KR20050093464A - Implant for tissue regeneration after microfracture - Google Patents

Abstract

The present invention relates to an implant for complementing tissue regeneration during microporation surgery, which comprises a biodegradable polymer as a polymer support together with a drug and has a rod shape.

The present invention is biodegradable and does not require additional removal surgery, and is rigidly configured so that it is easy and effective at the time of treatment, and effectively serves as a support, thereby ensuring sufficient space for tissue growth, and having a rod shape having a desired size. Provided is a biodegradable polymeric implant that can be prepared in a matrix and a method of making the same. In addition, the implant of the present invention may control the drug to be released slowly over a period of time.

Description

Implant for tissue regeneration after microfracture

The present invention relates to a tissue replenishment implant during microperforation surgery.

Tissue regeneration restores normal tissues through scaffold transplantation, cell / tissue transplantation, and drug delivery when certain tissues in the body are damaged or lost and lose their function. It should be stable, maintain a constant strength, release the contained drugs or factors as expected, decompose in the body after new tissue is formed, and the degradation products should not have toxicity in the body.

Tissue engineering is a technology based on the development of biological substituents for repair, reconstruction, replacement, and regeneration of biological tissues. The long-term goal of tissue engineering is to construct biomaterials that are biocompatible, biodegradable and capable of fusion with growth factors or cells. In general, there are two approaches. First, the target tissue is removed, modified or modified and transplanted again. Second, transplantation of cells for the construction or genetic regeneration of biomimetic tissue is performed. In the meantime, other ceramics, polymers (polylactic glycolic acid copolymer) collagen gels, and other polymers have been tested in vitro and in vitro. However, no clear results have yet been produced.

Articular cartilage damage is caused by fractures and other forms of arthritis caused by physical trauma, in which the cartilage slowly wears out, exposing the bones of the semicartilage, resulting in pain and other symptoms. Natural reactions occur in the body to repair articular cartilage (cartilage is limited by the extracellular matrix (ECM), which is low in blood vessel formation and rich in proteoglycans). Lesions that penetrate the bone form a tube that leads to vascular bone, thereby capturing bone and bone marrow cells originating at the site of the lesion to coagulate fibrin to form granular tissue. The deep parts of the granulation tissue reconstruct the plates of the parachondral bone, while the upper parts become fibrocartilage tissue. This tissue is temporarily hyaline (hyaline) cartilage tissue, but does not have mechanical features, so it cannot support in the physical environment, so there is a problem that degeneration occurs within the first year after trauma. However, thick lesions in immature joint cartilage are healed better than adults, and in the case of a fetus completely healed within a month without any help, age is also an important factor in the natural repair of cartilage tissue.

For damage to articular cartilage, tissue engineering can be applied to implanting various factors that induce viable cells or tissue regeneration in appropriate supports. The support for drug delivery is first a supporting factor. Several kinds of in vivo suitable supports are known to contribute to the repair of articular cartilage. Among many natural and synthetic materials, biodegradable polymers are considered to be the most promising materials for the repair of bone joint defects. The ideal support for cartilage regeneration is not yet clearly specified. But new biomaterials are under development.

 Attempts have been made to help regenerate damaged or missing articular cartilage tissue. Removal of irregular surfaces through shaving and debridement, perforation of the subchondral bone by drilling, crushing or abrasion to increase natural repair response, jointing the remaining cartilage Realignment or fracture of joints for use in formation, pharmacological and molecular biological control through delivery of drugs or growth factors, cell transplantation such as alografts or autografts, chondrocytes, etc. will be. Most importantly, while it is being done, the pathology of the patient, the reproducibility of the results, the time of operation, the price, the technical difficulties, and the recent clinical data supporting each method should be taken into account.

The replacement of articular cartilage with the soft tissues that make up the periosteum has been mainly studied because it is experimentally limited rather than clinically. The cambium layer adjacent to the bone interface is thought to be the origin of chondrocytes. New tissues from the periosteal flaps are promising because of histologically high levels of collagen type II. In this case, arthroscopy is not available, and the problem of fixing to normal cartilage tissue of the surroundings is revealed as a technical difficulty along with the possibility of necrosis around the wound site.

