KR101003749B1 - Method for producing porous material using polylactide - Google Patents

Abstract

The present invention relates to a method for preparing a porous material using a bioabsorbable polymer, and more specifically, to a surface having 1-5 um pore size using polylactide, and having a uniform pore size of 10-50 um inside. It relates to a method of synthesizing a material having. Thus, the polylactide produced by the present invention has the sustained release formulation properties of the active substance impregnated by its structural properties. In addition, as a scaffold made of a biocompatible polymer material, porous polylactide may be used by itself or used for reconstructing biological tissues by using an artificial bone coating material.

Polylactide, porous, sustained release formulation, artificial bone

Description

Formation method of porous material using polylactide

The present invention relates to a method for preparing a porous material using a bioabsorbable polymer, and more specifically, to a surface having 1-5 um pore size using polylactide, and having a uniform pore size of 10-50 um inside. It relates to a method of synthesizing a material having. This material can be used as a sustained-release agent to control drug release by injecting drugs into internal pores and implanting them in vivo, and also as a surface coating material to increase the biocompatibility of artificial bones. Can be used. It can also be used as a scaffold formed of a biocompatible polymer and used as a wound tissue reconstruction or wound dressing material.

As a method of preparing a porous material using a biopolymer, various methods including phase separation have been developed. Phase separation is used to make porosity by synthesizing NHAP and Ploy (L-lactic acid) (PLLA) and to create a porous structure with very small holes. In order to manufacture a porous material by such a phase separation method, it is necessary to prepare a freeze-drying method that requires time and cost. The freeze-drying method is a disadvantage in that the cost and drying time for quenching during freeze-drying are great by forming a polymer solution and a solvent in which phase separation may occur by mixing the freeze-drying and then slowly drying. Advantageously, the degree of porosity and pore size are controlled by various phase separation elements, and the phase separation method allows at least 89% or more of porosity regardless of the content of the two components. Phase separation involves two solvent systems, resulting in structures with different pores.

Another example of using phase separation is to create a scaffold using phase separation of Poly (D, L-lactic-co-glycolic acid). Solid discs of Poly (D, L-lactic-co-glycolic acid) seep into CO ₂ gas at high pressure (5.5 MPa) for 72 hours at room temperature and then infiltrate the CO ₂ gas into the polymer. By reducing the CO ₂ gas pressure at atmospheric levels, porous materials such as polymer sponges can be produced. Unlike conventional organic solvents, phase separation does not use organic solvents. Therefore, organic solvents in organic materials may be harmful to protein growth factors or cells when organic solvents are used.

In addition to the phase separation method, a porous structure may be formed by various methods such as electro spinning, gel casting, sponge method, and freeze drying method. The aforementioned methods generally make open and large openings for the growth and penetration of bone and chondrocyte cells. Phase separation, on the other hand, creates pores 10-100 μm in size that are optimal for the growth of connective tissue in tissue regeneration of the skin.

Electro spinning has been said to be difficult to control hole size by applying scaffolds where large holes of up to several hundred micrometers are required. Thin films made of electrical fibers, such as bone regeneration applications, In soft tissue scaffold systems it is so soft that it is difficult to use.

 Gel casting (gel casting) method is a manufacturing method that strengthens the skeleton of the porous material, but can make a strong mechanical skeleton, but the structure of low interconnection between the holes and the non-uniform pores are distributed. The sponge method creates a porous material with open cells through the form of porous polymers, the skeleton produced by this method having an adjustable pore size and a desirable bond structure with the exchanged pores but with a thin framework between the pores. Due to low mechanical force. In addition, studies have been published to combine these two methods to create a porous structure with high mechanical strength.

Freeze-drying is used to make biodegradable, porous scaffolds from a mixture of polylactic acid (PLA) and polyglycolic acid (PLGA). Lyophilization first mixes solid impurities such as sodium chloride (NaCl, salt) particles in a polymer solvent and disperses them to form a thin film of polymer and salt particles. The salt particles are then filtered together with water to form a porous membrane. The porosity of 87-91% and the pore size of 100-500㎛ are determined by the small amount of salt and the particle size of salt. It has a porosity of 91-95% and most of the pore sizes are 13-35 μm and also have pores larger than 200 μm. Such a method is difficult to control the formation of non-uniform pores according to the lyophilization conditions and the pore size and the pore size of the inside of the material surface.

