JPH0234325B2 - SHISHUSHITSUKANCHIRYOYOSOSEIBUTSU - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a composition for treating periodontal disease containing minocycline, which is a type of tetracycline antibiotic. The present invention relates to a composition for treating periodontal disease that exhibits a sustained effect. Conventional technologies and their problems Tetracycline antibiotics include tetracycline and several related compounds, including minocycline, but all of these are extremely unstable substances, and so tetracycline antibiotics have traditionally been used. Various studies have been made to stably incorporate substances into pharmaceutical compositions. For example, JP-A-52-90616 discloses that oxytetracycline, doxycycline, tetracycline, chlortetracycline, or their salts are chelated using an alkaline earth metal compound such as a magnesium compound in an aqueous 2-pyrrolidone solution. Discloses an injectable aqueous solution containing a stabilized tetracycline antibiotic. Furthermore, JP-A-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. ing. Additionally, U.S. Patent No.
No. 3,335,055 discloses a method for stabilizing tetracyclines with magnesium ions 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. By the way, various uses of tetracycline antibiotics in the dental field have been under consideration for several years.
It has been reported that when minocycline is orally administered to patients with periodontal disease, it arrives at a high concentration in the gingival crevicular fluid (GCF) and effectively treats the disease. [J.Periodontal.
51(9)530-534 (1980)]. In addition, it has recently been reported that oral administration of minocycline has good results in reducing gingival inflammation and changes in subgingival bacteria [J.Periodontal., 53(9), 557- 561
(1982)]. All of the above-mentioned applications of minocycline to dental materials are studies based on oral administration of minocycline hydrochloride preparations, and minocycline itself is not directly administered locally to the site of periodontal inflammation, which is the local area in the oral cavity. . It has also been proposed to combine tetracycline with polyethyl methacrylate or ethylene-vinyl acetate to obtain a solid preparation for topical application of periodontal disease [J.Periodontal, 53
(11), 693−699 (1982) and 54(10), 575−579
(1983)] are unsatisfactory and no such formulation has been proposed for minocycline. For periodontal diseases, minocycline itself can be administered directly into the oral cavity at the site of periodontal inflammation, such as the periodontal pocket, and minocycline can be present at a high concentration within the GOF. Minocycline is an unstable substance, and currently no stable medical composition for local administration containing minocycline for use in this disease has been obtained. Therefore, in recent years, there has been a demand for stabilization when using minocycline, especially when applying it to the dental field. In view of these circumstances, the present inventors first conducted intensive studies on stabilizing the formulation of minocycline into medical compositions, and found that minocycline can be stabilized by using a polyhydric alcohol containing a magnesium compound as a base. was stabilized, and I learned that this is a specific effect seen only in minocycline among tetracycline antibiotics.
A patent application regarding this point is already pending (Japanese Patent Publication No. 1-12728). When a composition in which minocycline is blended with a polyhydric alcohol base containing the above-mentioned magnesium compound is administered to a site of periodontal disease, such as a periodontal pocket, minocycline is retained at a high concentration in the GCF, and to some extent However, the concentration of minocycline in GCF was not sustained over a long period of time, and frequent administration was sometimes required. Therefore, the present inventors investigated the development of a composition for the treatment of periodontal diseases in which minocycline is stably blended and has long-lasting effects, and as a result, the above combination of magnesium compound, polyhydric alcohol, and minocycline was In addition, a composition containing an appropriate combination of a water-soluble polymer substance, a certain type of methacrylic acid copolymer, and its solubilizer can be used without impairing the stability of minocycline.
