Composite, method for producing the same, and molding filler composition using the same

Abstract

The present invention relates to a composite containing biodegradable particles and a water-soluble polymer, a method for producing the same, and a molding filler composition using the same, wherein the particle size distribution (PSD) of the biodegradable particles contained in the composite represented by the following formula 1 is controlled to be 1.0 to 2.5: [Formula 1] PSD = [Dv(90) - Dv(10)] / Dv(50) (In the formula, Dv(10) is the size within 10% of the biodegradable particle distribution, Dv(50) is the size within 50% of the biodegradable particle distribution, and Dv(90) is the size within 90% of the biodegradable particle distribution.) The composite of the present invention is excellent in long-term storage stability and distribution characteristics.

Description

Technical Field

[0001] The present invention relates to a composite of two or more components, a method for producing the same, and a plastic surgery filler composition (for example, a skin plastic surgery filler composition) using the same.

Background Art

[0002] For purposes such as correcting body functions and for cosmetic purposes, plastic surgery is performed in which a filler composition is injected subcutaneously or into tissues. Such a filler composition is preferably safe for the human body and has biocompatibility and biodegradability.

[0003] Such filler compositions contain natural polymers such as collagen, gelatin, hyaluronic acid, and dextran, and synthetic polymers such as polylactic acid, polyglutamic acid, polycaprolactone, and polyacrylamide.

[0004] However, since natural polymers or synthetic polymers begin to decompose after a certain period of time, the shelf life of filler compositions containing them is limited. In addition, many filler compositions are administered using a syringe. In such a case, if the viscosity of the filler composition is too high or the dispersibility is poor, it becomes difficult to inject the filler composition with a thin injection needle, and it is necessary to increase the force applied to the syringe (injection force), which may give discomfort or fatigue to the surgeon.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

[0006] (Solutions to Problems) An object of the present invention is to provide a composite excellent in long-term storage stability and dispersibility, which can improve the use environment of a filling composition for plastic surgery, and a method for producing the same.

[0007] Another object of the present invention is to provide a filling composition for plastic surgery that can be relatively easily implemented.

[0008] According to one embodiment of the present invention for achieving the above object, it contains biodegradable particles and a water-soluble polymer, The following formula 1: [Formula 1] PSD = [Dv(90) - Dv(10)] / Dv(50) (In the formula, Dv(10) is the size within 10% of the biodegradable particle distribution, Dv(50) is the size within 50% of the biodegradable particle distribution, and Dv(90) is the size within 90% of the biodegradable particle distribution.) A composite is provided in which the particle size distribution (PSD) of the biodegradable particles represented by the following formula is 1.0 to 2.5.

[0009] According to another embodiment of the present invention, a method for producing a composite is provided. This method includes: (1) a step of dissolving a biodegradable raw material in a first solvent to prepare a biodegradable solution; (2) a step of spraying the biodegradable solution into a second solvent having a freezing point lower than that of the first solvent to form biodegradable particles; (3) a step of sorting the biodegradable particles by size; (4) a step of adding the biodegradable particles sorted by size to a water-soluble polymer solution to prepare a mixed solution; (5) a step of filling the mixed solution into a container; and (6) a step of freeze-drying the mixed solution filled in the container to form a composite. The particle size distribution (PSD) of the biodegradable particles contained in the composite represented by the above formula 1 is 1.0 to 2.5.

[0010] According to another embodiment of the present invention, a filling composition for plastic surgery in which the composite is dispersed is provided.

[0011] (Advantageous effects of the invention) Since the composite according to the present invention contains biodegradable particles with a particle size distribution controlled within a specific range, it can be rapidly and uniformly dispersed in a solvent, and even when stored for a long period, the degradation of the biodegradable particles and / or water-soluble polymers contained in the composite can be minimized. Therefore, when the composite according to the present invention is used as a material for a forming surgical filler composition, the storage period of the material can be extended, and the convenience of storage and handling can be improved.

[0012] In addition, since the forming surgical filler composition according to the present invention is one in which a composite with excellent dispersibility is dispersed, even if a surgeon (a person performing the treatment) applies a relatively small force to a syringe, the treatment can be easily performed.

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0014] Hereinafter, the present invention will be described in detail. Here, the present invention is not limited to what is described below. Rather, it can be changed into various forms without changing the gist of the present invention.

[0015] In this specification, the term "comprising" is intended to identify a particular feature, region, step, method, element, and / or component. Unless otherwise stated, it does not preclude the presence or addition of other features, regions, steps, methods, elements, and / or components.

[0016] In this specification, when an element is described as being connected or coupled, it means all cases where an element is directly or indirectly connected or coupled to another element, either directly or through other elements.

[0017] In this specification, singular expressions are to be construed as encompassing singular or plural expressions, unless otherwise specified, based on the context.

[0018] All numerical values and expressions regarding the amounts of components, reaction conditions, etc. used in this specification may be modified by the term "about", unless otherwise specified.

[0019] Throughout the description of the embodiments, terms such as first, second, etc. are used to describe various components. However, the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another.

[0020] (Composite) The composite according to the present invention may be a composite of materials having biocompatibility and / or biodegradability. Specifically, the composite according to the present invention includes biodegradable particles with a particle size distribution (PSD) controlled within a specific range, as described below.

[0021] Biodegradable particles The biodegradable particles contained in the composite according to the present invention have the function of repairing or replacing damaged or aged human tissues (e.g., skin tissue).

