JP2010105965A - Vancomycin preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a vancomycin preparation having solubility and stability by finding a means for effectively inhibiting chemical decomposition of vancomycin without influencing solubility and safety of vancomycin. <P>SOLUTION: The vancomycin preparation comprises vancomycin or a pharmacologically acceptable salt thereof and a water-soluble acid amide. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a vancomycin preparation, and more particularly, to a vancomycin preparation excellent in stability and solubility.

  Vancomycin is a glycopeptide antibiotic derived from Streptomyces orientalis and is an effective antibacterial substance against gram-negative bacteria. When this vancomycin is used as an injection, its pharmaceutically acceptable salt is often used in the form of powder or lyophilized and dissolved immediately before administration.

  However, it has been known that the vancomycin salt undergoes chemical degradation when stored for a long period of time, even in a lyophilized state, resulting in coloring and a decrease in antibacterial properties. For this reason, in order to stably store vancomycin, for example, a method of replacing the inside of a vial enclosing vancomycin with an inert gas such as nitrogen or lowering the storage temperature as much as possible has been adopted.

Furthermore, in recent years, a method of adding a compound for imparting stability to a vancomycin preparation has also been developed. A method of adding an amino acid to a vancomycin salt (Patent Document 1), a method of adding a sugar alcohol (Patent Document) 2) A method such as a method of blending polyethylene glycol (Patent Document 3) has been reported. However, the effects of these methods have not been sufficient.
Japanese Patent Laid-Open No. 11-80022 JP-A-3-193735 WO 01/047542

  The present invention has been made in view of the above circumstances, and its problem is to find a means for effectively suppressing the chemical degradation without affecting the solubility and safety of vancomycin. Providing a vancomycin formulation.

  The present inventor has conducted extensive research on improving the stability of vancomycin preparations.By using a water-soluble acid amide in combination with vancomycin, the decomposition of vancomycin can be effectively suppressed. It was found that the addition did not interfere with the solubility of vancomycin and completed the present invention.

  That is, the present invention is a vancomycin preparation containing vancomycin or a pharmaceutically acceptable salt thereof and a water-soluble acid amide.

  According to the vancomycin preparation of the present invention, its storage stability can be enhanced without affecting the solubility of vancomycin itself.

  Vancomycin used in the vancomycin preparation of the present invention can be produced, for example, by the method described in US Pat. No. 30,670,995. Examples of the pharmaceutically acceptable salt of vancomycin include water-soluble salts of vancomycin, such as water-soluble inorganic salts such as hydrochloride and sulfate, and water-soluble organic salts, and hydrochloride is particularly preferable.

  On the other hand, the water-soluble acid amide used for improving the stability of vancomycin is an acid amide compound having a solubility in water of 1 mg / mL or more, more preferably 10 mg / mL. Examples of the water-soluble acid amide include nicotinic acid amide, urea, N, N-dimethylacetamide and the like, and among these, nicotinic acid amide is preferable.

  The content of the acid amide is not particularly limited, but is about 0.01 to 10% by mass (hereinafter referred to as “%”) in a dry preparation, and particularly 0.1 to 1 % For vancomycin, preferably about 0.01 to 10%, particularly preferably 0.1 to 15%.

  The vancomycin preparation of the present invention can be produced by combining the above two components according to a conventional method, but it is possible to add another component for further improving the stability.

  Examples of such components include sugars and sugar alcohols. Among them, examples of the sugar include monosaccharides such as glucose, fructose, mannose, sorbose, and xylose, and disaccharides such as maltose, saccharose, and lactose. Examples of the sugar alcohol include mannitol, sorbitol, inositol, and xylitol. Among them, mannitol is particularly preferable.

  The blending amount when sugar or sugar alcohol is used is not particularly limited, but it is about 0.1 to 50% in the dry preparation, particularly preferably 1 to 30%, with respect to vancomycin. For example, it is preferably about 1 to 50%, particularly 5 to 30%.

