Method for preparing poly-l-lactic acid filler, and poly-l-lactic acid filler prepared using preparation method

Abstract

The present invention relates to a method for preparing a poly-L-lactic acid filler, and a poly-L-lactic acid filler prepared using the preparation method, and, more specifically, to a method for preparing a poly-L-lactic acid filler in which a cross-link hyaluronic acid (HA) gel spherically encompasses the surface of solid microsphere PLLA particles.

Description

Method for producing poly-L-lactic acid filler and poly-L-lactic acid filler produced by the method

[0001] The present invention relates to a method for producing a poly-L-lactic acid filler and a poly-L-lactic acid filler produced by the method.

[0002]

[0003] The structure of human skin tissue is maintained by an extracellular matrix containing proteins such as collagen and elastin and glycosaminoglycans. When soft tissue defects occur due to external impact, disease, or aging, tissue augmentation, such as soft tissue augmentation, has been used for medical and cosmetic purposes. This augmentation is performed surgically through plastic surgery, or non-surgically by injecting biological tissue or synthetic polymer chemicals into the relevant area to increase and expand the volume of soft tissue, thereby restoring and correcting its shape. In this case, a substance similar to skin tissue is inserted into a specific area to expand the soft tissue, thereby cosmetically increasing the volume of areas such as cheeks, lips, breasts, and buttocks, and the substance used for wrinkle improvement or contour correction by reducing fine and deep wrinkles in the skin is called a soft tissue augmentation material, commonly referred to as a dermal filler. Among the first-generation dermal fillers developed in relation to these fillers, there are products such as Zyderm and Zyplast, which are made by extracting animal proteins such as those of cows or pigs, and Cosmoderm or Cosmoplast, which use human collagen. However, these products are rarely used these days due to the short duration of effect and the inconvenience of having to undergo a skin hypersensitivity test one month before the procedure.

[0004]

[0005] The second-generation filler is a hyaluronic acid (HA) filler, which has a longer duration of effect than collagen fillers and is composed of N-acetyl-D-glucosamine and D-glucuronic acid, which are polysaccharides similar to human body components, so it has fewer side effects such as skin hypersensitivity, is easy to administer and remove, and has the advantage of attracting water to maintain skin moisture, volume, and elasticity, making it suitable as a skin filler.

[0006]

[0007] However, hyaluronic acid itself has a short half-life of only a few hours in the human body, which limits its application, and research has been conducted to increase the half-life (persistence in the body) through crosslinking. For example, U.S. Patent No. 4,582,865 discloses a crosslinked hyaluronic acid derivative using divinylsulfone (DVS) as a crosslinking agent, and its hydrogel form is commercially sold under the trade name Hylaform®, and U.S. Patent No. 5,827,937 discloses a method for producing a crosslinked hyaluronic derivative using a multifunctional epoxy compound as a crosslinking agent. Among these, Restylane®, a hydrogel form of a crosslinked hyaluronic acid product produced using 1,4-butanediol diglycidyl ether (BDDE) as a multifunctional epoxy compound as a crosslinking agent, has been approved by the U.S. FDA and is commercially sold worldwide as a filler for tissue augmentation.

[0008]

[0009] These cross-linked hyaluronic acid fillers include those made in a single phase (monophasic HA filler) and those made in two phases (biphasic HA filler). Monophasic hyaluronic acid fillers are manufactured using a homogeneous solution containing cross-linked hyaluronic acid, so they generally have low elasticity and high cohesion. Accordingly, monophasic hyaluronic acid fillers are less likely to come off the injected site when injected into the skin, but they have the problem of not maintaining the injected shape for long, and the shape (shape) retention period is only about two months after the procedure. In addition, biphasic hyaluronic acid fillers are manufactured using cross-linked hyaluronic acid particles alone or by mixing them with non-cross-linked hyaluronic acid that is closer to a liquid (unprocessed, uncross-linked hyaluronic acid, linear HA), so they generally have high elasticity and low cohesion. Accordingly, bi-phase HA fillers, while capable of maintaining their shape for a long time when injected into the skin, have the potential to dislodge from the injected area. A representative example of such a bi-phase HA filler is the aforementioned Restylane® (Galderma).

[0010]

[0011] Typically, poly-L-lactic acid (PLLA) fillers are biocompatible and biodegradable polymeric synthetic materials that serve as a microsphere support. Additionally, hyaluronic acid (HA) is a biosynthetic natural substance found in abundance in the skin of animals and other animals. Hyaluronic acid (HA) fillers are used to increase facial volume without surgery.

