KR100186909B1 - Topical adhesive for therapy of oral disease - Google Patents

Abstract

The present invention relates to a topical dosage form for the treatment of oral diseases and a method for preparing the same, comprising mixing the drug-containing polymer microparticles with sodium alginate and adding distilled water to prepare a hydrogel, the hydrogel film or strip The topical formulation for the treatment of oral diseases prepared by the step of forming the coating and the step of coating and drying one side of the molded film or strip with a water-soluble agent of a divalent cation salt, can control the rate of drug release, single sodium alginate Because it is manufactured as a layer, the process is simple, and it is flexible in the oral cavity by using a polymer base that is hydrated, so it can be applied to any site, and only one side of the formulation has mucoadhesion, so there is no foreign matter or stickiness in the oral cavity, and it is applied. Slowly release the drug to have the property of being shown continuously.

Description

Topical attachments for the treatment of oral diseases

The present invention relates to a topical patch for treating oral diseases, and more particularly, to a topical patch for treating oral diseases with mucoadhesion, which is made of a sodium alginate monolayer film in which fine polymer particles containing drugs are uniformly distributed. will be.

The oral cavity is an inlet connected to the digestive organs and is easily infected by external microorganisms, and is prone to inflammation such as gingivitis, periodontitis and stomatitis due to chewing of food and friction with teeth. Since most of these oral diseases are local diseases, the local method of treatment is also known to be effective.

As a medicament for treating oral diseases, antimicrobial agents and anti-inflammatory drugs are commonly used in combination, and are used as topical dosage forms such as ointments and solution preparations. These topical formulations have the advantage of being able to apply the drug directly to the lesion, but not only do they have to be continuously administered because the drug does not stay in the lesion for a long time due to the ingestion of saliva and food secreted by the salivary glands in the oral cavity, There are disadvantages such as discomfort such as stickiness in the mouth.

Accordingly, studies are being actively conducted to develop preparations for the treatment of sustained-release oral diseases which can be directly attached to the lesion and gradually release the drug. U.S. Patent No. 4,292,299 discloses a formulation capable of directly adhering to a lesion, such as stomatitis, by containing a drug in a formulation consisting of a bilayer of a hydrophilic polymer layer and a non-adhesive polymer layer that are tacky to the oral mucosa. However, this formulation is difficult to apply to the flexion site in the oral cavity, there is a disadvantage that the feeling of foreign body due to the thickness of the formulation itself.

In addition, Korean Patent Publication No. 94-023469 discloses a double layered film-like patch prepared by compressing a pressure-sensitive adhesive layer film made of a water-soluble polymer containing a drug and a protective layer film made of a water-insoluble polymer. In Korean Patent Application Publication No. 95-013504, a patch for administering a G-MAL unqualified quantitative extract to periodontal tissue, and it is a water-soluble high-molecule such as hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone and polyvinyl alcohol. And a patch in which a drug was dispersed on a film formed by mixing and molding a water-insoluble polymer, ethyl cellulose. However, these patching agents contain a drug directly in the polymer layer, so the drug release rate is too fast to achieve sustained release, and there is a problem in that it is difficult to manufacture because it has a double layer structure.

On the other hand, sodium alginate, a water-soluble polymer, is a natural product that is harmless to the human body, and has adhesion to moisture-containing mucosa, but when combined with divalent or trivalent cation metals such as Ca ⁺² , Ba ⁺² and Al ⁺³ It is known to have the property of being hydrophilic and not sticky gel form. The inventors have used this property of sodium alginate to encode only one side of a film or strip molded with sodium alginate with a divalent cation aqueous solution, so that one side is tacky to the mucosa and the other side is not tacky. By including the polymer particles containing the drug in the inside of the film or strip of sodium alginate, it is possible to solve the problems of the above-mentioned topical formulation for oral use has led to the completion of the present invention.

That is, an object of the present invention is to provide a patch for the treatment of sustained-release oral disease that can be continually medicated over a period of time with excellent flexibility in the oral cavity, there is no foreign body and stickiness, and provides a simple and economical method for producing the same will be.

In accordance with the above object, the present invention provides a topical formulation for treating oral disease, characterized in that one side of the sodium alginate film or strip containing the polymer particles containing the drug is tacky but the other side is not tacky.

In addition, the present invention is to prepare a hydrogel by mixing the drug-containing polymer microparticles and sodium alginate and adding distilled water, forming the hydrogel into a film or strip and one side of the molded film or strip 2 It provides a method for producing a topical formulation for treating oral disease, comprising coating and drying with an aqueous solution of a cationic salt.

Hereinafter, the present invention will be described more similarly.

