คอมโพสิต, วิธีการผลิตสำหรับสิ่งนี้, และองค์ประกอบฟิลเลอร์ของศัลยกรรมเสริมความงามที่ใช้สารเดียวกัน

Abstract

DEPCT68 การประดิษฐ์นี้เกี่ยวข้องกับคอมโพสิต,เกี่ยวข้องกับกระบวนการสำหรับการเตรียมสาร เดียวกัน,และเกี่ยวข้องกับองค์ประกอบของฟิลเลอร์สำหรับศัลยกรรมตกแต่ง(plasticsurgery)ที่ใช้สาร เดียวกันคอมโพสิตประกอบรวมด้วยอนุภาคที่ย่อยสลายได้ทางชีวภาพที่แต่ละอนุภาคมีโครงสร้าง แบบตาข่ายในที่นั้น;และโพลีเมอร์ที่ละลายน้ำได้เนื่องจากคอมโพสิตมีสูตรผสมที่เป็นก้อน (cakeformulation)มันจึงสามารถมีการเก็บรักษาที่ยาวนานและมีความสามารถในการกระจายตัว (dispersibility)ที่ดีเยี่ยม;

Description

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

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

[0002] Plastic surgery is performed by injecting filler compositions subcutaneously or into tissues to correct human function or for cosmetic purposes. It is desirable for the filler composition to be safe for the human body, biocompatible, and biodegradable.

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

[0004] However, since the natural polymer or the synthetic polymer begins to decompose after a certain period of time, the filler composition containing them has a limited shelf life. In addition, most filler compositions are administered using syringes. However, if the viscosity of the filler composition is too high or the dispersibility is poor, it may be difficult to inject the filler composition with a thin injection needle, and since the force applied to the syringe (injection force) must be increased, the discomfort and fatigue of the practitioner increase.

[0005] [Prior Art Literature]

[0006] [Patent Document]

[0007] (Patent Document 1) Korean Patent Publication No. 2017-0123099 (November 7, 2017)

[0008] The present invention aims to provide a composite and a method for manufacturing the same, which can improve the treatment environment of a filler composition for molding by having excellent long-term storage properties and dispersibility.

[0009] In addition, the present invention aims to provide a filler composition for plastic surgery that can be performed relatively easily.

[0010] In order to solve the above problem, according to one embodiment of the present invention, a composite is provided, which comprises biodegradable particles having a network structure therein; and a water-soluble polymer, and has a cake formulation.

[0011] According to another embodiment of the present invention, a method for producing a composite is provided, including: (1) dissolving a biodegradable raw material in a first solvent to produce a biodegradable solution; (2) spraying the biodegradable solution into a second solvent having a lower freezing point than the first solvent to form biodegradable particles having a network structure therein; (3) sorting the biodegradable particles by size; (4) adding the biodegradable particles of which size has been sorted into a water-soluble polymer solution to produce a mixed solution; (5) filling the mixed solution into a container; and (6) freeze-drying the mixed solution filled into the container to form a composite having a cake formulation.

[0012] According to another embodiment of the present invention, a filler composition for molding is provided in which the complex is dispersed.

[0013] The composite according to the present invention comprises biodegradable particles having a network structure inside and has a fluffy cake-like texture, so that it can be dispersed quickly and evenly in a solvent. Furthermore, since the composite according to the present invention has a solid-phase cake-like formulation, even when stored for a long period of time, 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 molding filler composition, it is possible to achieve extended shelf life, improved ease of storage, and improved handling properties of the material.

[0014] In addition, since the filler composition for plastic surgery according to the present invention is a composite having excellent dispersibility, the procedure can be easily performed even if the practitioner (person performing the procedure) applies relatively little force to the syringe.

[0015] Figure 1 schematically illustrates a manufacturing process of a complex according to one embodiment of the present invention.

[0016] Figure 2 is a photograph confirming the formulation of the complex according to Example 1, Example 5, and Comparative Example 1 in Test Example 1.

[0017] Figure 3 is an image of a cross-section of a composite according to Example 1 in Test Example 2, obtained by scanning electron microscopy.

[0018] Figure 4 is an image of a cross-section of a composite according to Example 5 in Test Example 2, obtained by scanning electron microscopy.

[0019] Hereinafter, the present invention will be described in detail. Herein, the present invention is not limited to the contents disclosed below, and may be modified in various forms as long as the gist of the invention is not changed.

[0020] The word "comprising" or "including" in this specification is intended to specify particular features, regions, steps, processes, elements and / or components, and does not exclude the presence or addition of other features, regions, steps, processes, elements and / or components, unless specifically stated to the contrary.

[0021] In this specification, the description that one component is connected or coupled with another component includes both direct connection or coupling between these components or indirect connection or coupling through another component.

[0022] In this specification, singular expressions are interpreted to include the singular or plural as interpreted in the context, unless otherwise specified.