[0012]

[0013] Conventional PLLA manufacturing and usage methods involve mixing dried powder-type PLLA with CMC (carboxymethyl cellulose) and mannitol, freeze-drying the mixture, mixing the freeze-dried PLLA with sterile distilled water to create a suspension, and then drawing up the suspension with a disposable syringe for injection into the body. After 3 to 6 months, collagen is produced in the body, resulting in increased volume.

[0014]

[0015] However, this conventional technology has a limitation in that the distilled water and CMC components in the injected PLLA suspension are absorbed into the body within a few days, so the volume that was created immediately after injecting the PLLA suspension into the body disappears immediately, and the volume-enhancing effect does not appear after a few days after the injection, and the volume-enhancing effect gradually appears after several months (3 to 6 months) when the PLLA (Poly-L-lactic acid) breaks down and collagen is formed. In this way, in the conventional technology, several months must pass after injection into the body until collagen is formed, and this several-month period has been a cause of dissatisfaction in the recipients.

[0016] Furthermore, conventional pure PLLA fillers have the disadvantage that when PLLA particles are injected in a clumped state, excessive collagen is formed in certain areas, resulting in the formation of nodules and granulomas. For this reason, all existing PLLA fillers are distributed in the form of freeze-dried powder, and the practitioner dilutes the PLLA with water for injection or physiological water before injection. However, in this case, since the viscosity of distilled water is low, there is a high probability that the high-specific gravity PLLA particles will quickly settle or be injected in a clumped state.

[0017]

[0018] To compensate for these shortcomings, there was also the inconvenience of having to use other types of fillers, biomaterials for human tissue repair.

[0019]

[0020] Korean Patent No. 10-1852127 discloses a method for combining PLLA and HA. This method utilizes a hyaluronic acid solution (HA solution) instead of saline as the suspension, thereby preventing PLLA particles from easily settling or agglomerating in the high-viscosity hyaluronic acid solution (HA solution).

[0021] However, these fillers require the practitioner to directly mix PLLA and hyaluronic acid solution (HA solution). If the practitioner mixes solid PLLA powder and high-viscosity hyaluronic acid solution (HA solution) without specialized equipment, it is difficult to maintain a homogenous state, and the recommended mixing time in the instructions for use is only about 4 to 24 hours, which is still inconvenient to use. Therefore, there is a need for a poly-L-lactic acid filler that can improve this.

[0022] [Prior Art Literature]

[0023] (Patent Document 1) Korean Patent No. 10-1852127

[0024]

[0025] The purpose of the present invention is to provide a method for producing a poly-L-lactic acid filler that not only maintains a superior homogenized state but also maintains the homogenized state even after long-term storage.

[0026]

[0027] In addition, another object of the present invention is to provide a poly-L-lactic acid filler in a form in which cross-linked hyaluronic acid is spherically wrapped around the surface of poly-L-lactic acid particles manufactured by the above manufacturing method. In particular, by forming a form in which cross-linked hyaluronic acid is spherically wrapped around the surface of particles by the above manufacturing method, a poly-L-lactic acid filler is provided that can disperse aggregation between PLLA and form a homogeneous PLLA-HA mixture, thereby eliminating side effects such as nodules and granulomas caused by PLLA aggregation.

[0028]

[0029] In addition, another object of the present invention is to provide a poly-L-lactic acid filler with improved multi-complex safety and ease of use by providing it in a container that can be used immediately without requiring a separate mixing process.

[0030]

[0031] In order to achieve the above purpose, the present invention comprises the steps of: i) mixing sodium hyaluronate with an aqueous NaOH solution to produce a hyaluronic acid solution;

[0032] ii) a step of forming a cross-linked hyaluronic acid gel by adding a cross-linking agent to the hyaluronic acid solution;

[0033] iii) a step of passing the cross-linked hyaluronic acid gel through a plunger mill to form a granular microparticle gel;

[0034] iv) a step of mixing the granular microparticle gel with spherical microsphere-shaped PLLA (poly-L-lactic acid); and

[0035] v) a step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles using a vacuum mixer;

[0036] A method for manufacturing a poly-L-lactic acid filler is provided.

