WO2003070218A1

WO2003070218A1 - Sustained-release ointment for topical administration

Info

Publication number: WO2003070218A1
Application number: PCT/JP2003/001618
Authority: WO
Inventors: Kyohei Tokioka; Yasumitsu Shimizu
Original assignee: Sunstar Inc.
Priority date: 2002-02-19
Filing date: 2003-02-17
Publication date: 2003-08-28
Also published as: JP4202656B2; AU2003211235A1; JP2003238391A

Abstract

A sustained-release ointment for topical administration containing a biodegradable polymer, polyethylene glycol and a biologically active chemical which instantly solidifies when brought into contact with water; a process for producing the above sustained-release ointment which involves the step of heating the biodegradable polymer and polyethylene glycol to 70 to 120 °C and mixing and homogenizing in the liquid state; a kit for treating periodontal disease wherein the sustained-release ointment is enclosed in a syringe for the administration into a periodontal pocket; and a method of treating periodontal disease which comprises administering a therapeutically effective amount of the sustained-release ointment into a periodontal pocket.

Description

Description Topical-release sustained-release ointment Technical field

The present invention relates to a topically-administered sustained-release ointment suitably used for tissue regeneration, protection of a surgical resection, treatment of periodontal disease, and the like, a method for producing the same, and treatment of periodontal disease using the sustained-release ointment. The present invention relates to a kit, and a method for treating periodontal disease, wherein a therapeutically effective amount of the sustained-release ointment is administered to a periodontal pocket. Background art

Conventionally, many of the topical sustained-release preparations using biodegradable bolimers have been studied, which solidify or adhere after administration, stay at the administration site, and release the drug slowly. In particular, preparations suitable for administration by syringe include gel preparations in which a biodegradable polymer is dissolved in an organic solvent, and paste-form preparations in which an appropriate amount of an organic solvent is added to a biodegradable polymer and a uniform preparation is prepared. .

As a gel-form preparation, Japanese Patent Laid-Open Publication No. Hei 7-166654 discloses an implant precursor comprising a mixture of a biodegradable polymer and a water-soluble organic solvent. The invention disclosed herein is that a formulation prepared by dissolving a biodegradable polymer in a water-soluble organic solvent comes into contact with water to form an imprint. However, although this product solidifies immediately upon contact with water, when administered using a syringe, the drug solidifies at the tip of the syringe and adheres, so the drug does not come off the syringe and administration is easy. There is a disadvantage that it is not. In addition, the water-soluble organic solvent used in this preparation also has a drawback that it is difficult to stably blend a particularly water-soluble biological drug such as a tetracycline antibiotic. Furthermore, it is difficult to stabilize the formulation over time while uniformly blending the biodegradable polymer and the bioactive drug. Further, as an example of a gel-form preparation, a sustained-release composition using an organic solvent having low solubility in water is disclosed in Japanese Patent Application Laid-Open No. HEI 8-5-115828. However, gels using organic solvents with low solubility in water have the disadvantage that after administration, they do not immediately solidify in the presence of water.

The above gel-like preparations are all prepared by dissolving a biodegradable polymer in an organic solvent capable of dissolving the biodegradable polymer under non-heating conditions.Examples of paste-like preparations In Japanese Patent Application Laid-Open No. Hei 8-5-111528, the blending ratio of the biodegradable polymer and the organic solvent in the disclosed composition is changed to increase the blending amount of the biodegradable polymer. Accordingly, a paste in the form of a whole is disclosed. Although these are in a form that can be administered by syringe, they are still not sufficient in terms of adhesion at the tip of the syringe, stable blending of the bioactive drug, and immediate solidification after contact with water.

On the other hand, there have been disclosed many inventions applied to the treatment of periodontal disease as a typical application of the gel or base preparation containing the biodegradable polymer and the bioactive drug as described above. Among the disclosed information, it has been known that antibiotics, particularly tetracycline antibiotics, as biologically active drugs are effective as therapeutic agents for periodontal disease, and various attempts have been made. However, since tetracycline antibiotics are unstable to heat and water, it has been desired to develop a sustained-release formulation that stabilizes the tetracycline antibiotic and is suitable for administration by syringe. Disclosure of the invention

Therefore, the present invention has properties suitable for administration by syringe, and can be immediately solidified upon contact with water after administration, and even if it is an unstable bioactive drug such as a tetracycline antibiotic. A sustained-release softener that can be stably blended, a method for producing the same, a tooth that can easily administer the sustained-release softener to a periodontal vocket with a syringe An object of the present invention is to provide a periodontal disease treatment kit, and a method for treating periodontal disease, in which a therapeutically effective amount of the sustained-release ointment is administered to a periodontal boxet.

