JPS61148125A - Remedy for periodontosis - Google Patents

Abstract

PURPOSE:To obtain the titled remedy containing an antibiotic substance in stabilized form, and applicable easily and locally to the gingival space, by adding a tetracycline antibiotic to a anhydrous water-soluble ointment base obtained by mixing two kinds of polyethylene glycols having different molecular weights at a specific ratio. CONSTITUTION:The objective remedy for periodontosis is prepared by adding a tetracycline antibiotic (e.g. tetracycline, oxytetracycline, etc.) to an anhydrous water-soluble ointment base consisting of a mixture containing 40-90wt% polyethylene glycol having an average molecular weight of 400 and a polyethylene glycol solid at normal temperature and having an average molecular weight of >=400. The participation of Gram-negative bacteria in the gingival space in the periodontosis has been clarified, and the local administration of a tetracycline antibiotic has been desired to prevent the problem of constitutional side effects. The antibiotic compounded to the above base is stabilized and releasable easily from the medicinal preparation. The released antibiotic remains in the gingival space for a long period.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for periodontal disease, and more particularly to a therapeutic agent for periodontal disease containing a tetracycline antibiotic as an active ingredient.

Conventional technology In recent years, it has been revealed that Durum-negative bacteria in the gingival sulcus are involved in the cause of periodontal disease, and many clinical studies have been conducted on the treatment of periodontal disease with oral antibiotics, which have shown to be effective. sex has been reported.

Among various antibiotics, tetracycline antibiotics have been reported to be particularly effective. However, treatment of periodontal disease requires oral administration of relatively large amounts over a long period of time, and even with tetracycline antibiotics, which are said to have few side effects, there are concerns about various systemic side effects.

Under these circumstances, topical administration of tetracycline antibiotics is being considered. For example, tetracycline hydrochloride is filled into hollow cellulose acetate fibers or dialysis tubes, wrapped around each tooth, and inserted into the gingival sulcus, or hydroxypropyl cellulose formed into a paper strip is impregnated with tetracycline hydrochloride. ,
A method of inserting it into each gingival sulcus has been proposed. However, since each of these methods requires complicated operations, there is a desire to develop a formulation of a tetracycline antibiotic for the treatment of periodontal diseases that can be easily applied clinically to the gingival sulcus.

On the other hand, tetracycline antibiotics are known to be very unstable substances, and it is necessary to stabilize them when formulating them. Various stabilization measures for tetracycline antibiotics have been proposed. has been done. for example,
JP-A-52-90616 discloses the preparation of oxytetracycline, doxycycline, tetracycline, chlortetracycline, or salts thereof by chelating them with an alkaline earth metal compound such as a magnesium compound in an aqueous solution of 2-pyrrolidone. Discloses an injectable aqueous solution containing a stabilized antibiotic. In addition, JP-A No. 53-94028 discloses a pharmaceutical composition in which oxytetracycline is stabilized by blending alkaline earth metal ions, polyvinylpyrrolidone, and aliphatic amide to 1) H5,0 to 7.5. disclosing something. US Patent No. 3,335,055 discloses a method for stabilizing tetracyclines with magnesium ions and pyridine derivatives such as isonicotinamide. Furthermore, Belgian Patent No. 825656 discloses that oxytetracycline is a polyethylene glycol such as polyethylene glycol having an average molecular weight of 400.
Discloses an aqueous solution stabilized in the presence of magnesium ions in a 30% containing aqueous solution. Furthermore, The Indian Journal of Pharmacy Volume 34 (The
Indian J., Pharm, (1972)
34 (4)96-98) reported the results of testing the stability of tetracycline mixed into white petrolatum, and found that there was almost no decrease in the potency of tetracycline in white petrolatum. It is stated that when 5% of polyethylene glycol with an average molecular weight of 400 is added to the hydrate, the potency decreases.

However, in topical formulations for the treatment of periodontal disease, it is easy to apply and the release of tetracycline antibiotics from the formulation is good. It is necessary to create a dosage form that can be retained for a long time, and these stabilizing measures cannot necessarily be said to be suitable for preparations for treating periodontal diseases.

Problems to be Solved by the Invention The present invention provides a formulation that can be easily and locally administered to the gingival sulcus, stably contains a tetracycline antibiotic, and has good release of the antibiotic. The purpose of the present invention is to provide a therapeutic agent for periodontal disease in which an antibiotic can remain in the gingival sulcus for a long time.