Microfracture of subchondral bone for articular cartilage injury has advantages over other techniques of cartilage formation by arthroscopy. Other methods can cause thermal necrosis of bone and surrounding cartilage due to the high temperatures generated by the use of highway-operated equipment. However, microperforation surgery uses a cartilage awl made to puncture small needles, so that no heat is generated and the parachondral plate can be left untouched. Thus, the loaded and supported bone cortex can be protected, avoiding further damage, and can even replace the biomechanical properties of the treated area. Needless to say, because of the use of augers, drilling can be done in a more controlled state than in drills or burrs. The tip of the awl is relatively sharp, allowing you to make holes in the desired spot. Compared to other endoscopic instruments or tips, the auger is reusable and saves money. Rough surfaces created by microperforation also improve the accessibility of fibrocartilage.

When perforated cartilage is punctured by microporation, various blood cells, growth factors, and hormones emerge from the bone marrow, and blood coagulation tissue is formed by fibrin aggregation, and then the action of cells and hormones to regenerate tissue It begins. Since the degree and speed of such regeneration are greatly improved than when the microperforation surgery is not performed, a lot of microperforation surgery is performed. In fact, it is known that the degree of expression of type 2 collagen, which can be a marker of being close to normal cartilage tissue, is further increased after microporation surgery.

However, even if microporation induces cartilage tissue regeneration, the tissues do not grow enough to the damaged part.

SUMMARY OF THE INVENTION An object of the present invention is to provide an implant and a method for producing the same, which have structural stability and can help to effectively regenerate tissue by slowly releasing a drug containing therein for a period of time.

It is also an object of the present invention, especially in the case of joint cartilage damage can be applied together with microporation surgery, by slowly releasing the containing drug for a certain period of time to solve the problem that the tissue does not fill up to the damaged area during microporation surgery It is an object of the present invention to provide an implant and a method for manufacturing the same, which may help to effectively regenerate.

The present invention relates to an implant for complementing tissue regeneration during microporation surgery, which comprises a biodegradable polymer as a polymer support together with a drug and has a rod shape. (Figure 1)

Vehicles made of other non-biodegradable polymers are not desirable because they require surgical procedures that need to be removed again to aid tissue regeneration. Therefore, in the present invention, a biodegradable polymer was used as the polymer support.

As the form which can be applied as an implant using a biodegradable polymer, various forms such as general matrix, porous scaffold, and microsphere can be considered. However, since the inside of the joint cavity is a water environment filled with synovial fluid, it is difficult to apply the particles because they are not fixed, and a rod-type vehicle that can have the strength required for the procedure is preferable in the form that can be applied to the microperforation surgery. . Examples of the rod type include cylindrical, triangular, rectangular, pentagonal, and hexagonal columns. It is possible to release the drugs contained inside in a physically stable environment without exiting the hole created by microperforation surgery.

The diameter and length of the rod-shaped implant of the present invention can be variously applied depending on the size of the perforation during surgery, the diameter is preferably 0.5 to 2 mm, the length is 4 to 8 mm range, especially, for example, diameter 1.5 mm Particular preference is given to implants having a length of 5 mm or implants having a diameter of 0.7 mm and a length of 5 mm.

The implant of the present invention comprising a biodegradable polymer as the polymer support can be modified in various ways on the surface of the polymer support, can contain drugs and the like inside and outside, and can release the contained drugs and the like in a sustained release form. .

The present invention provides compositions for use in repairing, regenerating, reconstructing or expanding cartilage tissue or other tissues such as meniscus, ligaments, tendons, bones, skin, corneas, indwelling tissues, abscesses, resected cancers and ulcers.

In addition, the present invention provides a use of a polymer solution that can be mixed with physiological and pharmacological components, and that can recover, regenerate, reconstruct, or extend tissue by placing the mixture at a site of the body. Tissue to be repaired includes, but is not limited to, for example, cartilage, meniscus, ligaments, tendons, bones, skin, corneas, periodontal tissues, abscesses, resected cancers and ulcers.

In addition, the implant of the present invention can be applied in the case of similar as well as during microporation surgery.

The biological component is preferably based on blood, blood component or isolated cell of autologous or non-valent source, but is not necessarily limited thereto.

The drug is preferably at least one component selected from the group consisting of growth factors, hormones, anti-inflammatory agents and antibiotics,

For example, platelet-derived growth factor (PDGF), insulin-like growth factor (Epidermal growth factor) and transforming growth factor (Transforming growth factor); Flubiprofen, ibuprofen, naproxen, mefenamic acid, tetracycline, minocycline, oxytetracycline, metronidazole, chlorhexidine, dihydro-epiandrosterone (DHEA: Dehydro-epiandrosterone) and its sulfate (sulfate salt) or glucuronide Salts (glucuronide salts). Since DHEA and DHEA sulfate have been experimentally reported to have a function of inhibiting genes that destroy cartilage matrix, it is more preferable for application to damaged cartilage.