We have newly discovered that the drug remains at the site of administration for a long time and has a lasting effect, leading us to complete the present invention. Means and Effects for Solving the Problems That is, the present invention uses minocycline or a pharmaceutically acceptable salt thereof as an active ingredient, a magnesium compound, a water-soluble polymeric substance, a polyhydric alcohol, ethyl methacrylate, methacrylic acid, etc. The present invention provides a composition for treating periodontal disease, characterized in that it is formulated into a mixture consisting of a trimethylammonium ethyl acid chloride copolymer and a solubilizer. In this case, in one embodiment of the composition of the present invention, methane is added to a mixture obtained by blending minocycline or a pharmaceutically acceptable salt thereof and a magnesium compound into a hydrogel consisting of a water-soluble polymeric substance and a polyhydric alcohol. A composition for treating periodontal disease containing an ethyl acrylate/trimethylammonium ethyl methacrylate copolymer and a solubilizer is preferred. The composition for treating periodontal diseases of the present invention includes, in addition to the combination of magnesium compound-polyhydric alcohol-minocycline already proposed by the present inventors, in particular, a water-soluble polymeric substance and the methacrylate. The inclusion of an acid-based copolymer ensures the adhesion of the composition itself and the formation of fine particles in which the active ingredient, minocycline, is completely dissolved in the polyhydric alcohol, so when administered to the periodontal pocket, which is the site of periodontal disease. , long-term persistence of minocycline in GCF is achieved. The specific composition stably containing minocycline of the present invention provided as described above can be administered locally in the oral cavity, especially directly to the site of periodontal disease, such as the periodontal pocket, and its effects can be maintained for a long period of time. It is something that can be demonstrated. Therefore, until now, systemic side effects of orally administered minocycline, such as
Gastrointestinal side effects such as anorexia, nausea, and diarrhea, as well as biochemical side effects such as thrombocytopenia and eosinophilia, and bacterial replacement have been observed here and there; By using the composition for treating diseases, the occurrence of these side effects can be prevented as much as possible, and it can be said that the composition is particularly excellent clinically. Therefore, a particularly preferred object of the present invention is to provide a method for treating periodontal disease, which comprises applying a minocycline-containing composition stabilized as described above into a periodontal pocket. In the composition for treating periodontal diseases of the present invention, any magnesium compound may be used as long as it is pharmaceutically acceptable, such as magnesium chloride, magnesium acetate, magnesium sulfate, magnesium carbonate, magnesium gluconate, and the like. Examples include hydrates of magnesium, with magnesium chloride being particularly preferred. In general, good stability of minocycline can be achieved by blending the magnesium compound in an amount of 0.5 to 10% (weight %, same hereinafter), preferably 1 to 5%, based on the entire composition. Examples of polyhydric alcohols include glycerin, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, hexylene glycol, 1,5-pentanediol,
1,3-butylene glycol and the like are used alone or in combination to stabilize minocycline,
Glycerin is particularly preferred. Furthermore, minocycline to be incorporated into the composition of the present invention may be either a free form or a pharmaceutically acceptable acid addition salt such as hydrochloride, sulfate, trichloroacetate, etc., and from the viewpoint of medicinal efficacy, it is generally As free minocycline, it can be blended up to about 15%, usually about 0.1 to 5%, based on the entire composition. The water-soluble polymer substance used is preferably one that dissolves in polyhydric alcohol, such as polyvinyl alcohol, polyvinylpyrrolidone, carrageenan, locust bean gum, guar gum,
Hydroxyethylcellulose, xanthan gum,
Examples include gum tragacanth, starch, and succinoglucan, and these may be used alone or in combination of two or more. In particular, hydroxyethylcellulose is preferred for stabilizing minocycline and its sustained release effect. In the composition of the present invention, this water-soluble polymer substance forms a hydrogel together with polyhydric alcohol and exhibits a thickening effect for this purpose, and its content is 0.2 to 10% by weight based on the entire composition. It is preferable to set it as approximately. Ethyl methacrylate/trimethylammonium methacrylate ethyl chloride copolymer is a methacrylic acid-based copolymer known as Eudragit RS, and due to the performance of the resulting composition, it can be blended in an amount of about 0.5 to 10% by weight based on the entire composition. preferable. The solubilizer used in the present invention is one that dissolves the methacrylic acid copolymer, and is preferably one that is incompatible with polyhydric alcohol in view of the performance of the composition. Examples of such solubilizer include triacetin, tributyrin, Esters of lower polyhydric alcohols and lower fatty acids, such as diacetyl ethylene glycol, diethyl sebacate, diethyl phthalate,
Dibutyl phthalate, diisopropyl adipate,