[0023] All numbers and expressions indicating the amounts of components, reaction conditions, etc. described in this specification can be modified by the term “about” in all cases unless otherwise specified.

[0024] The terms first, second, etc. described in this specification are used to describe various components, and the components should not be limited by the terms, and the terms are used only for the purpose of distinguishing one component from another.

[0025]

[0026] complex

[0027] 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 comprises biodegradable particles having a network structure inside; and a water-soluble polymer, and has a cake formulation, which is described as follows.

[0028]

[0029] biodegradable particles

[0030] The biodegradable particles included in the complex according to the present invention function to restore or replace damaged or aged human tissue (e.g., skin tissue).

[0031] The biodegradable particles may be particles having a network structure within them. Specifically, the biodegradable particles may have a three-dimensional network structure formed within them, either regular, irregular, or a combination thereof. Due to the presence of this network structure within the biodegradable particles, the biodegradable particles may possess high strength, thereby enabling them to efficiently restore or replace human tissue. Furthermore, due to the high strength of the biodegradable particles, the strength of a composite containing the particles may be increased, thereby improving the handleability of the composite.

[0032] The biodegradable particles may include commonly known biodegradable polymers. Specifically, the biodegradable particles may include at least one selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyvalerolactone (PVL), polyhydroxybutyrate (PHB), and polyhydroxyvalerate (PBV), but are not limited thereto. Preferably, the biodegradable particles may be polylactic acid (PLA) particles.

[0033] The biodegradable particles may have a weight average molecular weight of 50,000 to 400,000 g / mol, but is not limited thereto. Specifically, the biodegradable particles may have a weight average molecular weight of 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 the dispersibility of the composite can be improved.

[0034] These biodegradable particles may have a tap density of, but is not limited to, 0.1 to 0.25 g / ml. Specifically, the biodegradable particles may have a tap density of 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. When the tap density of the biodegradable particles is within the above range, the biodegradable particles are densely distributed within the composite, thereby increasing the strength of the composite and improving the dispersibility of the composite.

[0035] Meanwhile, the biodegradable particles may have a particle size distribution (PSD) according to Equation 1 below of 0.4 to 2.5, 0.5 to 2.2, 0.6 to 2.0, 0.65 to 1.9, 0.7 to 1.8, 0.8 to 1.7, 1.0 to 2.5, 1.0 to 2.3, 1.0 to 2.0, 1.01 to 1.6, 1.02 to 1.5, 1.03 to 1.4, or 1.05 to 1.3, but is not limited thereto. When the particle size distribution of the biodegradable particles is within the above range, the dispersibility of the complex in a solvent may be excellent. In addition, when the complex is used as a material for a filler composition for molding, the filler composition for molding can be administered well by applying a small force to the syringe even when a thin injection needle is used.

[0036] <Formula 1>

[0037] PSD = (Dv(90) - Dv(10)) / Dv(50)

[0038] In the above equation 1,

[0039] Dv(10) is the size of the biodegradable particle distribution within 10% (the size of the particle at the 10% position by volume when arranging the particle sizes from smallest to largest in the biodegradable particle distribution).

[0040] Dv(50) is the size at which the biodegradable particle distribution is within 50% (the size of the particle at the 50% position by volume when arranging the particle sizes from the smallest to the largest in the biodegradable particle distribution).

[0041] Dv(90) is the size at which the biodegradable particle distribution is within 90% (the size of the particle at the 90% position by volume when arranging the particle sizes from smallest to largest in the biodegradable particle distribution).

[0042] Specifically, in the above 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.

[0043]

[0044] water-soluble polymers

[0045] The water-soluble polymer included in the complex according to the present invention functions as a carrier that moves biodegradable particles and as a matrix that disperses and fixes the biodegradable particles.

[0046] The water-soluble polymer may include a polymer having a commonly known water solubility property. Specifically, the water-soluble polymer may 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. Preferably, the water-soluble polymer may be hyaluronic acid (HA). Specifically, the water-soluble polymer may be non-crosslinked hyaluronic acid.

[0047] The hyaluronic acid (HA) may be a high molecular weight hyaluronic acid such as sodium hyaluronate crosspolymer or sodium hyaluronate; a medium molecular weight hyaluronic acid such as hydroxypropyltrimonium hyaluronate or sodium acetylated hyaluronate; a low molecular weight hyaluronic acid such as potassium hyaluronate, hydrolyzed hyaluronic acid, or hydrolyzed sodium hyaluronate; an ultra-low molecular weight hyaluronic acid such as hyaluronic acid; or a combination thereof.

[0048] The water-soluble polymer may have a weight average molecular weight of 1 to 4 million g / mol, but is not limited thereto. Specifically, the water-soluble polymer may have a weight average molecular weight of 1.2 to 4 million g / mol, 1.3 to 4 million g / mol, 1.5 to 4 million g / mol, 1.8 to 4 million g / mol, 2 to 4 million g / mol, 2.1 to 3.8 million g / mol, or 2.2 to 3.6 million g / mol. When the weight average molecular weight of the water-soluble polymer is within the above range, processing into a complex is easy, and the dispersibility of the complex can be improved.

