JPH04108737A - Corticortopin-releasing factor-containing pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain the subject freeze-dried pharmaceutical, containing an additive selected from a water-soluble polymer and a basic amino acid and stable for a long period. CONSTITUTION:A corticotropin-releasing factor (CRF)-containing freezedried pharmaceutical is obtained by adding a water-soluble polymer selected from gelatin, albumin, dextran and polyvinylpyrrolidone or/and a basic amino acid selected from arginine, lysine and histidine in an amount of 10-500 pts.wt. based on 1 pt.wt. CRF thereto. Furthermore, an isotonizing agent, a solubilizing agent, a preservative, a pH adjuster, etc., as necessary, are added. The pH of the aforementioned pharmaceutical is preferably within the range of pH3-4 or 6.5-8 in aspects of stability of the CRF itself and solubility of the CRF.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to corticotropin-releasing factor (Corti
cotropin Releasing Factor
, hereinafter sometimes abbreviated as CRF. ), and more specifically to long-term stable CRF-containing freeze-dried preparations.

[Prior art and problems to be solved by the invention] CR
F is a polypeptide consisting of 41 amino acids, and is a type of hormone secreted from the hypothalamus that is known to exist in rats, sheep, humans, etc. CRF is adrenocorticotropic hormone (adrenocorticotropic hormone).
It has the effect of acting on cells producing ACTH and promoting the secretion of ACTH, and is expected to be used as a diagnostic and therapeutic agent for pituitary gland, adrenal gland function, etc.

Like other physiologically active peptides, CRF cannot be administered orally because it is degraded by digestive juices in the gastrointestinal tract and is poorly absorbed, so it is usually administered by injection, especially intravenously.

However, CRF is extremely unstable in solution and solid state, and when developed as a pharmaceutical product, it was expected that it would be extremely difficult to ensure stability from manufacture to use.

Generally, known methods for stabilizing peptide preparations include adding sugars such as glucose, sucrose, and lactose, and sugar alcohols such as mannitol, sorbitol, and xylitol, and then freeze-drying them. Regarding this compound, we also attempted to study a system in which several types of saccharides were added, but no good results were obtained. Further, since the main decomposition product is an oxidized product of methionine contained in the CRF molecule, attempts were made to add an antioxidant, but no good effect was obtained.

[Means for solving the problem] As a result of intensive studies to improve the stability, it was discovered that the stability of CRF was significantly improved by adding a water-soluble polymer and/or a basic amino acid. The present inventors have discovered that the present invention has been completed.

That is, the present invention resides in a frozen preparation containing adrenocorticotropin-releasing factor, which contains one or more additives selected from water-soluble polymers and basic amino acids.

The present invention will be explained in detail below.

Examples of water-soluble polymers used in the present invention include gelatin, albumin, dextran, polyvinylpyrrolidone, etc., and examples of basic amino acids include arginine, lysine, histidine, etc.

One or more of these water-soluble polymers and basic amino acids are used in appropriate combination. The amount of water-soluble polymer and basic amino acid to be added is preferably 10 to 500 parts by weight per 1 part by weight of CRF.

If the amount added is less than the above range, it is difficult to store CRF stably for a long time, and if it is more than the above range, the solubility of the additive becomes a problem, which is not preferable.

The preparation of the present invention can contain pharmaceutically acceptable isotonic agents, solubilizers, preservatives, pH adjusters, etc., as necessary.

Examples of the above-mentioned tonicity agent include sodium chloride, glucose, mannitol, etc. Preservatives include paraoxybenzoic acid esters, chlorobutanol, phenol, etc., and pH adjusters include citric acid, acetic acid, phosphorus, etc. Acids include tartaric acid, lactic acid, and their sodium salts, potassium salts, and sodium hydroxide.

In addition, the pH is preferably pH 3 to 8 from the viewpoint of stability of CRF itself, but at pH 4 to 6.5, the solubility of CRF is 0.1.
It is not preferable because it is less than μg/ml. Therefore, the pH of the formulation is preferably in the range of pH 3 to 4 or pH 6.5 to 8.

[Example 1] The present invention will be explained in more detail with reference to Examples and Test Examples below, but the present invention is not limited by these Examples.

Example I Dissolve 10 mg of CRF and 100 mg of purified gelatin in water for injection and adjust the pH to 3.5 with citric acid, total volume 50 ml.
And so. This solution was aseptically filtered, dispensed into vials in 0.5 ml portions, and lyophilized using a conventional method to prepare an injection.

Example 2 10 mg of CRF and 100 mg of human serum albumin were dissolved in water for injection, adjusted to pH 3.5 with citric acid, and the total amount was 5.
It was set to 0m1. This solution was aseptically filtered, dispensed into vials in 0.5 ml portions, and lyophilized using a conventional method to prepare an injection.

Example 3 Dissolve 10 mg of CRF and 200 mg of L-arginine in water for injection and adjust the pH to 7.5 with citric acid, total amount 50 m
It was set to 1. This solution was aseptically filtered, dispensed into vials in 0.5 ml portions, and lyophilized using a conventional method to prepare an injection.

Example 4 Dissolve 200 mg of CRFlomg and L-histidine in water for injection and adjust the pH to 7.5 with citric acid, total volume 50 ml.
And so. This solution was aseptically filtered, dispensed into vials in 0.5 ml portions, and lyophilized using a conventional method to prepare an injection.

Example 5 10 mg of CRF, 200 mg of L-arginine and 100 mg of purified gelatin were dissolved in water for injection, and the pH was adjusted to 7.5 with citric acid to make the total volume 50 ml. This solution was aseptically filtered, LO was dispensed into vials in 5 ml portions, and lyophilized using a conventional method to prepare an injection.

Comparative Example I Dissolve CRF Long and 200 mg of mannitol in water for injection and adjust the pH to 3.5 with citric acid, total volume 50 ml.
And so. This solution was aseptically filtered, dispensed into vials in 0.5 ml portions, and lyophilized using a conventional method to prepare an injection.

Comparative Example 2 10 mg of CRF and 200 mg of mannitol were dissolved in water for injection and adjusted to pH 7.5 with citric acid, total volume 50 ml.
And so. This solution was aseptically filtered, dispensed into vials in 0.5 ml portions, and lyophilized using a conventional method to prepare an injection.

Test Examples The injections prepared in Examples 1 to 4 and Comparative Examples 1 and 2 were stored in a constant temperature bath at 50°C, and the C
The residual rate of RF was measured by HPLC. The results are shown in Table 1, and it was found that the injection of the present invention had excellent stability.

〔Effect of the invention〕

In a lyophilized formulation containing CRF, by adding a water-soluble polymer and l or basic amino acids,
A long-term stable CRF formulation is obtained.

Claims (1)

[Claims] 1) 1 selected from water-soluble polymers and basic amino acids;
2) The formulation according to claim 1, wherein the water-soluble polymer is selected from gelatin, albumin, dextran, and polyvinylpyrrolidone. 3) The basic amino acid is arginine, The formulation according to claim 1, selected from lysine and histidine.