[0022] The biodegradable particles have a particle size distribution (PSD) of 1.0 to 2.5 according to the following formula 1. Specifically, the particle size distribution of the biodegradable particles according to the following formula 1 may be, but is not limited to, 1.0 to 2.3, 1.01 to 2.0, 1.02 to 1.9, 1.03 to 1.95, 1.04 to 1.9, 1.05 to 1.8, 1.05 to 1.6, 1.05 to 1.5, 1.08 to 1.4, 1.09 to 1.3, or 1.1 to 1.3. Since the particle size distribution of the biodegradable particles is within the above range, the composite containing the same may have excellent dispersibility in a solvent. In particular, when the composite according to the present invention is used as a raw material for a forming surgical filler composition, the excellent dispersibility of the composite enables the forming surgical filler composition to be prepared in a short time. Further, since the forming surgical filler composition of the present invention is prepared using a composite in which biodegradable particles having a particle size capable of efficiently repairing or replacing human tissue are uniformly dispersed, even when a thin injection needle is used, the forming surgical filler composition can be successfully administered by applying a small force to the syringe.

[0023] The following formula 1: [Formula 1] PSD = (Dv(90) - Dv(10)) / Dv(50) In the formula, Dv(10) is the size at which the biodegradable particle distribution is within 10% (the particle size at the 10% position based on the volume listed from the minimum particle size of the biodegradable particle distribution), Dv(50) is the size at which the biodegradable particle distribution is within 50% (the particle size at the 50% position based on the volume listed from the minimum particle size of the biodegradable particle distribution), and Dv(90) is the size at which the biodegradable particle distribution is within 90% (the particle size at the 90% position based on the volume listed from the minimum particle size of the biodegradable particle distribution).

[0024] Specifically, in Formula 1, Dv(10) may be 5 to 35 μm, 7 to 33 μm, 10 to 30 μm, 11 to 28 μm, 12 to 25 μm, or 12 to 22 μm, Dv(50) may be 10 to 50 μm, 13 to 47 μm, 15 to 45 μm, 17 to 43 μm, 19 to 42 μm, or 20 to 42 μm, and Dv(90) may be 20 to 90 μm, 25 to 85 μm, 27 to 82 μm, 29 to 80 μm, 30 to 78 μm, or 32 to 75 μm, but is not limited thereto.

[0025] The biodegradable particles may each be particles having a network structure therein. Specifically, a three-dimensional network structure that is regular, irregular, or a combination thereof may be formed inside each biodegradable particle. Since a network structure exists inside each biodegradable particle, the biodegradable particles can have high strength, whereby human tissues can be efficiently repaired or replaced. Also, since the biodegradable particles have high strength, the strength of the composite containing the biodegradable particles is improved, thereby improving the handleability of the composite.

[0026] The biodegradable particles may contain generally known biodegradable polymers. Specifically, the biodegradable particles may contain at least one selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactic acid-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyvalerolactone (PVL), polyhydroxybutyrate (PHB), and polyhydroxyvalerate (PBV), but is not limited thereto. Preferably, the biodegradable particles may be polylactic acid (PLA) particles.

[0027] The biodegradable particles may have a weight average molecular weight of 50,000 to 400,000 g / mol, but are not limited thereto. Specifically, the weight average molecular weight of the biodegradable particles may be 60,000 to 350,000 g / mol, 70,000 to 300,000 g / mol, 90,000 to 250,000 g / mol, 100,000 to 200,000 g / mol, 130,000 to 190,000 g / mol, or 150,000 to 180,000 g / mol. Since the weight average molecular weight of the biodegradable particles is within the above range, processing into a composite is easy, and it is possible to improve the dispersibility of the composite.

[0028] The biodegradable particles may have a tap density of 0.1 to 0.25 g / mL, but are not limited thereto. Specifically, the tap density of the biodegradable particles may be 0.1 to 0.24 g / mL, 0.11 to 0.23 g / mL, 0.12 to 0.21 g / mL, 0.13 to 0.18 g / mL, or 0.13 to 0.17 g / mL. Since the tap density of the biodegradable particles is within the above range, it is possible to disperse the biodegradable particles at a high density in the composite, thereby improving the strength of the composite and improving the dispersibility of the composite.

[0029] Water-soluble polymer The water-soluble polymer contained in the composite according to the present invention has a function as a carrier for transporting the biodegradable particles and a function as a matrix for dispersing and fixing the biodegradable particles.

[0030] The water-soluble polymer may include polymers having water solubility that are generally known. Specifically, the water-soluble polymer may include, but is not limited to, at least one selected from the group consisting of hyaluronic acid (HA), methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose (CMC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxymethyl methacrylate (HEMA), polyvinyl alcohol (PVOH), polyvinylpyrrolidone (PVP), and starch. Preferably, the water-soluble polymer may be hyaluronic acid. Specifically, the water-soluble polymer may be non-crosslinked hyaluronic acid.

[0031] Hyaluronic acid may be high-molecular hyaluronic acid such as sodium hyaluronate cross-polymer and sodium hyaluronate, medium-molecular hyaluronic acid such as hydroxypropyltrimonium hyaluronate and sodium acetylated hyaluronate, low-molecular hyaluronic acid such as potassium hyaluronate, hydrolyzed hyaluronic acid, and sodium hydrolyzed hyaluronate, ultra-low-molecular hyaluronic acid such as hyaluronic acid, or a combination thereof.

[0032] The water-soluble polymer may have a weight average molecular weight of 1,000,000 to 4,000,000 g / mol, but is not limited thereto. Specifically, the weight average molecular weight of the water-soluble polymer may be 1,200,000 to 4,000,000 g / mol, 1,300,000 to 4,000,000 g / mol, 1,500,000 to 4,000,000 g / mol, 1,800,000 to 4,000,000 g / mol, 2,000,000 to 4,000,000 g / mol, 2,100,000 to 3,800,000 g / mol, or 2,200,000 to 3,600,000 g / mol. Since the weight average molecular weight of the water-soluble polymer is within the above range, processing into a composite can be easily carried out, and the dispersibility of the composite can be improved.