The present inventors have conducted intensive studies on a topically-administered sustained-release preparation containing a biodegradable polymer and a bioactive drug. The inventors have found that a conventional ointment preparation having the property of solidifying immediately can be obtained, and have completed the present invention.

The present invention

(1) A topically-administered sustained-release ointment containing a biodegradable polymer, polyethylene glycol, and a bioactive drug, which has the property of solidifying immediately upon contact with water. ,

(2) The production of the sustained-release ointment according to the above (1), comprising a step of heating the biodegradable polymer and polyethylene glycol to a temperature of 70 to 120 ° C., and mixing and homogenizing the mixture by liquefaction. Method,

(3) A periodontal disease treatment kit in which the sustained-release ointment according to (1) is enclosed in a syringe for periodontal pocket administration, and

(4) A method for treating periodontal disease, wherein a therapeutically effective amount of the sustained release ointment according to (1) is administered to a periodontal box.

About. BEST MODE FOR CARRYING OUT THE INVENTION

The sustained-release ointment of the present invention is a topically-administered sustained-release ointment containing a biodegradable polymer, polyethylene glycol and a bioactive drug, and has a property of solidifying immediately upon contact with water. It is characterized by having.

In the present invention, “solidifies on contact with water” means that the sustained-release ointment of the present invention has fluidity, but immediately solidifies on contact with water and loses fluidity. Specifically, 100 mg of ointment is a 5 mm diameter glass cylinder with open both sides. When the ointment is placed in water and dropped in water, the fluidity of the ointment decreases, and the ointment retains its formability to the extent that it retains its cylindrical shape even after the cylinder is removed.

"Immediate" means that the time required for the ointment to maintain its moldability in the above test is within 10 minutes, preferably within 1 minute, more preferably within 10 seconds. .

As the biodegradable polymer in the present invention, various polymers having biodegradable activity can be used. Specifically, polylactic acid, polyglycolic acid, polyprolactone, polyp, which are used as pharmaceutical raw materials Preference is given to at least one member selected from the group consisting of tyrolactone, polypropiolactone, polytrimethylene carbonate, polyamino acids, borosuccinic acid imids, and copolymers of two or more thereof.

The molecular weight of the biodegradable polymer is preferably 100 to 100,000, more preferably 500 to 500, from the viewpoint of obtaining sustained release properties and properties of the ointment.

The content of the biodegradable polymer is preferably 5% by weight or more from the viewpoint of sustained release, and is preferably 50% by weight or less to obtain the properties of the ointment. Therefore, the content of the biodegradable polymer is preferably 5 to 50% by weight, more preferably 10 to 40% by weight. Polyethylene glycol in the present invention is contained as an ointment base, and preferably 20% by weight or more, more preferably 30 to 90% by weight, in a sustained release ointment. Further, the polyethylene glycol is preferably a mixture of a liquid and a solid at 25 ° C. and 1 atmospheric pressure to make the preparation into an ointment.

The molecular weight of the liquid polyethylene glycol is preferably 100 or less, more preferably 600 or less. The molecular weight of the solid polyethylene glycol is preferably at least 2000, more preferably at least 300.

From the viewpoint of sustained release, the content of liquid polyethylene glycol in the sustained release ointment

, 70% by weight or less, more preferably 50% by weight or less. In addition, solid From the viewpoint of sustained release, the content of polyethylene glycol is preferably 5% by weight or more, more preferably 10% by weight or more, in the sustained release soft drink.

Furthermore, the weight ratio (liquid / solid) of liquid polyethylene glycol to solid polyethylene glycol is preferably 10 to 10 Z1, more preferably 1 Z2 to 5 Z1. Therefore, macrogol ointment generally known as a one-to-one mixture of polyethylene glycol 400 and polyethylene glycol 400 can also be used in the present invention.

As the biologically active drug in the present invention, various drugs which are usually used pharmaceutically can be used, and in particular, a tetracycline antibiotic which is known to be effective in treating periodontal disease is preferable. It is known that tetracycline antibiotics are unstable to heat and water and their titers tend to decrease, and it is known that the color changes significantly when the titer decreases. It is possible to stably maintain the titer, the coloration of the preparation and the like without changing over time. Examples of the tetracycline antibiotic include minocycline, tetracycline, doxycycline, and salts thereof (hydrochloride and the like). Of these, minocycline and its salts are preferable. The content of the bioactive drug is preferably 0.1 to 50% by weight, more preferably 1 to 30% by weight in the sustained-release ointment in order to obtain a pharmacological effect as an antibiotic.

