Multilayer microsphere with core-shell structure composed of heterogeneous biocompatible polymer compounds, and method for producing same

Abstract

The present invention relates to a multilayer microsphere with a shell-core structure composed of heterogeneous biocompatible polymer compounds and a method for producing the microsphere. The present invention can eliminate the inconvenience of repeated procedures as with conventional single-component polymer microspheres, thereby alleviating discomfort of patients undergoing the procedure. The present invention can also offer therapeutic effects comparable to those achieved through multiple procedures, significantly enhancing both the value of the procedure and patient convenience. Furthermore, since the decomposition and absorption times as well as the tissue reaction of the shell and core of the microsphere within the body after the procedure can be controlled, it is possible to maximize the ease of treatment and procedure and the long-term stability of the cosmetic effect.

Description

Multilayer microspheres having a core-shell structure composed of heterogeneous biocompatible polymer compounds and a method for manufacturing the microspheres

[0001] The present invention relates to multilayer microspheres having a core-shell structure formed by heterogeneous biocompatible polymer compounds and a method for producing the microspheres, and two examples are presented.

[0002] As life expectancy increases due to the advancement of modern medicine and improvements in diet, we are entering an aging society, and the rapid increase in the aging population is leading to the imminent entry into a super-aged society.

[0003] With the increase in the aging population, the need for delaying or preventing aging is increasing explosively, and to meet this need, various treatment methods, procedures, and treatments are continuously appearing on the market through research and development in an attempt to develop therapeutic approaches for preventing and delaying aging.

[0004] Various methods have been proposed to reduce facial wrinkles and maintain skin elasticity. For example, not only treatment devices such as beauty devices and laser treatments that utilize high frequency or ultrasound, but also various minimally invasive treatments and procedures have been attempted, such as fillers processed from traditional hyaluronic acid and fillers that promote bio-collagen regeneration using polymer compounds, and each method has its own advantages and disadvantages.

[0005] In particular, among the various procedures or treatment methods mentioned above, fillers that induce collagen production by injecting polymer microspheres subcutaneously are recently being manufactured using various polymer compounds, and their effectiveness is being verified.

[0006] For example, among the types of fillers mentioned above, hyaluronic acid (Ha) filler is one of the most widely used.

[0007] The above-mentioned hyaluronic acid (Ha) filler helps to retain moisture and add volume naturally found in the skin, and has the characteristics of viscoelasticity that provides natural results when injected, moisture retention and biocompatibility, reversibility that can be dissolved with an enzyme called hyaluronase if necessary, and versatility that allows for customized treatment to the facial area by being available in various formulations depending on the difference in cross-linking and concentration.

[0008] Hyaluronic acid (Ha) fillers have various characteristics and advantages, such as safety with low allergic reactions, immediate effect that appears immediately after injection, natural appearance and feel, lasting for a certain period of time after the procedure but can be adjusted as facial features change over time, and can be dissolved and resolved with hyaluronase when the results are not satisfactory or complications occur, as well as the ability to return to daily activities immediately after the procedure.

[0009] However, despite these characteristics and advantages, there are problems such as the fact that it is highly dependent on the skill and experience of the practitioner, such as the discomfort that can commonly occur during the procedure, such as redness, swelling, and bruising, as well as the fact that the treatment effect does not last, the initial shape is not maintained, or the shape becomes undesirable, and in rare cases, there is a risk of side effects such as vascular occlusion, and the Tyndall effect that can be seen when the procedure is performed on thin skin.

[0010] In addition, side effects have been confirmed, such as rapid decomposition in the body after hyaluronic acid (Ha) filler treatment, or the injection site clumping together depending on the formulation, or the appearance of an unnatural appearance due to movement in an undesirable direction caused by the active movement of facial muscles.

[0011] Therefore, to compensate for the disadvantage of rapid decomposition in the body, chemical crosslinking is performed, but the crosslinking agent causes unwanted side effects, negatively affecting short-term and long-term results, and the number of patients refusing treatment using hyaluronic acid (Ha) fillers is increasing for various reasons.

[0012] To overcome the shortcomings of hyaluronic acid (Ha) fillers, fillers made from biodegradable synthetic polymers are being commercialized.

[0013] Examples of the biodegradable synthetic polymer fillers mentioned above include Ultracol (UltraV, Republic of Korea), a polydioxanone (PDO) filler; Sculptra, a product or procedure known as a filler that contains poly-L-lactic acid (PLLA), a synthetic biodegradable polymer, as an active ingredient and acts as a collagen stimulant, which is one of the injectable fillers used in beauty and cosmetic procedures to help alleviate wrinkles by promoting collagen production as the PLLA component breaks down, restoring skin elasticity; and other commercialized products or procedures such as Olidia and Ellanse, which are being introduced in Korea as well as the United States.