The biodegradable polymer is preferably at least one component selected from the group consisting of natural polysaccharides and synthetic biodegradable polymers,

More preferably, the natural polysaccharide is a group consisting of chitosan and alginic acid, and the synthetic biodegradable polymer is a group consisting of polylactic acid, polyglycolic acid, polycaprolactone and copolymers of two or more thereof,

Especially preferably, the biodegradable polymer is a homopolymer of lactic acid of 50,000 to 370,000 lactic acid or a copolymer of lactic acid and glycolic acid of molecular weight of 50,000 to 350,000.

Natural polymers obtained from humans and animals such as collagen, hyaluronic acid and gelatin are not suitable for drug delivery implants due to their low strength and fast decomposition by body degrading enzymes.

The implant for complementing tissue regeneration at the time of microperforation surgery of the present invention may further include a ceramic. The ceramics include, for example, tricalcium phosphate ceramics, calcium sulfate ceramics, calcium carbonate ceramics, hydroxyapatite, apatite fluoride, and apatite carbonate, with calcium triphosphate ceramic being particularly preferred.

In the microporous surgery of the present invention, the tissue regenerating complement implant is preferably 1 to 140 parts by weight based on 100 parts by weight of the biodegradable polymer,

The content of the ceramic is preferably 1 to 60 parts by weight, more preferably 10 to 50 parts by weight based on 100 parts by weight of the biodegradable polymer. The implant of the present invention can increase its strength by further including the ceramic.

Another aspect of the present invention is to prepare a biodegradable polymer solution by dissolving the biodegradable polymer in a solvent, (2) emulsifying the drug and other components in the biodegradable polymer solution by itself or as a solution thereof, Dispersing or dissolving, (3) the emulsion, dispersion or solution prepared in step (2) to the molding die, comprising the step of molding and drying, the method for producing a tissue regeneration complement during microporation surgery will be.

The concentration of the biodegradable polymer in the biodegradable polymer solution is preferably 5 to 75 parts by weight, more preferably 25 to 50 parts by weight based on 100 parts by weight of the solvent.

When the ceramic is added, the concentration is preferably used in an amount of 1 to 60 parts by weight, more preferably 20 to 50 parts by weight, based on 100 parts by weight of the solvent.

Step (2) of the preparation method according to the invention is the step of emulsifying, dispersing or dissolving a therapeutically effective amount of a drug. When drugs such as platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, and transforming growth factor are applied to the biodegradable polymer implant, emulsified in a biodegradable polymer solution using a surfactant such as Span 80 to form a water-in-oil emulsion. After preparation, the implant can be prepared.

The content of the drug at this time; Emulsified, dispersed or dissolved forms of the drug; Concentration of biodegradable polymer solution; And drugs can be controlled release from the rod-shaped implant according to the content of the added ceramics and the like.

The production method according to the invention comprises the step (3) of adding to the mold and shaping, hardening, separating and drying. When applied to cartilage, the diameter and height can be determined to create a rod-type implant that is suitable for drilling perforations for microperforation surgery. After making a mold suitable for it, a rod-type implant of a suitable size can be obtained by adding and solidifying and drying a polymer mixed solution containing the drug or growth factor prepared above.

Methylene chloride, chloroform, dimethylsulfoxide, tetrahydrofuran, acetone, and the like may be used as a solvent used to make the implant according to the present invention, but methylene chloride is relatively less toxic, and is used throughout the entire range of molecular weight of biodegradable polymer. It is a good solvent to dissolve evenly.

When the biodegradable polymer solution is added to the mold, methylene chloride (boiling point 39.75 ° C.) is easily evaporated and the porous pores may be formed as the site becomes micropores. In addition, as the implant begins to decompose over time, the precipitated polymer is attached to the ceramics around it and the movement is inhibited, so that the polymer is subjected to tension and micropores are formed in the spaces between the ceramics to form a porous structure on the surface.

The implant according to the invention releases the drug, growth factor, and other factors it contains when placed in the aquatic environment, which initially diffuses out of the support and is further released by the lost gap when the support itself begins to disintegrate. do. The rate and pattern at which the drug or factor is released can be controlled differently depending on the concentration contained, the method of making the implant, and the site of application. Particularly, when applied to cartilage, release over a period of 3-4 weeks is preferred.

