JP2008208137A - Heparin pharmaceutical preparation and method for stabilizing it - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a highly stable heparin pharmaceutical preparation obtained from livers, lungs or intestinal mucosa of healthy edible animals and having actions for blood anticoagulation and clarification of lipid serum. <P>SOLUTION: The heparin pharmaceutical preparation is stabilized by blending heparin or its salt, and citric acid, phosphoric acid, carbonic acid, tris(hydroxymethyl)aminomethane or their salts as a stabilizer. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

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

  Heparin is obtained from the liver, lungs or intestinal mucosa of healthy edible animals and has blood coagulation inhibitory action and fat serum clearing action. Heparin is a sulfate of mucopolysaccharide, and has a structure in which uronic acid and glucosamine are alternately linked by 1,4. The molecular weight is about 5000 to 20000.

  As heparin preparations, sodium salts, calcium salts and the like are known. Sodium salt is a Japanese pharmacopoeia product. Heparin sodium injection is an injection containing 1000 units of heparin sodium per mL and is colorless to pale yellow clear aqueous, pH is 5.5 to 8, and osmotic pressure ratio is about 1 (ratio to physiological saline) ) Etc.

  In addition, this preparation contains preservatives such as benzyl alcohol, methyl paraoxybenzoate, propyl paraoxybenzoate as additives. These additives have been added for the purpose of preserving and preserving, but in particular, benzyl alcohol has been reported to cause dyspnea and allergic reactions when administered in large amounts (Drug Intel. Clin. Pharm., 9, p154, 1975) Issue), and it is not necessarily safe. Further, since benzyl alcohol is adsorbed to 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 ( Non-patent document 1).

In addition, intermittent methods such as intermittent sterilization have been adopted as sterilization methods for these preparations, but these methods alone cannot be reliably and completely sterilized, so they can be used in combination with preservatives and preservatives. This is the current situation. Therefore, the above problems are still not solved. In addition to using the preservatives and preservatives described above, methods such as sterile filtration are adopted, but since heparin sodium does not have a pH buffering capacity, the titer decreases as the pH decreases during the storage period. Is recognized.
Pharmaceutical Additive Handbook, 316 pages, Maruzen Co., Ltd., published in 1988

  The subject of this invention is providing the heparin formulation excellent in stability.

  As a result of conducting research in consideration of the above circumstances, the present inventors have incorporated citric acid, phosphoric acid, carbonic acid, trishydroxymethylaminomethane, or a salt thereof as a stabilizer, which can be used during heat sterilization for a long time. The inventors have found that a heparin preparation excellent in stability during storage can be prepared, and have completed the present invention. The present invention is described in detail below.

  According to the present invention, it is possible to provide a heparin preparation having excellent stability without blending a preservative / preservative like conventional heparin preparations. That is, it is possible to provide a heparin preparation that ensures stability during long-term storage and heat sterilization.

Known heparins can be used. (1) It is obtained from the liver, lungs or intestinal mucosa of a healthy edible animal, and has blood coagulation inhibitory action and fat serum clearing action. (2) Mucopolysaccharide sulfate, with uronic acid and glucosamine alternately (3) The molecular weight should just be about 5000-20000.

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

  Examples of heparin salts include sodium salts and calcium salts. Sodium salt is available as a Japanese pharmacopoeia product, and calcium salt is available as a British pharmacopoeia product.

  Heparin sodium may be any white or ash-brown powder or granule that has no odor, is slightly soluble in water, hardly dissolves in ethanol or ether, and is hygroscopic.

  In the present invention, the stability of the heparin preparation can be secured 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 added concentration is exemplified by about 0.1 to 10 mM.

  The pH of this preparation is preferably about 6-8. In the present preparation, the stability of the present preparation can be ensured / improved by providing a buffer capacity of pH 6 or higher. Specifically, the pH of the present preparation can be adjusted to 6 or more, and a known pH adjusting agent having a buffering ability at the pH can be blended.

  In order to increase safety, this preparation does not contain preservatives and preservatives that are included in conventional heparin preparations.

  This preparation can be subjected to heat sterilization treatment, and a safe preparation with guaranteed sterility can be provided. A specific method of heat sterilization includes high pressure steam sterilization. The stability during high-pressure steam sterilization is ensured by blending the above-mentioned stabilizer. Suitable conditions for high-pressure steam sterilization include a temperature of 105 to 130 ° C. and a time of about 1 to 60 minutes.

