KR19980084302A - Topical Dose Biodegradable Sustained Release Periodontitis Therapeutic Composition and Method for Preparing the Same - Google Patents

Abstract

The present invention relates to a topical dosage form of biodegradable sustained-release periodontitis therapeutic composition and a method for preparing the same, and more particularly, contains a bioactive substance effective for treating periodontitis in a microsphere made of a biodegradable polymer, and is water-soluble. It is mixed with a polymer to form a film or strip, and in addition, the agent is coated with an aqueous solution of a metal cation salt to obtain a continuous drug effect over a long period of time, and to control the disintegration time of the agent It relates to a topical dosage form biodegradable sustained release periodontitis therapeutic composition prepared for long-term stay in periodontal pocket.

The topically administered biodegradable sustained release periodontitis therapeutic composition of the present invention prepared in this manner can be easily administered to the periodontal sac by tweezers, etc., and the side effects of non-lesion sites by continually releasing the required minimum amount of drug over a long period of time. May be minimized, the therapeutic effect may be maximized, and the discomfort may not be inconvenienced to the patient.

Description

Topical Dose Biodegradable Sustained Release Periodontitis Therapeutic Composition and Method for Preparing the Same

The present invention relates to a topical dosage form of biodegradable sustained release periodontitis therapeutic agent and a method for preparing the same, and specifically, contains a bioactive substance effective for treating periodontitis in a microsphere made of a biodegradable polymer, which is a water-soluble polymer. It is mixed with and prepared in the form of a film or strip, and in addition to coating the preparation with an aqueous solution of a metal cation salt such as calcium or barium, to obtain a long-term sustained drug effect, the disintegration time of the preparation It relates to a topical dosage form biodegradable sustained release periodontitis therapeutic composition prepared to control the long term in the periodontal pocket.

Periodontitis is an inflammation of the supporting tissues around the teeth by toxins, a metabolite of the oral microorganisms. If the gingivitis is left as it is, the gums swell and develop into periodontitis with bleeding and severe bad breath. If periodontitis continues, the collagen supporting the periodontal membrane is destroyed and the alveolar bone supporting the tooth dissolves, which causes the periodontal ligament to separate and form the periodontal sac, and in severe cases, develops a periodontal disease that damages the tooth.

Most of the pathogens causing periodontitis are gram-negative bacteria, anaerobic bacteria, which secrete collagenase to destroy ligaments, which are the connective tissue of the root fascia, and the resulting metabolite causes periodontitis.

Removal of periodontal plaque is essential for the prevention and treatment of advanced periodontal disease. Methods for the removal of bacterial plaque can be divided into mechanical and chemotherapy. Mechanical methods include scaling and root abrasion, and require a patient's ability to continuously maintain plaque, but has the disadvantage of having limited effects on areas that are difficult to anatomically brush. In order to make up for this drawback, studies of plaque control through chemotherapy have been conducted, and this method has been reported to be very effective in removing bacteria present in deep areas that are difficult to reach.

There are many types and methods of chemotherapy, but the important thing to pursue clinically is to ensure that effective concentrations of plaque-modulating substances can be maintained for a long time without side effects.

Chemotherapy is a method of washing the infected area with antibiotic solution or administering antibiotics systemically. Local treatment of antibiotic solutions is known to limit the removal of the causative agent of periodontal disease because antibiotics cannot reach the deep areas of the gingival swallowing or have a short duration. Systemic administration has been reported to be effective in the treatment of periodontal disease, but in order to maintain effective drug concentrations at the site of infection, it is necessary to administer an excessive amount of drug, resulting in side effects, increase in resistant bacteria and harmful effects on intestinal bacteria. Have Therefore, in order to overcome these disadvantages, studies have been conducted to directly administer the drug into the periodontal pocket. When the topical administration of tetracycline (tetracycline), the same effect can be obtained with a dose of 1 / 1,000 of the systemically administered drug. (Goodson, JM et al., J. Periodontol, 56 265-272, 1985).

Therefore, the local drug delivery system using a controlled release system containing bioactive substances such as antimicrobials as a method for obtaining the least side effects and maximum effects while solving the above problems. Development has been attempted.

In order to treat periodontitis using a topical drug delivery system, there are some problems to be solved.

First, in order to deliver bioactive substances such as antibacterial agents to the periodontal sac, a substance capable of carrying a drug is required. Many of the delivery materials developed to date are bioabsorbable materials that must be removed after the drug is completely released, and if left unremoved, they are a continuous stimulus and interfere with the regeneration of periodontal tissue.

U.S. Patent No. 5,599,553 reports a formulation in which minocycline HCl and polycaprolactone are mixed in a strip form to release the drug in the periodontal sac for 7 days. The polycaprolactone is degraded in vivo. Since too much time is required, this agent must be removed after drug release is finished.

