Liquid composite composition

Abstract

The present invention relates to a liquid composite composition comprising biodegradable polymer particles and a water-soluble or water-swellable polymer. The liquid composite composition of the present invention has a particle size distribution (SV) value of 0.4 to 1.0 of biodegradable polymer particles and a complex viscosity (η*) of 5 Pa·s to 200 Pa·s measured under conditions of 25°C and a frequency of 0.1 Hz. According to the present invention, by satisfying a specific range of particle size distribution and complex viscosity, a tissue repair filler composition is provided that has excellent suspension stability even during long-term storage, can be used immediately without a separate rehydration process to significantly reduce the preparation time for the procedure, offers excellent convenience for the procedure with low injection force, and can simultaneously provide an immediate volume improvement effect and a long-term tissue regeneration effect.

Description

Technology Field

[0001] The present invention relates to a liquid composite composition and a method for manufacturing the same. More specifically, the present invention relates to a tissue repair filler composition comprising a biodegradable polymer particle and a water-soluble or water-swellable polymer, which has excellent suspension stability and ease of procedure, and a method for manufacturing the same. Background Technology

[0002] Recently, various dermal filler products have been developed and are being used for purposes such as improving skin wrinkles caused by aging, augmenting areas of reduced volume, and shaping facial contours. Dermal fillers are broadly classified into permanent fillers and biodegradable fillers; while permanent fillers provide long-term effects as they do not decompose in the body, their use is limited due to a high risk of side effects such as foreign body reactions, nodule formation, and migration.

[0003] In contrast, biodegradable fillers offer high safety as they decompose slowly within the body and utilize biodegradable polymers such as polylactide (PLA), polycaprolactone (PCL), and poly(lactide-co-glycolide) (PLGA) as their main components. In particular, poly-L-lactide (PLLA) is an FDA-approved biocompatible material known to provide a natural volume-enhancing effect by promoting collagen production as it decomposes within the body.

[0004] Most commercially available biodegradable polymer filler products are supplied in the form of freeze-dried particle powder. Before the procedure, the practitioner rehydrates the particles by adding sterile water, water for injection, or physiological saline solution, and then injects them using a syringe. However, these freeze-dried formulations have the following problems.

[0005] First, if the dispersibility of particles is poor during the rehydration process, the particles aggregate or clump together and do not spread homogeneously. This may result in uneven distribution at the treatment site, and particle aggregates can clog the injection needle, hindering the procedure.

[0006] Second, if the suspension stability of the rehydrated suspension is insufficient, particles settle due to gravity over time, causing phase separation. This results in the inconvenience of having to repeatedly shake the vial or syringe during the procedure and makes it difficult to perform a uniform procedure.

[0007] Third, the rehydration process is very cumbersome and time-consuming. For some products, stirring or mixing for tens of minutes to several hours is required to obtain a uniform suspension, and there are even products that must be prepared the day before the procedure. This increases preparation time, prolongs patient waiting times, and reduces procedure efficiency.

[0008] Fourth, freeze-dried formulations have limited immediate volume effects due to the scarcity or insufficiency of water-soluble components after the procedure. Since the water used for rehydration is rapidly absorbed by the body, the volume formed immediately after the procedure significantly decreases within 1 to 2 weeks. As the collagen-stimulating effect of biodegradable polymer particles appears only after 4 weeks, patients find it difficult to experience satisfactory volume improvement in the early stages of the procedure.

[0009] Due to these problems, there are limitations such as reduced convenience of the procedure, decreased patient satisfaction, and increased economic and time costs. Prior art literature

[0011] Korean Published Patent No. 20250150810 The problem to be solved

[0012] The objective of the present invention is to provide a liquid composite composition having excellent suspension stability and ease of use.

[0013] Another objective of the present invention is to provide a method for manufacturing the above-mentioned liquid composite composition.

[0014] Another objective of the present invention is to provide a tissue repair filler composition capable of simultaneously providing an immediate volume improvement effect and a long-term tissue regeneration effect. means of solving the problem

[0015] To solve the above problem, the present invention provides a liquid-type composite composition comprising: biodegradable polymer particles; and a water-soluble or water-swellable polymer, wherein the biodegradable polymer particles have a particle size distribution (SV) value according to Formula 1 below of 0.4 to 1.0, and the composite composition has a complex viscosity (η*) of 5 Pa·s to 200 Pa·s measured under conditions of 25°C and a frequency of 0.1 Hz:

[0016] [Equation 1]

[0017] Particle size distribution (SV) = [ D(90) - D(10) ] / D(50)

[0018] (Here, D(10), D(50), and D(90) are particle sizes corresponding to 10%, 50%, and 90% of the cumulative particle distribution, respectively)

[0019] In one embodiment of the present invention, the D (50) value of the biodegradable polymer particles may be 1 μm to 80 μm.

[0020] In one embodiment of the present invention, the total content of the biodegradable polymer particles and the water-soluble or water-swellable polymer with respect to the total weight of the composite composition may be 2% to 8% by weight.

[0021] In one embodiment of the present invention, the content of the water-soluble or water-swellable polymer may be 0.2% to 6% by weight with respect to the total weight of the composite composition.

[0022] In one embodiment of the present invention, the biodegradable polymer may be one or more selected from the group consisting of polylactide (PLA), polycaprolactone (PCL), poly(lactide-co-glycolide) (PLGA) and polyglycolide (PGA).

[0023] In one embodiment of the present invention, the water-soluble or water-swellable polymer may be one or more selected from the group consisting of hyaluronic acid, polynucleotide, and cross-linked hyaluronic acid.

[0024] In one embodiment of the present invention, the liquid composite composition may have suspension stability in which sedimentation or phase separation of biodegradable polymer particles does not occur when stored at room temperature for more than one month.

[0025] In one embodiment of the present invention, the yield stress (τy) of the liquid-type composite composition may be 1.4 Pa to 15.5 Pa.

[0026] The present invention also provides a method for preparing a liquid composite composition comprising: (a) dissolving a biodegradable polymer in a first solvent to prepare a biodegradable polymer solution; (b) dispersing the biodegradable polymer solution in a second solvent in which an emulsifier is dissolved to form biodegradable polymer particles; (c) sorting and drying the biodegradable polymer particles by size to obtain biodegradable polymer particles having a particle size distribution (SV) value of 0.4 to 1.0 according to Formula 1 below and a D (50) value of 1 μm to 80 μm; (d) dissolving a water-soluble or water-swellable polymer in a third solvent to prepare a polymer solution; and (e) mixing the obtained biodegradable polymer particles and the water-soluble or water-swellable polymer solution with a fourth solvent to prepare a composite composition solution having a complex viscosity (η*) of 5 Pa·s to 200 Pa·s measured under conditions of 25°C and a frequency of 0.1 Hz.

[0027] [Equation 1]

[0028] Particle size distribution (SV) = [D(90) - D(10)] / D(50)

[0029] (Here, D(10), D(50), and D(90) are particle sizes corresponding to 10%, 50%, and 90% of the cumulative particle distribution, respectively) Effects of the invention

[0030] The liquid composite composition according to the present invention has the following effects.

[0031] First, by controlling the particle size distribution of biodegradable polymer particles within a specific range, it possesses excellent suspension stability, preventing particle sedimentation or phase separation even during long-term storage.

[0032] Second, by controlling the complex viscosity of the composite composition to an optimal range, a balance between suspension stability and injection convenience is achieved, allowing the operator to perform the procedure precisely and comfortably with low injection force.

[0033] Third, it is provided in the form of a ready-to-use liquid product that can be used immediately without a separate rehydration process, significantly reducing preparation time for the procedure, which offers significantly superior convenience compared to existing freeze-dried formulations.

[0034] Fourth, the inclusion of water-soluble or water-swellable polymers provides an immediate volume improvement effect right after the procedure, and simultaneously provides a long-term tissue regeneration effect through collagen production by biodegradable polymer particles, thereby improving patient satisfaction with the procedure.

[0035] Fifth, by controlling the size of biodegradable polymer particles within an appropriate range, it provides an appropriate residence time in the body and an effective collagen-generating effect without clogging during injection via a needle.

[0036] Sixth, the manufacturing method of the present invention can precisely control the particle size distribution and the rheological properties of the composite composition, thereby enabling the mass production of reproducible and uniformly high-quality products.

[0037] Seventh, it possesses excellent biocompatibility and safety, and can be used safely without nodule formation or severe inflammatory reactions. Specific details for implementing the invention

[0039] The present invention will be described in detail below. However, the following description is intended only to aid in understanding the present invention and does not limit the scope of the present invention.

[0040] The present invention relates to a liquid composite composition comprising biodegradable polymer particles and a water-soluble or water-swellable polymer. The composite composition of the present invention is provided in the form of a liquid finished product that can be injected immediately without a separate rehydration process, maintains excellent suspension stability even during long-term storage, and features improved ease of use with low injection force during procedures.

[0041] The liquid composite composition of the present invention comprises biodegradable polymer particles and water-soluble or water-swellable polymers.

[0042] The biodegradable polymer particles used in the present invention are components that gradually decompose in the body to induce tissue regeneration, and may include one or more selected from the group consisting of polylactide (PLA), polycaprolactone (PCL), poly(lactide-co-glycolide) (PLGA), polyglycolide (PGA), etc. Specifically, poly-L-lactide (PLLA) may be used, and these polymers may be used alone or in a mixture of two or more types. PLA may include PLA, PLLA, PDLA, etc.