[0014]

[0015] Each of the commercialized product groups or procedures described above can be understood as injecting these polymer compounds into the subcutaneous tissue for the purpose of improving facial wrinkles or supplementing soft tissue defects. Each of the above examples may have advantages and disadvantages.

[0016] For example, PDO fillers have a treatment effect that lasts for about 6 to 8 weeks after the procedure, and after 6 months, they are completely broken down in the subcutaneous tissue, making it difficult to expect further effects, so they require repeated procedures periodically.

[0017] However, compared to other PLA and PCL polymers, it has the advantage of rarely causing chronic inflammation and nodule formation.

[0018] In contrast, fillers made of PLA and PCL polymers, unlike the PDO fillers mentioned above, decompose very slowly, so they have the advantage of long-lasting therapeutic effects. However, because it takes a long time for collagen production to be completed after injection into the subcutaneous tissue, there is a problem that they sometimes cause chronic inflammation due to excessive foreign body reaction, and in some cases, they cause nodule formation due to excessive collagen formation in a specific area.

[0019] It is generally known that PLA takes about two years to decompose, and PCL takes slightly longer.

[0020] Meanwhile, as mentioned above, polydioxanone (PDO) is known as a biodegradable polymer with excellent physical properties and biocompatibility, and is widely used as a material for absorbable sutures and surgical clips.

[0021] As mentioned above, fillers made of PLA and PCL polymers and PDO fillers all have their own advantages, but they also have disadvantages.

[0022] Korean Patent Publication No. 10-2022-0072094, ‘Core-shell microparticles and their manufacturing method’ is disclosed.

[0023] According to the above-mentioned prior art patent publication, a core-shell microparticle comprising a core comprising a cross-linked biocompatible polymer and a shell comprising polyurethane and lipid is presented (claim 1).

[0024] And the biocompatible polymer is specifically selected from the group consisting of hyaluronic acid, collagen and gelatin, and a core-shell microparticle having a constant spherical shape with a highly monodisperse average diameter and a method for producing the same are disclosed.

[0025] The above prior art patent publication discloses a method for obtaining a three-way fluid channel device by connecting 30G, 24G, and 18G needles with PVC tubes and glass capillaries, and finishing the joints with epoxy to prevent leakage or reflux, and for each fluid channel, in the case of the first fluid, 0.25 wt% hyaluronic acid, 10 wt% collagen, and 8 wt% gelatin are contained in 5 mL of distilled water, and 0.05 wt% 4-(4,6-dimethoxy-1,3,5-triazin-2-yl) 4-methoxymorpholinium chloride (DMTMM) is added as a crosslinker for crosslinking thereof, and in the case of the second fluid, 24 mg of dipalmitoylphosphatidylcholine (DPPC), 12 mg of cholesterol, and polycaprolactone are added to 6 mL of chloroform (CF). 120 mg of triol (Mn=900), 240 mg of toluene diisocyanate (TDI), and 0.05 mL of dibutyltin dilaurate as a polyurethane bonding catalyst were added, and for the third fluid, a liquid containing 2 wt% polyvinyl alcohol (PVA) in distilled water was formed, and a complex process of generating microparticles was performed by providing a constant flow rate for each fluid.

[0026] However, as already explained, the biocompatible hyaluronic acid polymer has the disadvantage of being rapidly decomposed in the body, which is a problem mentioned above.

[0027] That is, a core having biocompatible properties, which is composed of one or more selected from the group consisting of cross-linked hyaluronic acid, collagen and gelatin, is obtained by a microparticle composed of a shell made of polyurethane and lipid surrounding the outside thereof.

[0028] Such prior art may cause the following problems:

[0029] First, the polymer core cross-linked with the shell containing polyurethane and lipids can cause an immune response or inflammation when interacting with subcutaneous tissue, and especially when synthetic materials that are not naturally found in the body are used, there is a high possibility of causing a foreign body reaction or inflammation, and there is a problem of causing adverse effects in biocompatibility such as causing an allergic reaction.

[0030] Second, shells made of a mixture of polyurethane and lipids may have irregular or unpredictable biodegradability, and the byproducts produced during the decomposition of synthetic materials such as polyurethane that make up the shell may be toxic and harmful to the human body.

[0031] Third, the shell, which is a mixture of polyurethane and lipid, may decompose relatively more slowly than the core, which has biocompatible properties and is composed of one or more selected from the group consisting of hyaluronic acid, collagen, and gelatin.