[0033] According to the present invention, the weight ratio of the biodegradable particles to the water-soluble polymer can be 40:60 to 95:5, but is not limited thereto. Specifically, the weight ratio of the biodegradable particles to the water-soluble polymer contained in the composite can be 45:55 to 95:5, 45:55 to 90:10, 50:50 to 90:10, 55:45 to 85:15, 60:40 to 85:15, 65:35 to 85:15, 70:30 to 85:15, 75:25 to 85:15, 80:20 to 85:15, or 70:30 to 80:20. Since the weight ratio is within the above range, the composite has excellent dispersibility and can be efficiently used as a material for a forming surgical filler composition.

[0034] On the other hand, the composite according to the present invention may have a compressive strength of 0.02 to 1.5 MPa, but is not limited thereto. Specifically, the compressive strength of the composite according to the present invention can be 0.025 to 1.3 MPa, 0.03 to 1.2 MPa, 0.033 to 1.0 MPa, 0.035 to 1.0 MPa, 0.035 to 0.8 MPa, 0.035 to 0.6 MPa, 0.036 to 0.5 MPa, 0.036 to 0.45 MPa, 0.036 to 0.43 MPa, 0.037 to 0.4 MPa, 0.037 to 0.39 MPa, 0.037 to 0.38 MPa, or 0.037 to 0.37 MPa.

[0035] Furthermore, the composite according to the present invention may have an apparent volume of 10 to 40 mL / g, but is not limited thereto. Specifically, the apparent volume of the composite according to the present invention can be 10 to 35 mL / g, 10 to 32 mL / g, 10 to 30 mL / g, 12 to 29 mL / g, 14 to 29 mL / g, 15 to 28 mL / g, 15.5 to 28 mL / g, or 16 to 28 mL / g.

[0036] Furthermore, the composite according to the present invention may have a porosity of 90 to 97.5% by volume, but is not limited thereto. Specifically, the porosity of the composite according to the present invention can be 90 to 97% by volume, 90 to 96% by volume, or 90 to 95% by volume. The porosity may refer to the volume of pores present in the composite out of the total volume of the composite.

[0037] Since the composite according to the present invention has a compressive strength, apparent density, and porosity within the above-specified ranges, it may be excellent in long-term storage stability, handling convenience, and dispersibility. In particular, since the composite according to the present invention contains biodegradable particles with a controlled particle size distribution and the compressive strength is adjusted within a specific range, when dispersed in a solvent for preparing a forming surgical filler composition, it can be uniformly dispersed in a short time.

[0038] Specifically, the suspension time of the composite according to the present invention in an aqueous solvent may be 30 minutes or less, but is not limited thereto. More specifically, the suspension time of the composite according to the present invention in an aqueous solvent may be 1 to 30 minutes, 5 to 30 minutes, 10 to 30 minutes, 10 to 29 minutes, 10 to 25 minutes, 10 to 20 minutes, or 12 to 19 minutes. Here, the aqueous solvent may specifically be water, distilled water, deionized water, ultrapure water, etc., but is not limited thereto.

[0039] The composite according to the present invention may be in the form of a cake-like preparation having a fluffy texture. Since the composite is a cake-like preparation, it can be excellent in long-term storage stability and dispersibility in a solvent.

[0040] Specifically, the composite according to the present invention may have a cylindrical shape, but is not limited thereto. Furthermore, the composite may have an average diameter of 1 to 5 cm, 1 to 3 cm, 1 to 2.5 cm, 1.2 to 2.2 cm, or 1.5 to 2.0 cm, and an average height of 0.2 to 5 cm, 0.3 to 3 cm, 0.5 to 3 cm, or 0.5 to 2.5 cm, but is not limited to these.

[0041] (Method for producing the composite) The present invention can provide a method for manufacturing the above composite. Specifically, the method for manufacturing the composite according to the present invention includes: (1) a step of dissolving a biodegradable raw material in a first solvent to prepare a biodegradable solution; (2) a step of spraying the biodegradable solution into a second solvent having a freezing point lower than that of the first solvent to form biodegradable particles; (3) a step of sorting the biodegradable particles by size; (4) a step of adding the biodegradable particles sorted by size to a water-soluble polymer solution to prepare a mixed solution; (5) a step of filling the mixed solution into a container; and (6) a step of freeze-drying the mixed solution filled in the container to form a composite.

[0042] Step (1) is a step of dissolving a biodegradable raw material in a first solvent to prepare a biodegradable solution. Specifically, step (1) can be carried out by adding a biodegradable raw material to a first solvent in which two or more organic solvents are mixed and stirring.

[0043] Specifically, the biodegradable raw material may include at least one selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactic acid-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyvalerolactone (PVL), polyhydroxybutyrate (PHB), and polyhydroxyvalerate (PBV), but is not limited thereto.

[0044] The weight average molecular weight of the biodegradable raw material may be 50,000 to 400,000 g / mol, but is not limited thereto. Specifically, the weight average molecular weight of the biodegradable raw material may be 60,000 to 350,000 g / mol, 70,000 to 300,000 g / mol, 90,000 to 250,000 g / mol, 100,000 to 200,000 g / mol, 130,000 to 190,000 g / mol, or 150,000 to 180,000 g / mol.

[0045] The first solvent may specifically be at least two selected from the group consisting of dimethyl sulfoxide, diethyl sulfoxide, ethylene carbonate, propylene carbonate, dimethyl carbonate, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-hydroxyethyl-2-pyrrolidone, N-cyclohexyl-2-pyrrolidone, N-methylformamide, N,N-dimethylformamide, N-ethylformamide, N,N-ethylformamide, N-methylacetamide, N,N-dimethylacetamide, N,N-diethylacetamide, isopropyl acetate, ethyl acetate, methyl acetate, dimethyl ketone, diethyl ketone, methyl ethyl ketone, isopropyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, tetrahydrofuran, etc., but is not limited thereto.

