JP2002104976A - Heparin pharmaceutical preparation and method for stabilizing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a heparin pharmaceutical preparation excellent in stability. SOLUTION: This heparin pharmaceutical preparation comprises a heparin or its salt and is obtained by formulating citric acid, phosphoric acid, carbonic acid, trishydroxymethylaminomethane or its salt as a stabilizer. The method for stabilizing the heparin pharmaceutical preparation is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a heparin preparation and a method for stabilizing the preparation.

[0002]

2. Description of the Related Art Heparin is obtained from the liver, lung or intestinal mucosa of healthy edible animals and has an anticoagulant effect and a fat serum effect. Heparin is a sulfate ester of mucopolysaccharide and has a structure in which uronic acid and glucosamine are alternately 1,4 bonded. The molecular weight is about 5,000 to 20,000.

[0003] Sodium salts, calcium salts and the like are known as heparin preparations. Sodium salt is Japanese Pharmacopoeia product. Heparin sodium injection is an injectable solution containing 1000 units of sodium heparin per mL, and is a colorless to pale yellow clear aqueous solution.
5-8, the osmotic pressure ratio is about 1 (ratio to physiological saline).

[0004] This preparation also contains preservatives such as benzyl alcohol, methyl paraoxybenzoate and propyl paraoxybenzoate as additives. These additives are added for the purpose of preservation and preservation. In particular, benzyl alcohol is reported to cause respiratory distress and allergic reaction when administered in large amounts (Drug Intell. Cli).
n. Pharm. , 9, p154, published in 1975), and it cannot be said that there is no problem in terms of safety.
Since benzyl alcohol is adsorbed on a butyl rubber stopper, it is necessary to use a rubber stopper coated with Teflon (registered trademark) or the like, and since it is decomposed by light, it is necessary to store the preparation under light shielding ( Pharmaceutical Excipient Handbook, 316 pages, published by Maruzen Co., Ltd., 1988).

[0005] Furthermore, intermittent sterilization and the like have been adopted as sterilization methods for the preparations. However, since it is difficult to completely and completely sterilize these preparations alone, preservatives and preservatives must be used. It is currently used in combination. Therefore, the above problem has not been solved. In addition to using the preservatives and preservatives described above, techniques such as sterile filtration have been adopted.However, since heparin sodium does not have a pH buffering ability, the titer decreases as the pH decreases during the storage period. Is recognized.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a heparin preparation having excellent stability.

[0007]

Means for Solving the Problems The present inventors have conducted research in consideration of the above circumstances, and have found that citric acid, phosphoric acid, carbonic acid, trishydroxymethylaminomethane or a salt thereof is compounded as a stabilizer. Thus, the present inventors have found that a heparin preparation having excellent stability during heat sterilization and long-term storage can be prepared, and the present invention has been completed. Hereinafter, the present invention will be described in detail.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS As the heparin of the present invention, known ones can be used. That is, it is a sulfate of mucopolysaccharide obtained from the liver, lung or intestinal mucosa of a healthy edible animal and having a blood coagulation inhibitory action and a fat serum clearing action, in which uronic acid and glucosamine are alternately 1,4-linked. What is necessary is just to have a structure and a molecular weight of about 5000-20,000.

[0009] Heparin is prepared according to a known method. For example, a method disclosed in the Japanese Pharmacopoeia can be used.

Examples of the salt of heparin include sodium salt, calcium salt and the like. Sodium salt is available in the Japanese Pharmacopoeia and calcium salt is available in the British Pharmacopoeia.

[0011] Heparin sodium is a white or grayish brown powder or granules having no odor, slightly soluble in water, hardly soluble in ethanol or ether, and hygroscopic. Good.

In the present invention, the stability of the heparin preparation can be ensured and improved by blending citric acid, phosphoric acid, carbonic acid, trishydroxymethylaminomethane or a salt thereof. Examples of the salt include alkaline earth metal salts such as sodium and potassium, alkali metal salts such as calcium, and hydrochloride. The additive concentration is 0.
About 1 to 10 mM is exemplified.

The pH of the present preparation is preferably about 6 to 8. In the present preparation, the stability of the present preparation can be ensured and improved by providing a buffer capacity of pH 6 or more. Specifically, the pH of the present preparation can be adjusted to 6 or more, and a known pH adjuster having a buffering ability at the pH can be added.

In the present preparation, preservatives and preservatives, which are used in conventional heparin preparations, are not added in order to enhance safety.

The present preparation can be subjected to a heat sterilization treatment, thereby providing a safe preparation whose sterility is guaranteed. As a specific method of the heat sterilization, high-pressure steam sterilization and the like can be mentioned. The stability during autoclaving is ensured by the incorporation of the above stabilizer. Suitable conditions for high-pressure steam sterilization include a temperature of 105 to 1
For example, 30 ° C. and a time of about 1 to 60 minutes are exemplified.

The concentration of heparin or a salt thereof in the present preparation is, for example, about 1 to 1000 units / mL.
The osmotic pressure ratio may be a physiologically acceptable level, and specifically, is about 1 (ratio to physiological saline).

The preparation may be mixed with a salt such as sodium chloride and a saccharide such as glucose as a tonicity agent. PH of sodium hydroxide, potassium hydroxide, hydrochloric acid, etc.
You may mix | blend as a regulator.

The present preparation preferably has a sulfuric acid concentration equal to or less than the value determined by the following formula.

Sulfuric acid concentration (mmol / L) = heparin concentration (unit / mL) × 0.0006

That is, if the concentration of sulfuric acid contained in the present preparation is lower than the above value, the stability of the preparation is good, and if it exceeds the above value, the stability of the preparation deteriorates.