[0032] In such cases, there is a problem that if the core melts before the shell forming the outer skin, the structure collapses and the shell forming the outer skin is absorbed in both directions, resulting in the overall promotion of decomposition and absorption in the body.

[0033] Accordingly, the present invention has been devised to solve the above-mentioned problems, etc., and its purpose is to maximize the therapeutic effect when administered to human subcutaneous tissue by complementing the shortcomings and maximizing the advantages of single polymer component microspheres.

[0034] In addition, the present invention aims to obtain microspheres made of PDO, PLLA, PLA, and PCL, which have excellent biocompatibility, thereby minimizing side effects of stability and biocompatibility.

[0035] In addition, the present invention aims to achieve satisfactory cosmetic results after a procedure, to innovatively reduce the number of procedures, and to control the time for decomposition and absorption in the body and tissue reaction, thereby providing convenience in treatment and procedure and obtaining long-term stable cosmetic effects.

[0036] The present invention to achieve the above purpose,

[0037] A core comprising a first biocompatible polymer compound having a relatively rapid biodegradation rate;

[0038] An outer shell made of a second biocompatible polymer compound having a relatively slower biodegradation rate than the core, which surrounds the core;

[0039] Multilayer microspheres having a shell-core-like structure composed of a heterogeneous biocompatible polymer compound are presented.

[0040] In addition, the present invention,

[0041] A method for manufacturing multilayer microspheres having a shell core-shaped structure made of a heterogeneous biocompatible polymer compound is presented, comprising a PLLA core manufacturing step, a PCL solution manufacturing step, a polymer-acetone dispersion manufacturing step, a dispersion coating step, a final microsphere acquisition step by shell formation, and a washing and drying step.

[0042] According to the present invention, the disadvantages of the existing single-component polymer microspheres in terms of the decomposition speed and duration of the therapeutic effect are overcome, and by controlling the decomposition speed through an appropriate combination of the core and the shell, side effects are minimized and the therapeutic effect is maximized. In addition, if it is possible to arrange a composition in the future in which a polymer component with a slow decomposition speed is placed in the core and a polymer component with a fast decomposition speed but relatively fewer side effects such as nodule formation is added, the inconvenience of multiple treatments can be avoided.

[0043] In addition, as mentioned above, it is possible to expect treatment effects similar to those of multiple treatments, which can greatly increase the value of the treatment and the convenience of the patient receiving the treatment.

[0044] Figure 1 is a process flow diagram corresponding to the first embodiment of the present invention.

[0045] Figure 2 is a process flow diagram corresponding to the second embodiment of the present invention.

[0046] Figure 3 is a process flow diagram showing the process for obtaining each core in the PLLA Core manufacturing step in the first embodiment of the present invention and the PDO Core manufacturing step in the second embodiment.

[0047] The present invention is described in two embodiments in the form of the invention.

[0048] One is a biocompatible composite polymer microsphere having a heterogeneous dual structure in which polydioxanone forms a core and polylactic acid L isomer (PLLA) forms an outer shell, and the other is a biocompatible composite polymer microsphere having a dual structure in which polylactic acid L isomer (PLLA) forms a core and polycaprolactam (PCL) forms an outer shell, and a method for manufacturing the microspheres are presented as the best form.

[0049] Any specific structural or functional descriptions of embodiments according to the concept of the present invention disclosed herein are merely illustrative for the purpose of describing embodiments according to the concept of the present invention.

[0050] Embodiments according to the concept of the present invention can have various changes and can have various forms, and therefore include all changes, equivalents, or substitutes included in the spirit and technical scope of the present invention, and terms or words used in the specification and claims are not to be interpreted as limited to their usual or dictionary meanings, and should be interpreted as meanings and concepts that are consistent with the technical idea of ​​the present invention, based on the fact that the inventor can appropriately define the concept of the term in order to explain his or her own invention in the best way.

[0051] Therefore, the embodiments described in the specification of the present invention and the configurations illustrated in the drawings are only the most preferred embodiments of the present invention and do not represent all of the technical ideas of the present invention. It should be understood that various equivalents and modified examples that can replace them are possible or may exist at the time of filing of the present invention.

[0052] Additionally, unless otherwise defined in the specification of the present invention, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention belongs.

[0053] Terms defined in commonly used dictionaries should be interpreted to have a meaning consistent with their meaning in the context of the relevant technology, and will not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0054]

[0055] Hereinafter, a preferred embodiment of the present invention will be described with reference to the attached drawings.