  The concentration of heparin or a salt thereof in this preparation is exemplified by about 1 to 1000 units / mL. Moreover, the osmotic pressure ratio should just be a physiologically acceptable grade, and specifically, about 1 (ratio with respect to physiological saline) is illustrated.

  In this preparation, salts such as sodium chloride and saccharides such as glucose may be added as an isotonic agent. Moreover, you may mix | blend sodium hydroxide, potassium hydroxide, hydrochloric acid, etc. as a pH regulator.

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

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

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

  The heparin preparation of the present invention thus prepared is excellent in stability during heat sterilization and long-term storage. Moreover, the light stability is also kept favorable.

  Efficacy effects of this preparation include treatment of generalized intravascular blood coagulation syndrome, prevention of blood coagulation at the time of using extracorporeal circulation device, insertion of vascular catheter, blood transfusion and blood test, prevention treatment of thrombosis, etc. . At the time of use, it is injected as it is or diluted with glucose solution, physiological saline, Ringer's solution or the like to about 10 to 30 units / mL, and then injected intravenously, subcutaneously or intramuscularly.

  EXAMPLES Examples and experimental examples for explaining the present invention in more detail are given below, but the present invention is not limited by these.

Example 1
A heparin preparation (injection) having the following composition was prepared. That is, heparin sodium (Japanese Pharmacopoeia) 1000 units, sodium chloride 9.0 mg and sodium citrate (final concentration 1 mM) 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. It was. Glass ampules were filled and subjected to autoclaving at 121 ° C. for 15 minutes. The obtained heparin preparation was a colorless and clear aqueous solution, and had properties such as 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, 1000 units of sodium heparin (Japanese Pharmacopoeia) and sodium citrate (final concentration: 1 mM) were dissolved in an appropriate amount of water for injection, and an appropriate amount of sodium hydroxide solution was added to make the total volume 1 mL. Glass ampules were filled and subjected to autoclaving at 121 ° C. for 15 minutes.

Comparative Example A heparin preparation (injection) having the following composition was prepared. That is, 1000 units of heparin sodium (Japanese Pharmacopoeia) 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 the total volume 1 mL. Glass ampules were filled and subjected to autoclaving at 121 ° C. for 15 minutes. The obtained heparin preparation was a colorless and clear aqueous solution, and had properties such as pH of 6.11, and osmotic pressure ratio of about 1 (ratio to physiological saline).

Experimental example 1
The heparin preparations obtained from Example 1 and the comparative example were stored at 80 ° C. for 7 days. The pH and heparin titer after storage were measured, and the residual rate was calculated for the titer. The results are shown in Table 1.

Experimental example 2
A heparin preparation (injection) having the following composition was prepared. That is, 1000 units of heparin sodium (Japanese Pharmacopoeia), 9.0 mg of sodium chloride and various additives were blended and dissolved in an appropriate amount of water for injection to make a total volume of 1 mL. The additive concentration (excluding sodium hydroxide) was adjusted to 1 mM and pH was adjusted to 6-8. High-pressure steam sterilization was performed at 121 ° C. for 20 minutes, and the pH and heparin titer when stored at 80 ° C. for 7 days were measured. The residual titer rate when the titer before sterilization was 100% was calculated. The results are shown in Table 2.

  The stability of heparin was good when sodium citrate, sodium bicarbonate, and phosphate buffer were used.

Experimental example 3
The formulation to which sodium hydroxide was added exemplified in Experimental Example 2 was 25 ° C. (7 months), 40 ° C. (2 months), 80 ° C. (7 days), and the formulation to which sodium citrate was added was 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. The results are shown in Table 3.

  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 the production of sulfuric acid was not observed.

Claims (7)

  A heparin preparation containing heparin or a salt thereof and containing sodium citrate as a stabilizer and sodium hydroxide as a pH regulator, and does not contain preservatives and preservatives.   The heparin preparation according to claim 1, wherein the pH of the preparation is 6 or more. The heparin preparation according to claim 1, wherein the sulfuric acid contained in the preparation is not more than a concentration determined by the following formula.
Sulfuric acid concentration (mmol / L) = heparin concentration (titer / mL) × 0.0006   The heparin preparation according to claim 1, which has improved light stability.   The heparin preparation according to any one of claims 1 to 4, which is subjected to autoclaving.   A method for stabilizing a heparin preparation containing no preservative and preservative, comprising a step of blending sodium citrate and sodium hydroxide with heparin or a salt thereof.   Furthermore, the stabilization method of Claim 6 including the process of performing high pressure steam sterilization.