Sustained release preparation carriers should have the property of uniformly releasing the active substance over a long period of time at a constant rate, as well as without bioimmunity rejection when used in or outside the body. In addition to the safe storage of various active substances that can be adapted to a particular treatment, the active ingredients must be released at a substantially constant rate in external stimuli or changes.

As the sustained-release preparation carrier, bioabsorbable polymers are mainly used, and polylactide and co-polymers thereof have been studied. Polylactide is a medical material used as a fixation plate or pin for bone bonding, and is used as a material that does not need to be removed after surgery because it is hydrolyzed and absorbed in vivo. As such, due to its absorption in vivo, it has been studied for the purpose of topical treatment or topical administration by mixing with drugs.

WO 1998/24504 prepared a sustained release formulation by mixing an active ingredient with a bioabsorbable polymer such as PLGA. This process is made by mixing the active ingredient (AP) and PLGA at 70:30 and compressing it in a compression mold. This method can be prepared without applying heat compared to other techniques, and is prepared by dissolving in a carrier such as a solvent. There is no need to do so has the advantage of maintaining the active ingredient. This method is advantageous to obtain the product of drug suspension while maintaining the state of weak molecules such as recombination protein, but it is difficult to expect uniform drug dissolution.

Korean Patent No. 10-0119778-0000 discloses suspending the active substance in a bioabsorbable polymer solution such as D and L-polylactide, drying the precipitated suspension to form a film, and then cutting to a desired size to prepare a sustained release formulation. It was. Such a method can uniformly mix the active material with the bioabsorbable polymer, thereby enabling the bioabsorbable polymer to release as much of the active material as it decomposes in the body, thereby providing uniform sustained release. However, the method is limited to drugs in which the active substance may exist in a suspended state in a solvent, and there are limitations to various sustained-release drug carrier materials due to the heterogeneity of pores in which the active substance is impregnated.

Existing developed materials are difficult to use as a sustained release material after impregnating active materials because the pore size is uneven and the pore size formed on the surface and the pore size formed inside are the same. In addition, the pore size was uneven and the pores and pores were not connected to each other to effectively impregnate the active material. Therefore, it is an effective sustained-release material, which is connected to each other inside and has uniform pores, and the surface is impregnated with active substances sufficiently by developing a material having pores of about 1/10 to 1/5 of the size of internal pores. It is necessary to produce a porous structure in which small pores on the surface gradually release the active material therein. However, in order to manufacture such a material by the known technology, there is a big problem in time and economic cost because it must be manufactured by lyophilization method.

In the case of wound dressings, the fibrous gauze is easily impregnated with bacteria from the outside by impregnating the drug with the gauze itself, which greatly increases the risk of infection. In general, resinous gauze has no pores in the gauze itself. It is easy to do this, but the moisture generated from the wound itself does not evaporate, and it does not come into contact with oxygen in the air, which acts as an inhibitor of skin tissue activity. Therefore, it is necessary to develop a material that has pores that can impregnate drugs inside, and at the same time, it is easy to release moisture generated from wounds and easily contact with oxygen in the air. In addition, moisture and air ventilation is good, but it is necessary to develop a material composed of pores that can prevent the invasion of external bacteria.

Accordingly, an object of the present invention is to provide a method for producing a material formed of economical and uniform pores as a porous material using polylactide. In particular, the pores formed inside form a uniform pore of 10 ~ 50um to serve as a carrier of the active material and the pores formed outside form a uniform pore of 1 ~ 5um to allow the active material to have sustained release I will use it as a sanction. In addition, the surface porosity of 1-5um is intended to prevent the invasion of bacteria from the outside at the same time as the moisture generated in the wound evaporated when used as a wound coating dressing material and the outside breathability.

Porous hydroxyapatite, which is used as an artificial bone, is weak in vivo and easily broken, and bone cell growth is generally slowed because there is no nutrient in the artificial bone itself. In this case, impregnating nutrients inside the artificial bone and coating porous polylactide on the surface of the artificial bone not only increases the strength of the artificial bone, but also slowly elutes the nutrient, thereby increasing bone cell growth. Let's do it. In addition, when reconstructing the skin tissue, not only a uniform and three-dimensionally connected scaffold should be used, but also it must be able to effectively impregnate active substances such as collagen for cell deposition and proliferation. However, previously developed products do not satisfy all of these characteristics. Therefore, there is a need for the development of materials under these conditions that are biocompatible and capable of proliferating skin tissue cells.