[0056]

[0057] The present invention provides a microsphere comprising a core made of a first biocompatible polymer compound and an outer shell made of a second biocompatible polymer compound that surrounds the outer side of the core, and a manufacturing method for manufacturing the microsphere.

[0058]

[0059] According to the present invention, microspheres composed of heterogeneous polymers are provided by combining two biocompatible polymer compounds, and the microspheres are manufactured with a dual structure of an outer shell and a core (sheath-core structure) to obtain composite polymer microspheres having a dual structure.

[0060] In order to obtain the above-mentioned dual-structured composite polymer microspheres, one method can be considered, which comprises PPLA as a core and PLC as an outer shell, and the other method can be considered, which comprises PDO as a core and PLLA as an outer shell.

[0061]

[0062] Each of the above microparticle manufacturing methods is described sequentially.

[0063]

[0064] - Example 1 -

[0065]

[0066] The first embodiment of this embodiment, as described above, describes an example in which PPLA is configured as a core and PLC is configured as an outer shell.

[0067] For this implementation, acetone is used as a solvent.

[0068] The process for manufacturing microspheres having a dual structure using a heterogeneous biocompatible polymer compound of this example is described step by step in a time series manner.

[0069]

[0070] PLLA Core Manufacturing Step; S100

[0071] In an embodiment of the present invention, PPLA is configured as a core.

[0072] In order to obtain such PPLA microparticle core factors, the process may be comprised of a raw material preparation process (S101), a solvent selection process (S102), an emulsification process (S103), a stabilization process (S104), a solvent removal process (S105), a washing and drying process (S106), and a classification process (S107).

[0073] The above raw material preparation process (S101) can be said to be a process for preparing PPLA (poly-L-lactic acid), a biodegradable polymer compound.

[0074] The above solvent selection process (S102) is a process of selecting a solvent capable of dissolving PPLA, and organic solvents such as chloroform and dichloromethane can generally be used.

[0075] The above emulsification process (S103) involves a strong stirring process to emulsify the PPLA solution in water, and the PPLA solution forms fine particles as it mixes with water.

[0076] The above stabilization process (S104) is to add a stabilizer to prevent the particles emulsified through the above emulsification process (S103) from sticking to each other, and this is to help maintain the size and shape of the microspheres constant.

[0077] As a stabilizer used in this stabilization process (S104), any one of polyvinyl alcohol (PVA), which is highly soluble in water and has effective emulsifying properties, polyvinylpyrrolidone (PVP), which is one of the water-soluble polymers to help control the size and shape of PLLA particles, and natural emulsifiers such as gelatin or lecithin can be used.

[0078] The above solvent removal process (S105) is a process for removing the solvent from the microparticle particles that have undergone the stabilization process (S104) after the stirring process of the above emulsification process (S103) is completed. Through this process, the microparticle-formed PPLA particles harden.

[0079] Meanwhile, the solvent can be removed through evaporation or filtration.

[0080] The above washing and drying process (S106) involves washing the microparticles with water or another solution after the solvent has been removed to remove any remaining solvent or stabilizer, and then drying them.

[0081] The above classification process (S107) is a process for selecting microparticles having a required particle size, and preferably, a process for classifying and selecting PLLA having a square structure within a size range of 40 to 120 μm is performed.

[0082]

[0083] PCL solution manufacturing step; S200

[0084] This step refers to the process of manufacturing a PCL solution by placing PCL polymer in a sealed container containing acetone having a concentration of 5 to 13% wt / v and subjecting it to pressurization, heating, and stirring.

[0085] At this time, the heating temperature is about 71 to 110 ℃, and the PCL solution can be obtained based on the temperature condition and the pressure range of 1.3 to 4.1 atm.

[0086]

[0087] Polymer-acetone dispersion preparation step; S300

[0088] In this step, the PCL solution obtained by the PCL solution preparation step (S200) is placed in a stirring vessel containing a surfactant aqueous solution, and then stirred using a stirring device or the like provided in the stirring vessel, thereby obtaining an oil-in-water polymer-acetone dispersion.

[0089] The concentration of the above surfactant aqueous solution is preferably in the range of 0.8 to 1.5% wt / v, and at least one of nonionic surfactants of the polyvinyl alcohol type, polyvinylpyrrolidone type, polyethylene oxide-polypropylene oxide-polyethylene oxide type, polyoxyethylene alkyl ether type, and polyoxyethylene alkyl phenyl ether type, anionic surfactants of the alkylbenzene sulfonic acid type, and alkyl sulfate ester salt type, cationic surfactants of the tetraalkyl ammonium salt type, and trialkyl benzylammonium salt type, and polysaccharide surfactants such as alginate and alkyl cellulose may be used.