The heparin preparation of the present invention thus prepared has excellent stability during heat sterilization and long-term storage. Also, the light stability is well maintained.

The efficacy of this preparation is as follows: treatment of generalized intravascular blood coagulation syndrome, prevention of blood coagulation during use of extracorporeal circulation device, insertion of vascular catheter, transfusion and blood test,
Prophylactic treatment of thromboembolism and the like. When using, use as is or with glucose solution, physiological saline solution, Ringer's solution, etc.
Dilute to about 30 units / mL and inject intravenously, subcutaneously or intramuscularly.

[0023]

The present invention will be described in more detail with reference to Examples and Experimental Examples, which by no means limit the present invention.

Example 1 A heparin preparation (injection) having the following composition was prepared. That is, heparin sodium (Japanese Pharmacopoeia) 1
000 units, 9.0 mg of sodium chloride and sodium citrate (1 mM in final concentration) are dissolved in an appropriate amount of water for injection, and an appropriate amount of sodium hydroxide solution is added to make a total volume of 1 mL.
And Glass ampules were filled and subjected to high-pressure steam sterilization at 121 ° C. for 15 minutes. The obtained heparin preparation is a clear and colorless aqueous solution, having a pH of 6.55 and an osmotic pressure ratio of about 1
(Ratio to physiological saline).

Example 2 A heparin preparation (injection) having the following composition was prepared. That is, heparin sodium (Japanese Pharmacopoeia) 1
000 units of sodium citrate (1 mM in final concentration) were dissolved in an appropriate amount of water for injection, and an appropriate amount of sodium hydroxide solution was added to make a total volume of 1 mL. Glass ampules were filled and subjected to high-pressure steam sterilization at 121 ° C. for 15 minutes.

Comparative Example A heparin preparation (injection) having the following composition was prepared. That is, heparin sodium (Japanese Pharmacopoeia) 1
000 units and 9.0 mg of sodium chloride were dissolved in an appropriate amount of water for injection, and an appropriate amount of sodium hydroxide solution was added to make a total volume of 1 mL. Fill into glass ampoules, 121
Autoclaved at 15 ° C. for 15 minutes. The obtained heparin preparation was a clear and colorless aqueous solution, and had properties such as a pH of 6.11 and an osmotic pressure ratio of about 1 (ratio to physiological saline).

Experimental Example 1 The heparin preparations obtained from Example 1 and Comparative Example were
Stored at 7 ° C for 7 days. The pH and heparin titer after storage were measured, and the residual ratio was calculated for the titer. Table 1 shows the results.

[0028]

[Table 1]

Experimental Example 2 A heparin preparation (injection) having the following composition was prepared. That is, heparin sodium (Japanese Pharmacopoeia) 1
000 units, 9.0 mg of sodium chloride and various additives were mixed and dissolved in an appropriate amount of water for injection to make a total volume of 1 mL. The concentration of the additive (excluding sodium hydroxide) was adjusted to 1 mM, and the pH was adjusted to 6 to 8. The autoclave was subjected to high-pressure steam sterilization at 121 ° C. for 20 minutes, and the pH and the heparin titer after storage at 80 ° C. for 7 days were measured. The residual ratio of the titer was calculated assuming that the titer before sterilization was 100%. Table 2 shows the results.

[0030]

[Table 2]

When sodium citrate, sodium bicarbonate and phosphate buffer were used, the stability of heparin was good.

EXPERIMENTAL EXAMPLE 3 Formulations to which sodium hydroxide was added as exemplified in Experimental Example 2 were used at 25 ° C. (7 months), 40 ° C. (2 months), 80 ° C. (7 months).
Day) at 80 ° C.
(7 days). However, 100 units of heparin sodium were used. The heparin titer after storage and the sulfuric acid concentration in the solution were measured. Table 3 shows the results.

[0033]

[Table 3]

[0034] In the preparation to which sodium hydroxide was added, the sulfuric acid concentration increased as the titer decreased. On the other hand, in the preparation to which sodium citrate was added, the titer was maintained, and no generation of sulfuric acid was observed.

[0035]

According to the present invention, a heparin preparation having excellent stability can be provided without adding a preservative or preservative as in a conventional heparin preparation. In other words, it is possible to provide a heparin preparation that ensures stability during long-term storage and heat sterilization.

 ──────────────────────────────────────────────────の Continuing on the front page (72) Inventor: Munechi Matsuda 955, Koideku, Yoshitomi-cho, Chikami-gun, Fukuoka Prefecture Inside Wellfed Co., Ltd. 955 celebration, inside the Yoshitomi Plant of Wellfide Co., Ltd. (72) Shoko Nakagawa 2-6-9, Hirano-cho, Chuo-ku, Osaka-shi F-term in Wellfide Co., Ltd. 4C076 AA12 BB11 CC14 DD22Q DD23 DD30 DD41Q DD43Q DD50Q FF36 4C086 AA02 EA27 MA03 MA05 NA03 ZA54

Claims (5)

[Claims] 1. A heparin preparation containing heparin or a salt thereof and comprising citric acid, phosphoric acid, carbonic acid, trishydroxymethylaminomethane or a salt thereof as a stabilizer. 2. The heparin preparation according to claim 1, wherein the pH of the preparation is 6 or more. 3. The heparin preparation according to claim 1, wherein the concentration of sulfuric acid contained in the preparation is not more than the concentration determined by the following formula. Sulfuric acid concentration (mmol / L) = heparin concentration (titer /
mL) × 0.0006 4. The heparin preparation according to claim 1, wherein the photostability is improved. 5. A method for stabilizing a heparin preparation, wherein heparin or a salt thereof is mixed with citric acid, phosphoric acid, carbonic acid, trishydroxymethylaminomethane or a salt thereof.