[0043] The above-mentioned biodegradable polymer particles may have a spherical or substantially spherical shape and may have a porous structure on the particle surface. The porous structure can enhance tissue regeneration effects by promoting cell penetration and collagen production after injection into the body.

[0044] One of the key features of the present invention is that the particle size distribution of the biodegradable polymer particles is controlled within a specific range. Specifically, the biodegradable polymer particles satisfy a particle size distribution (SV) value according to Formula 1 below in the range of 0.4 to 1.0, preferably 0.4 to 0.9, and more preferably 0.5 to 0.8:

[0045] [Equation 1] Particle Size Distribution (SV) = [ D(90) - D(10) ] / D(50)

[0046] Here, D(10), D(50), and D(90) represent particle sizes corresponding to 10%, 50%, and 90% of the cumulative particle distribution, respectively. The SV value is an indicator of particle size uniformity, and a lower SV value indicates a more uniform particle size distribution.

[0047] The reason for limiting the SV value to 0.4 to 1.0 in the present invention is as follows. If the SV value is less than 0.4, the particle size is excessively uniform, which lowers the yield of the manufacturing process and reduces economic efficiency. If the SV value exceeds 1.0, the variation in particle size increases, causing a difference in the sedimentation rate of particles within the liquid composition, which may lead to layer separation during long-term storage and a decrease in suspension stability.

[0048] The D (50) value of the above biodegradable polymer particles, i.e., the median particle size based on volume, may be in the range of 1 μm to 80 μm, 1 μm to 70 μm, 1 μm to 60 μm, 5 μm to 80 μm, 5 μm to 70 μm, 5 μm to 60 μm, 10 μm to 70 μm, 10 μm to 60 μm, etc. If the D (50) value is less than 1 μm, the particles are too small and may be rapidly removed by macrophages in the body, which may reduce the sustained effect; if it exceeds 80 μm, it may be difficult to inject through a needle or blockage may occur during injection, and there is a concern that a particle sensation may be felt at the treatment site or nodule formation may occur.

[0049] In particular, in one embodiment of the present invention, it is possible to control the composition so as not to substantially include microparticles with small particle sizes, such as 5 μm or less, 3 μm or less, or 1 μm or less. Since microparticles can induce an immune response after injection into the body or act as nuclei for aggregation to form unwanted aggregates, minimizing them can simultaneously improve safety and suspension stability.

[0050] The intrinsic viscosity (IV) of the above biodegradable polymer may be in the range of 0.16 dl / g to 2.4 dl / g, preferably 0.2 dl / g to 2.0 dl / g. Intrinsic viscosity is an indicator related to the molecular weight of the polymer; if the intrinsic viscosity is too low, the mechanical strength of the particles weakens and they decompose rapidly in the body, and if the intrinsic viscosity is too high, it may be difficult to form particles during the emulsification process.

[0051] The water-soluble or water-swellable polymer used in the present invention serves as a carrier that uniformly disperses biodegradable polymer particles within a liquid medium and maintains a suspension state. The water-soluble or water-swellable polymer may be one or more selected from the group consisting of hyaluronic acid (HA), cross-linked hyaluronic acid, polynucleotide (PN), polydeoxyribonucleotide (PDRN), cellulose derivatives, chitosan, dextran, etc. Preferably, hyaluronic acid, polynucleotide, or cross-linked hyaluronic acid may be used.

[0052] Polynucleotides can have a molecular weight of, for example, 1000 to 2000 kDa.

[0053] Hyaluronic acid and nucleotides are ingredients with excellent biocompatibility that have long been widely used as main ingredients in filler products. They offer high safety and provide excellent moisturizing effects and appropriate physical properties. In particular, cross-linked hyaluronic acid has a slower rate of degradation in the body compared to non-cross-linked hyaluronic acid, which improves the sustained effect. Additionally, it imparts excellent viscoelasticity, which is advantageous for ensuring the suspension stability of biodegradable polymer particles.

[0054] The above-mentioned crosslinked hyaluronic acid can be prepared using commonly used crosslinking agents, and crosslinking agents such as 1,4-butanediol diglycidyl ether (BDDE), divinylsulfone (DVS), and diepoxyoctane may be used. The degree of crosslinking can be adjusted according to the application, and generally, viscosity and yield stress tend to increase as the degree of crosslinking increases.

[0055] In the composite composition of the present invention, water-soluble or water-swellable polymers may be used alone or in a mixture of two or more types. For example, by using cross-linked hyaluronic acid and polynucleotides in combination, not only suspension stability but also skin regeneration effects can be simultaneously improved.

[0056] In the composite composition of the present invention, the content of biodegradable polymer particles and water-soluble or water-swellable polymers can be adjusted to achieve desired rheological properties and clinical effects.

[0057] The total content of biodegradable polymer particles and water-soluble or water-swellable polymers with respect to the total weight of the composite composition may be 2% to 8% by weight, preferably 2.5% to 7% by weight, and more preferably 3% to 6% by weight. If the total polymer content is less than 2% by weight, the complex viscosity becomes excessively low, making it easy for particles to settle and resulting in a lack of immediate volume effect after injection; if it exceeds 8% by weight, the complex viscosity becomes excessively high, making injection through a syringe difficult and reducing the convenience of the procedure.

[0058] The content of the above water-soluble or water-swellable polymer may be 0.2% to 6% by weight, preferably 0.5% to 5% by weight, and more preferably 1% to 4% by weight, based on the total weight of the composite composition. If the content of the water-soluble or water-swellable polymer is less than 0.2% by weight, the viscosity is insufficient to suspend the particles, so sedimentation may occur, and if it exceeds 6% by weight, the complex viscosity becomes excessively high, which may increase the injection force and reduce the convenience of the procedure.

[0059] The composite composition of the present invention is provided in the form of a liquid finished product and is designed to satisfy specific rheological properties. Specifically, the composite composition satisfies a complex viscosity (η*) measured at 25°C and a frequency of 0.1 Hz in the range of 5 Pa·s to 200 Pa·s, preferably 10 Pa·s to 180 Pa·s, and more preferably 15 Pa·s to 150 Pa·s.

[0060] Complex viscosity is a rheological parameter that reflects both the viscosity and elasticity of a material and is closely related to the ease of injection and suspension stability of composite compositions. If the complex viscosity is less than 5 Pa·s, the viscosity is too low, making it easy for biodegradable polymer particles to settle due to gravity and cause phase separation; if it exceeds 200 Pa·s, the viscosity is excessively high, requiring excessive force when injecting with a syringe, which can increase operator fatigue and make precise injection difficult.

[0061] In one embodiment of the present invention, the injection force of the composite composition may be 20 N or less, preferably 16 N or less, and more preferably 10 N or less when injected at a speed of 12 mm / min using a 25G needle. If the injection force exceeds 20 N, the physical burden felt by the operator increases and precise procedures may become difficult.

[0062] The composite composition of the present invention can satisfy a yield stress (τy) in the range of 1.4 Pa to 15.5 Pa, preferably 1.7 Pa to 14.1 Pa, and more preferably 2.1 Pa to 11.9 Pa.

[0063] Yield stress is the critical stress value at which a material resists deformation like a solid until it begins to flow, and it is an important factor in determining suspension stability. For biodegradable polymer particles to settle due to gravity, the gravity-derived stress acting on the particles must exceed the yield stress of the carrier polymer. Therefore, if the yield stress is sufficiently high, the particles can maintain a suspended state for an extended period.

[0064] The yield stress (τy) can be measured using a rheometer. Specifically, a PP25 plate is mounted on an Anton Paar rheometer (Anton Paar, MCR series), and measurements are taken in the flow curve, controlled shear stress mode under conditions of a gap size of 1.000 mm and a measurement temperature of 25°C. During measurement, the shear stress range is 1 Pa to 100 Pa, and the yield stress (τy) is calculated by fitting the flow curve data obtained from measurements at 1 s / point and a total of 200 points to the Herschel-Bulkley model (τ = τy + K·γⁿ).

[0065] If the yield stress is less than 1.4 Pa, there is insufficient force to support the particles, so sedimentation is likely to occur, and if it exceeds 15.5 Pa, the initial resistance increases when injecting through a syringe, making injection difficult.

[0066] The composite composition of the present invention can also control the rheological properties of the water-soluble or water-swellable polymer alone. Specifically, the water-soluble or water-swellable polymer can satisfy a complex viscosity (η*) of 5 Pa·s to 200 Pa·s and a yield stress (τy) of 1.4 Pa to 15.5 Pa under conditions of 25°C and a frequency of 0.1 Hz.

[0067] The composite composition of the present invention has excellent suspension stability in which no sedimentation or phase separation of biodegradable polymer particles occurs when stored at room temperature (about 20~25℃) for a period of 1 month or more, 3 months or more, 4 months or more, 5 months or more, 6 months or more, etc.

[0068] Suspension stability can be evaluated through visual observation or instrumental analysis. For example, if a composition contained in a transparent container is visually observed after storage for a certain period and there is no difference in color or turbidity between the upper and lower parts, it can be determined that the suspension stability is excellent. Alternatively, it can be quantitatively evaluated by measuring changes in transmitted light and backscattered light over time using instruments such as Turbiscan.

[0069] The composite composition of the present invention may further include additional components in addition to biodegradable polymer particles and water-soluble or water-swellable polymers.