Second, in order to treat periodontitis, effective drug concentration must be maintained in the periodontal pocket for a long time. Antibacterial agents, such as minocycline HCl, have been reported to maintain effective drug concentrations for at least 7 to 10 days for the treatment of periodontitis (Lawter JR et al., Int. Symp. Cont. Rel. Bioact. Mater ., 230-231 (1990), Dental disease is a chronic disease, so the therapeutic agent should be present in the oral cavity for as long as possible (Friedman M. et al., Pharmaceutical Research, Vol. 7, No., 4,313-317, 1990). In addition, research findings that oral medications were effective in treating periodontitis when administered for two weeks or more are well known (Liljenberg B. et al., J. Clin. Periodontol. , 7, 48-61 , 1980).

U. S. Patent No. 4,933, 182 describes a formulation in which microparticles composed of polymers are dispersed in a continuous phase composed of water-soluble polymers and containing one or more drugs therein. Such formulations have the advantage of being able to release one or more drugs in an independent form and not causing discomfort to the patient, but have the problem that frequent administration is necessary because all drugs are released in about 6 hours.

Third, quantitative administration should be based on the drug used and convenient to administer.

U.S. Patent No. 4,175,326 reports a formulation containing a drug in a hollow fiber device made of cellulose acetate. In order to administer the preparation to the periodontal sac, it is necessary to cut the fiber to the length corresponding to the dose of the drug, wrap it around the tooth, and push it slightly toward the periodontal sac. This method is inconvenient for quantitatively administering the drug to the periodontal sac. There is this.

WO A1 92/07555 and U.S. Patent No. 5,324,520 report an in situ gel which is present in the liquid phase prior to administration and is present in the gel at a location where it is administered to the periodontal pocket and slightly hardened in contact with body fluid or body temperature. . Since these preparations are in a liquid state before administration, a special administration device in the form of a syringe is required for administration, and also has a problem in that it is inconvenient for quantitative administration.

On the other hand, as a preparation for solving the above two problems of biodegradability and sustained drug release, microsphere formulations made of biodegradable polymers that are slowly decomposed to continuously release the drug when administered to the periodontal sac are known. For example, the pool of PLGA microspheres containing the tetracycline ruro Nick ^R F127 gel (Pluronic ^R F127 gel) were suspended been reported an example of injecting the prepared formulations in pockets in (EP A1 244118) In addition, the minocycline in PLGA Direct injection of the included microspheres into the periodontal sac has been reported to maintain effective drug concentrations in the periodontal sac for 14 days (Lawter JR et al., Int. Symp. Cont. Rel. Bioact. Mater. , 230-231 , 1990), US Pat. No. 5,366,733 which patents it. These biodegradable microspheres treatment of periodontitis can maintain the effective drug concentration in the periodontal sac for a single administration for a long time, and because it is made of fine particles, there is no feeling of foreign body and it is biodegradable, so there is no inconvenience to remove after treatment. There is this. However, since microspheres are decomposed by water, they cannot be prepared in the form of long-term storage gels, and are inconvenient to be prepared immediately before use. In addition, a special administration device is required to inject the gel into the periodontal pocket. When the microparticles are injected directly into the periodontal sac, there is a problem that it is difficult to effectively administer a certain amount to the periodontal sac.

Therefore, in order to develop an ideal periodontitis treatment, a biodegradable substance should be used to control the release of the drug, maintain a sustained effective concentration, conveniently administered, and make the patient feel uncomfortable.

Therefore, the present inventors have been working to develop an ideal periodontitis treatment that improves the three problems mentioned above, and mixed biodegradable microspheres containing a bioactive substance effective for treating periodontitis with a hydrogel of a water-soluble polymer. After molding into a thin film or strip, the formulation is placed in the periodontal sac, where the water-soluble polymer is in contact with the saliva and gingival sac in the periodontal sac slowly disintegrating and ultimately leaving only the microspheres in the periodontal sac for long-term efficacy. In addition, by discovering that spray coating an aqueous solution of a cationic salt such as Ca ²⁺ or Ba ²⁺ to the formulation can control the disintegration time of the formulation, the present invention can be used to develop a more effective periodontitis treatment to complete the present invention. Was done.

It is an object of the present invention to provide a topical dosage form biodegradable sustained release periodontitis therapeutic composition and a method for preparing the same, which can be easily and quantitatively injected into the periodontal sac continuously for a long time.

1 is a graph comparing the plaque index of the experimental group administered the therapeutic agent of the present invention and the control group not administered the therapeutic agent,

2 is a graph comparing the gingival index of the experimental group to which the therapeutic agent of the present invention is administered and the control group not to administer the therapeutic agent,

Figure 3 is a graph comparing the depth of the periodontal pocket of the experimental group and the control group not administered the treatment of the present invention,

4 is a graph comparing the bleeding index of the experimental group to which the therapeutic agent of the present invention was administered and the control group not to which the therapeutic agent was administered,

Figure 5 is a graph showing the change in the ratio of cocci, inactive bacilli, active bacilli and helix among the total microorganisms of the control group not administered the treatment of the present invention,

Figure 6 is a graph showing the change in the proportion of cocci, inactive bacilli, active bacilli and helix among the total microorganisms during each week of the experimental group administered the therapeutic agent of the present invention,

7 is a graph showing that the colonization unit of the black stained bacteroid in the experimental group to which the therapeutic agent of the present invention was reduced compared to the control group to which the therapeutic agent was not administered,

8 is a graph showing the result of bacterial culture in aerobic blood agar plate, in which the colony forming unit was decreased in the experimental group to which the therapeutic agent of the present invention was administered, compared to the control group to which the therapeutic agent was not administered,

9 is a graph showing the result of bacterial culture in anaerobic blood agar plate, in which the colony forming unit was decreased in the experimental group to which the therapeutic agent of the present invention was administered compared to the control group to which no therapeutic agent was administered.