[0037] In addition, the present invention provides a method for manufacturing a poly-L-lactic acid filler, characterized in that, in the step of forming the granular microparticle gel, a plunger mill having holes of 50 to 150 μm in size and capable of pushing out a drug solution is passed through the plunger mill, thereby forming a granular microparticle gel of 50 to 150 μm in size.

[0038] In addition, the present invention provides a method for producing a poly-L-lactic acid filler, characterized in that, in the step of mixing the granular microparticle gel with spherical microsphere-shaped PLLA (poly-L-lactic acid), the size of the microsphere PLLA particles is 30 to 70 μm.

[0039] In addition, the present invention provides a method for manufacturing a poly-L-lactic acid filler, characterized in that, in the step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles using the above-described rotating mixer, the step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles in a spherical shape is performed by using a rotating mixer, and a mixture of the above-described granular fine particle gel and spherical microsphere-formed PLLA (poly-L-lactic acid) is subjected to a) a rotating process, and then b) an orbital process.

[0040] In addition, the present invention provides a method for manufacturing a poly-L-lactic acid filler, characterized in that, in the step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles using the above-described rotating mixer, a) the rotating process causes the PLLA (poly-L-lactic acid) particles to be densely packed toward the edge of the chamber, and b) the rotating process causes the PLLA (poly-L-lactic acid) particles to rotate on the cross-linked hyaluronic acid.

[0041] In addition, the present invention provides a method for manufacturing a poly-L-lactic acid filler, characterized in that, in the step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles using the above-described rotating mixer, the a) rotating process is performed at a speed of 100 to 1000 rpm for 0.5 to 2 hours.

[0042] In addition, the present invention provides a method for manufacturing a poly-L-lactic acid filler, characterized in that, in the step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles using the above-described oscillatory mixer, the above-described b) oscillatory rotation process is performed at a speed of 100 to 1000 rpm for 0.5 to 2 hours.

[0043] In addition, the present invention provides a method for manufacturing a poly-L-lactic acid filler, characterized in that, in the step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles using the above-described rotating mixer, the a) rotating process is performed at a speed of 300 to 500 rpm for 0.5 to 1 hour.

[0044] In addition, the present invention provides a method for manufacturing a poly-L-lactic acid filler, characterized in that, in the step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles using the above-described gyroscopic mixer, the above-described b) gyroscopic rotation process is performed at a speed of 300 to 500 rpm for 0.5 to 1 hour.

[0045] In addition, the present invention provides a method for manufacturing a poly-L-lactic acid filler, characterized in that the poly-L-lactic acid filler has a spherical shape in which cross-linked hyaluronic acid is coated on the surface of solid microsphere PLLA particles.

[0046] In addition, the present invention provides a poly-L-lactic acid filler having a form in which cross-linked hyaluronic acid is spherically coated on the surface of solid microsphere PLLA particles manufactured by the method for manufacturing a poly-L-lactic acid filler described above.

[0047] In addition, the present invention provides a filler composition for molding comprising a poly-L-lactic acid filler having a shape in which cross-linked hyaluronic acid is spherically coated on the surface of the solid microsphere PLLA particles.

[0048]

[0049] In the case of the poly-L-lactic acid filler manufactured according to the present invention, by forming a form in which cross-linked hyaluronic acid is wrapped in a spherical shape on the surface of poly-L-lactic acid particles, not only is a filler containing only poly-L-lactic acid maintained in a superior homogenized state compared to a filler simply mixing only poly-L-lactic acid, but it also exhibits excellent long-term storage properties in which the homogenized state is maintained even after long-term storage. As a result, even when stored in a storage container for a long period of time, the PLLA particles do not move or aggregate, allowing them to be used immediately, thereby exhibiting significantly improved ease of distribution and use.

[0050]

[0051] In addition, in the case of the poly-L-lactic acid filler manufactured according to the present invention, by coating the surface of the poly-L-lactic acid particles with a cross-linked hyaluronic acid gel, the primary filler effect can be expressed by the cross-linked hyaluronic acid gel in the early stage of the procedure, and the PLLA filler effect can be expressed secondarily. This is because the hyaluronic acid gel is used as a substitute for the technical problem of the prior art in which the effect cannot be expressed until collagen is formed in the body (about 3 to 6 months) after the procedure, which is a shortcoming of the PLLA filler, so that the advantages of the existing hyaluronic acid filler and PLLA filler, as well as their respective roles and functions, can all be exhibited.

