JPS61130228A - Composition stably blended with minocycline - Google Patents

Abstract

PURPOSE:The titled composition useful for remedying spastic skin disease and perodontosis, having high stability of minocycline, obtained by adding minocycline with a base consisting of a polyhydric alcohol, containing a magnesium compound. CONSTITUTION:A base consisting of a polyhydric alcohol (e.g., glycerin), containing a magnesium compound (e.g., magnesium chloride) is blended with mynocycline or its salt, to give a composition. Minocycline is a tetracycline antibiotic, but it is very unstable. The addition of the base showed specifically stabilized effects among tetracycline antibiotics. The base is further blended with 0.2-3wt% based on the polyhydric alcohol of a water-soluble high polymer compound (e.g., sodium carboxymethyl cellulose), and the composition is preferably a nonaqueous system.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to the stabilized formulation of minocycline, a member of the tetracycline antibiotic family, into pharmaceutical compositions.

Background of the Invention Tetracycline antibiotics include tetracycline and several related compounds including minocycline, but all of these are extremely unstable substances, and it has traditionally been difficult to use tetracycline antibiotics in pharmaceutical compositions. Various studies have been conducted to stably incorporate it into products.

For example, JP-A-52-906)6 discloses that oxytetracycline, doxycycline, tetracycline, chlortetracycline or salts thereof are chelated using an alkaline earth metal compound such as a magnesium compound in an aqueous 2-pyrrolidone solution. discloses stabilized aqueous solutions of these tetracycline antibiotics for injection. Furthermore, JP-A No. 53-94028 discloses a pharmaceutical composition in which oxytetracycline is stabilized by blending alkaline earth metal ions, polyvinylpyrrolidone, and an aliphatic amide to adjust the pH to 5.0 to 7.5. Disclosed. Additionally, U.S. Patent No. 3335
No. 055 discloses a method for stabilizing tetracyclines with magnesium ions B and pyridine derivatives such as isonicotinamide.

However, with respect to minocycline, which is a type of tetracycline antibiotic, there have been no studies on the stabilization of minocycline. - In recent years, there has been a demand for stabilization of minocycline when using it.

In view of these circumstances, the present inventors have conducted extensive studies on stabilizing the incorporation of minocycline into pharmaceutical compositions.

As a result, we learned that minocycline is stabilized by using a polyhydric alcohol containing a magnesium compound as a base, and that this is a specific effect seen only in minocycline among tetracycline antibiotics. was completed.

Summary of the Invention The present invention provides a composition stably containing minocycline, which is characterized in that minocycline or a pharmaceutically acceptable salt thereof is blended into a base consisting of a polyhydric alcohol containing a magnesium compound. be. In the second aspect of the present invention, if desired, a water-soluble polymer compound may be added to the base, and it is preferable that the base is in the form of a water-soluble non-aqueous paste.

Detailed Description of the Invention The magnesium compound used may be any pharmaceutically acceptable compound, and examples include magnesium chloride, magnesium acetate, magnesium sulfate, magnesium carbonate, and magnesium gluconate. preferable. Generally, the magnesium compound is 0.5 to 10% (M@%) based on the total composition.
, hereinafter the same), preferably at a ratio of 1 to 5% (this allows good stability of minocycline to be achieved).

Polyhydric alcohols include glycerin, ethylene glycol, diethylene glycol, propylene glycol,
dipropylene glycol, hexylene glycol, l,
5-bentanediol, 1,3-gutylene gelicol, etc. are used alone or in combination, and glycerin is particularly preferred from the viewpoint of stabilizing minocycline.

In addition, the minocycline to be blended may be either free or a pharmaceutically acceptable acid addition salt such as hydrochloride, sulfate, trichloroacetate, etc. From the viewpoint of medicinal efficacy,
Generally, as free minocycline, it is blended up to about 15%, usually about 0.1 to 5%, based on the total composition.

The composition of the present invention is basically a viscous liquid or paste composition in which minocycline is blended with a mixture of a magnesium compound and a polyhydric alcohol. However, from the viewpoint of the stability of minocycline, it is desirable to use a non-aqueous system.

The compositions of the invention can be prepared according to conventional formulation techniques, for example by dissolving the magnesium compound in a polyhydric alcohol and then adding minocycline or a salt thereof to obtain the desired composition. can be done, if necessary,
Heating may also be performed.

Further, if desired, components such as water-soluble polymer compounds, plasticizers, surfactants, etc. that do not impair the stabilization of minocycline may be added. Water-soluble polymer compounds such as sodium carboxymethyl cellulose, alginic ef-thorium, polyvinyl alcohol, carrageenan, locust bean gum, guar gum, hydroxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, tragacanth gum, starch, and succinoglucan are mixed with polyhydric alcohols. By adding minocycline at a rate of about 0.2 to 3% to form a water-soluble, non-aqueous paste composition, the stability of minocycline is further improved and administration becomes easier.