[0070] For example, phosphate buffered saline (PBS), sodium bicarbonate, etc. may be included as pH adjusters, and the pH of the composite composition may be adjusted to a range of 5.0 to 8.0, preferably 6.0 to 7.5, considering biocompatibility.

[0071] Sodium chloride, potassium chloride, calcium chloride, etc., may be included as isotonic agents, and the osmotic pressure of the complex composition can be controlled to a level similar to body fluids.

[0072] Small amounts of benzyl alcohol, phenoxyethanol, parabens, etc., may be included as preservatives, but in the case of a composition for infusion into the body, it is preferable to provide it in a sterile state without including preservatives.

[0073] Ascorbic acid, tocopherol, etc., may be included as antioxidants.

[0074] Anesthetics may include lidocaine, procaine, bupivacaine, etc., and can alleviate pain during the procedure.

[0075] The present invention also provides a method for preparing the liquid composite composition. The method mainly consists of the steps of preparing biodegradable polymer particles, preparing a water-soluble or water-swellable polymer solution, and mixing these to prepare a composite composition.

[0076] First, biodegradable polymer particles can be prepared by various methods such as emulsion-solvent evaporation, emulsion-solvent extraction, spray drying, and phase separation, but preferably, emulsion-solvent evaporation or emulsion-solvent extraction may be used.

[0077] Specifically, a biodegradable polymer solution is prepared by dissolving a biodegradable polymer in a first solvent. The first solvent is an organic solvent capable of dissolving the biodegradable polymer, and may be dichloromethane (DCM), chloroform, ethyl acetate, acetone, tetrahydrofuran (THF), dimethylformamide (DMF), etc., and preferably dichloromethane or chloroform may be used.

[0078] The concentration of the biodegradable polymer may be 1% to 30% by weight, preferably 3% to 20% by weight, based on the total weight of the first solvent. If the polymer concentration is too low, the particle formation efficiency is reduced, and if it is too high, the viscosity of the solution becomes excessively high, making it difficult to achieve uniform emulsification.

[0079] Next, the biodegradable polymer solution is dispersed in a second solvent in which an emulsifier is dissolved to form biodegradable polymer particles. The second solvent is a solvent that is not miscible or is only partially miscible with the first solvent, and typically, an aqueous solvent is used. For example, distilled water, deionized water, water for injection, etc., may be used.

[0080] The above emulsifier serves to stabilize droplets of a biodegradable polymer solution and promote particle formation, and may use polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), poloxamer, sorbitan ester, polysorbate, etc. Preferably, polyvinyl alcohol may be used, and the concentration of the emulsifier may be 0.1% to 5% by weight, preferably 0.5% to 3% by weight, based on the total weight of the second solvent.

[0081] The volume ratio of the biodegradable polymer solution to the second solvent may be 1:5 to 1:100, preferably 1:10 to 1:50.

[0082] Emulsification can be performed using homogenizers, ultrasonic processors, stirrers, etc., and particle size can be controlled by adjusting emulsification conditions (stirring speed, time, temperature, etc.). For example, particle size tends to decrease as the stirring speed increases.

[0083] After emulsification, the first solvent is evaporated or extracted to obtain solidified particles. In the case of the solvent evaporation method, the first solvent can be evaporated while stirring at room temperature or under heated conditions, and in the case of the solvent extraction method, the first solvent can be extracted by adding a large amount of water or another solvent.

[0084] After recovering the particles, the residual solvent and emulsifier are removed by washing using methods such as centrifugation and filtration. Washing can typically be performed three or more times with distilled water or a buffer solution.

[0085] Next, biodegradable polymer particles are sorted by size. Particle sorting can be performed by methods such as sieving, centrifugation, filtration, and classification. Preferably, only particles within a specific size range can be sorted through multi-stage sieving. For example, large particles larger than 100 μm can be removed by passing through a 100 μm sieve, and then fine particles can be removed by passing through a 1 μm or 5 μm sieve, thereby obtaining particles in the range of 1 to 80 μm.

[0086] The selected particles are dried to remove moisture. Drying can be performed by methods such as freeze-drying, vacuum drying, hot air drying, or spray drying, and preferably, freeze-drying may be used. Freeze-drying is advantageous for maintaining the structure and porosity of the particles and can ensure long-term storage stability.

[0087] The particle size distribution of the dried particles is measured to obtain biodegradable polymer particles with an SV value of 0.4 to 1.0 and a D (50) value of 1 μm to 80 μm. The particle size distribution can be measured by laser diffraction, dynamic light scattering, microscopic observation, etc., and preferably, laser diffraction can be used.

[0088] Next, a polymer solution is prepared by dissolving a water-soluble or water-swellable polymer in a third solvent. The third solvent is a solvent capable of dissolving the water-soluble or water-swellable polymer, and typically, an aqueous solvent is used. For example, distilled water, deionized water, water for injection, physiological saline, phosphate-buffered saline, etc., may be used.

[0089] The concentration of the water-soluble or water-swellable polymer can be adjusted according to the viscosity and content of the desired final composite composition, and generally may be 0.5% to 10% by weight, preferably 1% to 8% by weight, based on the total weight of the third solvent.

[0090] The preparation of the polymer solution can be carried out by stirring or mixing at room temperature for a sufficient amount of time until the polymer is completely dissolved or swollen. For example, in the case of hyaluronic acid, hydration and swelling may take several hours to 24 hours.

[0091] Finally, the obtained biodegradable polymer particles and the water-soluble or water-swellable polymer solution are mixed with a fourth solvent to prepare a composite composition solution. The fourth solvent is an aqueous solvent, and distilled water, deionized water, water for injection, physiological saline, phosphate-buffered saline, etc., may be used.

[0092] Mixing can be performed using a stirrer, mixer, ultrasonic processor, etc., and is mixed sufficiently until the biodegradable polymer particles are uniformly dispersed in a water-soluble or water-swellable polymer solution. The mixing time can typically be 10 minutes to 2 hours.

[0093] The amount of biodegradable polymer particles and water-soluble or water-swellable polymer added is adjusted so that the total content of biodegradable polymer particles and water-soluble or water-swellable polymer in the final composite composition is 2% to 8% by weight, and the content of water-soluble or water-swellable polymer is adjusted so that it is 0.2% to 6% by weight.

[0094] The amount of the fourth solvent added is adjusted so that the complex viscosity of the final composite composition is 5 Pa·s to 200 Pa·s under conditions of 25°C and a frequency of 0.1 Hz. The complex viscosity can be measured using a rheometer, and the desired viscosity range can be achieved by adjusting the amount of the fourth solvent as needed.

[0095] After mixing is complete, additional ingredients such as pH adjusters, isotonic agents, antioxidants, and anesthetics may be added as needed.

[0096] Finally, the composite composition is sterilized. Sterilization can be performed by methods such as autoclave sterilization, radiation sterilization, or filtration sterilization, and an appropriate method is selected considering the thermal stability of the biodegradable polymer and the water-soluble or water-swellable polymer. Preferably, autoclave sterilization or gamma ray sterilization may be used.

[0097] The sterile composite composition is filled into containers such as syringes, vials, and pre-filled syringes and sealed.

[0098] The liquid composite composition of the present invention can be used as a tissue repair filler. Specifically, it can be used for purposes such as improving skin wrinkles, increasing volume, forming contours, and filling tissue defects. For example, it can be used to improve nasolabial folds, forehead wrinkles, temple depressions, reduced cheek volume, and jawline contours.

[0099] Since the composite composition of the present invention is provided in the form of a liquid finished product, it can be used immediately without a separate rehydration process, thereby reducing preparation time for the procedure and improving convenience. In addition, the particle size distribution of the biodegradable polymer particles and the rheological properties of the composite composition are optimized, resulting in excellent suspension stability even during long-term storage and enabling precise procedures with low injection force.

[0100] Furthermore, the inclusion of water-soluble or water-swellable polymers provides immediate volume improvement starting right after the procedure, while biodegradable polymer particles gradually decompose within the body to induce collagen production, offering long-term tissue regeneration effects. Consequently, patient satisfaction with the procedure can be enhanced.

[0102] Examples

[0103] Preparation Example 1: Preparation of biodegradable polymer particles

[0104] 10 g of poly-L-lactide (PLLA, intrinsic viscosity 0.55 dl / g) was dissolved in 100 mL of dichloromethane (DCM) to prepare a 10 wt% PLLA solution. Separately, 2 g of polyvinyl alcohol (PVA, degree of polymerization 500, degree of saponification 88%) was dissolved in 1000 mL of distilled water to prepare a 0.2 wt% aqueous PVA solution.

[0105] The above PLLA solution was added to an aqueous PVA solution and emulsified using a homogenizer at 5,000 rpm for 5 minutes. PLLA particles were formed by evaporating the DCM for 4 hours while stirring the emulsion at 300 rpm at room temperature.

[0106] The formed PLLA particles were recovered by centrifugation (3,000 rpm, 10 min) and washed three times with distilled water. The washed particles were sorted by size through sieving. First, large particles larger than 100 μm were removed by passing them through a 100 μm sieve, and then particles that did not pass through a 5 μm sieve were recovered to obtain particles in the range of 5 to 100 μm.

[0107] The selected particles were freeze-dried to remove moisture, and finally, dried PLLA particles were obtained.

[0108] The particle size distribution of the obtained PLLA particles was measured by laser diffraction (Mastersizer 3000, Malvern), and D(10) = 22 μm, D(50) = 40 μm, D(90) = 62 μm, and the SV value according to Equation 1 was 1.00.