[0052]

[0053] Figure 1 is a flow chart showing a method for manufacturing a poly-L-lactic acid filler in which a cross-linked hyaluronic acid gel (cross-link HA gel) is spherically coated on the surface of a solid microsphere PLLA particle of the present invention.

[0054]

[0055] Hereinafter, preferred embodiments of the present invention will be described in detail so that a person having ordinary skill in the art to which the present invention pertains can easily practice the present invention.

[0056]

[0057] In the following description, numerous specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, specific embodiments may be practiced with one or more of these specific details, or with other known methods and configurations. In other instances, well-known processes and manufacturing techniques are not described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Thus, the appearances of "one embodiment" or "an embodiment" in various places throughout this specification are not necessarily referring to the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0058]

[0059] Unless otherwise specifically defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

[0060]

[0061] The present invention is described in detail below.

[0062] First, hyaluronic acid (hereinafter referred to as 'HA') included in the filler of the present invention is a linear polysaccharide in which repeating units composed of N-acetyl-D-glucosamine and D-glucuronic acid are linearly linked, and is one of the glycosamino glycans present in the extracellular matrix (ECM), synovial fluid of joints, and the support that constitutes cartilage. Hyaluronic acid is also a biopolymer substance that plays an important role as a signaling molecule in cell motility, cell differentiation, wound healing, and cancer metastasis, and is found in large quantities in the vitreous humor of the eye, synovial fluid of joints, and rooster combs, and because it has excellent biocompatibility, it is widely used in medical and medical devices such as ophthalmic surgical adjuvants, joint function improving agents, drug delivery materials, eye drops, and wrinkle improving agents, as well as for cosmetic purposes. Furthermore, hyaluronic acid presents no immunological problems, making it a highly biocompatible biomaterial suitable for tissue engineering and drug delivery systems. Hyaluronic acid and hyaluronic acid oligosaccharides possess a three-dimensional structure in solution, which leads to extensive internal hydrogen bonding, limited polymer chain mobility, and unique secondary (helical) and tertiary (coiled coil) reactions.

[0063]

[0064] Additionally, hyaluronic acid generally has a molecular weight of approximately 1,000 to 10,000,000 Da and, as mentioned above, has unique physicochemical properties and specific biological functions.

[0065]

[0066] In addition, hyaluronic acid plays a major role in the homeostasis of cell tissues and the lubrication of joints, and through specific binding with specific proteins on the cell surface, it plays a very important role in cell fluidity, growth factor action, and inflammatory response. It is being developed and used as a medical ingredient for tissue repair (replacement and reconstruction of human tissue) both domestically and internationally, and is also widely used in the fields of skin beauty and plastic surgery.

[0067]

[0068] The hyaluronic acid included in the filler of the present invention may refer to a salt thereof in addition to hyaluronic acid. The salt of hyaluronic acid includes, but is not limited to, inorganic salts such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, and cobalt hyaluronate, and organic salts such as tetrabutylammonium hyaluronate. In addition, preferably, the hyaluronic acid or its salt may be crosslinked by an appropriate crosslinking agent.

[0069]

[0070] Cross-linked hyaluronic acid derivatives can be prepared by cross-linking hyaluronic acid itself or a salt thereof using a cross-linking agent. For cross-linking, a method using a cross-linking agent in an alkaline aqueous solution can be used. The alkaline aqueous solution may include, but is not limited to, NaOH, KOH, and preferably, NaOH aqueous solution. In this case, the NaOH aqueous solution may be used at a concentration of 0.1 N to 0.5 N. The cross-linked hyaluronic acid included in the filler of the present invention exhibits high rheological properties (viscoelasticity, cohesiveness) and lift capability, and exhibits low injection pressure, even when using a particularly low concentration and a small amount of cross-linking agent.

[0071]

[0072] The crosslinking agent may be a compound containing two or more epoxy functional groups and may be various, and preferred examples thereof include 1,4-butandiol diglycidyl ether (BDDE), ethylene glycol diglycidyl ether (EGDGE), 1,6-hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, Examples include glycerol polyglycidyl ether, trimethylpropane polyglycidyl ether, bisepoxypropoxyethylene (1,2-(bis(2,3-epoxypropoxy)ethylene), pentaerythritol polyglycidyl ether, and sorbitol polyglycidyl ether, and among them, 1,4-butanediol diglycidyl ether, which is a biepoxide, is particularly preferable in terms of low toxicity.