In accordance with the above object, in the present invention, a topically administered biodegradable sustained-release periodontitis therapeutic composition in the form of a film or strip containing a biodegradable polymer microsphere and a water-soluble polymer containing a bioactive substance effective for the treatment of periodontitis and Ca in the composition ^It is coated with an aqueous solution of a cationic salt such as ²⁺ or Ba ²⁺ to provide a topically administered biodegradable sustained release periodontitis therapeutic composition of which disintegration time is controlled.

In addition, the present invention provides a method for preparing the composition.

Hereinafter, the present invention will be described in more detail.

Bioactive substances that can be used in the treatment of periodontitis of the present invention include antibacterial agents, local anesthetics, anti-inflammatory analgesics and corticosteroids.

Antimicrobial agents include ampicillin, amoxicillin, erythromycin, tetratracycline, minocycline, oxytetracycline, and doxycyclin commonly used to treat periodontitis. Metronidazole, meciidazol, bacitracin, kitasamycin, spiramycin, ornidazole, and salts thereof;

Local anesthetics include lidocaine, procaine, dibucaine, benzocaine and the like;

Anti-inflammatory analgesics include diclofenac, flubiprofen, ibuprofen, ketoprofen, aspirin, mefenamic acid and acetaminophen; And

Examples of corticosteroids include dexamethasone, triamcinolone acetonide, hydrocortisone, and epihydrocortisone.

Biodegradable polymers used to prepare the microspheres of the present invention include, but are not limited to, derivatives of alpha hydroxy carboxylic acid derivatives that can be hydrolyzed and decomposed into water and carbon dioxide, which are harmless to the human body, for example, glycolic acid polymers. (Hereinafter abbreviated as PGA), lactic acid polymer (poly lactic acid, abbreviated as PLA) or copolymer of lactic acid and glycolic acid (polylactic-co-glycolic acid, abbreviated as PLGA) is preferable. The molecular weight of these polymers has a very important influence on the drug release duration and degradation of the microspheres. Polymers of these PLA, PGA, and PLGA systems usually take longer to release and degrade drugs as molecular weight increases. PLA takes longer than PGA and L-PLA takes longer than D, L-PLA. Therefore, in the case of PLGA, a copolymer of lactic acid and glycolic acid, it takes more time to release and decompose drugs as the ratio of lactic acid increases and the use of L-lactic acid. Take advantage of these properties and you're in control of the microsphere drug release period. Thus, when the drug release period is set to about 2 weeks for the treatment of periodontitis, the molecular weight range of 4,000 to 50,000 is preferred, and the range of 5,000 to 15,000 is most preferred. Meanwhile, in order to administer the aforementioned drugs in combination, microspheres may be separately prepared using polymers having different molecular weights for each drug. In this case, each drug may have a release pattern that is independent of each other.

The present inventors devised a method for quantitatively administering microspheres containing a bioactive substance to the periodontal pocket to prepare a film or strip by mixing a hydrogel and microspheres of a water-soluble polymer. That is, when the microspheres are mixed with the hydrogel of the water-soluble polymer while maintaining the original form and manufactured in the form of a film or strip, the amount of the microspheres in each film or strip becomes constant. The mixing ratio determines the amount of drug actually administered to the periodontal sac, thereby enabling quantitative administration.

The water-soluble polymer used in the composition of the present invention is harmless to the human body and is soluble in water to be tacky in an aqueous solution, and is preferably capable of being molded into a film or strip after drying. As the water-soluble polymer to be used, a polysaccharide-based polymer is preferable, and examples thereof include pectin, carrageenan, gellan, sodium alginate, and chitosan. have.

In the present invention, after preparing the microsphere-containing water-soluble polymer film or strip, it is possible to extend the disintegration time of the film or strip by coating it with an aqueous solution of a cationic salt. When a film or strip made of a water-soluble polymer is directly administered to the periodontal sac, when it is in contact with body fluids such as saliva or gingival fissure fluid, the film or strip begins to swell immediately, and a part of the film or strip may be pushed out of the periodontal sac. Therefore, even before the drug is released into the periodontal pocket, there is a possibility that a part of the agent may be lost, and in this case, the amount of drug actually delivered to the periodontal pocket may be reduced, thereby preventing a desirable therapeutic effect. In order to eliminate this possibility, the inventors have devised a complex of a water-soluble polymer and a metal ion. That is, when the water-soluble polymer is complexed with the cation of the metal, the solubility in water is reduced and the rate of swelling is also slowed. As a result, it is unlikely that a portion of the preparation will be lost out of the periodontal pocket at the beginning of the administration, and the administered formulation will more reliably stay in the periodontal pocket and release the drug.