Examples include esters of lower alcohols and dicarboxylic acids such as dibutyl succinate. These may be used alone or in combination of two or more, and are used in a proportion of 5 to 25% by weight based on the entire composition. Particularly preferred is triacetylene. Further, from the viewpoint of stabilizing minocycline and its sustained release effect, it is preferable that the weight ratio of the methacrylic acid copolymer to the solubilizer is 1:2 to 1:25. The composition of the present invention basically contains minocycline in a mixture of a magnesium compound, a water-soluble polymeric substance, and a polyhydric alcohol, and further includes:
It is a viscous liquid or paste composition containing the methacrylic copolymer and a solubilizer, and it is possible to contain up to a few percent of water, but from the viewpoint of the stability of minocycline. Preferably, it is non-aqueous. Therefore, a preferable composition for treating periodontal diseases of the present invention has the following formulation: Minocycline or its salt 0.5-5.0% by weight Water-soluble polymer substance 0.2-10.0% by weight Magnesium compound 0.5-10.0% by weight Possible A more preferable composition is: solubilizer 5.0-25.0% by weight, methacrylic acid copolymer 0.5-10.0% by weight, balance polyhydric alcohol, and a more preferable composition is: Minocycline hydrochloride 0.5-5.0% by weight Hydroxyethyl cellulose 0.2-10.0% by weight Magnesium chloride The formulation consists of 0.5-10.0% by weight, triacetin 5.0-25.0% by weight, Eudragit RS 0.5-10.0% by weight, and the remainder glycerin. The composition for treating periodontal disease of the present invention can be prepared according to conventional formulation techniques. For example, a magnesium compound and a water-soluble polymeric substance are dissolved in a polyhydric alcohol, and then minocycline or a pharmaceutically acceptable salt thereof is added to obtain a mixture. On the other hand, a desired composition can be obtained by preparing a solution in which the methacrylic acid-based copolymer is dissolved in a solubilizer, and mixing and blending this with the mixture containing minocycline or a pharmaceutically acceptable salt thereof. can. In this case, heating may be performed if necessary, for example at 40 to 200°C.
Conditions are good. It goes without saying that the preparation of the composition of the present invention is not limited to the above, and can be carried out by blending the predetermined components in any order. May be added. Examples of the composition of the present invention thus prepared are as follows. Example 1 Component % Minocycline hydrochloride 3.0 Hydroxyethylcellulose 4.0 Magnesium chloride hexahydrate 5.0 Triacetin 12.0 Eudragit RS 2.0 Glycerin 74.0 Hydroxyethylcellulose and magnesium chloride were dispersed in glycerin and dissolved by heating to 100°C. After dissolving, cool to 50°C, add minocycline hydrochloride, and mix uniformly to obtain a mixture.
On the other hand, a solution is prepared by dissolving Eudragit RS in triacetin, and this is added to the mixture and mixed uniformly to obtain a desired composition. Example 2 components % Minocycline 0.1 Magnesium chloride hexahydrate 0.5 Hydroxyethyl cellulose 4.0 Triacetin 12.0 Eudragit RS 2.0 Glycerin 81.4 A mixture of minocycline, magnesium chloride hexahydrate, hydroxyethyl cellulose and glycerin was prepared in the same manner as in Example 1, Add triacetin to this, then finely ground Eudragit RS.
was added to obtain the desired composition. Example 3 A desired composition was obtained in the same manner as in Example 1 except that the same amount of carrageenan was used instead of hydroxyethyl cellulose. Example 4 A desired composition was obtained in the same manner as in Example 1 except that the same amount of xanthan gum was used instead of hydroxyethyl cellulose. Example 5 A desired composition was obtained in the same manner as in Example 1 except that magnesium acetate was used instead of magnesium chloride. Example 6 A desired composition was obtained in the same manner as in Example 1 except that the same amount of magnesium sulfate was used instead of magnesium chloride. Example 7 A desired composition was obtained in the same manner as in Example 1 except that the same amount of dibutyl phthalate was used instead of triacetin. Example 8 In the formulation of Example 1, propylene glycol was used instead of glycerin to obtain the desired composition. Next, the stability of the composition of the present invention will be explained. Stabilization test for minocycline The stability of a composition containing a polyhydric alcohol containing a magnesium compound as a base and containing minocycline has already been investigated by the present inventors (Japanese Patent Application No. 59-253788). ). Therefore, a stabilization test of minocycline in the composition of the present invention was conducted according to this method. The composition of the present invention based on the formulation of Example 1 was filled into a vial, stored at 40°C, and the titer of the antibiotic was measured after 1 and 3 months according to the Japanese Antibiotic Standard Commentary (1982 edition). The residual titer rate (%) was calculated based on the titer at the time of blending. In addition, as a control, the following formulation was similarly tested. Control 1 Ingredients % Minocycline hydrochloride 3 Hydroxyethyl cellulose 2 Magnesium chloride 5 Glycerin 90 Control 2 Ingredients % Minocycline hydrochloride 3 Hydroxyethyl cellulose 4 Eudragit RS 2 Triacetin 12 Glycerin 79 Control 3 Ingredients % Minocycline hydrochloride 3 Hydroxyethyl cellulose 4 Magnesium chloride 5 Eudragit RS 2 Triacetin 12 Distilled water 74 The results are shown in Table 1.