[0073]

[0074] First, poly-L-lactic acid (hereinafter referred to as "PLLA"), which is included in the filler of the present invention, can be manufactured from natural materials, such as lactic acid or lactide, and its use as a general-purpose polymer, rather than simply a biodegradable polymer, is also being considered. Furthermore, polylactic acid is highly transparent and strong, but is easily hydrolyzed in the presence of water and decomposes without polluting the environment after disposal, making it a resin with a low environmental impact. Furthermore, although the melting point of polylactic acid is approximately 170°C, it is difficult to say that this is sufficient for use as a general-purpose polymer, and improved heat resistance is required.

[0075]

[0076] Meanwhile, it is known that a stereocomplex polylactic acid is formed by mixing poly-L-lactic acid (PLLA), which is composed of only L-lactic acid units, and poly-D-lactic acid (PDLA), which is composed of only D-lactic acid units, in a solution or molten state. This stereocomplex polylactic acid has been found to exhibit a higher melting point and higher crystallinity than PLLA or PDLA.

[0077]

[0078] Typically, poly-L-lactic acid (PLLA) fillers are biocompatible and biodegradable polymeric synthetic materials that serve as a microsphere support. Conventional PLLA manufacturing and use methods involve, as described above, mixing freeze-dried PLLA with sterile distilled water to create a suspension, which is then injected into the body. After 3 to 6 months, collagen is produced in the body, resulting in increased volume.

[0079]

[0080] However, such prior art exhibits the problems described above, and in order to solve the problems described above, the present invention provides a poly-L-lactic acid filler in the form of a cross-linked hyaluronic acid gel (cross-linked HA gel) coated in a spherical shape on the surface of solid microsphere poly-L-lactic acid (PLLA) particles obtained through the manufacturing method described below.

[0081]

[0082] The present invention provides, as one embodiment, a method for producing a poly-L-lactic acid filler, comprising the steps of: i) mixing sodium hyaluronate with an aqueous NaOH solution to produce a hyaluronic acid solution; ii) adding a cross-linking agent to the hyaluronic acid solution to form a cross-linked hyaluronic acid gel; iii) passing the cross-linked hyaluronic acid gel through a plunger mill to form a granular microparticle gel; iv) mixing the granular microparticle gel with spherical microspheres of PLLA (poly-L-lactic acid); and v) coating the surface of solid microsphere PLLA particles with cross-linked hyaluronic acid using a rotary mixer.

[0083]

[0084] Specifically, in the step of producing the hyaluronic acid solution, a sodium hydroxide solution can be prepared using NaOH having a concentration of 0.1 N to 0.5 N.

[0085]

[0086] Additionally, in the step of forming the cross-linked hyaluronic acid gel, a cross-linking agent may be added to the hyaluronic acid solution, and then a stabilization time may be allowed to pass before producing the cross-linked hyaluronic acid gel.

[0087] As the crosslinking agent, a compound containing two or more epoxy functional groups may be used, and preferred examples thereof include 1,4-butandiol diglycidyl ether (BDDE), ethylene glycol diglycidyl ether (EGDGE), 1,6-hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, Examples include glycerol polyglycidyl ether, trimethylpropane polyglycidyl ether, bisepoxypropoxyethylene (1,2-(bis(2,3-epoxypropoxy)ethylene), pentaerythritol polyglycidyl ether, and sorbitol polyglycidyl ether, and among them, 1,4-butanediol diglycidyl ether, which is a biepoxide, is particularly preferable in terms of low toxicity.

[0088]

[0089] In addition, in the step of forming the granular microparticle gel, the cross-linked hyaluronic acid gel may be first passed through a plunger mill facility equipped with holes of 50 to 150 μm in size to push out the drug solution, thereby forming a granular microparticle gel having a particle size of 50 to 150 μm. In addition, the process of passing the gel through the plunger mill facility may be repeated two or more times.

[0090]

[0091] The particle size of the above granular microparticle gel may be 50 to 150 μm, and preferably about 100 μm. When the particle size of the above granular microparticle gel satisfies the above range, a poly-L-lactic acid filler can be manufactured in which a cross-linked hyaluronic acid gel is uniformly coated in a spherical shape on the surface of the solid microsphere PLLA particles.