According to a preferred embodiment of the present invention for achieving the above object of the present invention,

A first organic solvent composed of polylactide (molecular weight (Mw) 100,000 to 400,000) and at least one selected from methylene chloride, ethylene acetate, ethyl acetate and chloroform in a weight ratio of 1: 100 to 100 10: preparing a first mixed solution by mixing to 100 to prepare a mixed solution;

The first mixed solution and a second organic solvent composed of at least one selected from methyl alcohol, ethyl alcohol and acetone are agitated at a volume ratio of 10: 1 to 10:10 to obtain a mixed solution. Preparing a second mixed solution;

Putting the second mixed solution into the mold and naturally drying at room temperature;

It provides a method for producing a porous material using a polylactide comprising; at a temperature of 30 to 60 ℃ temperature and vacuum conditions, removing the residual organic solvent of the naturally dried shape.

In addition, according to another embodiment of the present invention,

A first organic solvent composed of polylactide (molecular weight (Mw) 100,000 to 400,000) and at least one selected from methylene chloride, ethylene acetate, ethyl acetate and chloroform in a weight ratio of 1: 100 to 100 10: preparing a first mixed solution by mixing to 100 to prepare a mixed solution;

The first mixed solution and a second organic solvent composed of at least one selected from methyl alcohol, ethyl alcohol and acetone are agitated at a volume ratio of 10: 1 to 10:10 to obtain a mixed solution. Preparing a second mixed solution;

After putting the artificial bone in the second mixed solution, the step of taking out and naturally drying at room temperature;

It provides a method for producing a porous material using a polylactide comprising; at a temperature of 30 to 60 ℃ and vacuum conditions, removing the residual organic solvent of the naturally dried artificial bone.

Method for producing a porous polylactide material according to a preferred embodiment of the present invention, firstly, the pore size of the surface is 1-5um micropores are formed so that the ease of evaporation of moisture in the upper body when used as a dressing material for wound treatment Of course, the oxygen supply in the air is also smooth, there is an excellent effect in preventing bacterial infiltration by the fine pores.

Second, there are more than 95% of regular pores of 10-50um are formed in the interior can impregnate the active material into the internal pores, it can be impregnated with any active material that can be produced in solution regardless of the polarity of the active material.

Third, the pores formed inside are three-dimensionally connected to the pores and pores so that it is easy to grow small cells such as skin tissue cells, and since the tissue is grown in vivo because it is made of a bioabsorbable polylactide Absorbed in, no secondary procedure is required.

Fourth, the internal pores are formed with regular pores of 10-50um and the surface is formed with micropores of 1-5um, so that the active material impregnated inside the porous polylactide is slowly eluted when used as a sustained release material. .

Fifth, it is effective to increase the strength of artificial bones when used as an artificial bone coating agent, and nutrients are slowly eluted from the pores of the coating surface when impregnated with nutrients in artificial bones due to the porous polylactide coating. have.

Hereinafter, the configuration and effects of the present invention will be described in detail with reference to the accompanying drawings. However, it is apparent from the position of those skilled in the art that the presently presented embodiments are merely examples for describing the present invention and do not limit the scope of the present invention.

1 is an enlarged view of the surface of the porous polylactide manufacturing method according to an embodiment of the present invention, Figure 2 is an internal structure by cutting the cross section of the porous polylactide prepared according to an embodiment of the present invention It is shown enlarged. Figure 3 shows an enlarged view of the surface coated with a porous polylactide on the artificial bone surface in accordance with a preferred embodiment of the present invention.

In order to manufacture a sustained release material or a wound dressing according to an embodiment of the present invention, the following manufacturing method is performed.

