test of nitroglycerin.
Absorbability was determined by comparing the nitroglycerin concentration in plasma with Pete S.
K. et al. ["J. Pharm. Soc." Vol. 67, p. 584 (1978)
Year)]]. b) Test results Both test and control groups reached the maximum concentration after 15 minutes, and the nitroglycerin concentration value was 14 mg / ml in the test group.
And the control group was 11 mg / ml. This indicates that the calidinogenase enhances the transdermal absorbability of nitroglycerin, in other words, the calidinogenase itself has the transdermal absorbability. Test Example 4 (Usage Test) Targeted at persons who feel numbness in the fingers during cold weather and persons who have keratoderma symptoms and are considered to have quasi-peripheral vascular disease. The topical cream was given for 10 days and used as an alternative to hand cream for 10 days, after which the symptom i) improved, ii) I think it is improving, iii) It remained the same as before, and iv) It worsened. As a result of conducting a questionnaire survey on the therapeutic effect in each category, all respondents answered “improved” or “I think it is improving”, and the effectiveness of the therapeutic agent according to the present invention was confirmed. EFFECTS OF THE INVENTION Conventionally, the formulation of the calidinogenase administered for the purpose of treating peripheral vascular disorders is oral or injectable, and therefore, a large amount is required to ensure that a sufficient amount of the drug reaches the affected area. It was necessary to administer the drug, and it took a long time to treat this kind of disease, which could cause side effects. Therefore, it has been considered to use human urinary calidinogenase in place of porcine pancreatic calidinogenase, which has a high possibility of causing side effects, but there is still concern about the possibility of side effects due to large-scale and long-term use. On the other hand, the therapeutic agent for peripheral vascular disorders according to the present invention contains calidinogenase as an active ingredient, but is an external preparation, and since calidinogenase is percutaneously absorbed and acts on the affected area, conventional oral preparations and injections are used. When compared with the above, the amount reaching the affected area increases and the possibility of side effects is low.

Claims (1)

What is claimed is: 1. A therapeutic agent for peripheral vascular disorders, which is an external preparation containing calidinogenase as an active ingredient. [2] The therapeutic agent for peripheral vascular disorders according to claim 1, wherein the dosage form is selected from a cream for external use, a gel ointment for external use, a liquid preparation for external use, and a hap. [3] A therapeutic agent for peripheral vascular disorders, which is an external preparation containing carizinogenase as an active ingredient and containing citrate. [4] Sodium citrate 0.1-
The therapeutic agent for peripheral vascular disorders according to claim 3, characterized in that it is contained in an amount of 10% by weight.