The production method of the present invention may further comprise the step of coating with a thin biodegradable polymer solution for the dry molding prepared in step (3).

The solvent of the thin biodegradable polymer solution is preferably methylene chloride, and the concentration of the biodegradable polymer is preferably 5 to 20 parts by weight based on 100 parts by weight of the biodegradable polymer.

By the above additional coating step, the drug release can be controlled once again by the degree of coating. Therefore, the implant of the present invention may provide a sustained release drug delivery system capable of slowly releasing the drug to the desired degree according to the indication and the type of drug applied.

The present invention is the first attempted formulation in view of designing an implant that can be implanted into a perforation after surgery to compensate for the deficiency of the conventional microperforation surgery.

In the case of the previously designed implant or support for inducing tissues such as cartilage, it was mainly a sponge or fibrous support, and even though the drug was contained, most of the drug content was released in a relatively short time during the dissolution test.

However, in the present invention, the density of the support was increased by the significant concentration in dissolving the biodegradable polymer in the solvent. Therefore, the rate at which the drug is released from the support is controlled to allow release for more than two weeks. In addition, it was possible to have the strength required for the post-production procedure.

Increasing the amount of dispersion (content) of the drug increases the rate at which the drug diffuses out of the support at some point. Therefore, in the present invention, this point is improved by further comprising coating the support surface with a dilute polymer solution.

Thus, when the implant of the present invention is provided in a sustained release form, by releasing the drug containing the drug for a long time after transplantation with microporation surgery, cells and factors related to cartilage tissue regeneration come out of the bone marrow to induce the regeneration of cartilage tissue. It will continue to stimulate.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not necessarily limited thereto.

Example 1

Polylactic acid glycolic acid copolymer (50:50) (molecular weight: about 70,000, Purac) was dissolved in methylene chloride at a concentration of 1 g / 2 mL. Tricalcium phosphate ceramic and tetracycline were added and dispersed in the ratio of 0.5g and 0.1g per 1g of copolymers here, respectively. This mixed solution was added to a cylindrical molding die prepared in advance, left for 24 hours to harden, then taken out, and dried for 24 hours. The rod-shaped implants produced were cylindrical with a diameter of 1.5 mm and a length of 5 mm.

The rod-shaped biodegradable polymer matrix according to the present invention prepared above was able to confirm that the three-dimensional structure was maintained even after being separated from the rod-shaped mold (FIG. 2). The cross section of the plant is 1.5 mm in diameter and 5 mm in length. As a result of observing the surface and the cut surface of the prepared bar matrix under a differential scanning microscope, it is shown in FIG.

Example 2

Polylactic acid glycolic acid copolymer (50:50) (Purac) was dissolved in methylene chloride at a concentration of 1 g / 2 mL. The tricalcium phosphate ceramic and DHEA sulfate were added and dispersed in a ratio of 0.5 g and 0.2 g per 1 g of the copolymer, respectively. This mixed solution was added to the same molding die as in Example 1, left to solidify for 24 hours, taken out, and dried for 24 hours.

Example 3

Polylactic acid glycolic acid copolymer (50:50) and polylactic acid (molecular weight: about 350,000) were mixed in a 1: 1 weight ratio, and then tricalcium phosphate ceramic and DHEA sulfate were mixed at a ratio of 0.5g and 0.2g per 1g of copolymer, respectively. Added and dispersed. This mixed solution was added to the same molding die as in Example 1, left to solidify for 24 hours, taken out, and dried for 24 hours.

Example 4

Polylactic acid glycolic acid copolymer (50:50) was dissolved in methylene chloride at 1 g / 2 mL, and then tricalcium phosphate ceramic and DHEA sulfate were added and dispersed at a ratio of 0.2 g and 1.2 g per 1 g of the copolymer, respectively. This mixed solution was added to the same molding die as in Example 1, left to solidify for 24 hours, taken out, and dried for 24 hours.

Example 5

The rod matrix prepared in Example 4 was coated with a thin polymer solution. As a dilute polymer solution, polylactic acid glycolic acid copolymer (50:50) was dissolved in methylene chloride at a concentration of 10%. The prepared rod matrix was immersed in this solution, taken out, dried in warm air, and the solvent was volatilized.