A first organic solvent composed of polylactide (molecular weight (Mw) 100,000 to 400,000) and at least one selected from methylene chloride, ethylene acetate, ethyl acetate and chloroform in a weight ratio of 1: 100 to 100 10: preparing a first mixed solution by mixing to 100 to prepare a mixed solution;

The first mixed solution and a second organic solvent composed of at least one selected from methyl alcohol, ethyl alcohol and acetone are agitated at a volume ratio of 10: 1 to 10:10 to obtain a mixed solution. Preparing a second mixed solution;

Putting the second mixed solution into the mold and naturally drying at room temperature;

At 30 to 60 ℃ temperature and vacuum conditions, to remove the residual organic solvent of the naturally-dried shape; to prepare a porous material using a polylactide.

If the molecular weight of polylactide is less than 100,000, even though porous polylactide is manufactured, it is difficult to use due to its weak compressive and tensile strength, and the porous structure is partially broken when the active material is injected. Preference is given to using. When the polylactide molecular weight exceeds 400,000, the compressive strength and tensile strength are excellent, but the absorption period is long in vivo, and sufficient pores are not formed inside.

In the step of preparing the first mixed solution, when the polylactide is mixed with less than 1 of the first organic solvent 100, the internal pore formation of the porous polylactide is not uniform, and the compressive strength tends to be lowered. When the mixture exceeds 10, the viscosity of the first mixed solution rises, making it difficult to prepare a uniform mixture when preparing the second mixed solution.

In this case, the first organic solvent may be one selected from methylene chloride, ethyl acetate, and chloroform, or may be appropriately mixed. Preferably methylene chloride is used.

In the step of preparing the second mixed solution, when the second organic solvent is mixed with less than 1 compared to the first mixed solution 10, no porosity is formed after drying, and the polylactide does not completely melt and partially precipitates when mixed more than 10. appear.

At this time, one solvent selected from methyl alcohol, ethyl alcohol and acetone may be used as the second organic solvent, or these may be appropriately mixed. Preferably, ethanol can be used.

The mold in the step of putting the second mixed solution into the mold refers to a mold of a shape (a shape made of a porous material) to be used as a sustained-release material, and the like, as long as it is generally used in the art. The step of natural drying at room temperature is dried by a natural drying method at room temperature 15 ℃ ~ 35 ℃. If the temperature is lower than 15 ° C., the drying rate is slow, and productivity decreases. If the temperature is higher than 35 ° C., internal pores are irregularly formed, and compressive strength is lowered.

In the above 30 to 60 ℃ temperature and vacuum conditions, the step of removing the residual organic solvent of the naturally dried shape is preferably applied for 10 to ³ torr and maintained for about 12 hours. At this time, the purpose of drying is to completely remove the organic solvent remaining in the shape, and below 30 ° C., the efficiency of removing the residual organic solvent decreases.

In order to manufacture a polylactide material (polylactide coated artificial bone) for artificial bone coating according to a preferred embodiment of the present invention, the following manufacturing method is performed.

A first organic solvent composed of polylactide (molecular weight (Mw) 100,000 to 400,000) and at least one selected from methylene chloride, ethylene acetate, ethyl acetate and chloroform in a weight ratio of 1: 100 to 100 10: preparing a first mixed solution by mixing to 100 to prepare a mixed solution;

The first mixed solution and a second organic solvent composed of at least one selected from methyl alcohol, ethyl alcohol and acetone are agitated at a volume ratio of 10: 1 to 10:10 to obtain a mixed solution. Preparing a second mixed solution;

After putting the artificial bone in the second mixed solution, the step of taking out and naturally drying at room temperature;

At 30 to 60 ℃ temperature and vacuum conditions, the method of producing a porous material using a polylactide comprising; removing the residual organic solvent of the artificially dried artificial bone.

The basic manufacturing method is the same as the method for producing a porous polylactide material for the sustained release material or wound dressing. This embodiment is for the coating of artificial bone has the following characteristics.

The artificial bone may include an artificial bone impregnated with nutrients. When porous polylactide is used as an artificial bone coating, it has the effect of increasing the strength of artificial bones, and when it is used as a coating on artificial bones impregnated with nutrients, nutrients are slowly eluted from the pores of the coating surface, which is excellent for cell growth. It works.

The second mixed solution may further include an artificial bone coating solution. The second mixed solution may be coated by further mixing the coating liquid of the artificial bone conventionally used in the art. By doing this, the thickness of the coating layer can be adjusted.