[0109] Preparation Example 2: Preparation of biodegradable polymer particles under various conditions

[0110] PLLA particles were prepared using the same method as in Preparation Example 1, but with varying particle size distributions by adjusting emulsification conditions (stirring speed, time), PVA concentration, and sieving conditions. The results of measuring the particle size distribution of each particle and the production yield are shown in Table 1.

[0111] Particle size distribution and manufacturing yield of PLLA particles manufactured under various conditions

[0112] particle D(10) (μm) D(50) (μm) D(90) (μm) SV value Manufacturing yield (%) note Particle-1 22 40 62 1.00 68 SV upper limit Particle-2 18 35 50 0.91 72 SV median Particle-3 25 50 75 1.00 65 D(50) near the upper limit Particle-4 10 25 38 1.12 70 Exceeding SV (for comparison) Particle-5 8 20 32 1.20 68 Exceeding SV (for comparison) Particle-6 15 30 43 0.93 70 SV median Particle-7 12 45 63 1.13 66 Exceeding SV (for comparison) Particle-8 0.5 0.8 1.5 1.25 65 D(50) Less than lower limit (for comparison) Particle-9 50 87 125 0.86 70 D(50) Exceeding the upper limit (for comparison) Particle-10 3 8 13 1.25 63 Exceeding SV (for comparison) Particle-11 40 75 110 0.93 67 D(50) near the upper limit Particle-12 28 42 59 0.74 55 SV median, yield reduction Particle-13 32 45 58 0.58 42 Near the lower limit of SV (for comparison) Particle-14 35 48 60 0.52 38 Near the lower limit of SV (for comparison) Particle-15 38 50 61 0.46 32 Near the lower limit of SV (for comparison) Particle-16 40 52 62 0.42 25 Near the lower limit of SV (for comparison) Particle-17 42 54 64 0.41 22 Near the lower limit of SV (for comparison) Particle-18 44 55 65 0.38 18 Less than SV lower limit (for comparison)

[0113] Explanation of manufacturing yield:

[0114] As the particle size distribution became more uniform (lower the SV value), the proportion of particles corresponding to the desired particle size range decreased, resulting in a lower manufacturing yield. When the SV value was in the range of 0.5 to 1.0, economic production was possible with a yield of 55 to 72%, but as the SV value decreased near 0.4, the yield dropped sharply, falling to 18% at 0.38. This is because, in order to obtain excessively uniform particles, only particles within a very narrow range must be selected, causing most of the particles to be discarded.

[0115] Preparation Example 3: Preparation of Cross-linked Hyaluronic Acid Solution

[0116] 20 g of hyaluronic acid (molecular weight 1,000,000 Da) was added to 100 mL of solvent and stirred for 24 hours to completely hydrate the hyaluronic acid. 0.5 g of 1,4-butanediol diglycidyl ether (BDDE) was added to the hydrated hyaluronic acid solution, the pH was adjusted to 11, and the reaction was carried out at 50°C for 4 hours to proceed with the crosslinking reaction.

[0117] After the reaction was complete, the pH was neutralized to 7.0, and unreacted crosslinking agent and low molecular weight impurities were removed by dialysis. Finally, a crosslinked hyaluronic acid solution of 2 wt% was obtained.

[0118] The rheological properties of the obtained cross-linked hyaluronic acid solution were measured using a rotational rheometer (MCR102e, Anton Paar). Complex viscosity (η*) was measured at 25°C and a frequency of 0.1 Hz under conditions of a PP25 plate, gap size of 1.000 mm. Yield stress (τy) was measured using the same instrument with a PP25 plate mounted, under conditions of a gap size of 1.000 mm and 25°C, in shear stress control mode (Flow curve, Controlled Shear Stress, shear stress range 1→100 Pa, 1 s / point, total 200 points), and the yield stress was calculated by fitting the obtained flow curve data to the Herschel-Bulkley model (τ = τy + K·γⁿ). Measurement results, complex viscosity (η*) = 95 Pa·s, storage factor (G') = 210 Pa, loss factor (G") = 48 Pa, tan δ = 0.23, yield stress (τy) = 7.9 It was Pa.

[0119] Preparation Example 4: Preparation of cross-linked hyaluronic acid solutions of various viscosities

[0120] Cross-linked hyaluronic acid solutions were prepared using the same method as in Preparation Example 3, but cross-linked hyaluronic acid solutions with various rheological properties were prepared by adjusting the concentration of hyaluronic acid, the amount of cross-linking agent, and the cross-linking reaction conditions. The results of measuring the rheological properties of each solution are shown in Table 2.

[0121] Rheological properties of cross-linked hyaluronic acid solutions prepared under various conditions

[0122] solution Concentration (wt%) η (Pa·s) * G' (Pa) G" (Pa) tan δ τy (Pa) note HA-1 2.0 95 210 48 0.23 7.9 Intermediate viscosity HA-2 1.5 58 135 38 0.28 5.2 low viscosity HA-3 2.5 145 325 68 0.21 11.5 High viscosity HA-4 3.0 185 415 88 0.21 14.4 Very high viscosity HA-5 1.0 32 72 26 0.36 3.3 Very low viscosity HA-6 3.2 230 515 108 0.21 17.7 Excessive viscosity (for comparison) HA-7 0.5 12 28 15 0.54 1.9 The shortcomings are also (for comparison) HA-8 2.8 165 370 78 0.21 13.0 High viscosity

[0123] Example 1: Preparation of a liquid composite composition (SV upper limit, medium viscosity)

[0124] 3.0 g of PLLA particles (particle-1) prepared in Preparation Example 2 and 150 g of cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 were placed in a mixing container. 47 g of water for injection was added to this, and the mixture was stirred using a stirrer at 500 rpm for 30 minutes to ensure that the PLLA particles were uniformly dispersed within the cross-linked hyaluronic acid solution.

[0125] The pH of the mixed composition was measured and adjusted to 7.0, and each component was sterilized separately and then mixed under aseptic conditions. Finally, 200 g of the sterilized liquid composite composition was obtained.

[0126] Composition of the final composition:

[0127] PLLA particles: 1.5 wt%

[0128] Cross-linked hyaluronic acid: 1.5 wt%

[0129] Total polymer content: 3.0 wt%

[0130] Rheological properties of the obtained liquid-type composite composition: complex viscosity (η*) = 52 Pa·s, yield stress (τy) = 4.8 Pa, D(50) = 40 μm, SV = 1.00

[0131] Example 2: Preparation of a liquid composite composition (medium SV value, low viscosity)

[0132] A liquid composite composition was prepared by mixing 3.0 g of PLLA particles (particle-2) prepared in Preparation Example 2 and 133 g of cross-linked hyaluronic acid solution (HA-2) prepared in Preparation Example 4 in the same manner as in Example 1.

[0133] Composition of the final composition:

[0134] PLLA particles: 1.5 wt%

[0135] Cross-linked hyaluronic acid: 1.0 wt%

[0136] Total polymer content: 2.5 wt%

[0137] Rheological properties: Complex viscosity (η*) = 35 Pa·s, Yield stress (τy) = 3.5 Pa, D(50) = 35 μm, SV = 0.91

[0138] Example 3: Preparation of a liquid composite composition (near the upper limit of D(50), high viscosity)

[0139] A liquid composite composition was prepared by mixing 4.0 g of PLLA particles (particle-3) prepared in Preparation Example 2 and 145 g of cross-linked hyaluronic acid solution (HA-3) prepared in Preparation Example 4 in the same manner as in Example 1.

[0140] Composition of the final composition:

[0141] PLLA particles: 2.0 wt%

[0142] Cross-linked hyaluronic acid: 1.8 wt%

[0143] Total polymer content: 3.8 wt%

[0144] Rheological properties: Complex viscosity (η*) = 98 Pa·s, Yield stress (τy) = 8.1 Pa, D(50) = 50 μm, SV = 1.00

[0145] Example 4: Preparation of a liquid composite composition (medium SV value, medium viscosity)

[0146] A liquid composite composition was prepared by mixing 4.0 g of PLLA particles (particle-6) prepared in Preparation Example 2 and 150 g of cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0147] Composition of the final composition:

[0148] PLLA particles: 2.0 wt%

[0149] Cross-linked hyaluronic acid: 1.5 wt%

[0150] Total polymer content: 3.5 wt%

[0151] Rheological properties: Complex viscosity (η*) = 68 Pa·s, Yield stress (τy) = 5.9

[0152] Pa, D(50) = 30 μm, SV = 0.93

[0153] Example 5: Preparation of a liquid composite composition (low total polymer content)

[0154] A liquid composite composition was prepared by mixing 2.5 g of PLLA particles (particle-2) prepared in Preparation Example 2 and 67 g of cross-linked hyaluronic acid solution (HA-2) prepared in Preparation Example 4 in the same manner as in Example 1.

[0155] Composition of the final composition:

[0156] PLLA particles: 1.25 wt%

[0157] Cross-linked hyaluronic acid: 0.5 wt%

[0158] Total polymer content: 2.0 wt% (near lower limit)

[0159] Rheological properties: Complex viscosity (η*) = 28 Pa·s, Yield stress (τy) = 3.0 Pa, D(50) = 35 μm, SV = 0.91

[0160] Example 6: Preparation of a liquid composite composition (high total polymer content)

[0161] A liquid composite composition was prepared by mixing 5.5 g of PLLA particles (particle-1) prepared in Preparation Example 2 and 148 g of cross-linked hyaluronic acid solution (HA-4) prepared in Preparation Example 4 in the same manner as in Example 1.