[0049]

[0050] According to the present invention, the weight ratio of the biodegradable particles and the water-soluble polymer may be, but is not limited to, 40:60 to 95:5. Specifically, the weight ratio of the biodegradable particles and the water-soluble polymer included in the composite may 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. When the weight ratio is within the above range, the composite has excellent dispersibility and can be efficiently used as a material for a filler composition for molding.

[0051]

[0052] Meanwhile, 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 composite according to the present invention may have a compressive strength of 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.

[0053] Additionally, the complex according to the present invention may have an apparent volume of 10 to 40 ml / g, but is not limited thereto. Specifically, the complex according to the present invention may have an apparent volume of 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.

[0054] In addition, the composite according to the present invention may have a porosity of 90 to 97.5 vol%, but is not limited thereto. Specifically, the composite according to the present invention may have a porosity of 90 to 97 vol%, 90 to 96 vol%, or 90 to 95 vol%. The porosity may refer to the volume of pores present in the composite among the total volume of the composite.

[0055] The composite according to the present invention can exhibit excellent long-term storage properties, handling properties, and dispersibility due to its compressive strength, apparent density, and porosity within the specific ranges described above. In particular, the composite according to the present invention can be uniformly dispersed in a solvent within a short period of time when the composite is dispersed for the purpose of preparing a filler composition for molding, as the compressive strength is controlled within the specific range described above.

[0056] Specifically, the complex according to the present invention may have a suspension time in an aqueous solvent of 30 minutes or less, but is not limited thereto. More specifically, the complex according to the present invention may have a suspension time in an aqueous solvent of 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. In this case, the aqueous solvent may specifically be water, distilled water, deionized water, ultrapure water, etc., but is not limited thereto.

[0057] The complex according to the present invention may have a cake-like formulation with a fluffy texture. Since the complex has a cake-like formulation, it may exhibit excellent long-term storage properties and dispersibility in solvents.

[0058] Specifically, the complex according to the present invention may have a cylindrical shape, but is not limited thereto. In addition, the average diameter of the complex may be 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 the average height of the complex may be 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 thereto.

[0059]

[0060] Method for manufacturing a complex

[0061] The present invention provides a method for producing the above-described complex. Specifically, the method for producing the complex according to the present invention comprises the steps of: (1) dissolving a biodegradable raw material in a first solvent to produce a biodegradable solution; (2) spraying the biodegradable solution into a second solvent having a lower freezing point than the first solvent to form biodegradable particles having a network structure therein; (3) sorting the biodegradable particles by size; (4) adding the size-sorted biodegradable particles to a water-soluble polymer solution to produce a mixed solution; (5) filling a container with the mixed solution; and (6) freeze-drying the mixed solution filled in the container to form a complex having a cake formulation, which will be described below with reference to FIG. 1.

[0062]

[0063] The above step (1) is a step of preparing a biodegradable solution by dissolving a biodegradable raw material in a first solvent. Specifically, the above step (1) may be performed by adding the biodegradable raw material to a first solvent in which two or more types of organic solvents are mixed and stirring.

[0064] The biodegradable raw material may specifically include at least one selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyvalerolactone (PVL), polyhydroxybutyrate (PHB), and polyhydroxyvalerate (PBV), but is not limited thereto.

[0065] The biodegradable raw material may have a weight average molecular weight of 50,000 to 400,000 g / mol, but is not limited thereto. Specifically, the biodegradable particles may have a weight average molecular weight of 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.

[0066] The first solvent may be, but is not limited to, two or more 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, and tetrahydrofuran.

[0067] Specifically, the first solvent may be a solvent in which the first organic solvent and the second organic solvent are mixed in 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 solvent in which dimethyl sulfoxide and ethylene carbonate are mixed, but is not limited thereto.

[0068]

[0069] The above step (2) is a step of forming biodegradable particles having a network structure inside by spraying the biodegradable solution into a second solvent having a lower freezing point than the first solvent. Specifically, the above step (2) may be performed by spraying the biodegradable solution into a second solvent that is not mixed with the first solvent and is phase separated, and has a freezing point that is 50 to 150°C (specifically, 90 to 120°C) lower than the freezing point of the first solvent.

[0070] The temperature of the second solvent during the above injection may be specifically -45 to 0°C, -40 to -5°C, -35 to -10°C, or -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 a network structure inside can be formed well.

[0071] 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.

[0072] The injection speed of the biodegradable solution injected into the second solvent may be, but is not limited to, 1 to 20 ml / min, 3 to 15 ml / min, or 5 to 10 ml / min.

[0073]

[0074] The above step (3) is a step for sorting the biodegradable particles by size. Specifically, the above step (3) may be performed by feeding the biodegradable particles into a particle sorter and sorting out particles having a required size.