[0046] Specifically, the first solvent may be a solvent in which a first organic solvent and a second organic solvent are mixed at a weight ratio of 70:30 to 98:2, 75:25 to 98:2, 80:20 to 95:5, 85:15 to 95:5, or 85:15 to 90:10. More specifically, the first solvent may be a mixed solvent of dimethyl sulfoxide and ethylene carbonate, but is not limited thereto.

[0047] Step (2) is to spray the biodegradable solution into a second solvent having a freezing point lower than the freezing point of the first solvent to form biodegradable particles having a network structure therein respectively. Specifically, step (2) can be carried out by spraying the biodegradable solution into a second solvent that is not mixed with the first solvent for phase separation and has a freezing point 5 to 150 °C (specifically, 90 to 120 °C) lower than the freezing point of the first solvent.

[0048] The temperature of the second solvent during spraying may specifically be any of -45 to 0 °C, -40 to -5 °C, -35 to -10 °C, -30 to -10 °C, but is not limited thereto. When the temperature of the second solvent is within the above range, biodegradable particles having a desired particle size distribution and network structure can be formed well.

[0049] The second solvent may be at least one selected from the group consisting of pentane, hexane, heptane, octane, nonane, and decane, but is not limited thereto.

[0050] The spraying rate of the biodegradable solution sprayed onto the second solvent may be 1 to 20 mL / min, 3 to 15 mL / min, or 5 to 10 mL / min, but is not limited thereto.

[0051] Step (3) is a step of sorting biodegradable particles by size. Specifically, step (3) can be carried out by putting the biodegradable particles into a particle sorter and sorting the particles having the required size.

[0052] Specifically, the biodegradable particles may be put into a particle sorter that sorts particle sizes using buoyancy. At that time, the criteria for sorting particle sizes are not particularly limited, but the particle sizes may be sorted so that Dv(50) (average particle size) is 10 to 60 μm (specifically, 13 to 47 μm or 15 to 45 μm). By performing the above steps, the particle size distribution of the biodegradable particles can be controlled within a specific range. Since a composite is manufactured using the biodegradable particles with a controlled particle size distribution, it is possible to manufacture a composite having excellent dispersibility in a solvent.

[0053] Step (4) is a step of adding the biodegradable particles sorted by size to a water-soluble polymer solution to prepare a mixed solution. Specifically, step (4) may be carried out by adding the biodegradable particles sorted by particle size to a solution with the concentration of the water-soluble polymer controlled and stirring.

[0054] The water-soluble polymer contained in the water-soluble polymer solution may specifically include at least one selected from the group consisting of hyaluronic acid (HA), methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose (CMC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxymethyl methacrylate (HEMA), polyvinyl alcohol (PVOH), polyvinylpyrrolidone (PVP), and starch, but is not limited thereto.

[0055] The water-soluble polymer may have a weight average molecular weight of 1,000,000 to 4,000,000 g / mol, but is not limited thereto. Specifically, the weight average molecular weight of the water-soluble polymer may be 1,200,000 to 4,000,000 g / mol, 1,300,000 to 4,000,000 g / mol, 1,500,000 to 4,000,000 g / mol, 1,800,000 to 4,000,000 g / mol, 2,000,000 to 4,000,000 g / mol, 2,100,000 to 3,800,000 g / mol, or 2,200,000 to 3,600,000 g / mol.

[0056] The content of the water-soluble polymer contained in the water-soluble polymer aqueous solution may be 0.2 to 2% by weight, 0.4 to 1.5% by weight, 0.5 to 1.3% by weight, less than 0.5 to 1% by weight, or 0.6 to 0.95% by weight based on the total weight of the water-soluble polymer aqueous solution, but is not limited thereto. Since the content of the water-soluble polymer is within the above range, it is possible to enhance the dispersibility of the composite in the solvent while ensuring the strength of the composite.

[0057] The solvent contained in the water-soluble polymer aqueous solution may be a generally known aqueous solvent (for example, water, distilled water, etc.).

[0058] On the one hand, the water-soluble polymer solution and the biodegradable particles may be mixed such that the weight ratio (a:b) of the water-soluble polymer (a) and the biodegradable particles (b) contained in the water-soluble polymer solution is 40:60 to 95:5, 45:55 to 95:5, 45:55 to 90:10, 50:50 to 90:10, 55:45 to 85:15, 60:40 to 85:15, 65:35 to 85:15, 70:30 to 85:15, 75:25 to 85:15, 80:20 to 85:15, or 70:30 to 80:20.

[0059] Step (5) is to fill the mixed solution into a container. Specifically, step (5) may be carried out by filling the mixed solution into a specific container to form a composite having a cake-like preparation.

[0060] Specifically, the container may be a sealable glass bottle (for example, a vial), but is not limited thereto.

[0061] The amount of the mixed solution filled into the container may be 10 to 80% by volume, 15 to 70% by volume, 15 to 65% by volume, 20 to 60% by volume, or 25 to 55% by volume based on the total volume of the container, but is not limited thereto. Since the filling amount of the mixed solution is within the above range, a composite of a cake-like preparation having the required compressive strength can be formed.

[0062] Step (6) is a step of freeze-drying the mixed solution filled into the container to form a composite. Specifically, step (6) may include: (6-1) freezing the mixed solution at -60 to -10 °C to obtain a frozen product; (6-2) performing primary heating on the frozen product at -5 to 5 °C for 1 to 3 hours in a vacuum atmosphere; (6-3) performing secondary heating on the primarily heated frozen product at 20 to 25 °C for 8 to 15 hours in a vacuum atmosphere; and (6-4) drying the secondarily heated frozen product at 25 °C or higher for 20 to 40 hours in a vacuum atmosphere.

[0063] The freezing temperature of the mixed solution in step (6-1) may be any of -60 to -10°C, -50 to -20°C, or -40 to -30°C, but is not limited thereto. Also, the freezing time of the mixed solution may be any of 60 to 240 minutes, 90 to 180 minutes, or 120 to 150 minutes, but is not limited thereto.