Further, the sustained-release ointment of the present invention preferably contains an organic solvent having low solubility in water in order to further improve the sustained-release property. It is presumed that such an effect of improving the sustained release by the organic solvent is obtained by suppressing the initial burst of the bioactive drug. In the present invention, the organic solvent having low solubility in water refers to an organic solvent having a solubility in water of 30% by weight or less, preferably 20% by weight or less at 20 ° C. and 1 atm. Therefore, examples of such organic solvents include pharmaceutically acceptable solvents that are generally known to be slightly soluble in water. Specifically, selected from the group consisting of triacetin, triethyl quenate and propylene carbonate At least one is preferred.

The content of the organic solvent having a solubility in water of 30% by weight or less is 0.1 to 20% by weight in the sustained-release ointment in order to prevent the initial burst and to solidify the ointment more quickly. Preferably, it is more preferably 1 to 10% by weight.

The sustained-release ointment of the present invention includes a physiologically active substance having a pharmacological action such as anti-inflammation and tissue regeneration ability, a polyhydric alcohol usually used for pharmaceuticals, a surfactant, a thickener, an antioxidant, Agents, pH adjusting agents, and other additives may be appropriately contained within a range that does not impair the effects of the present invention.

In order to solidify the ointment, the solidified ointment is preferably blended so that the total content of the components that are liquid in 25 is at least 50% by weight or less. That is, the total content of the liquid polyethylene glycol, the organic solvent, and other liquid additives in the solidified ointment is preferably 50% by weight or less in the solidified ointment.

The sustained-release ointment of the present invention can be produced through a process in which a biodegradable polymer and polyethylene glycol are heated to a specific temperature, mixed and homogenized by liquefaction. That is, the biodegradable polymer and polyethylene glycol as an ointment base are heated at 70-120 and then liquidified, so that the biodegradable polymer is hydrolyzed to such an extent that it loses sustained release. Instead, they can be mixed and homogenized. Here, the heating temperature, in order to liquid saphenous of the biodegradable polymer in Helsingborg ethylene glycol, or 7 0 under 1 atm is preferably 9 0 ^e C or more, the biodegradable polymer additive In order to prevent the promotion of water splitting, the value is 120 or less, more preferably 110 or less. Therefore, the heating temperature is 70 to 120 ° C., preferably 90 to 110 °. The heating time is preferably 6 hours or less in order to prevent the promotion of hydrolysis of the biodegradable polymer.

The mixing method is not particularly limited. For example, in addition to manual operation, a method using a commercially available stirrer such as a magnetic stirrer, a propeller stirrer, or a homomixer can be used. You.

Therefore, the method for producing the sustained-release soft blue of the present invention is not particularly limited as long as the method has a step of heating and mixing the biodegradable polymer and polyethylene glycol under specific temperature conditions as described above. For example, there is a method in which a biodegradable polymer and polyethylene glycol at room temperature under 1 atm are heated and liquefied, mixed, and then cooled to room temperature again.

The bioactive drug can be added before or after heating the biodegradable polymer and polyethylene glycol.However, to maintain the bioactive drug stably, add it during or after cooling after heating. Is preferred.

The organic solvent having low solubility in water may be added before or after heating. However, from the viewpoint of uniformity of the preparation, it is desirable to add the organic solvent before adding or in a liquefied state. However, when polyethylene glycol which is solid at least at room temperature is used, it is more preferable to add it at a temperature not lower than its melting point.

The sustained-release ointment of the present invention is used as a topically-administered sustained-release ointment. The term “topically-administered” refers to a local site that is usually used pharmaceutically, and is described in the present invention. It refers to administration not only to the peripheral pocket but also to local sites such as external use, subcutaneous, and bone. The water for solidifying the ointment may be water from the body at the administration site or water from outside the body before or after the administration. Physical water at the site of administration is, for example, saliva or exudate in periodontal bockets.

The sustained-release ointment of the present invention can adjust its sustained-release property and viscosity by controlling the monomer and the degree of polymerization of the biodegradable polymer contained therein, and the molecular weight of the polyethylene glycol. Provided is a periodontal disease treatment kit in which a sustained release ointment is sealed in a syringe for periodontal vocket administration.