[0075] The size of the biodegradable particles selected through the particle sorter is not particularly limited, but may be selected based on a Dv(50) (average particle diameter) of 10 to 60 μm (specifically, 13 to 47 μm, or 15 to 45 μm). By performing this step, the particle size distribution of the biodegradable particles can be controlled within a specific range, and by manufacturing a composite using the biodegradable particles with the controlled particle size distribution, a composite having excellent dispersibility in a solvent can be provided.

[0076]

[0077] The above step (4) is a step of preparing a mixed solution by adding the biodegradable particles, whose size has been selected, to a water-soluble polymer solution. Specifically, the above step (4) may be performed by adding the biodegradable particles, whose size has been selected, to a solution of a water-soluble polymer having a controlled concentration and stirring the solution.

[0078] The water-soluble polymer contained in the above 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.

[0079] The water-soluble polymer may have a weight average molecular weight of 1 to 4 million g / mol, but is not limited thereto. Specifically, the water-soluble polymer may have a weight average molecular weight of 1.2 to 4 million g / mol, 1.3 to 4 million g / mol, 1.5 to 4 million g / mol, 1.8 to 4 million g / mol, 2 to 4 million g / mol, 2.1 to 3.8 million g / mol, or 2.2 to 3.6 million g / mol.

[0080] The content of the water-soluble polymer contained in the water-soluble polymer solution may be, but is not limited to, 0.2 to 2 wt%, 0.4 to 1.5 wt%, 0.5 to 1.3 wt%, 0.5 to less than 1 wt%, or 0.6 to 0.95 wt%, based on the total weight of the water-soluble polymer solution. When the content of the water-soluble polymer is within the above range, the strength of the complex can be secured while the dispersibility of the complex in the solvent can be increased.

[0081] The solvent included in the above water-soluble polymer solution may be a commonly known aqueous solvent (e.g., water, distilled water, etc.), but is not limited thereto.

[0082] Meanwhile, the water-soluble polymer solution and the biodegradable particles may be mixed so that the water-soluble polymer (a) and the biodegradable particles (b) contained in the water-soluble polymer solution have a weight ratio (a:b) of 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.

[0083]

[0084] The above step (5) is a step of filling the mixed solution into a container. Specifically, the above step (5) may be a process of filling the mixed solution into a specific container to form a complex having a cake formulation.

[0085] The above container may be, but is not limited to, a sealable glass bottle (e.g., a vial).

[0086] The amount of the mixed solution filled in the container may be, but is not limited to, 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. When the amount of the mixed solution filled is within the above range, a composite having a cake formulation and a required compressive strength can be formed.

[0087]

[0088] The above step (6) is a step of freezing the mixed solution filled in the container and then drying (evaporating) the solvent in a vacuum state to form a complex having a cake formulation. Specifically, the above step (6) may include: (6-1) a step of freezing the mixed solution at -60 to -10°C to obtain a frozen body; (6-2) a step of first heating the frozen body to a temperature of -5 to 5°C for 1 to 3 hours under a vacuum atmosphere; (6-3) a step of second heating the frozen body, which has been first heated, to a temperature of 20 to 25°C for 8 to 15 hours under a vacuum atmosphere; and (6-4) a step of drying the frozen body, which has been secondarily heated, at a temperature of 25°C or higher for 20 to 40 hours under a vacuum atmosphere.

[0089] The temperature at which the mixed solution is frozen in the above step (6-1) may be, but is not limited to, -60 to -10°C, -50 to -20°C, or -40 to -30°C. In addition, the time at which the mixed solution is frozen may be, but is not limited to, 60 to 240 minutes, 90 to 180 minutes, or 120 to 150 minutes.

[0090] The above steps (6-2) to (6-4) are steps for gradually increasing the temperature of the frozen body to dry (evaporate) the solvent present in the frozen body. At this time, the final vacuum level at each step may be, but is not limited to, 0.1 to 30 mtorr, 0.5 to 20 mtorr, or 1 to 10 mtorr.

[0091] Specifically, the above step (6-2) may be performed by first increasing the temperature of a frozen body having a temperature of -60 to -10°C to a temperature of -5 to 5°C, -3 to 3°C, or -1 to 1°C for 1 to 3 hours, or 1.5 to 2.5 hours, under a vacuum atmosphere.

[0092] The above step (6-3) may be performed by a process of secondarily raising the temperature of the first-heated frozen body to a temperature of 20 to 25°C, 22 to 25°C, or 24 to 25°C for 8 to 15 hours, or 9 to 11 hours, under a vacuum atmosphere.

[0093] The above step (6-4) may be performed by raising the temperature of the secondarily heated frozen body to 25°C or higher (specifically, 25 to 30°C) for 20 to 40 hours, or 22 to 30 hours, under a vacuum atmosphere, and then drying it.