On the other hand, since the solubility in water and the swelling rate vary depending on the type of cation of the metal, it is possible to select a suitable metal ion in consideration of the treatment period. Preferred cationic salts are calcium chloride, magnesium chloride, barium chloride and aluminum chloride, in particular calcium chloride is suitable for use in formulations which are hydrated by saliva or gingival fissures within a short period of 3 to 6 hours. Silver is suitable for long term formulations where the formulation is maintained for 1-2 weeks. Therefore, it is possible to prepare a film or a strip using a water-soluble polymer through a simple operation such as spray coating, the formulation is not bound to metal ions within 2 hours after administration, the calcium-polysaccharide formulation in 3 Within six hours, the barium-polysaccharide preparation will maintain its form in the periodontal pocket for at least one week after administration. Each disintegration causes the microspheres containing the drug to remain in the periodontal sac until the disintegration occurs, continually releasing the drug.

As a result, in the present invention, it is possible to quantitatively administer the drug to the periodontal sac by using a film- or strip-shaped preparation of a water-soluble polymer and microspheres. It is possible to more precisely control the retention of the.

Subsequently, the method of preparing the topical dosage form biodegradable sustained release periodontitis therapeutic composition of the present invention

1) dissolving the biodegradable polymer in a solvent and suspending finely pulverized drug particles therein, adding it to an aqueous solution containing a nonionic surfactant, emulsifying it, diluting with distilled water, and drying the solvent to form a microsphere ( Step 1);

2) preparing a hydrogel by mixing the microspheres prepared in step 1 and a water-soluble polymer and adding distilled water (step 2);

3) preparing a composition by molding the hydrogel prepared in step 2 into a film or strip (step 3); And

4) spray-coating and drying an aqueous solution of a cationic salt in the composition prepared in step 3 (step 4).

Methylene chloride is a solvent that can be used to prepare the topically administered biodegradable sustained release periodontitis therapeutic composition of the present invention.

Hereinafter, a method for preparing a topically administered biodegradable sustained release periodontitis therapeutic composition of the present invention will be described in detail step by step.

I. Stage 1

The microspheres used in the present invention are prepared by the method for producing sustained-release microspheres containing the water-soluble antibiotics filed by the present inventors and based on the claims of the present invention (Korean Patent Application No. 95-10671). In other words, in order to release the drug intensively in a short period of 2 weeks, the microspheres containing 20% by weight or more of the drug, the drug of the therapeutic concentration is released daily, and all the drugs are released in 2 weeks are prepared as follows. use. First, in the case of a water-soluble drug, the average particle diameter of the drug was pulverized using a jet-mill or the like so that the average particle diameter was 5 μm or less. This process is not necessary for fat-soluble drugs. The above-mentioned biodegradable polymer PLA or PLGA and the drug are mixed in an appropriate ratio, methylene chloride as a solvent is added and then mixed well and cooled to 20 ° C. or lower. The polymer solution thus prepared was emulsified by adding to an aqueous polyvinyl alcohol solution, which is a nonionic surfactant cooled below 10 ° C. in advance, and the emulsion was diluted with distilled water and methylene chloride was evaporated to prepare a microsphere. At this time, it is preferable that the concentration of the pre-cooled nonionic surfactant aqueous solution is 1 to 15% by weight, and the concentration of the diluted nonionic surfactant aqueous solution is preferably 0.1 to 1% by weight. When the microspheres were prepared according to the above method using D, L-PLA having an average molecular weight of 6,500 to 8,000, the drug was released over about two weeks, and the average molecular weight was 8,000 to 10,000 when using PLGA. Drug release was completed over about 2 weeks. The amount of drug contained in the microspheres is preferably about 10 to 30% by weight, most preferably 20 to 25% by weight. In addition, the particle size of the microspheres has a significant effect on the content of the drug and the release rate of the drug, microspheres having an average particle size of 1 to 500 μm can be used, preferably 10 to 200 μm, particularly 20 to 150 μm. Most preferred. The drug release properties of the microspheres are preferably released continuously for at least 7 days and terminate within 20 days.

II. 2 steps

Next, the steps of preparing the composition of the present invention by mixing the drug-containing microspheres with water-soluble polymers will be described.

First, the water-soluble polymer in the form of fine particles and the sustained-release microspheres containing the drug are mixed well to prepare a mixed composition, wherein the mixing ratio is not only an important factor in the dosage volume of the preparation, Hydration increases the volume, which greatly affects the degree of loss of microspheres from the periodontal pocket. Therefore, it is suitable to use the water-soluble polymer to the minimum possible, but the ratio of the water-soluble polymer in the total mixed composition is preferably 5 to 50% by weight, more preferably 5 to 30% by weight.

Subsequently, distilled water is added to the mixed composition of the water-soluble polymer and the microsphere and mixed well to prepare a hydrogel of the water-soluble polymer in which the microsphere is suspended. At this time, the concentration of the water-soluble polymer, that is, the amount of distilled water added is a very important factor in forming the composition into a film or strip. If the amount of distilled water is too large, it is difficult to form into a film or strip, and if the amount of distilled water is too small, It is difficult to uniformly disperse the microspheres in the gel, making it difficult to produce films or strips of uniform drug content. Therefore, in consideration of this point, it is preferable to add distilled water to form a hydrogel containing 50 wt% or less of water-soluble polymer, and more preferably, prepare a hydrogel so that the water-soluble polymer is 1 to 20 wt%. .