[0090] In particular, in the embodiments of the present invention, polyvinyl alcohol was used as a surfactant of PCL.

[0091] Meanwhile, the thickness of the outer shell of the microspheres, which will be described later, can be changed within the range of 80 to 150 ㎛ depending on the concentration of the PCL polymer, the concentration of the surfactant aqueous solution, and the stirring speed of the stirring device.

[0092]

[0093] Dispersion coating step; S400

[0094] This refers to a process of forming an outer shell by coating the dispersion obtained through the polymer-acetone dispersion manufacturing step (S200) several times with a core surface made of PLLA having a square structure within a size range of 40 to 120 ㎛ through the PLLA Core manufacturing step (S100).

[0095] At this time, the dispersion is coated multiple times on the core surface made of PLLA, and the ratio of the coating thickness applied by the core and the dispersion is adjusted to 3:1, and the particle size is formed within the size range of 200 to 300 ㎛. This process is repeated.

[0096]

[0097] Final microsphere acquisition step by shell formation; S500

[0098] This step refers to the step of evaporating the dispersion coated on the core surface by the dispersion coating step (S400) to form a cortex corresponding to the outer skin, thereby obtaining the final microspheres.

[0099]

[0100] Washing and drying stage; S600

[0101] The microspheres obtained by the final microsphere acquisition step (S500) through the above-mentioned shell formation are washed in distilled water, and then placed in a drying device or the like to be completely dried, thereby obtaining the composite microspheres having a dual structure of the present invention.

[0102]

[0103] - Example 2 -

[0104]

[0105] In the second embodiment of this embodiment, an example in which PDO is configured as a core and PLLA is configured as an outer shell is described.

[0106] For this implementation, dichloromethane is used as a solvent.

[0107] By placing PLLA polymer in a sealed container containing the above dichloromethane solvent and going through a pressurizing, heating and stirring process in an atmosphere of about 30°C, PDO having a square structure of 40 to 120 ㎛ in size is coated several times on the already completed microspheres, thereby obtaining a dual structure composite polymer microsphere by manufacturing the microspheres with a dual structure of an outer shell and a core.

[0108] The manufacturing process of the second embodiment for obtaining the above-mentioned microspheres is described in detail according to a time-series process.

[0109]

[0110] PDO Core Manufacturing Stage; S100'

[0111] In an embodiment of the present invention, unlike what was described above, the PDO is configured as a core.

[0112] The process for obtaining such a PDO microparticle core factor can be comprised of a raw material preparation process (S101'), a solvent selection process (S102'), an emulsification process (S103'), a stabilization process (S104'), a solvent removal process (S105'), a washing and drying process (S106'), and a classification process (S107'), which are the same processes as the process for obtaining the PLLA Core according to the first embodiment.

[0113] The above raw material preparation process (S101') can be said to be a process for preparing PDO (polydioxanone), a biodegradable polymer compound.

[0114] The above solvent selection process (S102') is a process of selecting a solvent capable of dissolving PDO, and organic solvents such as chloroform, dichloromethane, and ethyl acetate can generally be used.

[0115] The above emulsification process (S103') involves a strong stirring process to emulsify the PDO solution in water, and the PDO solution forms fine particles as it mixes with water.

[0116] The above stabilization process (S104') is intended to add a stabilizer to prevent the particles emulsified through the above emulsification process (S103') from sticking to each other, and this is intended to help maintain the size and shape of the microspheres at a constant level.

[0117] The stabilizer adopted in the stabilization process (S104') may be any one of polyvinyl alcohol (PVA), which is soluble in water, has effective emulsifying properties, prevents particles from agglomerating with each other, and stably maintains the size and shape of microspheres; poloxamer, which is one of the nonionic surfactants for stably mixing water and oil while increasing the stability of microspheres; and Tween-Span nonionic mixed surfactant, which is a nonionic surfactant for stably manufacturing microspheres with various particle sizes and acting as an emulsifier.

[0118] The above solvent removal process (S105') is a process for removing the solvent from the microparticle particles that have undergone the stabilization process (S104') after the stirring process of the above emulsification process (S103') is completed. Through this process, the microparticle-formed PDO particles harden.

[0119] Meanwhile, the solvent can be removed through evaporation or filtration.

[0120] The above washing and drying process (S106') involves washing the microparticles with water or another solution after the solvent has been removed to remove any remaining solvent or stabilizer, and then drying them.

[0121] The above classification process (S107') is a process for selecting microparticles having a required particle size, and preferably, a process for classifying and selecting PDO having a square structure within a size range of 40 to 120 μm is performed.