[0162] Composition of the final composition:

[0163] PLLA particles: 2.75 wt%

[0164] Cross-linked hyaluronic acid: 1.48 wt%

[0165] Total polymer content: 4.23 wt%

[0166] Rheological properties: Complex viscosity (η*) = 155 Pa·s, Yield stress (τy) = 12.3 Pa, D(50) = 40 μm, SV = 1.00

[0167] Example 7: Preparation of a liquid composite composition (near the upper limit of D(50), high polymer content)

[0168] A liquid composite composition was prepared by mixing 7.5 g of PLLA particles (particle-11) prepared in Preparation Example 2 and 193 g of cross-linked hyaluronic acid solution (HA-3) prepared in Preparation Example 4 in the same manner as in Example 1.

[0169] Composition of the final composition:

[0170] PLLA particles: 3.75 wt%

[0171] Cross-linked hyaluronic acid: 2.41 wt%

[0172] Total polymer content: 6.16 wt%

[0173] Rheological properties: Complex viscosity (η*) = 178 Pa·s, Yield stress (τy) = 13.9 Pa, D(50) = 75 μm, SV = 0.93

[0174] Example 8: Preparation of a liquid-type composite composition (near the upper limit of complex viscosity)

[0175] A liquid composite composition was prepared by mixing 6.0 g of PLLA particles (particle-1) prepared in Preparation Example 2 and 165 g of cross-linked hyaluronic acid solution (HA-8) prepared in Preparation Example 4 in the same manner as in Example 1.

[0176] Composition of the final composition:

[0177] PLLA particles: 3.0 wt%

[0178] Cross-linked hyaluronic acid: 2.31 wt%

[0179] Total polymer content: 5.31 wt%

[0180] Rheological properties: Complex viscosity (η*) = 192 Pa·s, Yield stress (τy) = 15.0 Pa, D(50) = 40 μm, SV = 1.00

[0181] Example 9: Preparation of a liquid composite composition (application of polynucleotide)

[0182] 197 g of a 1.5 wt% PN solution, prepared by dissolving 3.0 g of PLLA particles (particle-1) prepared in Preparation Example 2 and 3.0 g of polynucleotide (PN, molecular weight 1,000~2,000 kDa) in water for injection, was placed in a mixing container. The mixture was stirred at 500 rpm for 30 minutes using a stirrer to ensure that the PLLA particles were uniformly dispersed within the PN solution.

[0183] The pH of the mixed composition was adjusted to 7.0, and each component was sterilized separately and then mixed under aseptic conditions. Finally, 200 g of the sterilized liquid composite composition was obtained.

[0184] Composition of the final composition:

[0185] Rheological properties: Complex viscosity (η*) = 45 Pa·s, Yield stress (τy) = 4.3 Pa, D(50) = 40 μm, SV = 1.00

[0187] Example 10: Preparation of a liquid composite composition (application of PCL particles)

[0188] 10 g of polycaprolactone (PCL, intrinsic viscosity 0.62 dl / g) was dissolved in 100 mL of dichloromethane (DCM) to prepare PCL particles in the same manner as in Preparation Example 1. By adjusting the emulsification and sieving conditions, PCL particles with a particle size distribution of D (50) = 43 μm and SV = 0.95 were obtained.

[0189] A liquid composite composition was prepared by mixing 3.0 g of the above PCL particles and 150 g of the cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0190] Composition of the final composition:

[0191] Rheological properties: Complex viscosity (η*) = 53 Pa·s, Yield stress (τy) = 4.9 Pa, D(50) = 43 μm, SV = 0.95

[0193] Example 11: Preparation of a liquid composite composition (application of PDLLA particles)

[0194] 10 g of poly-DL-lactide (PDLLA, intrinsic viscosity 0.58 dl / g) was dissolved in 100 mL of dichloromethane (DCM) to prepare PDLLA particles in the same manner as in Preparation Example 1. By adjusting the emulsification and sieving conditions, PDLLA particles with a particle size distribution of D (50) = 44 μm and SV = 0.91 were obtained.

[0195] A liquid composite composition was prepared by mixing 3.0 g of the above PDLLA particles and 150 g of the cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0196] Composition of the final composition:

[0197] Rheological properties: Complex viscosity (η*) = 53 Pa·s, Yield stress (τy) = 4.9 Pa, D(50) = 44 μm, SV = 0.91

[0199] Example 12: Preparation of a liquid composite composition (application of PLGA particles)

[0200] 10 g of poly(lactide-co-glycolide) (PLGA, lactide:glycolide = 75:25, intrinsic viscosity 0.68 dl / g) was dissolved in 100 mL of dichloromethane (DCM) to prepare PLGA particles in the same manner as in Preparation Example 1. PLGA particles having a particle size distribution of D (50) = 48 μm and SV = 0.93 were obtained by adjusting the emulsification and sieving conditions.

[0201] A liquid composite composition was prepared by mixing 3.0 g of the above PLGA particles and 150 g of the cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0202] Composition of the final composition:

[0203] Rheological properties: Complex viscosity (η*) = 52 Pa·s, yield stress (τy) = 4.8 Pa, D(50) = 48 μm, SV = 0.93

[0205] Comparative example

[0206] Comparative Example 1: Liquid composite composition with an SV value exceeding the range (SV = 1.12)

[0207] A liquid composite composition was prepared by mixing 3.0 g of particle-4 (SV = 1.12) prepared in Preparation Example 2 and 150 g of cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0208] Composition of the final composition:

[0209] PLLA particles: 1.5 wt%

[0210] Cross-linked hyaluronic acid: 1.5 wt%

[0211] Total polymer content: 3.0 wt%

[0212] Rheological properties: Complex viscosity (η*) = 51 Pa·s, Yield stress (τy) = 4.7 Pa, D(50) = 25 μm, SV = 1.12

[0213] Comparative Example 2: Liquid composite composition with an SV value exceeding the range (SV = 1.20)

[0214] A liquid composite composition was prepared by mixing 3.0 g of particle-5 (SV = 1.20) prepared in Preparation Example 2 and 150 g of cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0215] Composition of the final composition:

[0216] PLLA particles: 1.5 wt%

[0217] Cross-linked hyaluronic acid: 1.5 wt%

[0218] Total polymer content: 3.0 wt%

[0219] Rheological properties: Complex viscosity (η*) = 49 Pa·s, Yield stress (τy) = 4.6 Pa, D(50) = 20 μm, SV = 1.20

[0220] Comparative Example 3: Liquid composite composition in which the D (50) value exceeds the range

[0221] A liquid composite composition was prepared by mixing 3.0 g of particle-9 (D(50) = 87 μm) prepared in Preparation Example 2 and 150 g of cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0222] Composition of the final composition:

[0223] PLLA particles: 1.5 wt%

[0224] Cross-linked hyaluronic acid: 1.5 wt%

[0225] Total polymer content: 3.0 wt%

[0226] Rheological properties: Complex viscosity (η*) = 54 Pa·s, Yield stress (τy) = 4.9 Pa, D(50) = 87 μm, SV = 0.86

[0227] Comparative Example 4: Liquid composite composition (microparticle) with a D (50) value below the range

[0228] A liquid composite composition was prepared by mixing 3.0 g of particle-8 (D(50) = 0.8 μm) prepared in Preparation Example 2 and 150 g of cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0229] Composition of the final composition:

[0230] PLLA particles: 1.5 wt%

[0231] Cross-linked hyaluronic acid: 1.5 wt%

[0232] Total polymer content: 3.0 wt%

[0233] Rheological properties: Complex viscosity (η*) = 56 Pa·s, Yield stress (τy) = 5.1 Pa, D(50) = 0.8 μm, SV = 1.25

[0234] Comparative Example 5: Liquid-type composite composition with complex viscosity exceeding the range (η = 225 Pa·s)*

[0235] A liquid composite composition was prepared by mixing 5.2 g of PLLA particles (particle-1) prepared in Preparation Example 2 and 158 g of cross-linked hyaluronic acid solution (HA-6) prepared in Preparation Example 4 in the same manner as in Example 1.

[0236] Composition of the final composition:

[0237] PLLA particles: 2.6 wt%

[0238] Cross-linked hyaluronic acid: 1.69 wt%

[0239] Total polymer content: 4.29 wt%

[0240] Rheological properties: Complex viscosity (η*) = 225 Pa·s, Yield stress (τy) = 17.4 Pa, D(50) = 40 μm, SV = 1.00

[0241] Comparative Example 6: Liquid composite composition with complex viscosity below the range

[0242] A liquid composite composition was prepared by mixing 2.0 g of PLLA particles (particle-2) prepared in Preparation Example 2 and 50 g of cross-linked hyaluronic acid solution (HA-7) prepared in Preparation Example 4 with 148 g of water for injection.

[0243] Composition of the final composition:

[0244] PLLA particles: 1.0 wt%

[0245] Cross-linked hyaluronic acid: 0.125 wt%

[0246] Total polymer content: 1.125 wt%

[0247] Rheological properties: Complex viscosity (η*) = 3.5 Pa·s, Yield stress (τy) = 1.3 Pa, D(50) = 35 μm, SV = 0.91

[0248] Comparative Example 7: Liquid composite composition with total polymer content exceeding the range

[0249] A liquid composite composition was prepared by mixing 11.0 g of PLLA particles (particle-1) prepared in Preparation Example 2 and 185 g of cross-linked hyaluronic acid solution (HA-4) prepared in Preparation Example 4 in the same manner as in Example 1.

