JPS6219531A - Stable human angiotensin agent - Google Patents

Abstract

PURPOSE:To provide the titled drug preparation containing human-type angiotensin in combination with a specific stabilizing agent and useful as a hypertensive agent. CONSTITUTION:The objective human-type angiotensin agent contains (A) human- type angiotensin and (B) one or more stabilizers selected from gelatin, albumin, acidic polysaccharide (e.g. chondroitin sulfate, dextran sulfate, heparin, etc.), acidic amino acid (e.g. glutamic acid, aspartic acid, etc.) and organic acid (e.g. citric acid, lactic acid, tartaric acid, malic acid, etc.). The amounts of gelatin and albumin are preferably 1-1,000pts.wt., and the amounts of the other components are 1-500pts.wt. each per 1pt.wt. of angiotensin. EFFECT:Since the decomposition of angiotensin in the dissolved solution is suppressed and the stability of angiotensin is improved remarkably, the agent is convenient for production, treatment and storage.

Description

[Detailed description of the invention] The present invention relates to stable human angiotensin formulations.

Angiotensin is an important peptide hormone that forms the renin-angiotensin system, known as the renal pressor system, and is said to exhibit the strongest pressor activity among known substances. For this reason, it has traditionally been used to treat patients in a state of shock, but in recent years, with advances in cancer chemotherapy, it has come to be widely used as a vasopressor agent in vasopressor cancer chemotherapy, which is one of the new treatment methods, and has been used clinically. It is also becoming an important therapeutic drug.

Angiotensin is a biological component of various animals, but some of the constituent amino acids differ depending on the animal species; for example, the amino acid at position 5 differs between humans and cows. Although bovine angiotensin and its derivatives have been used as conventional therapeutic agents, human angiotensin is most preferred as a therapeutic agent for humans.

Since angiotensin is rapidly metabolized and inactivated in vivo, it is usually provided as an injection. It can also be prepared as an injection solution that has been dissolved in advance, but since angiotensin gradually decomposes in the solution, it must be stored in a cool place or used as soon as possible. Therefore, it is preferable to use a lyophilized preparation that is dissolved before use.

However, since angiotensin has extremely strong pressor activity, the amount used at one time is very small (less than 1 da), and it is necessary to add appropriate excipients to form a freeze-dried preparation. However, when a freeze-dried preparation of angiotensin was prepared by adding sugars such as mannitol and glucose, which are commonly used as excipients for freeze-dried preparations, and a storage test was conducted, sufficient stability of angiotensin was not obtained. .

In view of the above situation, the present inventors conducted intensive research to obtain a stable preparation of angiotensin. By adding a specific compound to an aqueous solution of angiotensin, the present inventors found that by adding a specific compound to an aqueous solution of angiotensin, it was possible to obtain a stable preparation of angiotensin. We found that the stability of angiotensin in solution increases significantly after dissolving it.

The present invention is a human angiotensin preparation containing human angiotensin and one or more stabilizers selected from the group consisting of gelatin, albumin, acidic polysaccharides, acidic amino acids, and organic acids.

Angiotensin includes angiotensin 1, angiotensin ■, and angiotensin I, and the main physiologically active substance is angiotensin ■. Angiotensin I is converted to angiotensin ■ by a converting enzyme and shows pressor activity, but angiotensin 1 shows almost no activity. Therefore, the angiotensin used in the present invention is ASI) -Arg -Val -Tyr -11
eu -Hls -Pro -Phe -His -L
Human angiotensin expressed as eu! , Asp.
-Arg -Val -Tyr -11eu -His
-Pro -Phe human angiotensin n and their N-terminal Asp are β-ASpsβ-
They are derivatives of human angiotensin (2) and angiotensin (2) such as D-AGp and ASp (NH2).

The gelatin used in the present invention is obtained by treating animal bones etc. with acid or alkali to produce collagen and then heating and extracting it with water, as well as those obtained by repolymerizing them and other products used for pharmaceutical purposes. There is no particular limitation if
Those having a molecular weight of 2,000 to 10,000 are preferred. As albumin, bovine albumin, egg albumin, human albumin, etc. can be used, but human albumin is preferred from the viewpoint of antigenicity.

The amount of gelatin and albumin used is preferably 1 to 1000 parts by weight per 1 part by weight of angiotensin.

As the acidic polysaccharide, the polysaccharide ethyl sulfate is preferred, and in addition to natural products such as chondroitin sulfate and heparin, dextran sulfate obtained by sulfating dextran can be used. These acidic polysaccharides are usually used as sodium salts, but other salts such as potassium salts may also be used.
It may be a free acid. The amount used is preferably 1 to 500 parts by weight per 1 part by weight of angiotensin.