III. 3 steps

The hydrogel composition of the microsphere-containing water-soluble polymer prepared as described above is molded into a film or strip as follows to be injected into the periodontal pocket. First, the hydrogel is evenly spread on an acrylic plate or a metal plate, covered with a polyester film coated with silicon, and then pressed with a roller to make the thickness uniform. The polyester film is then removed and dried in air to obtain a film, which is cut to allow one injection into the periodontal sac. Alternatively, the hydrogel of the water-soluble polymer may be added to a mold having a uniform size, pressed, and then dried to obtain a strip. In manufacturing such a film or strip, the thickness of the film or strip is determined in consideration of the size of the periodontal pocket and the like. The thickness of the film or strip is preferably 2 mm or less, more preferably 0.1 to 1.0 mm. In addition, the size of each dosage form is preferably 6 mm long and 2 mm long, and particularly strip-shaped is preferably prepared in a wedge shape having a width of 6 mm long, 2 mm long and a thickness of 0.1 to 2 mm.

Ⅳ. 4 steps

In order to increase the retention of the preparation in the periodontal sac, it is preferable to prepare a film or strip in the same manner as described above, and then coat it with an aqueous solution of a cationic salt to remove the tack after hydration and to prolong the disintegration time of the preparation. Preferred cationic salts are calcium chloride, magnesium chloride, barium chloride and aluminum chloride, in particular calcium chloride is suitable for use in formulations which are hydrated by saliva or gingival fluid in a short period of time from 3 to 6 hours. Silver is suitable for long term formulations where the formulation is maintained for 1-2 weeks. The concentration of these cationic salts in the aqueous solution is preferably 1 to 10%, more preferably 2 to 5%. Coating methods include a method of dipping a film or strip in an aqueous solution of a cationic salt, followed by drying and a method of spraying an aqueous solution of a cationic salt in a film or strip, and a method of coating by spray is preferable.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Preparation Example 1 Preparation of Biodegradable Microspheres Containing Antimicrobial Agents

1.4 g of polylactic acid having a molecular weight of 7,500 and 0.6 g of minocycline HCl having a particle size of 5 μm or less were added to 2 ml of dichloromethane and stirred well to prepare a polylactic acid solution in which minocycline hydrochloride was dispersed. It was. The solution was added to an aqueous 5% polyvinyl alcohol solution, emulsified with stirring, and slowly evaporated to dichloromethane at room temperature to prepare a microsphere, followed by drying to obtain a minocycline-containing lactic acid polymer microsphere (average particle size 100 μm, drug Content 24% by weight).

Preparation Example 2 to Preparation Example 7

Except that the composition of the drug-containing microspheres as shown in Table 1, was carried out in the same manner as in Preparation Example 1 to prepare a drug-containing microspheres. Their particle size and drug content are shown in Table 1 below.

Drug-Containing Microspheres Results Polymer (average molecular weight) drug Size (μm average) Drug content (% by weight) Preparation Example 2 PLA (8,000) Minocycline HCl 120 22 Preparation Example 3 PLA (10,000) Tetracycline HCl 75 20 Preparation Example 4 PLGA (8,500) Minocycline HCl 100 23 Preparation Example 5 PLA (14,000) Metronidazole 110 25 Preparation Example 6 PLGA (8,500) Plubiprofen 100 27 Preparation Example 7 PLA (7,500) Dbucaine 120 21

Example 1: Preparation of microsphere-containing pectin film

After mixing 0.8 g of the microspheres of Preparation Example 1 and 0.2 g of pectin well, 2.0 g of distilled water was added thereto and mixed to prepare a microsphere-containing hydrogel. Apply the hydrogel to the bottom-closed box made of acrylic having a width of 10 cm, a height of 10 cm, and a depth of 0.5 mm, cover the polyester film with a silicone coating on the top, and press the roller to remove the polyester film. Dried at room temperature. Subsequently, the produced film was cut into a suitable size of about 6 mm wide and 2 mm long.

Example 2 Preparation of Microsphere-Containing Pectin Strips

After preparing a microsphere-containing hydrogel in the same manner as in Example 1, and added to the wedge-shaped mold having a width of 6 mm, length 2 mm and depth of 0.1 mm to 0.5 mm, evenly spread, the polyester film coated on the top surface Strips were pressed and pressed with a roller, then the polyester film was removed and dried at room temperature to separate the prepared strip from the mold.

Example 3: Preparation of microspheres containing sodium alginate film

After mixing 0.85 g of the microsphere of Preparation Example 2 and 0.15 g of sodium alginate well, 1.5 g of distilled water was added thereto and mixed to prepare a microsphere-containing hydrogel. The hydrogel obtained was then prepared in the same manner as in Example 1.