[0064] Steps (6-2) to (6-4) are steps of drying (evaporating) the solvent present in the frozen product by gradually increasing the temperature of the frozen product. At that time, the final degree of vacuum in each step may be any of 0.1 to 30 mTorr, 0.5 to 20 mTorr, or 1 to 10 mTorr, but is not limited thereto.

[0065] Specifically, step (6-2) may be carried out by first subjecting the frozen product at -60 to -10°C to a primary temperature increase to -5 to 5°C, -3 to 3°C, or -1 to 1°C over 1 to 3 hours or 1.5 to 2.5 hours in a vacuum atmosphere.

[0066] Step (6-3) may be carried out by subjecting the once-temperature-increased frozen product to a secondary temperature increase to 20 to 25°C, 22 to 25°C, or 24 to 25°C over 8 to 15 hours or 9 to 11 hours in a vacuum atmosphere.

[0067] Step (6-4) may be carried out by subjecting the twice-temperature-increased frozen product to a temperature increase to 25°C or higher (specifically 25 to 30°C) over 20 to 40 hours or 22 to 30 hours in a vacuum atmosphere and finally drying it.

[0068] Since lyophilization of the mixed solution is carried out by steps (6-1) to (6-4), it is possible to efficiently form a composite having a cake-like preparation.

[0069] On the other hand, the method for producing a composite according to the present invention may further include a step of sterilizing the composite.

[0070] Sterilization may be carried out by gamma ray sterilization, electron beam sterilization, ethylene oxide sterilization, steam sterilization, autoclaving, but is not limited thereto. Specifically, sterilization may be carried out at 30 to 40 °C for 150 to 180 minutes using ethylene oxide. By this method, it is possible to further enhance the long-term storage stability of the composite.

[0071] The size of the biodegradable particles contained in the composite produced by the above production method is not particularly limited, but the average particle diameter (Dv(50)) may be 15 to 60 μm. Specifically, the biodegradable particles are first biodegradable particles having a Dv(50) particle size distribution of 15 to 30 μm, 17 to 29 μm, 18 to 28 μm, 19 to 27 μm, 20 to 25 μm, or 21 to 23 μm, second biodegradable particles having a Dv(50) particle size distribution of 30 to 60 μm or more, 30 to 55 μm or more, 35 to 50 μm, 35 to 48 μm, 38 to 45 μm, or 40 to 43 μm, or a mixture thereof, but is not limited thereto.

[0072] Specifically, the biodegradable particles contained in the composite produced by the above production method are represented by the following formula 1: [Formula 1] PSD = [Dv(90) - Dv(10)] / Dv(50) (In the formula, Dv(10) is the size within 10% of the biodegradable particle distribution, Dv(50) is the size within 50% of the biodegradable particle distribution, and Dv(90) is the size within 90% of the biodegradable particle distribution.) The particle size distribution (PSD) of the biodegradable particles contained in the composite represented by may be 1.0 to 2.5, 1.0 to 2.3, 1.01 to 2.0, 1.02 to 1.9, 1.03 to 1.95, 1.04 to 1.9, 1.05 to 1.8, 1.05 to 1.6, 1.05 to 1.5, 1.08 to 1.4, 1.09 to 1.3, or 1.1 to 1.3, but is not limited thereto.

[0073] In the present invention, a composite is produced by filling a sealable container with a mixed solution obtained by mixing biodegradable particles having a specific particle size distribution and an aqueous solution of a water-soluble polymer, and then freeze-drying, so that a composite having a specific cake-like preparation and controlled compressive strength can be obtained.

[0074] The composite according to the present invention contains biodegradable particles with a controlled particle size distribution, and has a cake-like preparation, so it has excellent long-term storage stability and dispersibility, and its handling property is improved by controlling the compressive strength. Further, since the composite according to the present invention contains biodegradable particles and a water-soluble polymer, it can have biocompatibility and biodegradability.

[0075] Therefore, the composite according to the present invention can be advantageously used as a material for repairing or replacing human tissues. Furthermore, the composite according to the present invention can be used as a carrier for cells or drugs, a cell culture medium, and the like.

[0076] (Plastic surgery filler composition) The present invention provides a plastic surgery filler composition in which the above composite is dispersed. Specifically, the plastic surgery filler composition according to the present invention may be one in which a composite having the same composition and properties as described above is dispersed in a solvent.

[0077] The filling agent composition for plastic surgery according to the present invention can be manufactured in a short time (for example, within 30 minutes) by improving the dispersibility of the composite. That is, since a sealed composite having a cake-like preparation in the solid phase is used, the solubility and dispersibility are improved, and it becomes possible to manufacture the filling agent composition for plastic surgery in a short time. Therefore, in the present invention, it is possible to easily manufacture the filling agent composition for plastic surgery immediately before treatment. Further, since the composite contains biodegradable particles with a controlled particle size distribution, the filling agent composition for plastic surgery of the present invention obtained by dispersing this in a solvent enables an operator to easily perform treatment while applying a small force to a syringe even when using an injection needle with a thin diameter. Therefore, the filling agent composition for plastic surgery according to the present invention can improve the surgical environment and reduce the discomfort and fatigue of the operator.

[0078] For example, the filling material composition for plastic surgery according to the present invention (for example, a composition in which a composite having an average particle diameter (Dv(50)) of 60 μm or less is dispersed) has an injection force with respect to an injection needle having a gauge (G) of 26 of 2.0 N or less, specifically, it may be 0.3 to 1.5 N, 0.5 to 1.3 N, 0.7 to 1.25 N, or 0.9 to 1.20 N, but is not limited thereto. Further, the filling material composition for plastic surgery according to the present invention (for example, a composition in which a composite having an average particle diameter (Dv(50)) of 33 μm or less is dispersed) has an injection force with respect to an injection needle having a gauge (G) of 30 of 3.0 N or less, specifically, it may be 1.6 to 2.6 N, 1.7 to 2.4 N, 1.8 to 2.2 N, or 1.9 to 2.0 N, but is not limited thereto.