[Table] As is clear from Table 1, the composition in which a magnesium compound is blended with a polyhydric alcohol stabilizes minocycline as shown in Japanese Patent Publication No. 1-12728. Good stabilization can be obtained even if an agent is blended. As described above, the composition of the present invention stabilizes minocycline similarly to the composition previously proposed by the present inventors, but in particular, the composition of the present invention has a sustained release effect. It has been found. The sustained release effect will be demonstrated in a test. Minocycline Release Test The composition of the present invention based on the formulation of Example 1 and the composition based on the formulation of Control 1 above were tested, respectively.
200 mg each was taken and incubated in 20 ml of water at 37°C, and the amount of minocycline was determined by HPCL method. The results are shown in FIG. As is clear from these results, it is understood that the composition of the present invention elutes minocycline in a sustained manner. A similar test was conducted on a composition containing 3% minocycline hydrochloride in white petrolatum, but no release of minocycline was observed. Minocycline retention test The above test revealed that the composition of the present invention releases minocycline in a sustained manner.
It was actually administered into the gingival pocket, and the concentration of minocycline in the GCF was measured 1, 3, 7 and 24 hours after administration. Control patients: 3 males aged 29 to 42 Compositions administered: The composition of Example 1 and the composition of Control 1 The results are shown in FIG. As is clear from these results, it is clear that the composition of the present invention allows minocycline to remain in GCF at a high concentration for a long period of time. Therefore, it can be said that the periodontal disease treatment composition of the present invention has particularly long-lasting effects compared to conventional compositions. It has been found that the minocycline-containing medical composition of the present invention stabilized as described above is particularly suitable for application in the oral cavity as a therapeutic agent for periodontal diseases. Accordingly, the present invention provides a method for treating periodontal diseases using the above-mentioned medical composition stably containing minocycline. The effects of the medical composition of the present invention on periodontal diseases will be described below. Periodontal diseases, particularly periodontitis diseases, have traditionally been considered to be diseases caused by bacterial infections. In other words, it is understood to be an inflammatory disease that originates from the deposition of plaque and tartar and spreads deep into the gingival margin from the bacteria themselves or their metabolites in the plaque and tartar, and the causative bacteria are Gram-negative anaerobic bacilli. This is a major cause. Therefore, initial treatment for periodontal disease includes plaque control to remove plaque and scaling to remove tartar, but it also removes oral bacteria that cause periodontitis. This is the direct cause therapy. Therefore, the therapeutic composition stably containing minocycline of the present invention is applied directly to the periodontal disease area,
We investigated the changes in bacteria in the gingival pockets. Measurement of changes in the number of bacteria in periodontal pockets The therapeutic composition of the present invention based on the following formulation was used on patients with periodontitis, and changes in the number of bacteria in periodontal pockets were measured. (1) Method: A minocycline-containing composition of the present invention based on the following formulation was prepared and administered to periodontitis patients (6 males).
Approximately 40 to 50 mg per tooth was locally administered to the periodontal pockets using a micro cylinder, and changes in the number of bacteria in the periodontal pockets were observed on the 1st, 2nd, 1st, and 2nd week after administration. . Additionally, soluble formulations with no sustained release effect and placebo formulations not containing each minocycline were also observed. (2) Formulation: (A) Composition of Example 1 of the present invention (3% MINO
(B) The composition of Control 1 (described as 3% MINO solubility) (C) The composition of Example 1 of the present invention from which minocycline hydrochloride was removed (placebo sustained release) (D) The composition of Control 1, excluding minocycline hydrochloride (denoted as placebo-soluble) (3) Results: In each group, the total number of bacteria in the periodontal pocket before administration of each composition The average value is taken as 100%, and 1 after administration.
Figure 3 shows the fluctuations on the first day, second day, first week, and second week. Figure 4 also shows the fluctuations in motile rods and spirochetes, which are indicator bacteria for periodontal disease. As is clear from the results shown in FIGS. 3 and 4, the therapeutic composition stably containing minocycline of the present invention successfully reduces the number of bacteria in the gingival pockets, and the effect is long-lasting. It was found that minocycline was released in a sustained manner. Effects of the Invention As described above, considering that periodontal inflammation is caused by the proliferation of bacteria in the gingival pockets, the composition for treating periodontal diseases of the present invention significantly inhibits the proliferation of bacteria, It turns out that this method is effective as a treatment method for periodontitis. The composition of the present invention contains minocycline stably and has sustained release effects, so it can be said that it has great medical utility.