Example 4 Preparation of microspheres-containing calcium alginate film

A 2% calcium chloride aqueous solution was sprayed onto the microspheres-containing sodium alginate film prepared in Example 3, dried at room temperature, and dried in a vacuum pump to prepare a calcium alginate film.

Examples 5-16

Strips and films were prepared in the same manner as in Examples 1 to 4 using the drug-containing microspheres prepared in Preparation Examples 2 to 7. The results are shown in Table 2 below.

Results of Manufacturing Microsphere-Containing Films or Strips Microspheres Polysaccharides Microspheres / Polysaccharides shape coating Example 5 Preparation Example 2 Sodium alginate 80/20 strip - Example 6 Preparation Example 3 Sodium alginate 85/15 strip Calcium chloride Example 7 Preparation Example 3 Sodium alginate 85/15 strip Barium chloride Example 8 Preparation Example 4 pectin 90/10 film Calcium chloride Example 9 Preparation Example 4 pectin 90/10 film Barium chloride Example 10 Preparation Example 5 Carrageenan 90/10 film Calcium chloride Example 11 Preparation Example 3 Carrageenan 80/20 film Barium chloride Example 12 Preparation Example 4 Carrageenan 80/20 strip - Example 13 Preparation Example 4 Gellan 80/20 strip - Example 14 Preparation Example 6 Gellan 70/30 film Calcium chloride Example 15 Preparation Example 6 Gellan 80/20 film Barium chloride Example 16 Preparation Example 7 Gellan 75/25 film Barium chloride

Experimental Example 1 Drug Release Test

The film or strip prepared in the above example was placed in a phosphate buffer solution of pH 7.4 and the temperature was maintained in a constant temperature water bath at 37 ° C., and the amount of drug release was analyzed by UV absorbance. The results are shown in Table 3.

Drug Release Experiment Results Time (days) One 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Cumulative emissions (%) Example 1 20 30 39 47 55 61 69 77 84 90 94 97 99 100 - - Example 3 18 25 33 42 48 56 63 70 76 80 85 89 93 95 97 99 Example 4 19 26 34 43 49 57 64 70 76 81 86 89 93 95 98 100 Example 6 22 28 34 40 46 52 59 65 71 77 83 88 92 95 97 99 Example 7 21 27 33 39 45 51 57 63 69 75 80 85 90 94 97 99 Example 8 16 25 34 42 50 58 66 74 81 88 94 98 100 - - - Example 11 22 28 34 40 46 52 58 64 70 76 82 87 91 94 97 100 Example 12 17 26 35 433 51 58 66 74 80 87 93 97 100 - - - Example 13 18 28 34 42 502 58 66 74 80 87 93 97 100 - - - Example 14 20 28 36 44 52 60 67 75 82 89 96 99 100 - - - Example 15 20 28 36 44 52 60 67 75 82 89 96 99 100 - - - Example 16 21 28 36 44 52 60 67 75 82 89 94 97 99 100 - -

Experimental Example 2 Disintegration test of the formulation

In the above examples, each of the formulations prepared with sodium alginate or pectin, the formulations coated with an aqueous solution of calcium chloride, and the formulations coated with an aqueous solution of barium chloride were placed in a phosphate buffer solution having a pH of 7.4 and maintained at 37 ° C. in a constant temperature water bath. Measure the time it will disintegrate completely. The results are shown in Table 4.

Disintegration test results of the formulation Sample name Polysaccharides coating Time spent for disintegration of the formulation Example 3 Sodium alginate - 1 hours Example 6 Sodium alginate Ca ²⁺ 4 hours Example 7 Sodium alginate Ba ²⁺ 11 days Example 1 pectin - 1.5 hours Example 8 pectin Ca ²⁺ 5 hours Example 9 pectin Ba ²⁺ 12 days

Experimental Example 3 Drug Test on Animals

This experiment was performed only once when the topical administration of the periodontitis treatment, which contains the minocycline prepared in Example 3 and is composed of a PLA microsphere (polylactic acid microsphere) and sodium alginate (dog), In order to find out the efficacy and other pharmacological action was performed.

The drug in the form of a film was cut and administered to a size of 6mm in width and 2mm in length and measured at each clinical index at 0,1,2,4 weeks, by the type of bacteria by phase contrast microscope, and the colony count of bacteria by microbial culture. The test was performed statistically using ANOVA to determine the significance of before and after drug administration.

The gingival index, gingival index, and bleeding index were measured by Lo & Silness, and the periodontal pocket depth was measured by William's probe. The determination of each bacterial morphology by phase contrast microscopy was based on the distribution of cocci, non-motile rods, motile rods, and spirochete and week 0 for each week. When the change of each group was examined and the microbial culture measurement also measured the change rate according to the time change of each group on the basis of 0 weeks, the following results were obtained.

1. Clinical indices such as plaque index, gingival index, periodontal pocket depth and bleeding index showed significant difference compared to the control group (Table 5-8, Figures 1-4).

2. As a result of evaluating the change of bacterial species, the ratio of cocci and non-motile rods increased after administration of the drug, but the ratio of motile rods and spirals (spirochete) decreased. 9-12, Figs. 5-6)

3. As a result of bacterial culture on aerobic and anaerobic blood agar medium, Colony Forming Unit (CFU) of each medium was significantly reduced (Tables 13-15, FIGS. 7-9).