[ Example  One]

10 g of polylactide (molecular weight (Mw) 200,000) is dissolved in 100 g of methylene chloride to prepare a polylactide solution. 10 ml of the polylactide solution and 10 ml of ethyl alcohol are mixed to prepare a mixed solution. The mixed solution was placed in a 300φmm × 100mm mold and naturally dried at 25 ° C. for 8 hours to form a molded product, and maintained at 12 ° C. under 10 ⁻³ torr vacuum at 40 ° C. to remove residual organic solvent. Finally, the prepared porous polylactide surface was formed with 3 ~ 8um pores, the internal pore size is 50 ~ 100um, porosity was prepared from 97.4% ~ 99.2%.

[ Example  2]

10 g of polylactide (molecular weight (Mw) 200,000) is dissolved in 100 g of methylene chloride to prepare a polylactide solution. 10 ml of the polylactide solution and 8 ml of ethyl alcohol are mixed to prepare a mixed solution. The mixed solution was placed in a 300 φmm × 100mm mold and naturally dried at 25 ° C. for 8 hours to form a molded product, and then maintained at 12 ° C. under 10 ⁻³ torr vacuum at 40 ° C. to remove residual organic solvent. Finally, the prepared porous polylactide surface was formed with 1 to 5 um pores, an internal pore size of 10 to 50 um, and a porosity of 96.3% to 98.1%.

[ Example  3]

10 g of polylactide (molecular weight (Mw) 200,000) is dissolved in 100 g of methylene chloride to prepare a polylactide solution. 10 ml of the polylactide solution and 8 ml of ethyl alcohol are mixed to prepare a mixed solution. After completely inserting the artificial bone into the mixed solution, it was naturally dried at 25 ° C. for 8 hours. In addition, porous polylactide was finally coated on artificial bone by maintaining 10 hours by applying 10 ⁻³ torr vacuum at 40 ° C. to remove residual organic solvent. The surface pores of the polylactide coated on the artificial bone were formed from 2um to 5um, and the coating thickness was prepared to be 100um to 300um.

1 is an enlarged view of the surface pores of the porous polylactide prepared by the method for producing a porous material using the polylactide according to an embodiment of the present invention.

Figure 2 is an enlarged view of the pores formed in the porous polylactide produced by the method for producing a porous material using a polylactide according to an embodiment of the present invention.

Figure 3 is an enlarged view of the surface pores of the porous polylactide coated on the surface of the artificial bone prepared by the method for producing a porous material using a polylactide according to an embodiment of the present invention.

Claims (4)

A polylactide (molecular weight (Mw) 100,000 to 400,000), a first organic solvent composed of at least one selected from methylene chloride, ethyl acetate, and chloroform in a weight ratio of 1: 100 to 100 10: preparing a first mixed solution by mixing to 100 to prepare a mixed solution; The first mixed solution and a second organic solvent composed of at least one selected from methyl alcohol, ethyl alcohol and acetone are agitated at a volume ratio of 10: 1 to 10:10 to obtain a mixed solution. Preparing a second mixed solution; Putting the second mixed solution into the mold and naturally drying at room temperature; And Maintaining for 30 hours at 30 to 60 ℃ temperature and 10 ^-3 torr vacuum state, to remove the residual organic solvent of the naturally dried form; a method of producing a porous material using a polylactide comprising a. A polylactide (molecular weight (Mw) 100,000 to 400,000), a first organic solvent composed of at least one selected from methylene chloride, ethyl acetate, and chloroform in a weight ratio of 1: 100 to 100 10: preparing a first mixed solution by mixing to 100 to prepare a mixed solution; The first mixed solution and a second organic solvent composed of at least one selected from methyl alcohol, ethyl alcohol and acetone are agitated at a volume ratio of 10: 1 to 10:10 to obtain a mixed solution. Preparing a second mixed solution; After putting the artificial bone in the second mixed solution, the step of taking out and naturally drying at room temperature; And It is maintained for 30 hours at 30 to 60 ℃ temperature and 10 ^-3 torr vacuum, to remove the residual organic solvent of the naturally dried artificial bone; The artificial bones include artificial bones impregnated with nutrients, Method for producing a porous material using a polylactide, characterized in that further comprising an artificial bone coating solution in the second mixed solution. delete delete

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