[0250] Composition of the final composition:

[0251] PLLA particles: 5.5 wt%

[0252] Cross-linked hyaluronic acid: 2.78 wt%

[0253] Total polymer content: 8.28 wt% (exceeds upper limit)

[0254] Rheological properties: Complex viscosity (η*) = 272 Pa·s, Yield stress (τy) = 20.8 Pa, D(50) = 40 μm, SV = 1.00

[0255] Comparative Example 8: Liquid composite composition with an SV value below the range (SV = 0.38, reduced manufacturing yield)

[0256] A liquid composite composition was prepared by mixing 3.0 g of particle-18 (SV = 0.38) prepared in Preparation Example 2 and 150 g of cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0257] Composition of the final composition:

[0258] PLLA particles: 1.5 wt%

[0259] Cross-linked hyaluronic acid: 1.5 wt%

[0260] Total polymer content: 3.0 wt%

[0261] Rheological properties: Complex viscosity (η*) = 53 Pa·s, Yield stress (τy) = 4.9 Pa, D(50) = 55 μm, SV = 0.38

[0262] note : The manufacturing yield of particle-18 was 18%, which is about one-quarter of the level of particle-1 (SV = 1.00, yield 68%) manufactured under the same conditions. This is because most of the particles are discarded and economic efficiency is significantly reduced as only a very narrow range of particles must be selected to obtain excessively uniform particles.

[0263] Comparative Example 9: Freeze-dried formulation (rehydration required)

[0264] To prepare 30 mg of PLLA particles (particle-1) prepared in Preparation Example 2 in a freeze-dried form, 10 mg of HA was added as a support and freeze-dried in a vial. Before the procedure, 1 mL of water for injection was added to rehydrate the sample, and manual mixing for at least 60 minutes was required to obtain a uniform suspension.

[0265] Composition after rehydration:

[0266] PLLA particles: 3.0 wt%

[0267] Water-soluble carrier HA: 1.0 wt% Rheological properties: Complex viscosity (η*) = 3.1 Pa·s (close to the viscosity of water), yield stress (τy) approx. 1.2 Pa

[0268] Comparative Example 10: Liquid composite composition with an SV value exceeding the range (SV = 1.25, near the lower limit of D(50))

[0269] A liquid composite composition was prepared by mixing 3.0 g of PLLA particles (particle-10) prepared in Preparation Example 2 and 150 g of cross-linked hyaluronic acid solution (HA-1) prepared in Preparation Example 3 in the same manner as in Example 1.

[0270] Composition of the final composition:

[0271] PLLA particles: 1.5 wt%

[0272] Cross-linked hyaluronic acid: 1.5 wt%

[0273] Total polymer content: 3.0 wt%

[0274] Rheological properties: Complex viscosity (η*) = 50 Pa·s, Yield stress (τy) = 4.6 Pa, D(50) = 8 μm, SV = 1.25

[0275] note: Comparative Example 10 has an SV value of 1.25, which is outside the claimed range (0.4–1.0), but because D (50) is small (8 μm), the gravitational settling force is small, so there was no problem with suspension stability. This demonstrates that suspension stability is determined by complex factors such as the SV value, particle size, and yield stress. However, in a typical particle size range (e.g., D (50) = 30–50 μm), suspension stability decreases when the SV value falls outside the claimed range, so setting the SV range is important.

[0276] Comparative Example 11: Liquid composite composition with an SV value exceeding the range (PN applied, SV = 1.12)

[0277] A liquid composite composition was prepared by mixing 3.0 g of particle-4 (SV = 1.12, D(50) = 25 μm) prepared in Preparation Example 2 and 197 g of a 1.5 wt% PN solution prepared by dissolving 3.0 g of polynucleotide (PN) in water for injection in the same manner as in Example 9.

[0278] Composition of the final composition:

[0279] Rheological properties: Complex viscosity (η*) = 43 Pa·s, Yield stress (τy) = 4.1 Pa, D(50) = 25 μm, SV = 1.12

[0281] Experimental Example

[0282] Experimental Example 1: Evaluation of Suspension Stability

[0283] 2 mL of each liquid composite composition of Examples 1-8 and Comparative Examples 1-8 and 10 was filled into a clear glass vial, and suspension stability was evaluated while stored at 25°C. After 1 month, 3 months, and 6 months, visual observation was performed to evaluate whether sedimentation or phase separation occurred.

[0284] metewand:

[0285] ○: No sedimentation or phase separation observed (uniform suspension maintained)

[0286] △: Slight sedimentation or phase separation observed (redispersible upon shaking)

[0287] ×: Clear sedimentation or phase separation observed (difficult to redisperse even with shaking)

[0288] Suspension stability evaluation results

[0289] Sample 1 month 3 months 6 months SV value D(50) (μm) η (Pa·s) * τy (Pa) Overall evaluation Example 1 ○ ○ ○ 1.00 40 52 4.8 excellence Example 2 ○ ○ ○ 0.91 35 35 3.5 excellence Example 3 ○ ○ ○ 1.00 50 98 8.1 excellence Example 4 ○ ○ ○ 0.93 30 68 5.9 excellence Example 5 ○ ○ △ 0.91 35 28 3.0 Good Example 6 ○ ○ ○ 1.00 40 155 12.3 excellence Example 7 ○ ○ ○ 0.93 75 178 13.9 excellence Example 8 ○ ○ ○ 1.00 40 192 15.0 excellence Example 9 ○ ○ ○ 1.00 40 45 4.3 excellence Example 10 ○ ○ ○ 0.95 43 53 4.9 excellence Example 11 ○ ○ ○ 0.91 44 53 4.9 excellence Example 12 ○ ○ ○ 0.93 48 52 4.8 excellence Comparative Example 1 ○ △ × 1.12 25 51 4.7 error Comparative Example 2 ○ △ × 1.20 20 49 4.6 error Comparative Example 3 ○ △ × 0.86 87 54 4.9 error Comparative Example 4 ○ ○ △ 1.25 0.8 56 5.1 commonly Comparative Example 5 ○ ○ ○ 1.00 40 225 17.4 - Comparative Example 6 △ × × 0.91 35 3.5 1.3 error Comparative Example 7 ○ ○ ○ 1.00 40 272 20.8 - Comparative Example 8 ○ ○ ○ 0.38 55 53 4.9 - Comparative Example 10 ○ ○ ○ 1.25 8 50 4.6 excellence Comparative Example 11 ○ △ × 1.12 25 43 4.1 error

[0290] Result Analysis:

[0291] Examples 1-4 and 6-8, which had SV values ​​in the range of 0.4 to 1.0 and complex viscosity in the range of 5 to 200 Pa·s, maintained excellent suspension stability for 6 months. Example 5 had relatively low complex viscosity and yield stress, so slight sedimentation was observed after 6 months, but it was easily redispersed when shaken, so it was not a practical problem.

[0292] Comparative Example 10 has an SV value of 1.25, which is outside the claimed range, but because D (50) is small (8 μm), the gravitational settling force is small, so there was no problem with suspension stability. This demonstrates that suspension stability is determined by complex factors such as the SV value, particle size, and yield stress. However, in the general particle size range, suspension stability decreases when the SV value falls outside the claimed range, so setting the SV range is important.

[0293] Comparative Example 1-2, in which the SV value exceeded 1.0, had a non-uniform particle size distribution, so slight sedimentation was observed starting after 3 months, and after 6 months, clear layer separation occurred, making redispersion difficult even when shaken. In particular, sedimentation proceeded more rapidly as the SV value increased (1.12 → 1.20).

[0294] Comparative Example 3, in which the D(50) value exceeded 80 μm, sedimentation was observed after 3 months due to the rapid gravitational sedimentation of large particles, and clear layer separation occurred after 6 months.

[0295] Comparative Example 4, in which the D(50) value was less than 1 μm, showed slight sedimentation after 6 months as the fine particles acted as aggregation nuclei.

[0296] Comparative Examples 5 and 7, which had a complex viscosity exceeding 200 Pa·s, had excellent suspension stability due to high yield stress, but had problems in terms of injection force as described below.

[0297] Comparative Example 6, which had a complex viscosity of less than 5 Pa·s, had a very low yield stress, so slight sedimentation was observed after 1 month, and clear layer separation occurred after 3 months.

[0298] Comparative Example 8 had a very low SV value of 0.38, so although the suspension stability itself was excellent, the manufacturing yield was only 18%, so the economic feasibility was significantly low.

[0299] In the case of Comparative Example 10, although the SV value is outside the claimed range (1.25), suspension stability was maintained by chance because D (50) is very small (8 μm). However, this is due to the low gravitational settling force caused by the small particle size, and in the general particle size range (e.g., 30 to 50 μm), suspension stability decreases when the SV value is outside the claimed range. Therefore, it was confirmed that the numerical limitation of the present invention is not merely a design matter but an essential requirement for achieving critical effects that are difficult to predict.

[0300] Experimental Example 2: Evaluation of Injection Power

[0301] The liquid composite compositions of Examples 1-8 and Comparative Examples 1-8 and 10 were filled into a 1 mL syringe, a 25G needle (inner diameter 0.260 mm) was attached, and the injection force was measured using a force test stand (Mecmesin). The maximum force (N) required when injecting at a speed of 12 mm / min was measured (n=5, average value).