Example

[0079] Hereinafter, the present invention will be described in detail with reference to examples. However, the scope of the present invention is not limited to the examples.

[0080] (Example 1) 9 g of polylactic acid (PLA) having a weight average molecular weight of 170,000 g / mol was dissolved in 150 mL of a mixed solvent having a weight ratio of dimethyl sulfoxide to ethylene carbonate of 90:10 to produce a polylactic acid solution.

[0081] Next, the polylactic acid solution prepared in this way was sprayed into n-hexane cooled to -20°C or lower at a spraying rate of 4.5 mL / min and a spraying air volume of 6 L / min to form frozen polylactic acid particles in n-hexane. The thus formed frozen polylactic acid particles were obtained, added to water at 1 - 3°C, and stirred to remove the mixed solvent (dimethyl sulfoxide and ethylene carbonate) contained in the frozen polylactic acid particles, thereby producing polylactic acid particles (PLA particles).

[0082] Thereafter, the polylactic acid particles thus produced were sorted using a particle sorter to obtain polylactic acid particles with a particle diameter of 60 μm or less (Dv(50): 41.9 μm).

[0083] Next, the polylactic acid particles with a particle diameter of 60 μm or less were added to a 0.6% sodium hyaluronate solution (HA solution = 99.4 wt% distilled water + 0.6 wt% sodium hyaluronate) such that the weight ratio of polylactic acid particles to sodium hyaluronate (HA) was 85:15, and then mixed to prepare a mixed solution.

[0084] Next, 5.20 g of the thus prepared mixed solution (170 mg of polylactic acid particles and 30 mg of HA) was filled into a 10 mL vial.

[0085] Next, the mixed solution filled in the vial was frozen at -40 to -30°C to obtain a frozen product. The thus obtained frozen product was first heated from -30°C to 0°C over 2 hours under a vacuum atmosphere, and then further heated from 0°C to 25°C over 10 hours, and dried at 25°C for 24 hours to form a composite in the vial.

[0086] Thereafter, the vial containing the composite was sterilized with ethylene oxide (EO) gas, and the residual moisture was removed by vacuum drying to produce a composite with a diameter of 1.8 cm and a height of 2.2 cm in the vial.

[0087] (Examples 2 - 4) Composite bodies were prepared in the same procedure as in Example 1, except that the concentration of sodium hyaluronate (HA) in the mixed solution filled in the vial, the amount of the mixed solution filled, and the diameter and height of the composite bodies were prepared as shown in Table 1 below. JPEG2025519719000002.jpg81159

[0088] (Example 5) Poly(lactic acid) particles were sorted using a particle sorter to obtain poly(lactic acid) particles with a particle size of 33 μm or less (Dv(50): 21.1 μm), and composite bodies with a diameter of 1.8 cm and a height of 0.55 cm were prepared in the same procedure as in Example 1, except that they were added to a sodium hyaluronate solution.

[0089] (Comparative Example 1) Composite bodies with a diameter of 1.8 cm were prepared in the same procedure as in Example 1, except that a mixed solution (170 mg of PLA particles and 30 mg of HA) was filled in a vial and vacuum-dried at 25°C for 16 hours under a vacuum atmosphere (5 mTorr) (i.e., the freeze-drying and sterilization processes were not performed).

[0090] (Comparative Example 2) Poly(lactic acid) particles were sorted using a particle sorter to obtain poly(lactic acid) particles with a particle size of 300 μm or less (Dv(50) 41.7 μm), and composite bodies with a diameter of 1.8 cm and a height of 2.2 cm were prepared in the same procedure as in Example 1, except that they were added to a sodium hyaluronate solution.

[0091] (Test Example 1: Measurement of particle size distribution) For the poly(lactic acid) particles prepared in Example 1, 5 and Comparative Example 2, the particle size distribution was measured according to the following measurement methods, respectively. The results are shown in Table 2 below. Particle size distribution measurement method (1) The composite body was added to water and stirred for 30 minutes to prepare a suspension. (2) The prepared suspension was analyzed with a particle size distribution analyzer (manufacturer: Malvern Instrument, model name: Mastersizer 3000-Maz6140) to measure the particle size distribution of the poly(lactic acid) particles. (3) The particle size distribution (PSD) was calculated from the values measured in the above step (2) using the following formula 1: [Formula 1] PSD = [Dv(90) - Dv(10)] / Dv(50) (where Dv(10) is the size at which the biodegradable particle distribution is within 10%, Dv(50) is the size at which the biodegradable particle distribution is within 50%, and Dv(90) is the size at which the biodegradable particle distribution is within 90%). It was calculated using the following formula. JPEG2025519719000003.jpg37168

[0092] Referring to Table 2 above, the polylactic acid particles prepared in Examples 1 and 5 had particle size distributions in the range of 1.0 to 2.5, respectively. Here, since the particle size distribution of the polylactic acid particles was within the above range, the usability (practicality) of the composite could be improved according to the present invention. That is, if the particle size distribution is within the above range, the dispersibility of the composite is good, and even when a relatively small force (injection force) is applied to a syringe filled with a suspension in which the composite is dispersed, the suspension is smoothly discharged. This can be confirmed in Test Examples 7 and 8 described later.

[0093] On the other hand, the polylactic acid particles prepared in Comparative Example 2 had a particle size distribution outside the range of 1.0 to 2.5.