In the composition of the present invention, the stability of each component of the base used has been sufficiently confirmed, and the scope of its application is not particularly limited. It can also be used for the treatment of infectious periodontal diseases by intraoral application.

EXAMPLES Next, the present invention will be explained in detail with reference to examples.

Example 1 Ingredients % Minocycline 0.1 Magnesium chloride 0.5 Glycerin 99.4 Magnesium chloride was dispersed and dissolved in glycerin, and minocycline was mixed thereto to obtain a desired composition.

Example 2 Ingredients % Minocycline hydrochloride 3.0 Magnesium chloride 5.0 Glycerin 92.0 A desired composition was obtained in the same manner as in Example 1.

Example 3 Ingredients Polyminocycline 1.0 Magnesium Acetate 1.0 Ethylene Glycol 98.0 A desired composition was obtained in the same manner as in Example 1.

Example 4 Ingredients % Minocycline hydrochloride 5.0 Magnesium sulfate 2.5 Propylene glycol 97゛5 A desired composition was obtained in the same manner as in Example 1.

Example 5 Ingredients % Minocycline hydrochloride 5.0 Magnesium chloride 5°0 Glycerin 89.0 Hydroxyethylcellulose 1.0 Hydroxyethylcellulose and magnesium chloride were dispersed in glycerin and dissolved by heating to 100"C. After dissolution, 50% The mixture was cooled to "C" and minocycline hydrochloride was added and mixed uniformly to obtain the desired composition. This composition is particularly suitable for intraoral application as a therapeutic agent for periodontal diseases.

Various minocycline hydrochloride and tetracycline hydrochloride combination compositions having the formulations shown in Table 1 below were prepared;
Stored at 0°C, and measured the titers of these antibiotics after 1 month and 3 months according to the Japanese Antibiotic Standards Commentary (1982 edition), and the residual titer rate (%) with respect to the titer at the time of formulation.
was calculated. The results are shown in Table 1.

As shown in Table 1, the combination of a polyhydric alcohol and a magnesium compound, and moreover, specifically stabilizes only minocycline.

In addition, in Table 1,
The content of minocycline B and its main decomposition product, 4-epimocycline, was determined by high-performance liquid chromatography [J, Chromat.
o, Sci, 16) (1978) + P93~1
01]. The results are shown in Table 2. fLfj second
Each numerical value in the table indicates a relative proportion (%) to the blended amount.

S, standards were converted as hydrochloride salts.

As shown in Table 2, for compositions 1k1g and 2 that do not contain a magnesium compound and polyhydric alcohol, the temperature is 40°C.
After storage for 3 months, the ratio of minocycline and 4-epiminocycline was approximately 1:1, and the total amount decreased significantly compared to the amount blended, 8 and then shifted to other decomposition products. It is thought that this was done. On the other hand, in case 3 of the composition of the present invention, there was almost no decrease in minocycline itself after storage for 40°'03 months, and it is thought that there was no transfer to other decomposition products. As described above, minocycline is significantly stabilized by the combination of a magnesium compound and a polyhydric alcohol in the present invention.

Special liver applicant Sunstar Co., Ltd.

Claims (10)

[Claims] (1) A composition stably containing minocycline, which is characterized in that minocycline or a pharmaceutically acceptable salt thereof is blended into a base consisting of a polyhydric alcohol containing a magnesium compound. (2) The composition according to item 1 above, wherein the magnesium compound is selected from the group consisting of magnesium chloride, magnesium acetate, magnesium sulfate, magnesium carbonate, and magnesium gluconate, and is blended in an amount of 0.5 to 10% by weight based on the entire composition. . (3) The composition according to item (2) above, wherein the magnesium compound is magnesium chloride. (4) Polyhydric alcohol is glycerin, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, hexylene glycol, 1,5
- The composition according to any one of items (1) to (3) above, selected from the group consisting of pentanediol, 1,3-butylene glycol, and mixtures of two or more thereof. (5) Item (4) above, wherein the polyhydric alcohol is glycerin.
composition of the term. (6) The composition according to item (1) above, further comprising a water-soluble polymer compound added to the base. (7) The water-soluble polymer compound is selected from the group consisting of sodium carboxymethyl cellulose, sodium alginate, polyvinyl alcohol, carrageenan, locust bean gum, guar gum, hydroxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, tragacanth gum, starch, and succinoglucan; The composition according to item (6) above, which is blended in a proportion of 0.2 to 3% by weight based on the alcohol. (8) The composition according to any one of items (1) to (7) above, which is non-aqueous. (9) The composition according to any one of items (1) to (8) above, which is for external use on the skin. (10) Items (1) to (8) above for periodontal disease treatment.
) The composition of any one of the items.