[0122]

[0123] PLLA solution manufacturing step; S200'

[0124] In the PLLA solution manufacturing step, the PLLA polymer compound is placed in a sealed container containing dichloromethane having a concentration of 5 to 13% wt / v, and the PLLA solution is manufactured through pressurization, heating, and stirring processes.

[0125] At this time, the heating temperature is based on a temperature condition of approximately 28 to 42 ℃, and a PLLA solution can be obtained based on a pressure range of 1.3 to 4.1 atm.

[0126]

[0127] Polymer-dichloromethane dispersion preparation step; S300'

[0128] In this step, the PLLA solution obtained by the PLLA solution preparation step (S200') is placed in a stirring vessel containing a surfactant aqueous solution, and then stirred using a stirring device or the like provided in the stirring vessel, thereby obtaining an oil-in-water polymer-dichloromethane dispersion.

[0129] It is preferable that the concentration of the above surfactant aqueous solution be in the range of 0.6 to 1.2 % wt / v.

[0130] At this time, at least one or more of the following surfactants may be used: nonionic surfactants of the polyvinyl alcohol type, polyvinylpyrrolidone type, polyethylene oxide-polypropylene oxide-polyethylene oxide type, polyoxyethylene alkyl ether type, and polyoxyethylene alkyl phenyl ether type; anionic surfactants of the alkylbenzene sulfonic acid type and alkyl sulfate ester salt type; cationic surfactants of the tetraalkyl ammonium salt type and trialkyl benzylammonium salt type; and polysaccharide surfactants such as alginate and alkyl cellulose.

[0131] The type of surfactant is the same as that applied in the polymer-acetone dispersion preparation step (S300) described in the first embodiment, and in the second embodiment, a polyvinyl alcohol type surfactant was used in the polymer-dichloromethane dispersion preparation step (S300') as in the first embodiment.

[0132] Meanwhile, the thickness of the outer shell of the microspheres, which will be described later, can be changed within the range of 80 to 150 μm depending on the concentration of the PLLA polymer, the concentration of the surfactant aqueous solution, and the stirring speed of the stirring device.

[0133]

[0134] Dispersion coating step; S400'

[0135] This step refers to a step of forming an outer shell by coating the dispersion obtained by the polymer-dichloromethane dispersion preparation step (S300') several times with a core surface made of PDO having a square structure within a size range of 40 to 120 ㎛ by the PDO Core preparation step (S100').

[0136] At this time, the dispersion is coated multiple times on the core surface made of PDO, and the coating thickness ratio applied by the core and the dispersion is adjusted to reach 3:1, and the process is repeated so that the particle size is formed within the size range of 200 to 300 ㎛.

[0137]

[0138] Final microsphere acquisition step by shell formation; S500'

[0139] This step refers to the step of evaporating the dispersion coated on the core surface by the dispersion coating step (S400') to form a cortex corresponding to the outer skin, thereby obtaining the final microspheres.

[0140]

[0141] Washing and drying stage; S600'

[0142] The microspheres obtained by the final microsphere acquisition step (S500') through the above-mentioned shell formation are washed in distilled water, and then placed in a drying device or the like to be completely dried, thereby obtaining the composite microspheres having a dual structure of the present invention.

[0143]

[0144] In addition to the first and second embodiments described above, materials for forming biocompatible composite polymer microspheres having a dual structure with a sheath-core form may include, of course, Hydroxyapatite, Polyethylene glycol (PEG), Polylactide-co-glycolic acid (PLGA), Polyurethane, Polyethylene, Chitosam, etc. in addition to PDO, PCL, and PLLA.

[0145]

[0146] In this way, it is possible to obtain microspheres having a multi-composite sheath-core structure with a multi-layered layered structure, as well as microspheres having a dual structure obtained by each embodiment of the present invention.

[0147] It is important to understand that microspheres having such a dual or multi-composite structure refer to microspheres that are primarily manufactured, not the final microspheres that are injected into the patient.

[0148] Meanwhile, the size of microspheres having a multi-composite sheath-core structure with a layered structure can be changed within 80 to 200 μm depending on the concentration of the polymer corresponding to the sheath, the concentration of the surfactant aqueous solution, and the stirring speed of the stirring device.

[0149] That is, the size of the multi-composite sheath-core structure can be changed within 80 to 200 μm, which may be for the purpose of promoting collagen formation in subcutaneous tissue depending on the purpose of the microspheres, and for the purpose of filling the space for tissue repair when the facial bones are absorbed with age or the elasticity of the subcutaneous tissue decreases due to collagen loss.