In conclusion, the clinical index, microbial change and concentration of the drug in the periodontal sac have been proved to be a very effective therapeutic agent to treat periodontal disease for more than two weeks when the periodontitis treatment of the present invention is applied into the periodontal sac.

Comparison of plaque index State Control Experimental group 0 3.00 ± 0.00 3.00 ± 0.00 One 3.00 ± 0.00 2.71 ± 0.46 ^{* #} 2 2.42 ± 0.50 ^* 1.47 ± 0.60 ^{* #} 4 1.66 ± 0.48 ^* 1.33 ± 0.48 ^{* #} * Clearly different from baseline (0 weeks) # Clearly different from control

Gingival Index Comparison State Control Experimental group 0 3.00 ± 0.00 3.00 ± 0.00 One 2.71 ± 0.46 ^* 2.23 ± 0.43 ^{* #} 2 2.28 ± 0.46 ^* 1.47 ± 0.51 ^{* #} 4 2.00 ± 0.59 ^* 1.33 ± 0.48 ^{* #} * Clearly different from baseline (0 weeks) # Clearly different from control

Periodontal pocket depth comparison State Control Experimental group 0 5.85 ± 1.15 5.80 ± 1.12 One 5.42 ± 1.43 4.81 ± 0.58 ^{* #} 2 5.00 ± 0.00 ^* 4.19 ± 0.67 ^{* #} 4 4.50 ± 0.78 ^* 3.44 ± 0.85 ^{* #} * Clearly different from baseline (0 weeks) # Clearly different from control

Bleeding Index Comparison State Control Experimental group 0 3.00 ± 0.00 2.87 ± 0.32 One 2.85 ± 0.35 2.42 ± 0.50 ^{* #} 2 2.42 ± 0.50 ^* 1.90 ± 0.43 ^{* #} 4 1.50 ± 0.51 ^* 1.22 ± 0.42 ^{* #} * Clearly different from baseline (0 weeks) # Clearly different from control

Proportion of cocci among all microorganisms each week (specific bacteria / total bacteria × 100, average% ± standard deviation) State Control Experimental group 0 33.51 ± 11.86 32.92 ± 9.14 One 54.49 ± 12.08 ^* 59.25 ± 12.14 ^* 2 60.76 ± 9.81 ^* 60.11 ± 11.62 ^* 4 66.35 ± 8.42 ^* 65.01 ± 10.07 ^* * Clearly different from baseline (0 weeks)

Percentage of inactive bacilli in all microorganisms each week (mean% ± standard deviation) State Control Experimental group 0 20.47 ± 4.33 20.00 ± 6.41 One 19.65 ± 8.75 21.45 ± 9.13 2 21.68 ± 8.93 23.20 ± 11.24 4 22.96 ± 9.61 25.68 ± 9.90 * Clearly different from baseline (0 weeks)

Percentage of active bacilli in all microorganisms each week (mean% ± standard deviation) State Control Experimental group 0 27.99 ± 6.49 28.02 ± 6.43 One 20.01 ± 5.28 10.11 ± 7.01 ^* 2 15.21 ± 8.90 11.87 ± 7.03 ^* 4 6.61 ± 4.11 ^* 6.20 ± 4.43 ^* * Clearly different from baseline (0 weeks)

Percentage of spiral bacteria in all microorganisms each week (average% ± standard deviation) State Control Experimental group 0 17.94 ± 8.12 19.05 ± 7.19 One 7.51 ± 7.20 ^* 9.16 ± 5.37 ^* 2 5.86 ± 6.46 ^* 4.25 ± 3.77 ^* 4 4.32 ± 2.60 ^* 3.13 ± 3.19 ^* * Clearly different from baseline (0 weeks)

Comparison of black stained bacteroids (mean CFU% ± standard deviation) State Control Experimental group 0 100.00 ± 0.00 100.00 ± 0.00 One 94.31 ± 37.08 71.80 ± 16.53 ^{* #} 2 122.30 ± 48.34 ^* 71.07 ± 24.50 ^{* #} 4 136.72 ± 38.04 ^* 90.98 ± 26.02 ^# * Clearly different from baseline (0 weeks) # Clearly different from control

Comparison of aerobic blood agar plates (mean CFU% ± standard deviation) State Control Experimental group 0 100.00 ± 0.00 100.00 ± 0.00 One 109.21 ± 13.64 63.31 ± 43.11 ^{* #} 2 101.41 ± 19.48 29.18 ± 17.91 ^{* #} 4 113.75 ± 23.66 38.34 ± 18.69 ^{* #} * Clearly different from baseline (0 weeks) # Clearly different from control

Comparison of Anaerobic Blood Agar Plates (Mean CFU% ± Standard Deviation) State Control Experimental group 0 100.00 ± 0.00 100.00 ± 0.00 One 100.40 ± 20.34 73.17 ± 6.84 ^{* #} 2 92.85 ± 13.13 65.12 ± 15.17 ^{* #} 4 108.41 ± 13.47 67.48 ± 16.65 ^{* #} * Clearly different from baseline (0 weeks) # Clearly different from control

As described above, the periodontitis treatment composition of the present invention is injected into the periodontal sac produced by periodontitis as a film or strip-like preparation, and the water-soluble polymer is hydrated and dissolved by saliva, and only the biodegradable microspheres that release the drug into the periodontal sac The boy will be able to release the drug slowly for one to two weeks.