Means for Solving the Problems The present inventors have solved the problem by blending a tetracycline antibiotic into an anhydrous water-soluble ointment base made by mixing two types of polyethylene glycols with different average molecular weights in a specific ratio. Although the mechanism of action is not clear, the antibiotic is stabilized, the antibiotic is released well from the base material, and the released antibiotic is retained well in the gingival sulcus. It has been found that a periodontal disease therapeutic agent that can be easily locally administered to the gingival sulcus can be obtained. That is, the present invention consists of a mixture of polyethylene glycol having an average molecular weight of 400 and polyethylene glycol having an average molecular weight larger than that and which is solid at room temperature.
The present invention provides a therapeutic agent for periodontal disease, which is prepared by blending a tetracycline antibiotic into an anhydrous water-soluble ointment base containing 40 to 90% (weight %, same hereinafter) of 0% polyethylene glycol. Polyethylene glycol with an average molecular weight of 400 is liquid at room temperature, but by mixing it with solid polyethylene glycol, the therapeutic agent for periodontal disease of the present invention basically becomes a viscous paste-like to ointment-like anhydrous water-soluble It has an ointment dosage form.

Polyethylene glycols that are liquid at room temperature have an average molecular weight of 20 in addition to those with an average molecular weight of 400 used in the present invention.
0 to 300 can also be done manually, but even if these are used, the desired effect of the present invention cannot be achieved. In addition, in the present invention, polyethylene glycol with an average molecular weight of 400 is used in the ointment base at a ratio of 40 to 90%; too much will impair the stability of the tetracycline antibiotic, and too little will impair the stability of the tetracycline antibiotic. , it becomes too hard and difficult to administer locally to the gingiva d4.

As polyethylene glycol that is solid at room temperature, polyethylene glycol having an average molecular weight of 1000.4000.6000 can be used manually, and in the present invention, any of these can be used, and two or more types may be used in combination.

Tetracycline antibiotics used include tetrazycline, oquinotetracycline, chlortetracycline, methacycline, doxycycline, demeclocycline, penimocycline, loritetracycline, and pharmaceutically acceptable salts thereof. The amount of these antibiotics can be selected appropriately depending on the antibacterial properties of the antibiotic actually used, but usually, based on the entire therapeutic agent,
About 0°1-to% is sufficient.

Thus, the periodontal disease therapeutic agent of the present invention can be manufactured according to the usual formulation technique of adding and mixing desired ingredients. The obtained therapeutic agent contains a very stable combination of tetracycline antibiotics, and the therapeutic agent can be easily administered locally by, for example, filling the root canal and extruding it into the gingiva f4. can do. Although the dosage depends on the severity of the periodontal disease, an amount that provides, for example, 0.05 to 5 doses of tetrazycline per tooth is usually sufficient.

In addition, although the therapeutic agent of the present invention is anhydrous, it is water-soluble, and when applied to the gingival sulcus, it quickly releases the antibiotic contained in the exudate, etc. in the gingival sulcus. Antibiotics remain in the gingival sulcus for a relatively long period of time, maintaining their medicinal effects.

Therefore, although the therapeutic agent for periodontal diseases of the present invention can achieve a sufficient therapeutic effect even with one administration, it is usually administered at the above-mentioned dosage 1 to 5 times/week depending on the severity of the disease. It is preferable to administer at Note that the tetracycline antibiotic used in the therapeutic agent of the present invention is already known as a medicinal ingredient of a pharmaceutical preparation, and it is clear that its toxicity is acceptable for administration to humans.

According to the following recipe, desired ingredients were added and mixed to produce a viscous paste-like periodontal disease therapeutic agent.

Ingredients % Anhydrous water-soluble ointment base 97 (Mixture of 75 parts by weight of polyethylene glycol with an average molecular weight of 400 and 75 parts by weight of polyethylene glycol with an average molecular weight of m4000) Tetracycline hydrochloride 3 Effects of the invention Stability test of tetracycline antibiotics Using an anhydrous water-soluble ointment base obtained by mixing polyethylene glycols having various average molecular weights in various proportions, ointments were manufactured by blending a tetracycline antibiotic at a concentration of 3% with respect to the total amount. . After leaving this at 40℃ for one month,
The titer of the antibiotic was measured according to the Japanese Antibiotic Standard Manual (1982 edition), and the residual titer rate (%) was calculated by comparing it with the titer immediately after production. The results are shown in Table 1.