Preferred acidic amino acids include glutamic acid and aspartic acid, which are usually used as sodium salts.
Other salts such as potassium salts may be used, or free amino acids may be used. The amount used is preferably 1 to 500 parts by weight per 1 part by weight of angiotensin.

As the organic acid, oxyacids such as citric acid, lactic acid, tartaric acid, and malic acid are preferable, and these acids may be free acids,
It may also be a salt with sodium or the like. The amount used is preferably 1 to 500 parts by weight per 1 part by weight of angiotensin.

Note that glucose, fructose, mannitol, sorbitol, xylitol, dextran, etc., which are commonly used as excipients for freeze-dried preparations, can be added to the preparation of the present invention. It is also possible to add isotonizing agents such as sodium chloride, various buffering agents such as phosphates, and pH adjusting agents such as hydrochloric acid, acetic acid, and sodium hydroxide. The pH of the aqueous solution is 2.
0 to 8.0, particularly pH 4.0 to ZO.

To manufacture the formulation of the present invention, angiotensin, a stabilizer, a buffer, and excipients as necessary are dissolved in distilled water for injection, the pH is adjusted, sterile filtered, and then filled into ampoules etc. The solution may be prepared as an injection, or this solution may be freeze-dried using a conventional method to obtain a freeze-dried preparation.

The angiotensin preparation thus obtained is in an aqueous solution,
Since the decomposition of angiotensin in the lyophilized preparation and in the solution after dissolving the lyophilized preparation is suppressed and the stability is significantly improved, it is extremely convenient for the use of angiotensin in production processes, treatment, storage, etc.

Example 1 Human angiotensin l110m9 Gelatin 500m90.
02M phosphate buffer (1) H5,5) Total volume 100
m/! After preparing an aqueous solution with the above composition and sterile filtration, it is filled in 1 ml portions into vials and freeze-dried to obtain a freeze-dried preparation.

Aqueous solutions having the compositions of Examples 2 to 7 are prepared, and freeze-dried preparations are obtained in the same manner as in Example 1.

Example 2 Human angiotensin I 10 ■ Gelatin 5 oor 9 Glutamic acid 50 ■ Sodium hydroxide Appropriate amount Distilled water for injection Total volume 1 o Oml pH 5,5 Example 3 Human angiotensin II 10 ~
Gelatin 500 ■ Citric acid 20 (1 ■ Sodium hydroxide Appropriate amount Distilled water for injection
Total amount 100g pH5.0 Example 4 Human angiotensin II 10 ■ Sodium dextran sulfate 1250"'l;
'l; Distilled water total amount 100mJ
pH 6,0 Example 5 Human angiotensin field 1101n Sodium heparin 500 ~ Distilled water for injection Total amount 100 pH 6,
5 Example 6 Human angiotensin l 107Wl
;1 Citric acid 2001
n9 Mannitol 1250 ■ Sodium hydroxide Adequate amount Distilled water for injection Total amount 100 mJ pH 5,0 Example 7 Human angiotensin II 10 ■
Sodium chondroitin sulfate 5oo1n9 citric acid
2007Q Mannitol 125orn9 Sodium hydroxide Appropriate amount Distilled water for injection
Total volume 100ml pH 5.0 Example 8 Human angiotensin It 10~
Gelatin 10orru
y Salt 850■0.
02M acetate buffer (1) H5,5) Total volume 10
After preparing an aqueous solution with the above composition and sterile filtration, fill ampoules with 1 ml each and melt and seal to obtain an injection solution.

Comparative example human angiotensin II' l0m
9 Mannitol 1250m9
0.02M phosphate buffer (pH 5,5) total volume 1
00m/Above composition - An aqueous solution is prepared and treated in the same manner as in Example 1 to obtain a lyophilized preparation.

Test Examples The preparations of Examples 1 to 7 and the preparations of Comparative Example were stored at 40°C for 6 months or at 50°C for 6 months, and then the residual rate of human angiotensin (III) was determined by high performance liquid chromatography. The results are shown in the table below. The formulations of the present invention are known to be extremely stable compared to comparative formulations.

Applicant: Toa Eiyo Co., Ltd. Agent: Patent attorney: Tadashi Ko Hayashi, 1 Yugai Procedural amendment (voluntary) Near day October 1986

Claims (1)

[Claims] 1. Human angiotensin, gelatin, albumin,
A human angiotensin preparation comprising one or more stabilizers selected from the group consisting of acidic polysaccharides, acidic amino acids, and organic acids. 2. The human angiotensin preparation according to claim 1, wherein the acidic polysaccharide is chondroitin sulfate, dextran sulfate and/or heparin. 3. The human angiotensin preparation according to claim 1, wherein the acidic amino acid is glutamic acid and/or aspartic acid. 4. The human angiotensin preparation according to claim 1, wherein the organic acid is citric acid, lactic acid, tartaric acid and/or malic acid.