Syringes for periodontal pocket administration include, for example, “Periocrine” (trade name, manufactured by Sunstar), etc., which have been developed for the treatment of periodontal disease. Sustained-release ointments are preferably adjusted in advance to a viscosity suitable for administration with a syringe. Specifically, since the viscosity varies depending on the syringe used and the situation, it cannot be determined unconditionally, but a viscosity of 500 to 400,000 cps is preferable.

Therefore, the present invention provides a method for treating periodontal disease, which comprises administering a therapeutically effective amount of the sustained-release ointment of the present invention to a periodontal bucket. The therapeutically effective amount is preferably such that the bioactive drug is administered to the periodontium to the extent that it is effective in treating periodontal disease, and varies depending on the type of bioactive drug and its concentration in the preparation. If, for example, the bioactive drug is an antibiotic, it is desirable to administer the antibiotic in the periodontal pocket in an amount at least above the minimum inhibitory concentration (MIC) of the pathogenic bacterium . Specifically, in the case of minocycline, the minocycline should be present in the gingival crevicular fluid (GCF) in the periodontal pocket at least 0.1 g / m 1 or more, preferably 1 g Zm 1 or more. It is desirable to administer the sustained release ointment of the present invention.

In addition, as a treatment method, in addition to administering a therapeutically effective amount as described above, the sustained-release ointment of the present invention may be prepared as a preparation in which the amount of a bioactive drug is adjusted so that an effective amount can be administered in advance. However, it is simple and effective to administer so that the periodontal vocket is filled. The amount of sustained-release ointment that fills the periodontal boxet varies depending on the periodontal condition of the patient, but is preferably about 5 to 5 Omg. Hereinafter, the present invention will be described in more detail with reference to examples and the like, but the present invention is not limited to the examples. Example 1

A mixture of 1.5 g of liquid polyethylene glycol (molecular weight: 400), 2.5 g of solid polyethylene glycol (molecular weight: 400) and 0.5 g of triacetin was heated to 100. 3 g of a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid: 75/25, molecular weight: 1500) was added and liquefied, followed by stirring for 30 minutes. And made it even. The mixture was cooled to 50 ° C., and a solution of 1 g of minocycline hydrochloride uniformly dispersed in 1.5 g of liquid polyethylene glycol (molecular weight: 400) was added to obtain an ointment. Further, this ointment was enclosed in a syringe for periodontal pocket administration to obtain a periodontal disease treatment kit. Example 2

Heat a mixture of 1.5 g of liquid polyethylene glycol (molecular weight: 400), 2.5 g of solid polyethylene glycol (molecular weight: 4000) and 0.5 g of triethyl citrate to 100 3 g of lactone glycolic acid copolymer (prolactone / glycolic acid: 7030, molecular weight: 10,000) was added, and the mixture was liquefied and stirred for 30 minutes to be uniform. The mixture was cooled to 50 ° C., and a solution obtained by uniformly dispersing 0.5 g of minocycline hydrochloride and 2 g of liquid polyethylene glycol (molecular weight: 400) was added to obtain an ointment. Example 3

A mixture of 2 g of liquid polyethylene glycol (molecular weight: 300), 2 g of solid polyethylene glycol (molecular weight: 4000) and 0.3 g of propylene carbonate was heated to 100 ° C, and borsuccinimide (molecular weight: 1) was heated. 2 000 g) was added, and the mixture was liquefied, followed by stirring for 30 minutes to make it uniform. The mixture was cooled to 5 (TC), and 1 g of doxycycline hydrochloride, uniformly dispersed in 2.7 g of liquid polyethylene glycol (molecular weight: 300), was added to obtain an ointment.

A mixture of 3.5 g of liquid polyethylene glycol (molecular weight: 400) and 2.5 g of solid polyethylene glycol (molecular weight: 6000) was heated to 100 ° C, and 2 g of polylactic acid (molecular weight: 10000) was added. Add, liquefy, and stir for 30 minutes And made it even. The mixture was cooled to 50 ° C., and 0.5 g of tetracycline hydrochloride uniformly dispersed in 1.5 g of liquid polyethylene glycol (molecular weight: 400) was added to obtain an ointment. Comparative Example 1

3 g of polylactic acid (molecular weight: 10,000) was dissolved in 6 g of N-methyl-2-pyrrolidone at room temperature, and 1 g of minocycline hydrochloride was added to obtain a sustained-release gel. Furthermore, this gel was enclosed in a syringe for periodontal pocket administration, and a periodontal disease treatment kit was obtained.