Drugs that can be used in the topical patch for treating oral diseases of the present invention include antibacterial agents, local anesthetics, anti-inflammatory analgesics and corticosteroids. Antibacterial agents include ampicillin, amoxicillin, erythromycin, tetracycline, minocycline, metronidazole, bacitracin, pradiomycin sulfate, acetyl chitasamycin, which are commonly used for the treatment of oral inflammatory diseases such as periodontitis, gingivitis and stomatitis. Examples include spiramycin, ornidazole and cetelpyridine hydrochloride, and local anesthetics include lidocaine, procaine, dibucaine and benzocaine, and anti-inflammatory analgesics such as diclofenac, flubipropene, aspirin, mefenic acid And acetaminophen, and the adrenal cortical hormones include dexamethasone, triamcinolone acetonide, hydrocortisone, epihydrocortisone and the like.

Although these drugs can be used directly, the drug itself is preferable in that it can be used by incorporating it into microparticles made of synthetic polymers or natural polymers that are harmless to the living body. Synthetic polymers that can be used to prepare drug-containing polymer microparticles are preferably glycolic acid polymers, lactic acid polymers, copolymers of glycolic acid and lactic acid, and caprolactone polymers, and sodium alginate and pectin as natural polymers. . The amount of drug contained in the polymer particles is preferably 10 to 80% by weight, most preferably 20 to 60% by weight.

In the case of using a synthetic polymer, it is preferable to prepare the microparticles containing 20 to 30% by weight of the drug according to a known method. For example, first, a mixed solution is prepared by adding a lactic acid polymer, which is a synthetic polymer, and a drug to dichloromethane. In this case, the water-soluble drug is made of fine particles having a size of 1 to 10 μm and then suspended. The mixture was slowly heated to evaporate the solvent to obtain a mixture of the drug and the polymer, and then crushed using a mortar or jet mill to obtain fine particles having a size of about 10 to 200 μm and a drug content of 10 to 50 wt%. It can manufacture.

In the case of using sodium alginate as a natural polymer, it is preferable that the mixed solution obtained by adding the drug to the aqueous sodium alginate solution is added dropwise to the calcium chloride or barium chloride aqueous solution to lyophilize the resulting fine particles. For example, to 1 to 10% by weight aqueous solution of sodium alginate, which is a natural polymer, the drug is added at 10 to 60% by weight relative to sodium alginate and then mixed well to prepare a drug-containing sodium alginate gel. It is added dropwise to 2 to 5% by weight aqueous calcium chloride solution or 2 to 5% by weight aqueous solution of barium chloride or sprayed into a spray to produce microparticles, and then lyophilized to obtain calcium alginate or barium alginate beads having a size of 10 to 500 µm. You can get it.

When preparing the drug-containing polymer particles, either synthetic polymers such as lactic acid polymers or natural polymers such as alginate leaf particles may be used, but the drug-containing polymer particles may be selected in consideration of the type, release amount and release characteristics of the drug. For example, the water-soluble drug preferably uses lactic acid polymer, and the water-insoluble drug preferably uses alginate particles, but this is not necessarily the case. Existing patch has a problem that the drug released from the application is lost in a short time because the water-soluble drug is dispersed in a water-based base. However, in the present invention, since the water-soluble drug is dispersed in a hydrophobic polymer base to sustain drug release, there is an advantage that the sustained release property of the drug can be kept constant at all times.

As mentioned above, sodium alginate is hydrated in aqueous solution to show adhesion to mucous membranes.However, when sodium ions of sodium alginate are substituted with divalent or trivalent cations such as calcium, barium and aluminum, complexes with polycarboxy anions in alginic acid It is formed into a hydrogel that does not dissolve in water, the adhesion to the mucosa is lost. When the alginate compound thus obtained is in contact with body fluids such as saliva, divalent cations such as calcium and barium are substituted with sodium ions in the body fluid and gradually dissolved in water. Agents can be prepared.

In other words, sodium alginate in the patch of the present invention acts as a component that imparts adhesion to the oral mucosa and supports the drug-containing polymer particles. The sodium alginate used in the present invention preferably has a viscosity in a 2% aqueous solution of 2,000 to 10,000 centipoise, most preferably 4,000 to 7,000 centipoise.

Next, the step of preparing the patch of the present invention by mixing the drug-containing polymer microparticles and sodium alginate will be described.