[0302] metewand:

[0303] Excellent: 8 N or less

[0304] Good: 8-12 N

[0305] Usually: 12-16 N

[0306] Defective: Exceeds 16 N

[0307] Injection power evaluation results (25G needle)

[0308] Sample Injection power (N) η (Pa·s) * Total polymer (wt%) evaluation Example 1 7.8 52 3.0 excellence Example 2 5.5 35 2.5 excellence Example 3 12.8 98 3.8 commonly Example 4 9.5 68 3.5 Good Example 5 4.8 28 2.0 excellence Example 6 14.2 155 4.23 commonly Example 7 15.5 178 6.16 commonly Example 8 15.8 192 5.31 commonly Comparative Example 1 7.5 51 3.0 excellence Comparative Example 2 7.2 49 3.0 excellence Comparative Example 3 7.9 54 3.0 excellence Comparative Example 4 8.2 56 3.0 Good Comparative Example 5 18.5 225 4.29 error Comparative Example 6 1.8 3.5 1.125 - Comparative Example 7 22.5 272 8.28 error Comparative Example 8 7.8 53 3.0 excellence Comparative Example 10 7.3 50 3.0 excellence

[0309] Result Analysis:

[0310] Examples 1-8, with complex viscosity in the range of 5 to 200 Pa·s, had an injection force of 16 N or less when using a 25G needle, so the ease of procedure was above average. In particular, Examples 1, 2, 4, and 5, with complex viscosity of 100 Pa·s or less, showed very excellent ease of use with an injection force of 10 N or less.

[0311] Comparative Examples 1-4 and 10, which had similar complex viscosity, had good injection power itself, but Comparative Example 1-3 had problems in terms of suspension stability.

[0312] Comparative Example 5 (225 Pa·s), with a complex viscosity exceeding 200 Pa·s, had an injection force of 18.5 N, which exceeded 16 N, resulting in a heavy physical burden on the operator and making precise procedures difficult. Comparative Example 7 (272 Pa·s) had an even higher injection force of 22.5 N, which significantly reduced practicality.

[0313] Comparative Example 8 showed that although the SV value was below the range, the injection power itself was excellent, confirming that the setting of the lower limit of the SV value was mainly a limitation in terms of manufacturing economics.

[0314] Experimental Example 3: Evaluation of Injection Needle Penetration

[0315] The liquid composite compositions of Examples 1, 3, and 7 and Comparative Examples 3 and 4 were filled into a 1 mL syringe, and a 25G needle was attached to evaluate whether needle blockage occurred during injection. The number of needle blockages or increases in resistance were recorded while completely injecting 1 mL (n=5, average value).

[0316] Injection needle penetration evaluation results (25G needle)

[0317] Sample D(50) (μm) Number of needle blockages (times / mL) Injection uniformity evaluation Example 1 40 0 Very uniform excellence Example 3 50 0 Very uniform excellence Example 7 75 0 Very uniform excellence Comparative Example 3 87 5-7 Non-uniform error Comparative Example 4 0.8 0 uniform -

[0318] Result Analysis:

[0319] Examples 1, 3, and 7, in which the D(50) value is in the range of 1 to 80 μm, did not experience any blockage when injected through a 25G needle. Example 7 had a D(50) = 75 μm, which is close to the upper limit, but had no problem passing through a 25G needle (inner diameter 0.260 mm = 260 μm).

[0320] Comparative Example 3, in which the D(50) value exceeded 80 μm, experienced frequent clogging or increased resistance (average 5-7 times / mL) when large particles passed through the needle, resulting in discontinuous injection and significantly degrading the quality of the procedure. The operator had to replace the needle or tap the syringe several times during the injection to clear the clogging.

[0321] Comparative Example 4, in which the D(50) value was less than 1 μm, had no problem with needle penetration itself because the particles were small, but as described below, there was a problem in terms of safety.

[0322] Experimental Example 4: Clinical Evaluation of Procedure Convenience

[0323] Procedure preparation time and operator satisfaction were compared using the liquid composite composition of Example 1 and the lyophilized formulation of Comparative Example 9. Ten experienced operators performed simulated procedures using artificial dummies with each formulation and evaluated the procedure preparation time and ease of use on a 5-point scale (5 points: Very good, 4 points: Good, 3 points: Average, 2 points: Poor, 1 point: Very poor).

[0324] Comparative evaluation results of procedure convenience

[0325] Sample Procedure preparation time (minutes) Convenience of the preparation process Injection convenience Overall satisfaction Overall evaluation Example 1 (Liquid phase) 1-2 4.9 ± 0.3 4.7 ± 0.5 4.8 ± 0.4 Very excellent Comparative Example 9 (freeze-dried) 60-65 2.1 ± 0.7 2.4 ± 0.8 2.3 ± 0.6 error

[0326] Result Analysis:

[0327] The liquid composite composition of Example 1 could be used immediately without a separate rehydration process, so the preparation time for the procedure was only 1-2 minutes, and practitioners showed very high satisfaction with both the preparation process (4.9 points) and the ease of injection (4.7 points) (overall average 4.8 / 5.0).

[0328] The lyophilized formulation of Comparative Example 9 took an average of 60-65 minutes for rehydration, and operators pointed out the following inconveniences:

[0329] Particles aggregate during rehydration, making uniform dispersion difficult.

[0330] If not mixed sufficiently, needle clogging may occur during injection.

[0331] Even after rehydration, particle sedimentation proceeds rapidly, requiring repeated mixing during the procedure.

[0332] Long preparation times lead to increased patient waiting times and reduced procedure efficiency.

[0333] As a result, low satisfaction was observed in both the preparation process (2.1 points) and the ease of injection (2.4 points) (overall average 2.3 / 5.0).

[0334] Experimental Example 5: Evaluation of Initial Volume Effect

[0335] A rehydrated suspension of the liquid composite composition of Examples 1 and 4 and the freeze-dried formulation of Comparative Example 9 was injected subcutaneously by 0.2 mL each into Hairless mice (20-25 g, male) (n=5), and the volume was measured with a caliper immediately after injection and after 1 week, 4 weeks, 12 weeks, and 24 weeks to calculate the ratio of the remaining volume to the initial volume (%).

[0336] Remaining volume ratio over time

[0337] Sample Immediately after injection (%) 1 week later (%) After 4 weeks (%) After 12 weeks (%) After 24 weeks (%) Example 1 100 ± 0 93 ± 5 73 ± 4 69 ± 5 66 ± 3 Example 4 100 ± 0 91 ± 4 76 ± 5 71 ± 5 69 ± 4 Comparative Example 9 100 ± 0 47 ± 3 32 ± 2 29 ± 3 29 ± 4

[0338] Result Analysis:

[0339] The liquid composite compositions of Examples 1 and 4 contained cross-linked hyaluronic acid and exhibited excellent volume effects immediately after injection, and showed a high volume retention rate of approximately 90% even after one week. This means that patients can experience satisfactory volume improvement effects immediately after the procedure.

[0340] Afterwards, as hyaluronic acid gradually decomposed, the volume decreased slightly to 73-76% after 4 weeks, but as collagen production by PLLA particles proceeded in earnest, a stable volume of 66-71% was maintained even after 12 and 24 weeks.

[0341] The lyophilized formulation of Comparative Example 9 lacked a water-soluble carrier, so physical volume was formed immediately after injection, but after one week, the volume decreased rapidly to 47% as the water used for rehydration was rapidly absorbed. This means that patients may experience a significant decrease in volume immediately after the procedure, which may lead to lower satisfaction.

[0342] Subsequently, due to collagen production by PLLA particles, volume gradually recovers starting from 4 weeks later, reaching 29% after 12 weeks, which is significantly different from the examples. Therefore, it is expected that the overall effect, including initial volume, will be insufficient in actual clinical practice, making it disadvantageous in terms of patient satisfaction.

[0343] Experimental Example 6: Safety Evaluation

[0344] 0.2 mL of the microparticle-containing compositions of Examples 1 and 4 and Comparative Example 4 were injected subcutaneously into Hairless mice (20-25 g, male), and the injection sites were excised after 4 and 12 weeks for histological analysis. Inflammatory response, nodule formation, foreign body reaction, etc. were evaluated through hematoxylin-eosin (H&E) staining and immunohistochemical staining.

[0345] Inflammation response score criteria (0-4 points):

[0346] 0 points: No inflammatory cells

[0347] 1 point: Very few inflammatory cells (mild)

[0348] 2 points: A small number of inflammatory cells (moderate)

[0349] 3 points: Moderate inflammatory cells (severe)

[0350] 4 points: Multiple inflammatory cells (very severe)

[0351] Histological safety assessment results

[0352] Sample Acute inflammation (4 weeks) Chronic inflammation (12 weeks) Nodule formation granuloma Fibrosis (12 weeks) New Collagen (12 weeks) Overall evaluation Example 1 1.1 ± 0.4 0.3 ± 0.5 doesn't exist doesn't exist Kyungmi prominence safety Example 4 1.0 ± 0.5 0.2 ± 0.4 doesn't exist doesn't exist Kyungmi prominence safety Comparative Example 4 2.6 ± 0.7 1.9 ± 0.6 Observed Kyungmi moderate moderate Caution required Normal control group 0 0 doesn't exist doesn't exist doesn't exist normal -

[0353] Result Analysis:

[0354] In the liquid composite compositions of Examples 1 and 4, a mild acute inflammatory response (score 1.0-1.1) was observed 4 weeks after injection, but this was determined to be a normal foreign body reaction to the biodegradable polymer particles. After 12 weeks, the inflammatory response had almost disappeared (score 0.2-0.3), and new collagen was significantly generated around the particles, confirming the tissue regeneration effect.