Comparative Example 2

3 g of a lactic acid / glycolic acid copolymer (lactic acid / Z glycolic acid: 75/25, molecular weight: 15 000) was dissolved in 6 g of triacetin at room temperature, and 1 g of minocycline hydrochloride was added to obtain a sustained-release gel. Further, this gel was sealed in a syringe for periodontal pocket administration to obtain a periodontal disease treatment kit. Comparative Example 3

4.5 g of white petrolatum was heated to 100 ° C., and 3 g of polylactic acid (molecular weight: 10000) was added to homogenize. The mixture was cooled to 50, and a solution of 1 g of doxycycline hydrochloride uniformly dispersed in 1.5 g of white petrolatum was added. As a result, the composition did not soften and became a solid. Comparative Example 4

A mixture of 2.5 g of white deserin and 3 g of triethyl citrate was heated to 100 ° C., and 2 g of polylactic acid (molecular weight: 10,000) was added to homogenize the mixture. The mixture was cooled to 50 ° C and 1.0 g of tetracycline hydrochloride was converted to 1.5 g of white petrolatum. Upon addition of the homogeneous dispersion, the composition immediately separated into two phases, solid and gel, and no ointment was obtained. Comparative Example 5

A mixture of 4.0 g of gelled hydrocarbon and 0.5 g of triacetin was heated to 100 ° C., and 3 g of polylactic acid (molecular weight: 1000) was added to homogenize the mixture. The mixture was cooled to 50, and a solution of doxycycline hydrochloride (1.0 g) uniformly dispersed in gelled hydrocarbon (1.5 g) was added.This composition became a solid instead of an ointment.

Comparative Example 6

A mixture of 2.5 g of gelled hydrocarbon and 3 g of triacetin was heated to 100, and 2 g of polylactic acid (molecular weight: 100000) was added to homogenize. The mixture was cooled to 50, and a solution obtained by uniformly dispersing 1.0 g of minocycline hydrochloride in 1.5 g of gelled hydrocarbon was added to obtain a softened product. Further, this ointment was enclosed in a syringe for periodontal pocket administration to obtain a periodontal disease treatment kit. Test Example 1 [Syringe use test]

Using the periodontal disease treatment kits obtained in Example 1 and Comparative Examples 1, 2, and 6, the ease of administration was confirmed by pressing a lot of syringes, and evaluated according to the following evaluation criteria. Table 1 shows the results.

〔Evaluation criteria〕

〇: Can be administered by syringe

X: Cannot be administered by syringe Test Example 2 [Solidification test] 100 mg of each ointment obtained in Example 1 and Comparative Examples 1, 2, and 6 was placed in a glass cylinder having a diameter of 5 mm and opened on both sides. The moldability after removal and removal of the cylinder was evaluated according to the following evaluation criteria. Table of results

Shown in 1.

〔Evaluation criteria〕

+ Maintain cylindrical shape for more than 1 hour

+ 10 seconds or more and less than 1 hour, maintaining cylindrical shape

Time to be able to maintain or maintain a cylindrical shape is less than 10 seconds Test Example 3 [Antibiotics stability test (visual evaluation)]

The ointments obtained in Example 1 and Comparative Examples 1, 2, and 6 were allowed to stand at 40 ° C. for 2 weeks, then visually compared with the initial color of the ointment, and evaluated according to the following evaluation criteria. Table 1 shows the results.

〔Evaluation criteria〕

+: No change from initial

I: Slightly yellowing

11: Yellowing Test Example 4 [Antibiotics stability test (quantitative test)]

After leaving the ointment obtained in Example 1 and Comparative Examples 1, 2, and 6 at 40 ° C for 2 weeks, the antibiotic was quantified by high performance liquid chromatography (HPLC), and the amount of the antibiotic relative to the initial value was determined. Amount (weight was determined. The results are shown in Table 1. Test Example 5 [Slow release test]

10 Omg each of the ointments obtained in Example 1 and Comparative Examples 1, 2, and 6 was sealed in a dialysis tube (manufactured by Sanko Junyaku Co., Ltd., molecular weight cut off: 1200 to 1400). Things, 1 0 Place in OmL of PBS, exchange the external solution every day, and measure the amount of antibiotic in the external solution over time using a spectrophotometer. The results are shown in Table 1. Test Example 6 [Periodontal pocket administration test]