That is, 50 to 95% by weight of the polymer particles containing the previously prepared drug is mixed with 5 to 50% by weight of sodium alginate powder, and then 500 to 5000% by weight of tertiary distilled water with respect to the weight of sodium alginate is mixed and mixed well. Prepare a gel of sodium. At this time, the amount of distilled water added is a very important factor in preparing the patch. If the amount of distilled water is too large, it is difficult to process the patch in the form of a film, and it is difficult to use it because the elasticity decreases after drying. Too small a disadvantage is that the polymer particles containing the drug are not uniformly dispersed in the formulation. In view of such a point, the amount of distilled water added is preferably 500 to 5000% by weight, more preferably 1000 to 2000% by weight based on the weight of sodium alginate.

In the patch of the present invention, an adhesive aid may be added to the aqueous sodium alginate solution to increase the adhesion to the oral mucosa, if necessary. As the adhesion aid, polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymers, copolymers of acrylic acid derivatives, cellulose ether derivatives or mixtures thereof can be used, and copolymers of acrylic acid polymers or acrylic acid derivatives are particularly preferable. It is preferable to use such an adhesion aid in the range which does not exceed 50 weight% with respect to the said sodium alginate, It is more preferable that it does not exceed 20 weight% especially. That is, if possible, it is preferable to use the adhesion assistant in a minimum amount, and most preferably, it is not used.

Sodium alginate gel containing the drug-containing polymer prepared by the above method may be prepared in the form of a film or a strip using any one of the following two methods. One method is evenly spread by adding the sodium alginate gel to a bottom-blocked acrylic box having a width of 30 cm, a height of 5 cm, and a height of 0.1 to 5 mm, and then covering the polyester film coated with silicon on the top and then compressing with a roller. Subsequently, the polyester film on the upper surface is removed and dried at room temperature to prepare a film. Alternatively, a mold of a suitable size and a suitable shape may be prepared on an acrylic or metal plate having a thickness of 0.1 to 5 mm, and then pressed with sodium alginate gel, and then dried to form a strip.

The thickness of the film and strip may vary depending on the amount of drug contained in the patch, but 0.1 to 5 mm is preferable in consideration of foreign body feeling, adhesion time and flexibility in the oral cavity. Thinner thickness has the advantage of reducing foreign matter and flexibility, but has the disadvantage that the formulation is brittle. Considering this point, 0.5 to 2 mm is particularly preferable, and 0.5 to 1 mm is most preferable.

The sodium alginate film or strip prepared as described above is hydrated when it comes into contact with body fluids such as water or saliva, and both surfaces show adhesion to the oral mucosa. However, the surface that is not in direct contact with the oral mucosa should not be tacky even when hydrated, so that there is no stickiness in the oral cavity and the adhesion time to the mucosa can be maintained. In order to achieve such an effect, according to the method of the present invention, one side of the film or strip, i.e., the surface which is not in direct contact with the mucosa, is coated with an aqueous solution of calcium chloride or barium chloride to remove the adhesion to the mucosa.

That is, the film or strip of sodium alginate is well dried, and then 0.1 to 1% by weight of an aqueous solution of calcium chloride or barium chloride is sprayed onto one side of the film or strip by coding and immediately dried. Care should be taken when the film or strip is not well dried, since calcium chloride or barium chloride solubles may diffuse to the other side of the film or strip and mucoadhesiveness may be lost on both sides. The concentration of calcium chloride or barium chloride in the coating solution is preferably 0.1 to 1% by weight. If it is higher than this, it becomes very difficult to asymmetrically coat only one side. When coated with calcium chloride can remove the adhesive for about 1 to 6 hours in the oral cavity, when coated with barium chloride can remove the adhesive for about 1 to 2 weeks in the oral cavity. Therefore, it is preferable to coat with calcium chloride when the drug is released all within a few hours, and to barium chloride when the drug is released for a long time over 6 hours. However, even if the drug release is completed within 6 hours can be coated with barium chloride.

In order to distinguish the asymmetric surface of the film or strip formulation, if necessary, the color can be put on either side within the range that does not interfere with drug release and adhesiveness, and the colored polymer film can be attached and removed before use. have. In this case, any one of food coloring and natural coloring may be used, and the polymeric film may be any of colored polyester film and polyethylene film, and the size and shape necessary in consideration of the type and content of the drug. Use it after cutting.

The topical patch for the treatment of oral diseases of the present invention can control the rate of drug release because the drug is contained inside the polymer particles, and because it is made of a single layer of sodium alginate, the process is simple and the polymer base is used. Excellent flexibility in the oral cavity can be applied to any site. In addition, only one side of the film or strip formulation has mucoadhesiveness, so there is no foreign matter or stickiness in the oral cavity, and the drug is gradually released to the application area and has a continuous characteristic.

The topical patch for the treatment of oral diseases prepared by the present invention can be directly administered to the affected area for the treatment of dental diseases such as gingivitis and periodontitis caused by microbial infection, antimicrobial agents and anti-inflammatory agents for oral inflammation such as stomatitis, sulphitis. In addition to direct administration to the affected area, it can be applied to the relief of toothache and local anesthesia required for dental surgery. In addition, since it is a topical dosage form, only the minimum amount of drug required can be applied to the affected area, and it can be easily attached directly to the swollen part, and also has the advantage of maintaining long-term long-term efficacy compared to the existing formulation.

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

Example 1

(Step 1) Preparation of drug-containing polymer particles

A suspension was prepared by adding 1.4 g of poly D, L-lactic acid having an average molecular weight of 7,500 and 0.6 g of tetracycline hydrochloride crushed to a particle size of 5 μm or less to 5 ml of dichloromethane. The suspension was heated with stirring well to blow off dichloromethane to obtain a mixed composition of drug and polymer. This was finely ground in a mortar to obtain polymer particles having an average particle size of 100 μm.

(Step 2) Hydrogel Preparation

0.15 g of sodium alginate, such as 0.85 g of the polymer particles, was added to a vial and mixed well. Then, 1.5 g of tertiary distilled water was added and mixed to prepare a sodium alginate hydrogel including polymer particles containing drug.

(Step 3) Preparation of Dosage Formulation

The hydrogel was added to a mold made of acrylic having a width of 30 cm, a height of 5 cm, and a depth of 0.55 mm, and then evenly spread and covered with a silicone coated polyester film and pressed with a roller, and then the polyester film was removed and dried at room temperature. Subsequently, the top surface of the prepared film was sprayed with 0.5% aqueous calcium chloride solution and then dried well. The film was separated from the acrylic mold and cut into the required size and shape.

Example 2

A film was prepared in the same manner as in Example 1, except that the film prepared in (Step 3) was coated with an aqueous 0.5% barium chloride solution.

Example 3

(Step 1)

Minocycline hydrochloride-containing D, L-PLA (average molecular weight 7,500) microparticles were prepared in the same manner as in (Step 1) of Example 1 (average particle size 120 µm, drug content 35% by weight).

(Step 2)

In the same manner as in (Step 2) of Example 1, a hydrogel having the following composition was prepared.

Minocycline-containing polymer particles: 0.85g

Sodium alginate: 0.15 g

Adhesion Aid (Carboful): 7.5g

Distilled Water: 1.5g

(Step 3)

The hydrogel was added to a cylindrical mold having a diameter of 1 cm and a height of 1 mm prepared on an acrylic plate, and the polyester film coated with silicon was covered and pressed to prepare a disk-shaped strip. One side of the strip was coated with 0.5% aqueous barium chloride solution and then dried.

Example 4

A strip was prepared in the same manner as in Example 3, except that the strip prepared in (Step 3) was coated with an aqueous 0.5% calcium chloride solution.

Example 5

(Step 1)

Triamcinolone acetonide-containing D, L-PLA (average molecular weight 7,500) microparticles were prepared in the same manner as in (Step 1) of Example 1 (average particle size 50 μm, drug content 50 wt%).

(Step 2)

In the same manner as in (Step 2) of Example 1, a hydrogel having the following composition was prepared.

Drug-containing polymer particles: 0.70 g

Sodium alginate: 0.30 g

Adhesion Aid (Polyvinyl Alcohol): 30mg

Distilled Water: 3.0g

(Step 3)

A film was prepared in the same manner as in (Step 3) of Example 1 and coated with a 0.5% barium chloride aqueous solution.

Example 6

(Step 1)

Dibucaine-containing D, L-PLA (average molecular weight 7,500) microparticles were prepared in the same manner as in (Step 1) of Example 1 (average particle size 75 wt m, drug content 45 wt%).

(Step 2)

In the same manner as in (Step 2) of Example 1, a hydrogel was prepared to have the following composition.

Drug-containing polymer particles: 0.80 g

Sodium alginate: 0.20 g

Adhesion Aid (Polyvinyl Alcohol): 10mg

Distilled Water: 2.0g

(Step 3)

A film was prepared in the same manner as in (Step 3) of Example 1 and coated with 0.5% calcium chloride aqueous solution.

Example 7

(Step 1) Polymer Particle Manufacturing

A hydrogel having a composition of 0.5 g sodium alginate, 0.15 g sodium ampicillin, and 9.5 g distilled water was prepared. The hydrogel was placed in a syringe, and barium alginate beads were formed by dropwise adding 2% of barium chloride to an aqueous solution through a needle having a gauge of 30, and then separated and lyophilized (particle size 200 μm, drug content: 23 wt%). )

(Step 2) Preparation of Dosage Formulation

Barium Alginate Bead: 0.8g

Sodium alginate: 0.2 g

Adhesion Aid (Carboful): 20mg

Distilled Water: 2.5g

After preparing the hydrogel of the composition was prepared in the same manner as in step (step 3) of the disk strip, coated with a 0.5% barium chloride aqueous solution and dried.

Example 8

(Step 1)

Lidocaine-containing barium alginate beads were prepared in the same manner as in (Step 1) of Example 7 (particle size: 200 μm, drug content 30 wt%).

(Steps 2 and 3)

In the same manner as in (Step 2) of Example 7, a hydrogel having the following composition was prepared, and a modified strip was prepared to coat 0.5% of barium chloride with an aqueous solution:

Barium Alginate Bead: 0.85g

Alcingansodium: 0.15g

Distilled Water: 2.0g

Analytical Test Example 1 Drug Release Test

100 mg of each of the films prepared in Examples 1 to 3 and Example 7 was attached to a glass plate soaked in water, and then placed in a test tube containing 10 ml of phosphate buffer solution having a pH of 7.4, and left in a 37 ° C. constant temperature water bath. The amount of drug released at 1 hour intervals was analyzed by UV absorbance, and the results are shown in Table 1 below.

Assay Test Example 2: Adhesion Test

The films prepared in Examples 1 and 2 were cut into squares having a width of 1 cm and a length of 1 cm, and the disk strips of Examples 3 and 7 used themselves to attach the samples to glass plates soaked in water, respectively, at 37 ° C. , the glass plate was placed vertically in a phosphate buffer solution of pH 7.4 and the time taken for the sample to fall off the glass plate was measured.

The measurement results are shown in Table 2 below.

Claims (15)

A topical formulation for the treatment of oral disease, wherein one side of a sodium alginate filament or strip containing a polymeric microparticle containing a drug is coated with a divalent cation salt. The topical formulation of claim 1, wherein the drug is an antibacterial agent, a local anesthetic, an anti-inflammatory analgesic, a corticosteroid or a mixture thereof. The antimicrobial agent according to claim 2, wherein the antimicrobial agent is ampicillin, amoxicillin, erythromycin, tetracycline, minocycline, metronidazole, bacitracin, pradiomycin sulfate, acetyl chitasamycin, spiramycin, oridazol, cetylpyridine hydrochloride or these Topical formulations, characterized in that a mixture of. The topical formulation of claim 2 wherein the topical anesthetic is lidocaine, procaine, dibucaine, benzocaine or mixtures thereof. The topical formulation according to claim 2, wherein the anti-inflammatory analgesic is diclofenac, flubiprofen, aspirin, mefenic acid, acetaminophen or mixtures thereof. The topical formulation according to claim 2, wherein the corticosteroid is dexamethasone, triamcinolone acenonide, hydrocortisone, epihydrocortisone or mixtures thereof. The method of claim 1, wherein the polymer microparticles are at least one synthetic polymer selected from glycolic acid polymer, lactic acid polymer, copolymer of glycolic acid and lactic acid and caprolactone polymer or at least one natural polymer selected from sodium alginate and pectin Topical formulations. Preparing a hydrogel by mixing the drug-containing polymer microparticles with sodium alginate and adding distilled water, forming the hydrogel into a film or strip, and forming one side of the molded film or strip by 0.1 divalent cation salt. Method for preparing a topical formulation for treating oral diseases comprising coating and drying with an aqueous solution of 1% by weight to 1%. The method according to claim 8, wherein the polymer microparticles are prepared to have a particle size of 10 to 500 µm and a drug content of 10 to 80% by weight. The method of claim 9, wherein the synthetic polymer and the drug are mixed in a solvent, and then the solvent is evaporated to prepare a particle diameter of 10 to 200 µm and a drug content of 10 to 50% by weight. The bead having a particle diameter of 10 to 500 µm and a drug content of 10 to 60 wt% according to claim 9, wherein the drug is mixed in an aqueous solution of 1 to 10 wt% of the natural polymer and then dropwise added to an aqueous solution of 2 to 5 wt% of a divalent cation salt. Characterized in that it is obtained. 9. The method of claim 8, wherein distilled water is added at 500 to 5000% by weight of sodium alginate. The method of claim 8, wherein the divalent cation salt is calcium chloride or barium chloride. The method according to claim 8, wherein less than 50% by weight of polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymers, copolymers of acrylic acid derivatives, cellulose ether derivatives or mixtures thereof is added to the sodium alginate. The topical formulation of claim 1 wherein the divalent cation salt is calcium chloride or barium chloride.