[0094] (Test Example 2: Measurement of tap density) For the polylactic acid (PLA) particles obtained by the sorting method using the particle sorters of Examples 1 and 5, the tap density was measured according to the following measurement methods, respectively. The results are shown in Table 3 below. Measurement method of tap density (1) The weight of the graduated cylinder was measured, and 20 - 25 mL of polylactic acid particles were placed in the graduated cylinder. (2) The weight of the graduated cylinder containing the polylactic acid particles was measured to calculate the weight of only the polylactic acid particles. (3) A graduated cylinder containing polylactic acid particles was attached to a tap density meter (manufacturer: Bettersize, model name: BeDensi T1 Pro). (4) The tap density meter was operated under the conditions of a tapping speed of 250 times / minute and a tapping number of 1,250 times. (5) After the tapping was completed, the graduated cylinder was taken out, and the volume of the polylactic acid particles was measured. (6) The weight of the polylactic acid particles measured in the above step (2) was divided by the volume of the polylactic acid particles measured in the above step (5) to calculate the tap density (the tap density was measured for each of the 5 samples, and the average value was obtained). JPEG2025519719000004.jpg82155

[0095] Referring to Table 3 above, the polylactic acid particles prepared in Examples 1 and 5 had tap densities in the range of 0.1 to 0.2 g / mL, respectively. Here, in Example 5 where the particle size of the polylactic acid particles was smaller than that in Example 1, the tap density of the polylactic acid particles was higher. Therefore, it is expected that high-density binding can be achieved within the composite.

[0096] (Test Example 3: Measurement of Compressive Strength) For the composites prepared in Examples 1 to 4 and Comparative Examples 1 and 2, the compressive strength was measured using Instron 5848 (model name) respectively (measurement conditions: compression speed: 10 mm / minute, maximum compression ratio: 75%). The results are shown in Table 4 below. JPEG2025519719000005.jpg73148

[0097] Referring to Table 4 above, the composites of Examples 1 to 4 each had a compressive strength in the range of 0.03 to 1 MPa. Furthermore, it is understood that the concentration of sodium hyaluronate (HA) affects the compressive strength of the composite.

[0098] On the other hand, the composite of Comparative Example 2 had a lower compressive strength than the composites of Examples 1 to 4, and the composite of Comparative Example 1 was amorphous, so the compressive strength could not be measured.

[0099] (Test Example 4: Measurement of Apparent Volume) For the composites prepared in Examples 1 to 4 and Comparative Example 1, the apparent volume was measured using the diameter and height of the composites, respectively. The results are shown in Table 5 below. JPEG2025519719000006.jpg67148

[0100] Referring to Table 5 above, the composites of Examples 1 to 4 each had an apparent volume in the range of 10 to 40 mL / g. Furthermore, it is understood that in order to increase the porosity of the composite, it is desirable to lower the concentration of sodium hyaluronate (HA). Here, if the porosity of the composite is high, it can be quickly suspended in an aqueous solvent for use, improving the convenience of use of the composite. This can be confirmed in Test Examples 7 and 8 described later.

[0101] On the other hand, since the composite of Comparative Example 1 was amorphous, the apparent volume could not be measured.

[0102] (Test Example 5: Observation of Formulations) The formulations of the composites prepared in Examples 1, 5 and Comparative Example 1 were visually observed respectively. The results are shown in Figure 2.

[0103] Referring to Figure 2, the composites of Examples 1 and 5 were each cake-shaped (cylindrical). On the other hand, the composite of Comparative Example 1 did not have a regular shape because the mixed solution swelled during vacuum drying.

[0104] Here, since the composites of Examples 1 and 5 were each cake-shaped formulations, according to the present invention, the dispersibility and convenience of use of the composites can be improved. This can be confirmed in Test Examples 7 and 8 below.

[0105] (Test Example 6: Observation of the Internal Structure of Poly(lactic acid) Particles and the Structure of the Composite) The composites prepared in Examples 1 and 5 were each cut longitudinally, and the cross-section was observed using a scanning electron microscope (manufacturer: Hitachi High Technology, model name: Hitachisu5000). The results are shown in Figures 3 and 4.

[0106] Referring to (a) shown in FIGS. 3 and 4 respectively, in the composites of Example 1 and Example 5, the polylactic acid particles maintaining their shapes were uniformly present inside the composites. Further, referring to (b) shown in FIGS. 3 and 4 respectively, the polylactic acid particles present in the composites of Example 1 and Example 5 each had a network structure inside thereof.

[0107] (Test Example 7: Measurement of Suspension Time) For the composites prepared in Examples 1 to 4 and Comparative Example 1, the suspension time was measured according to the following measurement methods respectively. The results are shown in Table 6 below. Measurement Method of Suspension Time (1) 8 mL of distilled water was added to the vial containing the composite and left standing for about 5 minutes. (2) The rotation speed of the vortex mixer was set to 3,000, and the vial was stirred for 5 minutes. (3) It was visually confirmed whether the composite in the vial was completely dissolved and granulated. (4) The operation of the above step (2) was repeated until the composite was completely dissolved, and the time until granulation was measured. JPEG2025519719000007.jpg89161

[0108] Referring to Table 6 above, the composites of Examples 1 to 4 were rapidly suspended (dispersed) with a suspension time of 30 minutes or less respectively. Since suspension is achieved in a short time, the composite according to the present invention has excellent usability. For example, when the composite is suspended in an aqueous solvent at the treatment site of skin treatment, it can be suspended in a short time, and the treatment efficiency can be improved.

[0109] Here, the composite according to the present invention is a cake-like preparation, and since the particle size distribution, compression strength, and apparent volume are within a specific range, suspension in a short time is possible. This proves the importance of controlling the shape, compression strength, apparent volume, and particle size distribution of the polylactic acid particles of the composite.

[0110] Furthermore, it was confirmed that the lower the concentration of sodium hyaluronate (HA), the shorter the suspension time. Thus, in order to improve the usability of the complex, it is desirable to control the concentration of hyaluronic acid that forms the support structure (skeleton) of the complex.