Since the composition of the present invention is a topical dosage form, the minimum amount of drug required can be quantitatively injected into the periodontal pocket, thereby minimizing the side effects that can occur when the overdose is administered in the long term, and it contains a sustained release microsphere. Thus, a single dose can provide drug administration over a long period of about two weeks. In addition, since it is in the form of a film or strip, it can be easily administered using tweezers or the like, and since it is composed of only biodegradable substances, there is no need to remove it after the release of the drug is completed. Can stay more reliably. Therefore, there is an advantage that it is convenient to use while maximizing the administration effect of the drug.

Claims (12)

A topical dosage form of biodegradable sustained-release periodontitis therapeutic composition, characterized in that a composition in the form of a film or strip containing a biodegradable microsphere containing a physiologically active substance and a water-soluble polymer is coated with an aqueous solution of a cationic salt. The antimicrobial agent of claim 1, wherein the bioactive substance is an ampicillin, amoxicillin, erythromycin, tetracycline, minocycline, oxytetracycline, or doxycycline. ), Metronidazole (metronidazol), bacitracin, kitasamycin, spiramycin, ornidazole and salts thereof; Local anesthetics include lidocaine, procaine, dibucaine and benzocaine; Anti-inflammatory analgesics include diclofenac, flubiprofen, ibuprofen, ketoprofen, aspirin, mefenamic acid and acetaminophen; Corticosteroids include dexamethasone, triamcinolone acetonide, hydrocortisone and epihydrocortisone; Topical dosage form biodegradable sustained release periodontitis therapeutic composition, characterized in that at least one selected from the group consisting of. The method according to claim 1, wherein the biodegradable microspheres have a glycolic acid polymer (poly glycolic acid (PGA)), a lactic acid polymer (poly lactic acid, PLA) and a copolymer of lactic acid and glycolic acid having an average molecular weight in the range of 4,000 to 50,000 -co-glycolic acid, PLGA) A topical dosage form of biodegradable sustained release periodontitis therapeutic composition, characterized in that it is composed of at least one biodegradable polymer selected from the group consisting of. The topical dosage form of biodegradable sustained release periodontitis therapeutic composition according to claim 1, wherein the biodegradable microsphere contains at least 20% by weight of the bioactive substance and the bioactive substance is continuously released for 1 to 3 weeks. . The method of claim 1, wherein the water-soluble polymer is a polysaccharide-based polymer pectin (pectin), carrageenan (carrageenan), gellan (gelan), sodium alginate, chitosan (chitosan), characterized in that topical administration Biodegradable sustained release periodontitis therapeutic composition. The topical dosage form of biodegradable sustained release periodontitis therapeutic composition according to claim 1, wherein the cationic salt is a divalent cation chloride selected from the group consisting of calcium chloride, magnesium chloride, or barium chloride. 1) dissolving the biodegradable polymer in a solvent and suspending finely pulverized drug particles therein, emulsifying it in an aqueous solution containing a nonionic surfactant, diluting with distilled water and drying the solvent to form a microsphere (step) One); 2) preparing a hydrogel by mixing the microspheres prepared in step 1 and a water-soluble polymer and adding distilled water (step 2); 3) preparing a composition by molding the hydrogel prepared in step 2 into a film or strip (step 3); And 4) spray coating and drying an aqueous solution of a cationic salt to the composition prepared in step 3 (step 4) A method for producing a topical dosage form biodegradable sustained release periodontitis therapeutic composition according to claim 1, comprising: The method according to claim 7, wherein the drug particles in (step 1) is 5 μm or less in particle size, the nonionic surfactant is polyvinyl alcohol (polyvinyl alcohol), the concentration of the aqueous solution of nonionic surfactant is 1 to 15% by weight, A method for producing a topically administered biodegradable sustained release periodontitis therapeutic composition, wherein the temperature of the aqueous solution is maintained at 10 ° C. or lower, and the concentration of the nonionic surfactant in the diluent is 0.1 to 1% by weight. 8. The topical dosage form of biodegradable sustained release periodontitis according to claim 7, wherein the water-soluble polymer in (step 2) is a polysaccharide-based polymer and the mixing ratio of the water-soluble polymer and the microspheres is from 5:95 to 50:50 by weight. Method for preparing the therapeutic composition The method of claim 7, wherein the concentration of the water-soluble polymer in the hydrogel in (step 2) is 1 to 20% by weight. The method of claim 7, wherein the aqueous solution of the cationic salt in step 4 is a divalent cation chloride selected from the group consisting of calcium chloride, magnesium chloride or barium chloride. . 8. The method for producing a topically administered biodegradable sustained release periodontitis therapeutic composition according to claim 7, wherein the concentration of the aqueous solution of the cationic salt in (step 4) is 2 to 5% by weight.