Three people who have ever administered a commercially available ointment for periodontal disease to a canine periodontal boxet use the periodontal disease treatment kits obtained in Example 1 and Comparative Examples 1, 2, and 6. The ointment was administered three times to each of the dog periodontal vockets prepared by the Rigachia model, and the remaining ointment in the pocket after administration was visually observed to compare the number of successful administrations in all the number of vockets. Table 1 shows the results. Test Example 7 (Periodic boquette solidification test)

Using the periodontal disease treatment kits obtained in Example 1 and Comparative Examples 1, 2, and 6, an ointment was administered to a dog periodontal vocket created by a ligature model, and the solidification after administration was evaluated according to the following evaluation criteria. evaluated. Table 1 shows the results.

〔Evaluation criteria〕

++: solidifies in less than 10 seconds.

+: Solidifies in 10 seconds or more and less than 10 minutes.

1: Not solidified after 10 minutes. Test Example 8 (Periodic retention test in periodontal bocket)

Three people who have ever administered a commercially available ointment for periodontal disease to the canine periodontal pocket use the periodontal disease treatment kits obtained in Example 1 and Comparative Examples 1, 2, and 6. The ointment was administered three times to dog periodontal vockets prepared using the Rigachia model, and the retention of minocycline in the periodontal vockets was evaluated one week later. One week later, the exudate in the bocket was removed using filter paper (2 mm x 1 O mm). The samples were collected, and minocycline was detected by HPLC, and compared with the number of remaining minocycline boquettes in the total number of boquettes. Table 1 shows the results. table 1

From the above results, the ointment of Example I was excellent in immediate solidification and sustained release properties, and was excellent as a therapeutic agent for periodontal disease using a syringe, as compared with the ointment obtained in Comparative Example 26. It can be seen that it can be used appropriately. Industrial applicability

According to the present invention, it has properties suitable for administration by syringe, and can be solidified immediately after contact with water after administration, and stable even for unstable bioactive drugs such as tetracycline antibiotics It is possible to provide a sustained-release ointment which can be blended with the present invention and a production method thereof. Furthermore, the sustained-release ointment of the present invention is easily administered to a periodontal pocket with a syringe using a periodontal disease treatment kit in which the sustained-release ointment is enclosed in a syringe.

I 4 S ΐ

8T910 / C0df / X3d 8ΪΖΟ.0 / εθ OAV

Claims

The scope of the claims

1. A topically-administered sustained-release ointment containing a biodegradable polymer, polyethylene glycol, and a bioactive drug, which has the property of solidifying immediately upon contact with water. .

2. The sustained-release ointment according to claim 1, further comprising an organic solvent having a solubility in water of 30% by weight or less at 20 at 1 atm.

3. The content according to claim 2, wherein the content of the biodegradable polymer is 5 to 50% by weight, the content of the polyethylene glycol is 20% by weight or more, and the content of the organic solvent is 0.1 to 20% by weight. Sustained-release ointment.

4. The sustained-release ointment according to any one of claims 1 to 3, wherein the polyethylene glycol is 25 and is a mixture of a liquid and a solid at 1 atm.

5. The biodegradable polymer is polylactic acid, polyglycolic acid, polyproprolactone, polybutyrolactone, polypropiolactone, polytrimethylene carbonate, polyamino acid, borosuccinic acid imid, and copolymers of two or more thereof. The sustained-release ointment according to any one of claims 1 to 4, which is at least one member selected from the group consisting of:

6. The sustained-release ointment according to any one of claims 2 to 5, wherein the organic solvent is at least one selected from the group consisting of triacetin, triethyl quenate, and propylene carbonate.

7. Claim 1 comprising a tetracycline antibiotic as a bioactive drug. 7. The sustained release ointment according to any one of to 6 above.

8. The sustained-release ointment according to claim 7, wherein the tetracycline antibiotic is minocycline or a salt thereof.

9. The sustained-release ointment according to any one of claims 1 to 8, further comprising a step of heating the biodegradable polymer and polyethylene glycol to a temperature of 70 to 120 ° C, and mixing and homogenizing the mixture by liquefaction. Production method.

10. A periodontal disease treatment kit comprising the sustained release ointment according to any one of claims 1 to 8 enclosed in a syringe for periodontal bottle administration.

11. A method for treating periodontal disease, wherein a therapeutically effective amount of the sustained-release ointment according to any one of claims 1 to 8 is administered to a periodontal box.