[0111] (Test Example 8: Measurement of Injection Force) Regarding the complexes prepared in Example 1, 5 and Comparative Example 2, the injection force was measured according to the following measurement methods respectively. The results are shown in Table 7 below. Measurement Method of Injection Force (1) 5 mL of distilled water was added to the vial containing the complex, and it was stirred with a vortex mixer until the complex was dissolved and granulated (preparation of suspension). (2) 0.5 - 0.6 mL of the suspension in the vial was filled into a 1 mL disposable syringe. (3) A 26G or 30G injection needle was attached to the syringe, and with the injection needle facing downward, the syringe was fixed to the support part of a universal testing machine (manufacturer: TestOne, model: TO - 102). (4) The universal testing machine was operated, and the push bar attached to the syringe barrel was pushed at 1 mm / second until the syringe barrel was completely empty, and the measured force was recorded. (5) In the graph where the measured force was recorded, the average value (input force) of the forces measured at a point 5 mm to the right of the starting point, a point 5 mm to the left of the ending point, and the mid - point between these two points was calculated. JPEG2025519719000008.jpg48136

[0112] Referring to Table 7 above, for the complexes of Example 1 and 5, since the injection forces were small respectively, even when a relatively small force was applied, the suspension in which the complex was dispersed was smoothly discharged from the syringe. Because the injection force is small, the complex according to the present invention has excellent usability. For example, when using the suspension in which the complex is dispersed at the treatment site, even when a relatively small force is applied to the syringe, the suspension is smoothly discharged from the syringe and injected into the skin. Therefore, it is possible to improve the convenience of treatment.

[0113] On the other hand, the composite of Comparative Example 2 had a very large particle size during dispersion. Therefore, the suspension in which the composite of Comparative Example 2 was dispersed could not pass through the injection needle, and the injection force could not be measured because the injection needle was blocked. Thus, it is understood that the suspension in which the composite of Comparative Example 2 was dispersed can hardly be used for the treatment site.

[0114] This result supports the importance of controlling the shape, compressive strength, apparent volume, and particle size distribution of the polylactic acid particles of the composite.

Claims

1. A composite comprising biodegradable particles and a water-soluble polymer, wherein the particle size distribution (PSD) of the biodegradable particles contained in the composite represented by the following formula 1: [Formula 1] PSD = [Dv(90) - Dv(10)] / Dv(50) (wherein Dv(10) is the size within 10% of the biodegradable particle distribution, Dv(50) is the size within 50% of the biodegradable particle distribution, and Dv(90) is the size within 90% of the biodegradable particle distribution.) is 1.0 to 2.

5.

2. The composite according to claim 1, wherein the composite has a compressive strength of 0.02 to 1.5 MPa.

3. The composite according to claim 1, wherein in formula 1, Dv(10) is 5 to 35 μm and Dv(90) is 20 to 90 μm.

4. The composite according to claim 1, wherein the composite has an apparent volume of 10 to 40 mL / g.

5. The composite according to claim 1, wherein each of the biodegradable particles has a network structure therein.

6. The composite according to claim 1, wherein the biodegradable particles contain at least one selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactic acid-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyvalerolactone (PVL), polyhydroxybutyrate (PHB), and polyhydroxyvalerate (PBV).

7. The composite according to claim 1, wherein the water-soluble polymer contains at least one selected from the group consisting of hyaluronic acid (HA), methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose (CMC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxymethyl methacrylate (HEMA), polyvinyl alcohol (PVOH), polyvinylpyrrolidone (PVP), and starch.

8. The composite according to claim 1, wherein the suspension time of the composite in an aqueous solvent is 30 minutes or less.

9. (1) A step of dissolving a biodegradable raw material in a first solvent to prepare a biodegradable solution, (2) A step of spraying the biodegradable solution into a second solvent having a freezing point lower than the freezing point of the first solvent to form biodegradable particles, (3) A step of sorting the biodegradable particles by size, (4) A step of adding the biodegradable particles sorted by size to a water-soluble polymer solution to prepare a mixed solution, Step (5) of filling a container with the mixed solution, and Step (6) of freeze-drying the mixed solution filled in the container to form a composite are included, and the particle size distribution (PSD) of the biodegradable particles contained in the composite represented by the following Formula 1: [Formula 1] PSD = (Dv(90) - Dv(10)) / Dv(50) (wherein, Dv(10) is the size at which the biodegradable particle distribution is within 10%, Dv(50) is the size at which the biodegradable particle distribution is within 50%, and Dv(90) is the size at which the biodegradable particle distribution is within 90%).) A method for producing a composite, wherein the particle size distribution (PSD) of the biodegradable particles contained in the composite is 1.0 to 2.

5.

10. The freeze-drying step in step (6) is (6-1) freezing the mixed solution at -60 to -10°C to obtain a frozen product, (6-2) performing primary heating on the frozen product at -5 to 5°C for 1 to 3 hours in a vacuum atmosphere, (6-3) performing secondary heating on the primarily heated frozen product at 20 to 25°C for 8 to 15 hours in a vacuum atmosphere, (6-4) drying the secondarily heated frozen product at 25°C or higher for 20 to 40 hours in a vacuum atmosphere The method for producing a composite according to claim 9, comprising the above steps.

11. In step (4), the content of the water-soluble polymer contained in the water-soluble polymer solution is 0.2 to 2% by weight based on the total weight of the water-soluble polymer solution. The method for producing a composite according to claim 9.

12. A filling agent composition for plastic surgery in which the composite according to any one of claims 1 to 8 is dispersed.

13. The filling agent composition for plastic surgery according to claim 12, wherein the filling agent composition for plastic surgery has an injection force of 2.0 N or less with respect to an injection needle having a gauge (G) of 26. A filling agent composition for plastic surgery.

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