[0092]

[0093] In addition, in the mixing step of the granular microparticle gel and PLLA, a spherical microsphere-shaped PLLA (poly-L-lactic acid, molecular weight 100,000 kilodalton) raw material is prepared, and mixed with the 'granular microparticle gel of cross-linked hyaluronic acid gel (cross-linked HA gel)' using a power mixer facility, thereby obtaining a mixture in which solid PLLA microsphere particles are dispersed inside the cross-linked hyaluronic acid gel (cross-linked HA gel).

[0094]

[0095] The above microsphere-formed PLLA may have a particle size of 30 to 70 μm, preferably 40 to 60 μm, and more preferably about 50 μm. By satisfying the particle size of the microsphere-formed PLLA within the above range, a poly-L-lactic acid filler can be manufactured in which a cross-linked hyaluronic acid gel (cross-linked HA gel) is uniformly coated in a spherical shape on the surface of the solid microsphere PLLA particles that are finally manufactured. In particular, when the particle size of the microsphere-formed PLLA is less than the above range, the cross-linked hyaluronic acid gel (cross-linked HA gel) is not uniformly coated in a spherical shape on the surface of the PLLA particles, and when it exceeds the above range, a problem may arise in which the hyaluronic acid gel is not coated on some surfaces of the PLLA particles. Therefore, it is preferable that the particle size be satisfied within the above range.

[0096]

[0097] In addition, the viscosity of the mixture in which solid PLLA microsphere particles are dispersed inside the cross-linked hyaluronic acid gel (cross-linked HA gel) produced above may be 2,000 to 10,000 cp, preferably 5,000 to 10,000 cp, and more preferably 5,000 to 8,000 cp. By satisfying the above range of viscosity of the mixture, not only can a poly-L-lactic acid filler be produced in which the cross-linked hyaluronic acid gel (cross-linked HA gel) is uniformly coated in a spherical shape on the surface of the solid PLLA microsphere particles finally produced, but also the effect of the formulation not collapsing even when stored for a long period of time can be exhibited.

[0098]

[0099] In addition, in the step of coating the PLLA particle surface with cross-linked hyaluronic acid, a poly-L-lactic acid filler in the form of a cross-linked hyaluronic acid gel (cross-linked HA gel) spherically wrapped around the surface of solid microsphere PLLA particles can be manufactured using equipment having a rotation and revolution function (rotation mixer).

[0100]

[0101] Specifically, the step may include a) performing a rotation process on a mixture of the granular fine particle gel and spherical microsphere PLLA (poly-L-lactic acid) in a chamber container of a gyroelectric mixer, and then b) performing a rotation process.

[0102]

[0103] In addition, the above a) self-rotation process can cause the PLLA (poly-L-lactic acid) particles to be densely packed at the edge of the chamber, and the above b) process rotation process can cause the PLLA (poly-L-lactic acid) particles to rotate on the cross-linked hyaluronic acid.

[0104] In addition, the above a) self-rotation process may be performed at a speed of 100 to 1000 rpm for 0.5 to 2 hours, and preferably, may be performed at a speed of 300 to 500 rpm for 0.5 to 1 hour.

[0105] In addition, the above b) idle rotation process may be performed at a speed of 100 to 1000 rpm for 0.5 to 2 hours, and preferably, may be performed at a speed of 300 to 500 rpm for 0.5 to 1 hour.

[0106]

[0107] As a result, a poly-L-lactic acid filler can be manufactured in the form of a cross-linked hyaluronic acid gel uniformly coated in a spherical shape on the surface of solid microsphere PLLA particles.

[0108]

[0109] The poly-L-lactic acid filler manufactured by the above manufacturing method not only maintains a superior homogenized state, but also exhibits an excellent long-term storage effect in which the homogenized state is maintained even after long-term storage, and thus, can be used immediately even after long-term storage in a storage container, thereby exhibiting a significantly improved effect in terms of ease of distribution and use.

[0110]

[0111] One embodiment of the present invention provides a poly-L-lactic acid filler having a shape in which cross-linked hyaluronic acid is spherically coated on the surface of solid microsphere PLLA particles manufactured by the method for manufacturing a poly-L-lactic acid filler described above.

[0112]

[0113] Another embodiment of the present invention provides a filler composition for molding comprising a poly-L-lactic acid filler having a shape in which cross-linked hyaluronic acid is spherically coated on the surface of the solid microsphere PLLA particles.

[0114]

[0115] Hereinafter, the present invention will be described in more detail through examples. It will be apparent to those skilled in the art that the following examples are provided solely for the purpose of more concretely illustrating the present invention, and that the scope of the present invention is not construed as being limited by these examples.