In addition, in Table 1, TC is tetracycline hydrochloride, OX
Y represents oxincycline hydrochloride, DOXY represents doxycycline hydrochloride, CI-IL represents chlortetracycline hydrochloride, and M represents average molecular weight.

As shown in Table 1, polyethylene glycol with an average molecular weight of 400 and a polyethylene glycol with an average molecular weight of 4000 or 600 are solid at room temperature.
When the proportion of polyethylene glycol having an average molecular weight of 400 in the mixture is 40 to 90%, the tetracytalline antibiotic can be stabilized.

Release test The release test of the therapeutic agent obtained in the above example and the preparations obtained using various other ointment bases in place of the anhydrous water-soluble ointment base were conducted according to the Japanese Antibiotic Standards Commentary. Book (19
(1982 edition).

However, Pennine Cup (inner diameter 6mm, outer diameter 8mm,
10 mm in height) with each ointment, place it on a flat plate, and hold it for 24 hours.
After a period of time, the diameter of the blocking port was measured and compared with the blocking port diameter of a standard antibiotic measured in the same manner, and the release rate (%) was determined.
) was calculated. The results are shown in Table 2. In addition, in Table 2,
Commercial product A is a base of white petrolatum, and commercial product B is a base of white petrolatum, liquid paraffin, and plastibase in which sodium carboxymethyl cellulose is dispersed.

As is clear from Table 2, the periodontal disease therapeutic agent of the present invention specifically exhibits extremely excellent release properties.

Retention test The therapeutic agent of the above example was filled into the gingival sulcus of 5 patients whose gingival sulcus depth was 3 mm or more in a root canal syringe, and 30 mg per 1 tooth (1 liter as tetrazycline) was applied.
After administration at a rate of 1.0 mg), a filter paper was inserted into the gingival sulcus over time to collect exudate, and the concentration of tetrazycline in the exudate was measured by high performance liquid chromatography. Similarly, a white petrolatum-based drug containing 3% tetracycline hydrochloride (control treatment) was administered, and the concentration of tetracycline in the exudate was measured. The result is the third
Shown in the table.

Table 3 From the previously reported concentrations of tetracycline hydrochloride in gingival crevicular exudate and the minimum inhibitory concentration of tetracytalline against anaerobic Durum negative culm, the effective concentration in gingival crevicular exudate is 1 to 5 μ97 m (l). However, as shown in Table 3, with the control treatment, the tetracycline concentration drops below the effective concentration after 3 hours of administration, and after that, tetracycline is no longer detectable in the exudate.In contrast, the present invention The therapeutic agent maintains its effective concentration even 12 hours after administration, showing extremely excellent retention.

Clinical trial The therapeutic agent of the above example was filled into the gingival sulcus of five patients with severe periodontal disease using Root Canal Solino, and 1 g was administered at a time.
The dose was approximately 30 mg per week, three times a week for three weeks. Similarly, a composition containing No. 1 Yellow No. 4 (control treatment agent) in place of tetracycline hydrochloride in the formulation of the example was administered. Immediately after administration, the average pocket depth (mm) for each of the five teeth was measured every week, and changes therein were investigated. The results are shown in Table 4.

Table 4 (mn+) As shown in Table 4, no difference was observed immediately after the start of administration, but with the therapeutic agent of the present invention, the pocket depth was reduced orally, and an improvement in clinical symptoms was observed.

Claims (1)

[Claims] (1) Consisting of a mixture of polyethylene glycol having an average molecular weight of 400 and polyethylene glycol having a larger average molecular weight and solid at room temperature, the proportion of polyethylene glycol having an average molecular weight of 400 in the mixture is 40 to 40%.
90% by weight of an anhydrous water-soluble ointment base containing from the group consisting of tetracycline, oxytetracycline, chlortetracycline, methacycline, doxycycline, demeclocycline, penimocycline, loritetracycline and pharmaceutically acceptable salts thereof. A periodontal disease treatment agent characterized by containing selected tetracycline antibiotics.