[0150] Therefore, when performing a procedure using the microspheres ultimately obtained according to the treatment purpose, the treatment effect can be maximized and consumer satisfaction can be increased by varying the depth of the soft tissue injected according to the treatment area.

[0151] For example, when obtaining microspheres having such a multi-composite sheath-core structure, a sedimentation and washing process is required, and it is preferable that this process be performed more than once to separate the microspheres from the polymer-solvent dispersion and obtain only the microspheres.

[0152] After the sedimentation and washing of microspheres having a multi-composite sheath-core structure are completed, the microspheres are washed with distilled water and then dried in a drying device, thereby obtaining microspheres having excellent particle dispersion and surface lubricity.

[0153]

[0154] That is, the present invention describes a process for obtaining microspheres composed of a core and a sheath having a double structure, and further expands upon this process for obtaining microspheres having a multi-composite sheath-core composed of a core and multiple sheaths.

[0155] However, by combining the above-described examples and the described contents, it is necessary to understand that the materials of the polymer compounds constituting each core and shell are the same or similar to the manufacturing methods for application of biocompatible polymer compounds that are currently known or will be recognized in the future, as described above.

[0156] In such a case, it is obvious that it can be considered in a state that can be sufficiently predicted through the explanation of the present invention that appropriate changes should be made to the physical conditions such as temperature and pressure that cause changes in the solubility difference in solvent and the physical properties between the polymer compound corresponding to the central core and the polymer compound constituting the outer shell.

[0157] Therefore, when the microspheres of the present invention having a dual structure consisting of a core and an outer shell or a multilayer structure consisting of a core and a multilayered outer shell are used for subcutaneous tissue application, the outer shell biodegrades relatively faster than the core, inducing a human immune response and simultaneously forming collagen, and then the core biodegrades over time, inducing a secondary immune response.

[0158] On the other hand, it is of course possible to design the core so that its biodegradation rate is faster than that of the outer skin.

[0159] By inducing collagen formation through these primary and secondary immune processes, you can achieve effects similar to those of additional procedures and significantly reduce the number of procedures.

[0160] That is, the microspheres are formed into a double or multi-layer structure, and depending on the arrangement of the core and outer shell, various tissue reactions in the body can be induced and controlled.

[0161]

[0162] Although the present invention has been described with reference to limited embodiments and drawings, it is to be understood that the present invention is not limited to the above embodiments, and that various modifications and variations may be made from the above-described contents by a person having ordinary technical knowledge in the field to which the present invention pertains.

[0163] Therefore, the technical idea of ​​the present invention should be understood by the claims described below, but it is self-evident that all equivalent or equivalent modifications thereof fall within the scope of the technical idea of ​​the present invention.

[0164] The present invention is said to have industrial applicability by presenting a multilayer microsphere having a core-shell structure made of a heterogeneous biocompatible polymer compound capable of being repeatedly performed to obtain a skin wrinkle improvement effect that enables promotion of collagen formation in facial skin, and a method for producing the microsphere.

Claims

1. A core made of a first biocompatible polymer compound; An outer shell made of a second biocompatible polymer compound that surrounds the core; Multilayer microspheres having a core-shell structure composed of a heterogeneous biocompatible polymer compound including .

2. In paragraph 1, The first biocompatible polymer compound constituting the above core is made of PPLA, The second biocompatible polymer compound constituting the above outer shell is made of PLC; Multilayer microspheres having a core-shell structure composed of a heterogeneous biocompatible polymer compound including:

3. In paragraph 1, The first biocompatible polymer compound constituting the above core is made of PDO, The second biocompatible polymer compound constituting the above outer shell is made of PLLA; Multilayer microspheres having a core-shell structure composed of a heterogeneous biocompatible polymer compound including:

4. In any one of paragraphs 1 to 3, A multilayer microsphere having a core-shell structure made of a heterogeneous biocompatible polymer compound, wherein the shell comprises multiple layers.

5. In paragraph 1, The core and the outer shell have relatively different biodegradation rates; Multilayer microspheres having a core-shell structure composed of a heterogeneous biocompatible polymer compound including: 6.PLLA Core manufacturing step; PCL solution manufacturing step; Polymer-acetone dispersion preparation step; Dispersion coating step; The final step of obtaining microspheres by forming a shell; Washing and drying steps; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

7. PDO Core manufacturing stage; PLLA solution manufacturing step; Polymer-dichloromethane dispersion preparation step; Dispersion coating step; The final step of obtaining microspheres by forming a shell; Washing and drying steps; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