[0116]

[0117] Example 1. Preparation of poly-L-lactic acid filler

[0118] 1-1. Hyaluronic acid solution production steps

[0119] (a) A ‘sodium hydroxide solution (NaOH solution)’ was prepared by mixing 1 mass% of NaOH and 99 mass% of sterilized distilled water.

[0120]

[0121] Afterwards, (b) 15.04 mass% of sodium hyaluronate having a molecular weight of 1.4 Mda and the above sodium hydroxide solution (NaOH solution) were mixed to produce a 'hyaluronic acid solution'.

[0122]

[0123] 1-2. Formation steps of cross-linked hyaluronic acid gel

[0124] After adding 0.28 mass% of BDDE (butanediol diglycidyl ether) as a cross-linking agent to the above hyaluronic acid solution, a ‘cross-link hyaluronic acid gel’ was created after a stabilization period.

[0125] The above cross-linked hyaluronic acid gel is also called 'cross-link HA gel', and it becomes a solid with a certain level of elasticity.

[0126]

[0127] 1-3. Formation steps of granular microparticle gel

[0128] The 'cross-linked hyaluronic acid gel' was first passed through a plunger mill facility equipped with a 100 μm hole to push out the drug solution and then recovered. Thereafter, it was passed through the plunger mill facility a second time to produce a granular microparticle gel having a particle size of approximately 100 μm.

[0129]

[0130] 1-4. Mixing step of granular microparticle gel and PLLA

[0131] Prepare PLLA (poly-L-lactic acid, molecular weight 100,000 kilodalton) raw material in the form of spherical microspheres (particle size 30-70㎛),

[0132] It was mixed with 90 mass% of ‘granular microparticle gel of cross-linked hyaluronic acid gel’ using a power mixer facility of 1000 rpm.

[0133] The form of the above mixed gel is a form in which solid PLLA microsphere particles are dispersed inside a cross-linked hyaluronic acid gel (cross-link HA gel) having a viscosity of 2,000 to 10,000 cp.

[0134]

[0135] 1-5. Step of coating cross-linked hyaluronic acid on the surface of PLLA particles

[0136] (a) A mixture of the cross-linked hyaluronic acid gel (cross-linked HA gel) and PLLA microsphere particles manufactured above was placed in a chamber container of a device (rotating mixer) having rotation and revolution functions, and a rotation process was performed at a speed of 300 to 500 rpm for 1 hour. This is because it was confirmed that the PLLA particles were densely packed toward the periphery of the chamber container through this process. After that, a rotation process was performed at a speed of 300 to 500 rpm for 1 hour. Through this process, it was confirmed that the PLLA solid particles rotate on the cross-linked hyaluronic acid gel (cross-linked HA gel), and the cross-linked hyaluronic acid gel (cross-linked HA gel) was spherically wrapped around the surface of the solid microsphere PLLA particles.

[0137]

[0138] Comparative Example 1. Preparation of poly-L-lactic acid filler

[0139] A poly-L-lactic acid filler was manufactured in the same manner as in Example 1, except that step 1-5 of the manufacturing process of the poly-L-lactic acid filler of Example 1 was not performed.

[0140]

[0141] Test Example 1. Confirmation of Formulation

[0142] The formulations of the poly-L-lactic acid fillers manufactured in Example 1 and Comparative Example 1 were confirmed using a microscope (scanning electron microscope).

[0143]

[0144] As a result, in the case of poly-L-lactic acid manufactured by Example 1, it was confirmed that a cross-linked hyaluronic acid gel (cross-link HA gel) was uniformly coated on the surface of solid microsphere PLLA particles.

[0145] On the other hand, in the case of Comparative Example 1, which did not go through the step of coating the PLLA particle surface with cross-linked hyaluronic acid, it was confirmed that the solid PLLA microsphere particles were simply dispersed inside the cross-linked hyaluronic acid gel (cross-linked HA gel).

[0146]

[0147] In the case of the method for manufacturing the poly-L-lactic acid filler of Example 1, the surface of the solid microsphere PLLA particles is uniformly coated with a cross-linked hyaluronic acid gel (cross-linked HA gel), so that the filler can be maintained in an excellent homogenized state before use and during storage, and can be immediately injected into the skin using a syringe while stored in a storage container, so that the ease of use is significantly improved.

[0148]

[0149] Test Example 2. