KR100262142B1 - Drug loaded biodegradable membrane for periodontium regeneration and method for the preparation thereof - Google Patents

Abstract

PURPOSE: A bio-degradable cover sheet containing teeth and gums-regeneration medicine is provided, which can be used for regeneration treatment of alveolar bone by releasing medicine at equal rate during 2-4weeks. CONSTITUTION: A process for the preparation of bio-degradable cover sheet containing teeth and gums-regeneration medicine comprises the steps of: adding poly-D,L-lact-glycolic acid, tetracycline HCl in dichloromethane, and mixing to get a suspension; adding the suspension to a solution containing polyvinylalcohol, and shaking to get an emulsion; adding the emulsion to distilled water slowly, and centrifuging to separate microsphere; dissolving sodium alginate in pure water, adding the microsphere and dispersing to get microsphere dispersed solution; film-shaping the microsphere dispersed solution 40-50μm in thickness using a blade; and covering the prepared cover sheet on the almost dried film to get the final product.

Description

Drug-containing biodegradable shielding membrane for periodontal tissue regeneration and its manufacturing method {DRUG LOADED BIODEGRADABLE MEMBRANE FOR PERIODONTIUM REGENERATION AND METHOD FOR THE PREPARATION THEREOF}

The present invention relates to a biodegradable shielding membrane containing a drug for inducing regeneration of damaged alveolar bone and a method of manufacturing the same.

In order to treat alveolar bone damaged by periodontal disease, a new artificial membrane has recently been introduced into damaged periodontal tissues to promote the healing of periodontal tissues, to restore complete periodontal tissues, and to improve bone grafts, thereby inducing the production of new alveolar bones. Attempts are being made actively.

In an attempt to recover tissue and improve regeneration by surgically inserting a shielding membrane into damaged periodontal tissue, initial attempts have been made using Millipore cellulose acetate filter paper, but this method is difficult to remove after treatment, making it difficult to apply clinically. It was difficult.

In recent decades, treatment with new barrier materials has been actively studied, demonstrating the potential for tissue regeneration through animal and clinical trials. Clinically, the introduction of a shielding membrane effectively induced the regeneration of periodontal tissue [Ref. J. Gottlow et al., J. Clin. Perio. , 13 , 604-616 (1986)] has been reported to induce tissue regeneration using a variety of materials as a shielding membrane.

Expanded polytetrafluoroethylene, which is a mesh-like membrane, has been proven to be superior in tissue fusion, cell closure, clinical applicability, and biocompatibility for the past decade, and is actively researching tissue regeneration using it as a barrier material. However, this has caused problems such as gingival recession and subsequent exposure of the shielding membrane to the crown area during clinical application.

As another example, a bioabsorbable material such as silicone rubber, polyurethane, and polyester is applied to animal experiments and clinical trials as a shield for inducing tissue regeneration. However, these bionon-absorbing materials, including expanded polytetrafluoroethylene, are not only cumbersome to undergo secondary removal after the end of treatment, especially when inserted into the tissue through surgical procedures, At the time of the second operation, there is a problem that an abscess, epithelial down growth, periodontal pocket formation, and inflammation may occur in the newly formed tissue.

Therefore, in recent years, research into the development of a shielding film using a material that is biocompatible and absorbed in vivo has been actively conducted in an attempt to improve such a problem. That is, many biodegradable polymers are being actively used for one-step induction tissue regeneration treatment that introduces a shielding membrane in a single operation to be absorbed in vivo after a certain period of time.

As an example, the collagen barrier, a natural polymer, can be successfully applied for induction tissue regeneration or as a dressing material for skin or mucosal tissues, but these substances can cause inflammation and allergic reactions if proteins are not completely removed. And, there is a disadvantage that the decomposition rate in vivo is not constant. As another example, polyglycine in the form of woven or knitted fabrics made of polyglycolic fibers, a copolymer of lactic acid and glycolic acid called vicryl mesh, is a relatively small micropore, which replaces the oratex. It is used as a substance. As another example, the use of a mixture of polylactic acid and citric acid as a lattice porous bioabsorbable membrane has been reported to significantly reduce side effects such as subepithelial hyperplasia, gingival contraction, membrane exposure, periodontal pocket formation, infection, and inflammation.

As described above, attempts have been made to improve the recovery and regeneration of tissues by surgically inserting a shield into damaged periodontal tissues. However, acute inflammation due to initial infection around the shield or early immunization after buried in the body Subepithelial hyperplasia, gingival contraction, and the possibility of exposing the shielding membrane, which are manifested by the et al., Remain the biggest problems. Therefore, at present, the method of administering antibiotics to the patient for 1 to 2 weeks after the procedure of the shielding membrane is used, but it is necessary to improve the pain of the patient after the procedure.

In order to solve this problem, today, biodegradable polymers containing antibiotics or drugs that induce tissue regeneration are used. After the biodegradable membranes are implanted, the surface of the biodegradable polymers is eroded, releasing the drugs and the polymers themselves. As a result of the degradation and absorption, research on implantable polymers that can not only reduce the pain of patients but also obtain more effective therapeutic effects is being actively conducted. As the implantable polymer, synthetic polyester-based materials such as polylactic acid, polycaprolactone, polyglycolic acid, and polylactic-glycolic acid are mainly used. Polylactic acid is the first polymer used together with polyglycolic acid as a biodegradable implant. Both polymers are decomposed and absorbed into natural metabolites lactic acid and glycolic acid, respectively. These two macromolecules have been used mainly in the manufacture of matrixes or surgical materials for drug delivery systems. Has been applied and its application has been proven. In particular, Magnuson et al. Have reported that polylactic acid was used as a dental shield in induced tissue regeneration . J. Periodontol., 59 , 1-6 (1988).

The present inventors are conducting research to develop more effective periodontal tissue regeneration inducing drug and a drug-containing barrier that can improve the therapeutic effect, microspheres containing the drug in the biodegradable barrier membrane prepared using a biodegradable material The present invention has been completed by discovering that drug-containing biodegradable shielding membranes useful for alveolar bone regeneration can be prepared.

Disclosure of Invention An object of the present invention is to provide a drug-containing biodegradable shielding membrane for inducing periodontal tissue regeneration that has an effective periodontal tissue regeneration inducing function and an improved therapeutic effect, and a method of manufacturing the same.

1 is a comparison of the drug release characteristics of the drug-containing biodegradable barrier membrane for periodontal tissue regeneration and the conventional barrier membrane of the present invention,

Figure 2 shows a comparison of the material permeation characteristics of the drug-containing biodegradable shielding membrane for alveolar tissue regeneration of the present invention and the conventional shielding membrane.

In order to achieve the above object, in the present invention, a mesh is manufactured from polyglycolic acid-based fibers, a biodegradable polymer solution is applied to the mesh to prepare a shielding membrane, and microspheres containing a drug on one or both sides of the shielding membrane. A method for producing a drug-containing biodegradable shielding membrane for inducing periodontal tissue regeneration comprising adding a microsphere, and a drug for induction of periodontal tissue including a porous polyglycolic acid-based mesh, a biodegradable polymer layer and a drug-containing microsphere layer Containing biodegradable shielding membranes.

Hereinafter, the present invention will be described in detail.

According to the present invention, first, a basic mesh of a support is made of a biodegradable polymer fiber having good draw strength, and a thin film is coated by applying a polymer material that can act as a barrier until the desired therapeutic effect such as tissue regeneration is achieved. Biodegradable shielding membranes with good strength are prepared.

As the support mesh for coating a polymer solution, a polyglycolic acid system having a tensile strength of 5.5 g / denier or more and a fineness of 15-150 deniers, which is developed from a bioabsorbable surgical suture material, as known from Korean Patent No. 40,567 Fiber density of 20-100 bones / inch using multifiber or polyglycolic acid single fiber, or polylactic-glycolic acid or polylactic acid multifiber or single fiber having similar properties, or a mixture of these and blades Use knits or fabrics having The polyglycolic acid or polylactic acid-based polymer itself is very low in flexibility and plasticity, but it is possible to impart not only tensile strength but also flexibility and plasticity to the shielding film by forming a woven or knitted mesh.

Examples of the polymer used for the application of the mesh include polylactic acid, polylactic-glycolic acid, polycaprolactone, polyhydroxybutyric acid, polyhydroxybutyric-hydroxyvaleric acid or mixtures thereof. In addition, polymers with slow degradation, such as high molecular weights, do not degrade while maintaining sufficient morphology during treatment, while increasing flexibility for procedure convenience and tissue conjugation and minimizing local inflammation in the inserted tissue. A mixture of poly-L-lactic acid and poly-D, L-lactic acid or polylactic-glycolic acid, polycaprolactone, etc. having low molecular weight and crystallinity may be applied to the mesh. In general, biodegradable polymer materials are expanded or broken by water penetrating inside during hydrolysis. In order to eliminate these disadvantages, by mixing a low-molecular weight polymer having a low crystallinity and high flexibility, it is possible to prevent structural collapse of the shielding membrane during the treatment. Therefore, the biodegradable polymer to be applied to the mesh during the manufacturing of the shielding membrane, when prepared by mixing a high molecular weight material and a low molecular weight material in a mixing ratio of 1: 9 to 5: 5 in the human body for a period suitable for alveolar bone regeneration It can exhibit the best shielding effect. At this time, the high molecular weight material is preferably used to have a molecular weight of about 100,000 to 400,000, and the low molecular weight material has a decomposition and shielding effect during a suitable period of the material having a molecular weight of about 40,000 to 100,000. It is desirable to maintain. When the biodegradable polymer thus prepared is applied to the mesh, the weight ratio of the biodegradable polymer to the mesh is 3: 7 to 6: 4 to show the most effective shielding effect.

According to the present invention, drug-containing microspheres are added to the shielding membrane prepared as described above.

Drugs such as antibiotics used to provide a barrier with effective periodontal tissue regeneration function are effective to be administered within a relatively short period of 1 to 2 weeks for the treatment of inflammation after the procedure, and also to induce bone regeneration as well as antibiotic effects. Tetracycline-like antibiotics, such as minocycline, doxycycline, which have been reported to be effective, are maintained at low concentrations so that they are released for about 2 to 4 weeks, preferably about 2 to 3 weeks. It is preferable. In addition, growth factors that promote bone regeneration, such as insulin-like growth factors or platelet-derived growth factors, etc. are preferably released at a constant concentration of about 4 weeks or more to maximize their bone regeneration effect.

Therefore, the release rate should be controlled to release the drug at a constant concentration up to about 2 to 4 weeks depending on the drug to be administered after the shielding procedure, and 20% by weight or more in the microsphere to add as little microspheres as possible to the shielding membrane. The drug should be contained.

The biodegradable polymer used to prepare the microspheres used in the present invention should use a molecular weight of about 6,000 to 100,000 in order to maintain the release of the drug for 2 to 4 weeks, preferably in the range of 10,000 to 20,000 Biodegradable polymers having, for example, homopolymers of lactic acid or copolymers of lactic acid and glycolic acid. The microspheres used in the present invention preferably have a size in the range of 1 to 20 μm, and when smaller than 1 μm, the absolute content of the drug in the microspheres is less than 10 wt%, so that it is difficult to expect an adequate drug release effect. When microspheres larger than 탆 are added to the shielding film, it is important to introduce microspheres of appropriate size into the shielding film because the surface of the shielding film becomes rough and the surface unevenness occurs due to its own agglomeration phenomenon. It can be produced together.

For antibiotics that are soluble in organic solvents and relatively stable, homopolymers of lactic acid or copolymers of lactic acid and glycolic acid are dissolved in organic solvents, and finely pulverized drug powder up to 2 μm in diameter is added to the solution and then mixed well. To prepare a suspension. The drug particles are pulverized finely with a prober-type ultrasonic wave and cooled to 20 ° C. or lower, and the suspension is added to a previously prepared aqueous solution of 5 to 15% by weight of polyvinyl alcohol, followed by stirring to form an emulsion. When the particles of the emulsion become homogeneous, the resulting emulsion is diluted with excess distilled water cooled to 20 ° C. or lower, stirred slowly at room temperature, and the organic solvent is evaporated to prepare a microsphere.

In the case of protein-based drugs such as growth factors, care must be taken for stability and water solubility, so that the drug is pre-dissolved in phosphate buffer (pH = 7.4), and then span 80 in an organic solvent mixture in which the polymer is dissolved. Suspension such as the suspension is added (W / O emulsion method), and then prepared in the same manner as the microspheres.

Examples of drugs used in the present invention include flubiprofen, ibuprofen, indomethacin, naproxen, mefenamic acid, minocycline, tetracycline, doxycycline, oxytetracycline, metronidazole, platelet-derived growth factor, insulin-like growth factor, epidermal growth Factors, tumor growth factors or mixtures thereof.

The method of adding the prepared microspheres to the shielding film may vary depending on the type or characteristics of the shielding film. For example, the microspheres are dispersed in an aqueous solution of 0.5 to 10% by weight of a polysaccharide-based material such as carboxymethyl cellulose, methyl cellulose, hydroxy propyl methyl cellulose, alginate, and the like, and then directly coated on the shielding membrane, or micro After film casting the viscous solution in which the spear is dissolved, the film is placed on the film by using adhesive properties and then press-bonded by applying a slight pressure before the resulting film is completely dried to form a thin film-coated shielding film including microspheres. It can manufacture.

Care should be taken when adding the microspheres to the shielding film. The material used to add the microspheres must be insertable into the human body, and the intrinsic properties of the shielding film, such as material permeability or The physical properties of the microspheres, eg drug release properties, should not be altered.

Hereinafter, the present invention will be described in more detail with reference to the following examples. The following examples merely illustrate preferred embodiments of the invention and are not intended to limit the invention to these examples.

Preparation Example 1 Preparation of Shielding Membrane

Polyglycolic acid multifibers spun and stretched to 75 deniers of fineness were fabricated with a density of 30 bones / inch using a circular knitting machine. Subsequently, 2 g of polyvinylpyrrolidone having a molecular weight of 40,000 was dissolved in 70 ml of methylene chloride and 7 ml of ethanol mixed solvent, 3 g of poly-L-lactic acid having a molecular weight of 200,000 and 5 g of polylactic-glycolic acid having a molecular weight of 100,000 were added thereto. To make uniform pores inside and outside, 60g of additive sodium citrate is made into fine powder using a grinder or spray dryer, added to polymer solution, dispersed by ultrasonic wave and left at 30 ℃ for 12 hours or more to completely dissolve the polymer. The prepared polymer solution was applied on a polyglycolic acid mesh, dried and washed with water to prepare a shielding film.

Preparation Example 2 Preparation of Microspheres

Poly-D, L-lactic-glycolic acid (5 g) with an average molecular weight of 18,000 and tetracycline hydrochloride (2.2 g) with a particle size of 2 μm or less were added to dichloromethane (18 mL) and mixed well. Suspension was prepared. The suspension was added to an aqueous solution (180 mL) containing 5% by weight of polyvinyl alcohol (DP = 1,500) as a surfactant and then stirred (900 rpm) with a mechanical stirrer for 10 minutes to prepare an emulsion. It was slowly added to excess distilled water (500 mL) with stirring (150 rpm) over 1 hour at room temperature. The suspension solution containing the microspheres was centrifuged to separate the microspheres and washed well with distilled water. The average particle size of the produced microspheres was 10 µm, the content of tetracycline hydrochloride was 23% by weight, and the recovery was 94%.

Thus prepared, the physiological activity of the drug released from the microspheres containing 23% by weight of tetracycline hydrochloride is shown in Table 1, it can be seen that the drug is stable in binding to the polymer.

Take 30 μl each of the buffer solution replaced at 24 hour intervals, moisten the antibiotic-dispensing paper disk (6.4 mm in diameter), place it on agar plate pre-inoculated with Bacillus cereus, and incubate the agar plate. The biological activity of the drug released from the microspheres was measured by measuring the diameter of the region where the growth of bacteria was inhibited.

Hours One 2 3 4 5 6 7 8 9 10 11 12 Diameter of growth inhibition zone (mm) 20 21 21 20 20 20 21 20 20 19 18 14

Preparation Example 3 Preparation of Microspheres

Microspheres were prepared in the same manner as in Preparation Example 2, except that 2.4 g of minocycline hydrochloride was used instead of the tetracycline hydrochloride of Preparation Example 2 as a drug. The average particle size of the produced microspheres was 10 µm, the content of minocycline hydrochloride was 26% by weight, and the recovery was 95%.

Preparation Example 4 Preparation of Microspheres

Poly D, L-lactic acid (5 g) with an average molecular weight of 16,000 and flubiprofen (2.5 g) with a particle size of 2 μm or less were prepared using dichloromethane (20 mL) to prepare a suspension. Microspheres were prepared in the same manner as in Preparation Example 2. The average particle size of the produced microspheres was 10 µm, the content of flubiprofen was 27% by weight, and the recovery was 96%.

Preparation Example 5 Preparation of Microspheres

The platelet-derived growth factor (PDGF, 400 ng) was dissolved in about 0.5 ml of phosphate buffer solution (pH = 7.4), and then poly D, L-lactic acid (2 g) and span 80 having an average molecular weight of 16,000. (span 80) (0.09 g) and dichloromethane (9 mL) were added to the mixed solution and dispersed with a prober-type sonicator to prepare a W / O suspension. The suspension was added to an aqueous solution (70 mL) containing 10% by weight of polyvinyl alcohol (DP = 1,500) as a surfactant and then stirred (800 rpm) with a mechanical stirrer for 10 minutes to prepare an emulsion. It was slowly added to excess distilled water (250 mL) with stirring (150 rpm) over 1 hour at room temperature. The suspension solution containing the microspheres was centrifuged to separate the microspheres and washed well with distilled water. The resulting microspheres had an average particle size of 15 μm, a platelet derived growth factor content of 0.002 wt%, and a recovery rate of 94%.

An important factor in the delivery of peptide drugs is the maintenance of activity, and the microspheres of platelet-derived growth factors are compared by comparing the effects of platelet-derived growth factors on cell activity before and after microsphere production to examine the changes in activity after the introduction of the membrane. It was confirmed in the stability shown in Table 2 below.

The gingival fibroblasts were treated with 0.25% trypsin-EDTA solution and then incubated with about 50,000 cell lines in each well using a standard hemocytometer. Platelet-derived growth factors at the same concentration as the platelet-derived growth factors released from the microspheres were placed in each well plate, followed by addition of the culture solution to 200 μl, which were then incubated for 24 hours, followed by dissolution in physiological saline (MTT) 50 μl of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide) solution was added to each well and incubated for 4 hours, followed by removal of the MTT solution, followed by dimethyl sulfoxide in each well. 50 μL of side was added to dissolve formazone crystals. Absorbance was measured at 570 nm using an Elisa reader. As a control, α-MEM culture medium containing no sample was used.

Control PDGF-BB PDGF (MS) -5 PDGF (MS) -10 PDGF (MS) -20 PDGF (MS) -30 Cell activity (%) 100 123 121 119 122 115

PDGF-BB: Platelet-derived growth factor intact without microspheres

PDGF (MS) -5: Platelet derived growth factor released from microspheres (release date)

Example 1 Preparation of a Drug-Containing Membrane According to the Present Invention

After dissolving 1 g of sodium alginate in 15 ml of pure water, there was prepared a microsphere dispersion prepared by dispersing 0.7 g of the prepared microspheres as described in Preparation Example 2, and then using the bladder to prepare the dispersion. Film forming to form a film with a thickness of 40 to 50㎛, Alginic acid in which microspheres are uniformly dispersed on one side by compression bonding the shielding film prepared as in Preparation Example 1 when the resulting film is almost dried A shielding film to which a sodium thin film was added was prepared.

Example 2

1 g of hydroxypropylmethyl cellulose was dissolved in 15 ml of pure water, followed by dispersing 0.7 g of microspheres prepared in the same manner as in Preparation Example 3, using the dispersion prepared in the same manner as in Example 1 A sex shield was prepared.

Example 3

1 g of sodium alginate was dissolved in 15 ml of pure water, and then the drug-containing biodegradable shielding membrane was prepared in the same manner as in Example 1 using a dispersion prepared by dispersing 0.7 g of microspheres prepared in the same manner as in Preparation Example 4. Prepared.

Example 4

1 g of sodium alginate was dissolved in 15 ml of pure water, and then the drug-containing biodegradable shielding membrane was prepared in the same manner as in Example 1 using a dispersion prepared by dispersing 0.7 g of microspheres prepared in the same manner as in Preparation Example 5. Prepared.

Example 5

In order to further delay the drug release rate of the drug-containing biodegradable shielding membrane prepared in the same manner as in Example 1, the conversion of the ionic form of sodium alginate to calcium decreases the solubility of alginate in water. The shield was immersed in 5% by weight aqueous calcium chloride solution for about 3 minutes and then dried. In this way, the initial drug release rate was small and a shielding membrane that could control the release rate of the drug for about 4 weeks was prepared.

Comparative Example 1

In order to add the drug to the shielding film prepared as in Preparation Example 1, the shielding film was immersed in 10wt% of minocycline aqueous solution for 3 hours or more to allow the drug to sufficiently penetrate into the shielding film and added thereto, followed by vacuum drying for 24 hours at room temperature to contain the drug-containing shielding film. Was prepared.

Comparative Example 2

Dissolve 0.5 g of polyvinylpyrrolidone in 30 ml of methylene chloride and 8 ml of ethanol mixed solvent, and disperse ultrasonically by adding 1 g of poly-L-lactic acid with a molecular weight of 100,000 and 3 g of polylactic-glycolic acid with a molecular weight of 100,000 and 1 g of tetracycline. The mixture was allowed to stand at 30 ° C. for 12 hours, mixed thoroughly, and then coated and dried on 30 glycol / inch polyglycolic acid mesh to prepare a drug-containing shielding membrane.

Effect Test 1

The drug release rate of the drug-containing shielding membrane for periodontal tissue regeneration and the shielding membranes of Comparative Examples 1 and 2 according to the present invention prepared in Examples 1 to 5 were measured as follows: Contains phosphate buffer solution (20 ml). Each drug-containing shielding membrane (0.5 g) was added to the flask, and the UV absorbance was measured on a UV spectrometer while completely replacing the buffer solution at intervals of 24 hours while stirring at a rate of 50 rpm in a constant temperature water bath at 37 ° C ± 0.5 ° C. (The drug-containing barrier film prepared in Example 4 was measured by quantitatively analyzing the amount of drug released by the γ- scintillation counter).

1 is a comparison of the drug release characteristics of the drug-containing biodegradable barrier membrane for periodontal tissue regeneration of the present invention and the conventional barrier membrane.

Effect test 2

The material permeability of the drug-containing shielding membrane according to the present invention was measured as follows: A vertical membrane cell was installed in a water bath maintained at 37 ° C. ± 0.5 ° C. using a circulator, and bovine serum albumin was used in the drug sample section. ), 0.01M phosphate buffer (pH = 7.4) was added to the permeable part, and then the shielding membranes according to the present invention were placed in the center, and then the calculated amount of albumin over time was calculated and quantitatively measured. Phosphorus analysis was performed using an ultraviolet spectrophotometer.

Figure 2 is a comparison of the material permeation characteristics of the drug-containing biodegradable shield membrane for alveolar tissue regeneration of the present invention and the conventional shielding membrane, as shown here material permeability of the drug-containing microspheres coated shielding membrane prepared according to the present invention It can be seen that there is almost no difference in the permeability of the uncoated shielding film.

Biodegradable shielding membrane comprising drug-containing microspheres according to the present invention has a side effect such as down-proliferation or gingival contraction of epithelial cells by the initial inflammatory response by releasing the drug at a constant rate for a certain period of about 2 to 4 weeks Not only can it reduce the growth of the tissues in which the barrier is inserted, but also it can alleviate the discomfort of the patient due to continuous antibiotic administration after the procedure. By containing a compound that promotes the regeneration of the complex in the microspheres can increase the therapeutic effect can be useful in the treatment of alveolar bone regeneration.

Claims (8)

1) a mesh is made of polyglycolic acid fibers, 2) a biodegradable polymer solution is applied to the mesh, and 3) a drug-containing microsphere made of a biodegradable polymer on one or both sides of the polymer layer. Method of producing a drug-containing biodegradable shielding membrane for periodontal tissue regeneration comprising the addition of the microspheres by direct coating the dispersion prepared by dispersing in an aqueous solution or by molding the dispersion into a film and compression bonding. The method of claim 1, Compression bonding of the drug-containing microspheres, the drug-containing microspheres are dispersed in a 0.5 to 10% by weight aqueous solution of polysaccharide, and then the resulting dispersion is molded into a film of 40 to 50㎛ thickness and the film is completely dried By compression bonding the film before. The method of claim 1, Coating the drug-containing microspheres by coating a dispersion obtained by dispersing the drug-containing microspheres in an aqueous solution of 0.5 to 10% by weight of polysaccharide. The method of claim 2, wherein The polysaccharide is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxy propyl methyl cellulose, alginate and mixtures thereof. Meshes made of porous polyglycolic acid fibers; A polymer layer made of a biodegradable polymer selected from polylactic acid, polylactic-glycolic acid, polycaprolactone, polyhydroxybutyric acid, polyhydroxybutyric-hydroxyvaleric acid or a mixture thereof applied to the mesh; And a drug-containing microsphere layer made of a biodegradable polymer added to one or both sides of the polymer layer. The method of claim 5, And the microspheres are made of a biodegradable polymer selected from homopolymers of lactic acid having a molecular weight ranging from 6,000 to 100,000, copolymers of lactic acid and glycolic acid, or mixtures thereof. The method of claim 5, The microspheres range in size from 1 to 20 μm and the drug is released constantly over 2 to 4 weeks. The method of claim 5, The drug may be fluvifuropene, ibuprofen, indomethacin, naproxen, mefenamic acid, tetracycline, minocycline, doxycycline, oxytetracycline, metronidazole, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, tumor growth factor and Shielding film, characterized in that selected from the group consisting of a mixture thereof.

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