8. In paragraph 6, The above PLLA Core manufacturing steps are: Raw material preparation process for preparing PPLA (poly-L-lactic acid), a biodegradable polymer compound; A solvent selection process in which PPLA can be dissolved by selecting either chloroform or dichloromethane as an organic solvent; An emulsification process in which the PPLA solution is mixed in water through strong stirring to emulsify the PPLA solution in water and form fine particles; A stabilization process in which a stabilizer is added to prevent the particles emulsified through the above emulsification process from sticking to each other; A solvent removal process for removing the solvent from the microparticles that have undergone the stabilization process after the stirring process of the above emulsification process is completed; A washing and drying process in which the solvent is removed through the above solvent removal process, the microparticles are washed with water or another solution to remove the remaining solvent and stabilizer, and then dried; A classification process for classifying PLLA cores into particle sizes within the range of 40 to 120㎛ after the above washing and drying processes; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

9. In paragraph 8, The above stabilizer is, A method for manufacturing multilayer microspheres having a core-shell structure made of a heterogeneous biocompatible polymer compound comprising any one of polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and a natural emulsifier such as gelatin or lecithin.

10. In paragraph 6, The above PCL solution manufacturing step is: A PCL polymer is placed in a sealed container containing acetone having a concentration of 5 to 13% wt / v, pressurized in a pressure range of 1.3 to 4.1 atm, and a PCL solution is prepared by heating and stirring under temperature conditions based on 71 to 110°C; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

11. In paragraph 6, The above polymer-acetone dispersion manufacturing step is, A method for manufacturing multilayer microspheres having a core-shell structure made of a heterogeneous biocompatible polymer compound, comprising: obtaining a polymer-acetone dispersion in an oil-in-water form by stirring the PCL solution obtained by the above PCL solution manufacturing step in a stirring vessel containing a surfactant aqueous solution.

12. In paragraph 7, The above PDO Core manufacturing steps are: Raw material preparation process for preparing PDO (polydioxanone), a biodegradable polymer compound; A solvent selection process for selecting an organic solvent capable of dissolving the above PDO, such as chloroform, dichloromethane, or ethyl acetate; An emulsification process in which the PDO solution is stirred in water to emulsify the PDO solution, and the PDO solution is mixed with water to form fine particles; A stabilization process in which a stabilizer is added to prevent the particles emulsified through the above emulsification process from sticking to each other; A solvent removal process for removing the solvent from the microparticles that have undergone the stabilization process after the stirring process of the above emulsification process is completed; A washing and drying process in which the solvent is removed through the above solvent removal process, the microparticles are washed with water or another solution to remove the remaining solvent and stabilizer, and then dried; A classification process for classifying PLLA cores into particle sizes within the range of 40 to 120㎛ after the above washing and drying processes; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

13. In paragraph 12, The above stabilizer is, Consisting of one of polyvinyl alcohol (PVA), poloxamer, which is one of the nonionic surfactants, and Tween-Span nonionic mixed surfactant, which is a nonionic surfactant; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

14. In paragraph 7, The above PLLA solution manufacturing step is: A method of manufacturing a PPLA solution by placing a PLLA polymer compound into a sealed container containing dichloromethane having a concentration of 5 to 13% wt / v, pressurizing in a pressure range of 1.3 to 4.1 atm, and heating and stirring under temperature conditions based on 28 to 42°C; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

15. In paragraph 7, The above polymer-dichloromethane dispersion preparation step is, The PLLA solution obtained by the above PLLA solution manufacturing step is placed in a stirring vessel containing a surfactant aqueous solution, and then stirred in the stirring vessel to obtain a polymer-dichloromethane dispersion in an oil-in-water form; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

16. In either of paragraphs 11 or 15, The above surfactant is, At least one of nonionic surfactants of the polyvinyl alcohol type, polyvinylpyrrolidone type, polyethylene oxide-polypropylene oxide-polyethylene oxide type, polyoxyethylene alkyl ether type, and polyoxyethylene alkyl phenyl ether type, anionic surfactants of the alkylbenzene sulfonic acid type, and alkyl sulfate ester salt type, cationic surfactants of the tetraalkyl ammonium salt type, and trialkyl benzylammonium salt type, and polysaccharide surfactants composed of alginate and alkyl cellulose are used to form a surfactant aqueous solution. The concentration of the above-mentioned surfactant aqueous solution is in the range of 0.8 to 1.5 % wt / v; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound.

17. In either of paragraph 8 or paragraph 12, The above classification process is, Selecting square-structured microspheres having a particle size in the range of 40 to 120 μm; A method for manufacturing multilayer microspheres having a core-shell structure comprising a heterogeneous biocompatible polymer compound including .

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