[0355] No nodule or granuloma formation was observed, and only mild fibrosis was observed, so overall safety was evaluated as excellent.

[0356] On the other hand, Comparative Example 4, which contained microparticles with a D (50) of less than 1 μm (0.8 μm), showed moderate acute inflammation (score 2.6) after 4 weeks and chronic inflammation (score 1.9) after 12 weeks. In addition, micronodules and mild granulomas were observed in some samples (3 out of 8), and moderate fibrosis was observed.

[0357] It is believed that submicron particles are preferentially phagocytosed by macrophages and significantly contribute to the formation of nodules / fibrosis by amplifying the immune response due to their high surface area per unit mass and tendency to aggregate in the body. Therefore, it was confirmed that minimizing microparticles smaller than 1 μm is important for safety.

[0358] Experimental Example 7: Quantitative Evaluation of Suspension Stability According to SV Value

[0359] 5 mL of each of the liquid composite compositions of Example 1 (SV = 1.00), Example 4 (SV = 0.93), Comparative Example 1 (SV = 1.12), and Comparative Example 2 (SV = 1.20) were filled into clear glass vials, and the suspension stability was quantitatively evaluated using Turbiscan (Formulaction SA, France) while stored at 25°C.

[0360] Turbiscan is an instrument that quantitatively analyzes particle sedimentation, aggregation, and phase separation by measuring changes in the transmitted and backscattering of a sample. A lower Turbiscan Stability Index (TSI) indicates superior stability.

[0361] Quantitative evaluation of suspension stability using Turbiscan

[0362] Sample SV value TSI (1 month) TSI (3 months) TSI (6 months) evaluation Example 1 1.00 2.0 3.7 5.1 excellence Example 4 0.93 1.7 3.1 4.3 excellence Comparative Example 1 1.12 3.8 9.2 16.5 error Comparative Example 2 1.20 4.5 11.3 20.8 error

[0363] Result Analysis:

[0364] Examples 1 and 4, with an SV value of 1.0 or less, maintained a very stable suspension state with a TSI of 5.2 or less even after 6 months. In particular, it was confirmed that the lower the SV value (the more uniform the particle size), the lower the TSI, indicating excellent suspension stability.

[0365] On the other hand, Comparative Examples 1 and 2, in which the SV value exceeded 1.0, showed a rapid increase in TSI over time, reaching a high value of 16 or higher after 6 months. In particular, the higher the SV value (1.12 → 1.20), the faster the rate of increase in TSI (16.5 → 20.8). This quantitatively demonstrates that the difference in sedimentation velocity between small and large particles occurred due to the non-uniform particle size distribution, and that this led to the progression of layer separation.

[0366] This result is consistent with the visual evaluation result of Experimental Example 1 and quantitatively proves that limiting the SV value to 0.4 to 1.0 is essential for ensuring long-term suspension stability.

[0367] Experimental Example 8: Correlation between SV Value and Manufacturing Yield

[0368] The manufacturing yield of PLLA particles (particle-12 to particle-18) having various SV values ​​prepared in Preparation Example 2 was analyzed, and the correlation between the SV value and the manufacturing yield was evaluated. All particles were prepared under the same emulsification conditions, and various SV values ​​were achieved by varying only the sieving conditions.

[0369] Changes in manufacturing yield according to SV value

[0370] particle SV value Manufacturing yield (%) D(50) (μm) note Particle-2 0.91 72 35 For the example Particle-12 0.74 55 42 Yield reduction begins Particle-13 0.58 42 45 Medium yield reduction Particle-14 0.52 38 48 Medium yield reduction Particle-15 0.46 32 50 Significant decrease in yield Particle-16 0.42 25 52 Near the lower limit Particle-17 0.41 22 54 Near the lower limit Particle-18 0.38 18 55 Below the lower limit

[0371] Result Analysis:

[0372] When the SV value was 0.91, the manufacturing yield was good at 72%, but as the SV value decreased, the yield showed a tendency to decrease rapidly. When the SV value was 0.74, the yield decreased by about 24% to 55%, and when the SV value was 0.58, it decreased by about 42% to 42%.

[0373] When the SV value dropped to near 0.4, the yield decreased sharply to below 25%, and when the SV value was 0.38, it was only 18%, resulting in very low economic feasibility. This is because most particles are discarded as only particles within a very narrow range must be selected to achieve a uniform particle size distribution.

[0374] For example, when manufacturing particle-2 with SV = 0.91, particles in the range of 18–50 μm were recovered, achieving a yield of 72%, but when manufacturing particle-18 with SV = 0.38, only particles in a very narrow range of 44–65 μm had to be selected, so the yield dropped sharply to 18%.

[0375] Therefore, it was confirmed that setting the lower limit of the SV value to 0.4 is an essential condition for securing not only suspension stability but also manufacturing economics. When the SV value is less than 0.4, suspension stability may be excellent, but the manufacturing yield drops below 25%, making commercial production difficult.

[0377] Overall Conclusion:

[0378] Through the above examples and experimental examples, it was confirmed that the liquid composite composition of the present invention achieves excellent effects by satisfying the following specific conditions:

[0379] SV = 0.4~1.0 : Ensures long-term suspension stability and enables economical manufacturing through uniform particle size distribution

[0380] D(50) = 1~80 μm : Achieves a balance of 25G needle penetration, retention in the body, and collagen production

[0381] η* = 5~200 Pa·s *: Achieved a balance between suspension stability and injectability (injection force ≤16 N when using a 25G needle)

[0382] τy = 1.4~15.5 Pa Achieving balance between particle sedimentation prevention and injection force

[0383] Total polymer content = 2~8 wt% : Ensuring appropriate viscosity and clinical efficacy

[0384] Comparative examples that deviated from these conditions showed problems in terms of suspension stability, ease of injection, needle penetration, manufacturing cost-effectiveness, or safety.

[0385] In particular, in the case of Comparative Example 10, although the SV value is outside the claimed range (1.25), suspension stability was maintained by chance because D (50) is very small (8 μm). However, this is due to the low gravitational settling force caused by the small particle size, and in the general particle size range (e.g., 30 to 50 μm), suspension stability decreases when the SV value is outside the claimed range. Therefore, it was confirmed that the numerical limitation of the present invention is not merely a design matter but an essential requirement for achieving critical effects that are difficult to predict.

Claims

Claim 1 Biodegradable polymer particles; A liquid composite composition comprising a biodegradable polymer and a water-soluble or water-swellable polymer, wherein the biodegradable polymer particles have a particle size distribution (SV) value according to Formula 1 below of 0.4 to 1.0, the composite composition has a complex viscosity (η*) of 5 Pa·s to 200 Pa·s measured under conditions of 25°C and a frequency of 0.1 Hz, the biodegradable polymer is one or more selected from the group consisting of poly-L-lactide (PLLA), poly-DL-lactide (PDLLA), polycaprolactone (PCL), and poly(lactide-co-glycolide) (PLGA), and the water-soluble or water-swellable polymer is one or more selected from the group consisting of hyaluronic acid, cross-linked hyaluronic acid, and polynucleotide: [Formula 1] Particle size distribution (SV) = [ D(90) - D(10) ] / D(50) (where D(10), D(50), and D(90) are particle sizes corresponding to 10%, 50%, and 90% of the cumulative particle distribution, respectively). Claim 2 A liquid composite composition according to claim 1, wherein the D (50) value of the biodegradable polymer particles is 1 μm to 80 μm. Claim 3 A liquid composite composition according to claim 1, wherein the total content of the biodegradable polymer particles and the water-soluble or water-swellable polymer is 2% to 8% by weight with respect to the total weight of the composite composition. Claim 4 A liquid composite composition according to claim 3, wherein the content of the water-soluble or water-swellable polymer is 0.2% to 6% by weight. Claim 5 delete Claim 6 delete Claim 7 A liquid composite composition according to claim 1 having suspension stability in which sedimentation or phase separation of biodegradable polymer particles does not occur when stored at room temperature for more than one month. Claim 8 (a) a step of preparing a biodegradable polymer solution by dissolving a biodegradable polymer in a first solvent; (b) a step of forming biodegradable polymer particles by dispersing the biodegradable polymer solution in a second solvent in which an emulsifier is dissolved; (c) a step of sorting and drying the biodegradable polymer particles by size to obtain biodegradable polymer particles having a particle size distribution (SV) value of 0.4 to 1.0 according to Formula 1 below and a D (50) value of 1 μm to 80 μm; (d) a step of preparing a polymer solution by dissolving a water-soluble or water-swellable polymer in a third solvent; (e) a step of mixing the obtained biodegradable polymer particles and the water-soluble or water-swellable polymer solution with a fourth solvent to prepare a composite composition solution having a complex viscosity (η*) of 5 Pa·s to 200 Pa·s measured under conditions of 25°C and a frequency of 0.1 Hz; a method for preparing a liquid-type composite composition [Formula 1] Particle size distribution (SV) = [D(90) - D(10)] / D(50) (where D(10), D(50), and D(90) are the particle sizes corresponding to 10%, 50%, and 90% of the cumulative particle distribution, respectively).

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