[Brief explanation of drawings]

FIG. 1 is a graph showing the results of a release test of the composition of the present invention, FIG. 2 is a graph showing the results of a retention test, and FIGS. 3 and 4 are graphs showing the results of the composition of the present invention in the gingiva It is a graph showing changes in the number of bacteria in pockets.

Claims (1)

[Scope of Claims] 1. Minocycline or a pharmaceutically acceptable salt thereof as an active ingredient, a magnesium compound, a water-soluble polymer substance, a polyhydric alcohol, an ethyl methacrylate/trimethylammonium ethyl methacrylate chloride copolymer, and a solubilizer. 1. A composition for treating periodontal disease, characterized in that it is formulated with a periodontal disease treatment agent. 2 Magnesium compound at 0.5% of the entire composition
The composition according to item 1 above, containing ~10% by weight. 3. The composition according to item 1 above, wherein the magnesium compound is at least one selected from the group consisting of magnesium chloride, magnesium acetate, magnesium sulfate, magnesium carbonate, magnesium gluconate, and hydrates thereof. 4. The composition according to item 3 above, wherein the magnesium compound is magnesium chloride or a hydrate thereof. 5 Add 0.2 to 0.2% of the water-soluble polymer substance to the entire composition.
The composition according to item 1 above, containing 10% by weight. 6 The water-soluble polymer substance is polyvinyl alcohol,
The composition of item 1 selected from the group consisting of polyvinylpyrrolidone, carrageenan, locust bean gum, guar gum, hydroxyethylcellulose, xanthan gum, tragacanth gum, starch, and succinoglucan. 7. The composition of item 6 above, wherein the water-soluble polymeric substance is hydroxyethyl cellulose. 8 The polyhydric alcohol is glycerin, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, hexylene glycol, 1,5-pentanediol, 1,3-
The composition according to item 1 above, which is at least one selected from the group consisting of butylene glycol and mixtures of two or more thereof. 9 The above-mentioned No. 8, wherein the polyhydric alcohol is glycerin.
composition of the term. 10. The composition according to item 1 above, which contains 0.5 to 10% by weight of the ethyl methacrylate/trimethylammonium ethyl methacrylate chloride copolymer based on the entire composition. 11. The composition of item 1 above, wherein the solubilizing agent dissolves ethyl methacrylate and trimethylammonium ethyl methacrylate copolymer, but is incompatible with the polyhydric alcohol. 12. The composition according to item 1 above, which contains a solubilizer in an amount of 5.0 to 25% by weight based on the entire composition. 13. The composition according to item 1 above, wherein the solubilizing agent is selected from the group consisting of esters of lower polyhydric alcohols and lower fatty acids and esters of lower alcohols and dicarboxylic acids. 14 The solubilizer is triacetin, tributyrin,
14. The composition of item 13, selected from the group consisting of diacetyl ethylene glycol, diethyl sebacate, diethyl phthalate, dibutyl phthalate, diisopropyl adipate, and dibutyl succinate. 15. The first ethyl methacrylate/trimethylammonium methacrylate ethyl chloride copolymer: the solubilizer weight ratio is 1:2 to 1:25.
composition of the term. 16 A mixture obtained by blending minocycline or a pharmaceutically acceptable salt thereof and a magnesium compound with a hydrogel consisting of a water-soluble polymeric substance and a polyhydric alcohol, and an ethyl methacrylate/trimethylammonium methacrylate ethyl chloride copolymer and solubilized The composition according to any one of Items 1 to 15 above, which contains an agent. 17. The composition according to any one of Items 1 to 16 above, which contains 0.1 to 5.0% by weight of minocycline or a pharmaceutically acceptable salt thereof based on the total composition. 18 Formulated as follows: Minocycline hydrochloride 0.5-5.0% by weight Hydroxyethyl cellulose 0.2-10% by weight Magnesium chloride 0.5-10% by weight Triacetin 5.0-25% by weight Ethyl methacrylate/trimethylammonium methacrylate ethyl chloride copolymer
2. The composition according to item 1, comprising 0.5 to 10% by weight of glycerin and the balance, wherein the weight ratio of ethyl methacrylate/trimethylammonium methacrylate ethyl chloride copolymer to triacetin is 1:2 to 1:25.