[0094] By performing the above steps (6-1) to (6-4) and freeze-drying the mixed solution, a complex having a cake formulation can be efficiently formed.

[0095]

[0096] Meanwhile, the method for manufacturing a complex according to the present invention may further include a step of sterilizing the complex.

[0097] The above sterilization may be performed by, but is not limited to, gamma ray sterilization, e-beam sterilization, ethylene oxide sterilization, steam sterilization, or high-pressure steam sterilization. Specifically, the sterilization may be performed using ethylene oxide at 30 to 40°C for 150 to 180 minutes. By performing this process, the long-term storage properties of the complex can be further improved.

[0098]

[0099] The size of the biodegradable particles included in the composite manufactured through the above manufacturing method is not particularly limited, but may have an average particle diameter (Dv(50)) of 15 to 60 ㎛. Specifically, the biodegradable particles may be, but are not limited to, first biodegradable particles having a Dv(50) particle size distribution of 15 to 30 ㎛, 17 to 29 ㎛, 18 to 28 ㎛, 19 to 27 ㎛, 20 to 25 ㎛, or 21 to 23 ㎛; second biodegradable particles having a Dv(50) particle size distribution of more than 30 to 60 ㎛, more than 30 to 55 ㎛, 35 to 50 ㎛, 35 to 48 ㎛, 38 to 45 ㎛, or 40 to 43 ㎛; or a mixture of these particles.

[0100] Specifically, the biodegradable particles included in the composite manufactured through the above manufacturing method may have a particle size distribution (PSD) according to the following formula 1 of 0.4 to 2.5, 0.5 to 2.2, 0.6 to 2.0, 0.65 to 1.9, 0.7 to 1.8, 0.8 to 1.7, 1.0 to 2.5, 1.0 to 2.3, 1.0 to 2.0, 1.01 to 1.6, 1.02 to 1.5, 1.03 to 1.4, or 1.05 to 1.3, but are not limited thereto.

[0101] <Formula 1>

[0102] PSD = (Dv(90) - Dv(10)) / Dv(50)

[0103] In the above equation 1,

[0104] Dv(10) is the size at which the biodegradable particle distribution is within 10%,

[0105] Dv(50) is the size at which the biodegradable particle distribution is within 50%,

[0106] Dv(90) is the size at which the biodegradable particle distribution is within 90%.

[0107]

[0108] In this way, the present invention manufactures a composite by mixing biodegradable particles having a specific particle size distribution and a water-soluble polymer solution, filling the resulting mixed solution into a sealable container, and then freeze-drying the mixture solution, thereby obtaining a composite having a specific cake shape and controlled compressive strength.

[0109] The composite according to the present invention has a cake formulation, exhibiting excellent long-term storage properties and dispersibility, and controlled compressive strength, thereby exhibiting improved handling properties. Furthermore, the composite according to the present invention can exhibit biocompatibility and biodegradability by including biodegradable particles and water-soluble polymers.

[0110] Therefore, the complex according to the present invention can be usefully used as a material for restoring or replacing human tissue. Additionally, the complex according to the present invention can be utilized as a carrier for cells or drugs, as a cell culture medium, and more.

[0111]

[0112] Filler composition for plastic surgery

[0113] The present invention provides a molding filler composition in which the complex is dispersed. Specifically, the molding filler composition according to the present invention may be a composition in which a complex having the same composition and characteristics as described above is dispersed in a solvent.

[0114] The molding filler composition according to the present invention can be manufactured within a short period of time (e.g., within 30 minutes) due to the improved dispersibility of the complex. That is, since the use of a sealed complex in a solid cake form improves solubility and dispersibility, the molding filler composition can be manufactured within a short period of time, and thus the present invention can facilitate the manufacture of the molding filler composition immediately before a procedure. In addition, since the complex includes biodegradable particles with a controlled particle size distribution, the molding filler composition of the present invention, obtained by dispersing the same in a solvent, can be easily administered to a practitioner by applying little force to the syringe even when using a thin injection needle. Therefore, the molding filler composition according to the present invention can improve the procedure environment while reducing the practitioner's discomfort and fatigue.

[0115] For example, a filler composition for molding according to the present invention (e.g., a composition in which a complex having an average particle diameter (Dv(50)) of 60 ㎛ or less is dispersed) may have an injection force of 2.0 N or less for an injection needle having a gauge (G) of 26, and may be specifically, but not limited to, 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. In addition, the filler composition for molding according to the present invention (e.g., a composition in which a complex having an average particle diameter (Dv(50)) of 33 ㎛ or less is dispersed) may have an injection force of 3.0 N or less for an injection needle having a gauge (G) of 30, and specifically, 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.

[0116] The present invention is described in more detail through the following examples. However, the scope of the present invention is not limited to these examples.

[0117]

[0118] Example 1

[0119] A polylactic acid solution was prepared by dissolving 9 g of polylactic acid (PLA) having a weight average molecular weight of 170,000 g / mol in 150 ml of a mixed solvent of dimethyl sulfoxide and ethylene carbonate at a weight ratio of 90:10.

[0120] Next, the polylactic acid solution prepared in n-hexane cooled to -20°C or lower was sprayed at a spray amount of 4.5 ml / min and an air volume of 6 L / min to form frozen polylactic acid particles in n-hexane. After obtaining the formed frozen polylactic acid particles, they were placed in water at 1 to 3°C and stirred to remove the mixed solvent (dimethyl sulfoxide + ethylene carbonate) contained in the frozen polylactic acid particles, thereby producing polylactic acid particles (PLA particles).

[0121] Next, the manufactured polylactic acid particles were sorted using a particle sorter to obtain polylactic acid particles having a particle size of 60 ㎛ or less (Dv(50): 41.9 ㎛).

[0122] Next, polylactic acid particles having a particle size of 60 ㎛ or less were added to a 0.6% sodium hyaluronate solution (HA solution = 99.4 wt% distilled water + 0.6 wt% sodium hyaluronate) at a weight ratio of 85:15 for polylactic acid particles:sodium hyaluronate (HA), and mixed to prepare a mixed solution.

[0123] Next, 5.20 g of the prepared mixed solution (170 mg of PLA particles + 30 mg of HA) was filled into a 10 ml vial.

[0124] Next, the mixed solution filled in the vial was frozen at -40 to -30°C to obtain a frozen body. The temperature of the obtained frozen body was first increased from -30°C to 0°C over 2 hours in a vacuum atmosphere, and then the temperature was secondarily increased from 0°C to 25°C over 10 hours, and then dried at 25°C for 24 hours to form a complex inside the vial.

[0125] Afterwards, the vial containing the complex was sterilized using ethylene oxide (EO) gas, and residual moisture was removed through vacuum drying to produce a complex with a diameter of 1.8 cm and a height of 2.2 cm inside the vial.

[0126]

[0127] Examples 2 to 4

[0128] A complex was manufactured through the same process as Example 1, except that the concentration of sodium hyaluronate (HA) contained in the mixed solution filled in the vial, the amount of the mixed solution filled, the diameter and height of the complex, etc. were adjusted as shown in Table 1 below.

[0129]

[0130] ClassificationPLA / HA Concentration Mixed solution Filling amount (g)Weight ratio of PLA:HA=85:15Composite diameter (cm)Composite height (cm)PLA (mg)HA (mg)Example 1HA concentration: 0.6%PLA concentration: 3.4%5.20170301.82.2Example 2HA concentration: 0.8%PLA concentration: 4.5%3.95170301.81.5Example 3HA concentration: 1.0%PLA concentration: 5.7%3.20170301.81.2Example 4HA concentration: 1.2%PLA concentration: 6.8%2.70170301.80.8

[0131]

[0132] Example 5

[0133] Polylactic acid particles having a particle diameter of 33 ㎛ or less (Dv(50): 21.1 ㎛) were obtained through a process of sorting polylactic acid particles using a particle sorter, and a composite having a diameter of 1.8 cm and a height of 0.55 cm was manufactured through the same process as Example 1, except that the polylactic acid particles were added to a sodium hyaluronate solution.

[0134]

[0135] Comparative Example 1

[0136] A composite having a diameter of 1.8 cm was manufactured through the same process as Example 1, except that the mixed solution (170 mg of PLA particles + 30 mg of HA) was filled into a vial and vacuum-dried at 25°C for 16 hours under a vacuum atmosphere (i.e., no freeze-drying or sterilization process was performed).

[0137]

[0138] Test Example 1. Formulation Verification

[0139] The formulations of the complexes manufactured in Examples 1, 5 and Comparative Example 1 were visually confirmed, and the results are shown in Fig. 2.

[0140] Referring to Fig. 2, it can be confirmed that the composites of Examples 1 and 5 have a cake-like shape (cylindrical shape). On the other hand, it can be confirmed that the composite of Comparative Example 1 does not have a consistent shape due to the mixed solution swelling during the vacuum drying process.

[0141] Here, as in Examples 1 and 5, the present invention can improve the dispersibility and usability of the complex by having a cake formulation, which can be confirmed through Test Examples 7 and 8 described below.

[0142]

[0143] Test Example 2. Confirmation of the internal structure of polylactic acid particles and the composite structure.

[0144] The composites manufactured in Examples 1 and 5 were cut vertically and their cross-sections were examined using a scanning electron microscope (manufacturer: Hitachi high technology, model name: Hitachi su5000), and the results are shown in Figs. 3 and 4.

[0145] Referring to a) shown in each of FIGS. 3 and 4, it can be confirmed that the composites of Examples 1 and 5 have each polylactic acid particle uniformly present inside the composite while maintaining its shape.

[0146] Also, referring to b) shown in each of FIGS. 3 and 4, it can be confirmed that the polylactic acid particles present in the composites of Examples 1 and 5 have a network structure present therein.

[0147]

[0148] Test Example 3. Tap Density Measurement

[0149] The tap density of polylactic acid (PLA) particles obtained through the process of sorting with a particle sorter in each of Examples 1 and 5 was measured using the following measuring method, and the results are shown in Table 2 below.

[0150] * Tap density measurement method

[0151] 1) Measure the weight of the measuring cylinder and add 20 to 25 ml of polylactic acid particles to the measuring cylinder.

[0152] 2) Measure the weight of the measuring cylinder containing the polylactic acid particles to determine the weight of the pure polylactic acid particles.

[0153] 3) Mount the measuring cylinder containing polylactic acid particles on a tap density meter (Manufacturer: Bettersize, Model: BeDensi T1 Pro).

[0154] 4) Operate the tap density meter at a tapping speed of 250 times / minute and a tapping count of 1250 times.

[0155] 5) After tapping is complete, remove the measuring cylinder and measure the volume of the polylactic acid particles.

[0156] 6) The tap density is calculated by dividing the weight of the polylactic acid particles measured in step 2) by the volume of the polylactic acid particles measured in step 5) (the tap density is measured for each of five samples and the average value is obtained).

[0157]

[0158] Sample classification PLA particle size Weight (g) Volume (ml) Tap density (g / ml) Average tap density (g / ml) 133 ㎛ or less (Example 5) 3.1 19.4 0.160 0.165 23.0 17.6 0.170 33.2 18.10 177 43.2 19.8 0.16 25 3.1 19.8 0.157 160 ㎛ or less (Example 1) 2.0 14.8 0.135 0.138 22.9 19.8 0.146 33.0 20.8 0.144 42.9 22.00 132 5 2.4 18.00 133

[0159] Referring to Table 2 above, it can be confirmed that the polylactic acid particles manufactured in Examples 1 and 5 each have a tap density within the range of 0.1 to 0.2 g / ml. Here, in the case of Example 5, where the particle size of the polylactic acid particles is smaller than that of Example 1, it can be expected that the tap density of the polylactic acid particles is large, and thus high-density bonding will occur within the composite.

[0160]

[0161] Test Example 4. Particle Size Distribution Measurement

[0162] The particle size distribution of the polylactic acid particles manufactured in Examples 1 and 5 was measured using the following measuring method, and the results are shown in Table 3 below.

[0163] * Particle size distribution measurement method

[0164] 1) A suspension is prepared by adding the complex to water and stirring for 30 minutes.

[0165] 2) Analyze the manufactured suspension using a particle size distribution measuring device (Manufacturer: Malvern Instrument, Model: Mastersizer 3000-Maz6140) to measure the particle size distribution of polylactic acid particles.

[0166] 3) The values ​​measured in step 2) above are substituted into Equation 1 below to calculate the particle size distribution (PSD).

[0167] <Formula 1>

[0168] PSD = (Dv(90) - Dv(10)) / Dv(50)

[0169] In the above equation 1,

[0170] Dv(10) is the size at which the biodegradable particle distribution is within 10%,

[0171] Dv(50) is the size at which the biodegradable particle distribution is within 50%,

[0172] Dv(90) is the size at which the biodegradable particle distribution is within 90%.

[0173]

[0174] Classification Dv(10) Dv(50) Dv(90) Particle size distribution Example 120.9 ㎛41.9 ㎛73.9 ㎛1.265 Example 511.6 ㎛21.1 ㎛34.4 ㎛1.081

[0175] Referring to Table 3 above, it can be confirmed that the polylactic acid particles manufactured in Examples 1 and 5, respectively, have a particle size distribution within the range of 1.0 to 2.5. Here, since the particle size distribution of the polylactic acid particles is within the above range, the present invention can increase the usability (utility) of the composite. That is, by having the above particle size distribution, the dispersibility of the composite is excellent, and even if a relatively small force (injection input) is applied to a syringe filled with a suspension in which the composite is dispersed, the suspension is smoothly discharged. This can be confirmed through Test Examples 7 and 8 described below.

[0176]

[0177] Test Example 5. Compressive strength measurement

[0178] The compressive strength of the composites manufactured in Examples 1 to 4 and Comparative Example 1 was measured using an Instron 5848 (model name) device manufactured by Instron (measurement conditions - compression speed: 10 mm / min, maximum compression ratio: 75%), and the results are shown in Table 4 below.

[0179]

[0180] Classification HA concentration (%) Compressive strength (MPa) Example 10.6 0.0 37 50 Example 20.8 0.36 316 Example 31.0 0.50 605 Example 41.2 0.9 4671 Comparative example 10.6 Not measurable (irregular shape)

[0181] Referring to Table 4 above, it can be confirmed that the composites of Examples 1 to 4 exhibit a compressive strength within the range of 0.03 to 1 MPa. Furthermore, it can be seen that the concentration of sodium hyaluronate (HA) affects the compressive strength of the composite.

[0182] Meanwhile, the compressive strength of the composite of Comparative Example 1 could not be measured because it had an irregular shape.

[0183]

[0184] Test Example 6. Apparent Volume Measurement

[0185] The apparent volume of the composites manufactured in Examples 1 to 4 and Comparative Example 1 was measured using the diameter and height of the composites, and the results are shown in Table 5 below.

[0186]

[0187] Classification HA concentration (%) Apparent volume (ml / g) Example 10.6 27.9 Example 20.8 17.0 Example 31.0 15.2 Example 41.2 10.1 Comparative example 10.6 Not measurable (irregular shape)

[0188] Referring to Table 5 above, it can be confirmed that the composites of Examples 1 to 4 have apparent volumes in the range of 10 to 40 ml / g. Furthermore, it can be expected that lowering the concentration of sodium hyaluronate (HA) is desirable in order to increase the porosity of the composite. Here, when the composite has high porosity, when suspended in an aqueous solvent for use, the suspension is quickly formed, thereby increasing the usability of the composite. This can be confirmed through Test Examples 7 and 8 described below.

[0189] Meanwhile, the apparent volume of the complex of Comparative Example 1 could not be measured because it had an irregular shape.

[0190]

[0191] Test Example 7. Suspension Time Measurement

[0192] The suspension times of the complexes manufactured in Examples 1 to 4 were measured using the following measurement methods, and the results are shown in Table 6 below.

[0193] * Suspension time measurement method

[0194] 1) Add 8 ml of distilled water to the vial containing the complex and leave it for about 5 minutes.

[0195] 2) Set the vortex mixer's rpm to 3000 and stir the vial for 5 minutes.

[0196] 3) Visually check whether the complex inside the vial has been completely dissolved and granulated.

[0197] 4) Repeat the above step 2) process until all the complexes are dissolved and measure the time taken for particle formation to occur.

[0198]

[0199] Classification HA Concentration (%) Sample RPM Suspension Time (min) Average Suspension Time (min) Example 10.6 13,000 15 15.02 15 3 15 Example 20.8 13,000 20 18.32 15 3 20 Example 31.0 13,000 25 26.62 25 330 Example 41.2 13,000 25 28.32 30 330

[0200] Referring to Table 6 above, the complexes of Examples 1 to 4 were confirmed to be rapidly suspended (dispersed) within 30 minutes. This rapid suspension demonstrates the high usability of the complexes of the present invention. For example, when the complexes are suspended in an aqueous solvent at the treatment site for skin treatments, the rapid suspension can enhance the treatment efficiency.

[0201] Here, the fact that the suspension of the complex according to the present invention is achieved within a short period of time is possible because the complex is in a cake form and has a particle size distribution, compressive strength, and apparent volume within a specific range, which supports the importance of controlling the shape of the complex, compressive strength, apparent volume, and particle size distribution of polylactic acid particles.

[0202] Furthermore, it was confirmed that the lower the concentration of sodium hyaluronate (HA), the faster the suspension time, and thus it was confirmed that it is desirable to control the concentration of hyaluronic acid forming the support structure (frame) of the complex in order to increase the usability of the complex.

[0203]

[0204] Test Example 8. Injection force measurement

[0205] The injection force of the composites manufactured in Examples 1 and 5 was measured using the following method, and the results are shown in Table 7 below.

[0206] * Injection force measurement method

[0207] 1) Add 5 ml of distilled water to the vial containing the complex and stir with a vortex mixer until the complex is completely dissolved and granulated (suspension preparation).

[0208] 2) Aspirate 0.5 to 0.6 ml of the suspension in the vial using a 1 ml disposable syringe.

[0209] 3) After attaching a 26 G or 30 G injection needle to the syringe, secure the syringe to the support of the universal material testing machine (Manufacturer: TestOne, Model: TO-102) with the injection needle pointing downward.

[0210] 4) Operate the universal material testing machine and push the plunger mounted on the syringe at 1 mm / sec until the syringe is completely empty, and record the measured force.

[0211] 5) In the graph recording the measured force, the average value (main input) of the force 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 a point midway between these two points is calculated.

[0212]

[0213] Distinguishing Needle Gauge (G) Main Input (N) Example 1261.12 Example 5260.80301.80

[0214] Referring to Table 7 above, the complexes of Examples 1 and 5 have low injection force, and it can be confirmed that the suspension containing the complex is smoothly discharged from the syringe even with a relatively small force applied. As such, it can be seen that the complex according to the present invention has high usability due to the low injection force. For example, when applying the suspension containing the complex to a treatment site, even with a relatively small force applied to the syringe, the suspension is smoothly discharged from the syringe and injected well into the skin, thereby increasing the convenience of the treatment.

[0215] These results also support the importance of controlling the shape, compressive strength, apparent volume, and particle size distribution of polylactic acid particles of the composite.

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