  Furthermore, various additives can be added to the vancomycin preparation of the present invention in order to further increase the solubility of the preparation and to adjust the pH and osmotic pressure after the injection. These additives can be used without particular limitation as long as they are substances / addition amounts that are usually used as additives for pharmaceuticals. Examples thereof include the following. That is, hydrochloric acid, phosphoric acid, citric acid, malic acid, tartaric acid, succinic acid or salts thereof, sodium hydroxide, potassium hydroxide and the like as pH adjusting agents are exemplified. Moreover, salts, such as sodium chloride and potassium chloride, as an osmotic pressure regulator can be mentioned.

  The production of the vancomycin preparation of the present invention can be carried out, for example, according to a well-known method for producing a freeze-dried preparation. That is, in addition to vancomycin or a pharmaceutically acceptable salt thereof and a water-soluble acid amide, the above-described sugar or sugar alcohol, a pH adjusting agent, an osmotic pressure adjusting agent and the like are dissolved in an aqueous medium as necessary. And the like, and then dispensed into vials, trays, etc., and dried by freeze-drying or the like.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, this invention is not restrict | limited at all by these.

Example 1
Preparation of vancomycin lyophilized formulation:
(1) Invention Formulation D Mannitol 100 mg and nicotinamide 1.6 mg were dissolved in 5 ml of water for injection, and 0.5 g titer vancomycin hydrochloride was further dissolved therein. After adjusting the pH of this solution to about 3.4, it was filtered, filled into a glass vial, and freeze-dried to obtain a vancomycin freeze-dried preparation (formulation of the present invention).

(2) Comparative preparation 1
A comparative vancomycin freeze-dried preparation (Comparative preparation 1) was obtained by the same treatment as (1) except that 1.6 mg of nicotinamide was replaced with 100 mg of polyethylene glycol 400.

(3) Comparative preparation 2
A comparative vancomycin freeze-dried preparation (Comparative preparation 2) was obtained by the same treatment as in the above (1) except that 1.6 mg of nicotinamide was not used.
(4) Control preparation 0.5 g titer vancomycin hydrochloride was dissolved in 5 ml of water for injection, the pH of this solution was adjusted to the same value as in (1), filtered, filled into a glass vial, and lyophilized. Thus, a control vancomycin freeze-dried preparation (control preparation) was obtained.

Example 2
Performance evaluation of vancomycin lyophilized formulation:
About each formulation obtained in Example 1, solubility and stability were evaluated by the following method. The results are shown in Table 1.

<Test method>
(1) Solubility test 5 ml of 25 ° C. physiological saline was added to each preparation, and this was left lightly after shaking 5 times. The time until dissolution of each preparation (dissolution time; seconds) was recorded, and this was regarded as solubility. Further, the dissolved state after dissolution was observed.
(2) Stability test Each preparation was stored under conditions of 40 ° C. and 75% RH. After storage, it was taken out at 2, 4 and 6 months, and the total amount of related substances in each preparation was measured. For comparison, the amount of total related substances in the preparation was also measured for each preparation immediately after production. In addition, the measurement of the total amount of related substances was performed according to (2) related substances in the JP test “vancomycin hydrochloride for injection” purity test. In addition, the amount of increase relative to the amount of the initial analog is shown in [].

<Test results>

  As shown in Table 1, it took 60 to 120 seconds for the comparative preparation 2 and the control preparation to dissolve, and the dissolved state was foaming, which was a problem. On the other hand, the comparative preparation 1 and the preparation of the present invention were dissolved in about 20 seconds, and the dissolution state was excellent.

  However, in the stability test, the amount of the total related substances in the comparative preparation 1 increased after 4 months storage and after 6 months storage, and after 6 months storage both increased by 2% or more. On the other hand, the amount of the total related substances increased with storage time in the preparation of the present invention, but the ratio was less than 2%.

  The vancomycin preparation of the present invention can enhance the storage stability of vancomycin without affecting the solubility.

Therefore, it can be widely used in the medical field as a vancomycin preparation for infusion or injection.

Claims (5)

  A vancomycin preparation containing vancomycin or a pharmaceutically acceptable salt thereof and a water-soluble acid amide.   The vancomycin preparation according to claim 1, wherein the water-soluble acid amide is nicotinic acid amide.   The vancomycin preparation according to claim 1 or 2, further comprising a sugar or a sugar alcohol.   The vancomycin preparation according to claim 3, wherein the sugar or sugar alcohol is mannitol. The vancomycin preparation according to any one of claims 1 to 4, which is a freeze-dried preparation.