Example 6

Polylactic acid glycolic acid copolymer (50:50) (molecular weight: about 70,000, Purac) was dissolved in methylene chloride at a concentration of 1 g / 2 mL. Tetracycline was added and dispersed at a ratio of 0.1 g per 1 g of copolymer thereto. This mixed solution was added to a cylindrical molding die prepared in advance, left for 24 hours to harden, then taken out, and dried for 24 hours.

Example 7

Polylactic acid glycolic acid copolymer (50:50) (molecular weight: about 70,000, Purac) was dissolved in methylene chloride at a concentration of 1 g / 2 mL. Tricalcium phosphate ceramic and tetracycline were added and dispersed in the ratio of 0.5g and 0.1g per 1g of copolymers here, respectively. This mixed solution was added to a preformed square-cast mold, left to stand for 24 hours, hardened, and then taken out and dried for 24 hours. The prepared rod-shaped implants were rectangular pillars having a diameter of 0.7 mm on one side and a 5 mm length.

Experimental Example 1 Drug Release Experiment (1)

The rod matrix prepared in Example 1 was placed in 1 mL of 0.1 M phosphate buffer (pH 7.4) and maintained at 37 ° C. and 15 rpm in a stirred water bath. Emission liquids were taken at regular intervals, and the absorbance was measured at 276 nm using an ultraviolet absorbance spectrometer, and then the concentration of the released tetracycline was calculated. The results are shown in Figure 5a.

Experimental results showed that tetracycline maintains the effective amount of drug as it is continuously released for more than 4 weeks.

The rod-shaped matrix prepared in Example 6, which does not include tricalcium phosphate ceramic, was also subjected to the same experiment as above, and the results are shown in FIG. 5B. From the results similar to the above results, it was found that tricalcium phosphate ceramics did not significantly affect the drug release pattern.

Experimental Example 2 Drug Release Experiment (2)

The rod-like matrixes prepared in Examples 2 and 3 were placed in 1 mL of 0.1 M phosphate buffer (pH 7.4) as in Experiment 1, and then maintained at 37 ° C. and 15 rpm in a stirred water bath. The eluate was taken at regular intervals and the concentration of DHEA sulfate in the eluate was calculated using HPLC (High performance liquid chromatography). The results are shown in FIG.

Experimental results showed that DHEA sulfate was released from the matrix made of polylactic acid glycolic acid copolymer as a polymer for at least 4 weeks, and from matrix prepared by mixing the polylactic acid glycolic acid copolymer and polylactic acid at the same ratio. It was found to be released.

In the latter case, since polylactic acid having a relatively high molecular weight is mixed, it is thought that the decomposition rate of the matrix itself is slow and the release rate is also slow.

Experimental Example 3: Drug Release Experiment (3)

The bar matrix prepared in Example 4 was tested under the same conditions and methods as in Experimental Example 2. The results are shown in FIG.

Experimental results showed that DHEA sulfate was released for about 2 weeks, but the release amount was very high in the first 4 days. It is thought that the amount of drug dispersal relative to the weight of the polymer is larger than that of the above example, so that most of the drug is initially released at a rapid rate by diffusion.

Experimental Example 4: Matrix Degradation Test

The bar matrix prepared in Example 4 was subjected to the decomposition experiments at regular time intervals under the conditions of the drug release experiment. The results are shown in FIG.

It can be seen that over time, it degrades slowly and loses its weight.

Experimental Example 5: Drug Release Experiment (4)

The bar matrix prepared in Example 5 was tested under the same conditions and methods as in Experimental Example 2. The results are shown in FIG.

Experimental results Compared with Experimental Example 3, it can be seen that the release is more than two weeks. It is thought that a dilute polymer solution acts as a release control membrane, slowing the diffusion rate and allowing zero rate release of the drug.

The present invention is biodegradable and does not require additional removal surgery, and is rigidly configured so that it is easy and effective at the time of treatment, and effectively serves as a support to secure enough space for tissue growth (schedule until completely biodegradable). Strength and shape retention above), biodegradable polymeric implants that can be made into rod-shaped matrices of desired size, and methods of making the same. In addition, the implant of the present invention may control the drug to be released slowly over a period of time.

According to the manufacturing method of the present invention, it is possible to manufacture a matrix in a mold of any size, and is a delivery system useful for the delivery of drugs and growth factors in support of microperforation of cartilage tissue, and also for a certain period of time in the body And by releasing the growth factor has the advantage that can achieve the desired effect.

1 is a diagram showing the micro-puncture surgery and implant insertion

2 is an implant mold used in Example 1

Figure 3 is an implant of the present invention made in a rod (rod) in Example 1

4 is an initial surface, cross-sectional differential scanning micrograph (SEM image)

5A and 5B are elution graphs (PLGA, TC 10% loaded) of tetracycline from implants prepared in Examples 1 and 5, respectively;

FIG. 6 is a dissolution graph (PLGA only vs PLLA: PLGA blended, DHEA-s 20% loaded) of the dehydroepiandrosterone from implants prepared in Examples 2 (■) and 3 (□)

7 is a differential scanning micrograph after the dissolution test of the implant prepared in Example 2 (■) and Example 3 (□)

8 is a dissolution graph (PLGA, DHEA-s 120% loaded) of dihydroepiandrosterone from implants prepared in Example 4

9 is a result of a matrix decomposition experiment (Experimental Example 4) for the implant prepared in Example 4

FIG. 10 is an elution graph (PLGA, DHEA-s 120% loaded, coated with diluted solution) of dihydroepiandrosterone from the implant prepared in Example 5. FIG.

Claims (16)

Implants for supplementing tissue regeneration during microporation surgery, including biodegradable polymers and rod-shaped ones as a polymer support together with drugs. The implant of claim 1, wherein the drug is one or more components selected from the group consisting of growth factors, hormones, anti-inflammatory drugs, and antibiotics. The method of claim 2, wherein the drug is a platelet-derived growth factor (PDGF), Insulin like growth factor, Epidermal growth factor and transforming growth factor (Transforming growth factor) ); Flubiprofen, ibuprofen, naproxen, mefenamic acid, tetracycline, minocycline, oxytetracycline, metronidazole, chlorhexidine, dihydro-epiandrosterone (DHEA: Dehydro-epiandrosterone) and its sulfate (sulfate salt) or glucuronide Implants for complementing tissue regeneration during microporation surgery, which is at least one component selected from the group consisting of glucuronide salts. The implant of claim 1, wherein the biodegradable polymer is at least one component selected from the group consisting of natural polysaccharides and synthetic biodegradable polymers. The method of claim 4, wherein the natural polysaccharide is a group consisting of chitosan and alginic acid and the synthetic biodegradable polymer is a group consisting of polylactic acid, polyglycolic acid, polycaprolactone and two or more copolymers thereof. Implants to complement tissue regeneration. The implant of claim 5, wherein the biodegradable polymer is a homopolymer of lactic acid of 50,000 to 370,000 lactic acid or a copolymer of lactic acid and glycolic acid of 50,000 to 350,000 molecular weight. The implant of claim 1, further comprising a ceramic. 8. The implant for complementing tissue regeneration during microporation according to claim 7, wherein the ceramic is at least one component selected from the group consisting of tricalcium phosphate ceramic, hydroxyapatite, fluoride apatite and apatite carbonate. The implant of claim 1, wherein the drug content is 1 to 140 parts by weight based on 100 parts by weight of the biodegradable polymer. According to claim 7, The content of the ceramic is 1 to 60 parts by weight based on 100 parts by weight of the biodegradable polymer tissue repair complement implants during microporation surgery. (1) dissolving the biodegradable polymer in a solvent to prepare a biodegradable polymer solution, (2) emulsifying, dispersing or dissolving the drug and other components in the biodegradable polymer solution by itself or as a solution thereof, ( 3) A method for preparing a tissue regeneration-compensating implant during the microperforation of claim 1, comprising the step of molding and drying the emulsion, dispersion or solution prepared in step (2) in a mold. The process according to claim 11, wherein the solvent is methylene chloride. The method of claim 11, wherein the concentration of the biodegradable polymer in the biodegradable polymer solution is 5 to 75 parts by weight of the biodegradable polymer based on 100 parts by weight of the solvent. The method of claim 13, wherein the concentration of the biodegradable polymer in the biodegradable polymer solution is 25 to 50 parts by weight of the biodegradable polymer with respect to 100 parts by weight of the solvent. 12. The process according to claim 11, further comprising the step of coating with a thin biodegradable polymer solution on the dry molding prepared in step (3). The method according to claim 15, wherein the solvent of the thin biodegradable polymer solution is methylene chloride, and the concentration of the biodegradable polymer is 5 to 20 parts by weight based on 100 parts by weight of the biodegradable polymer.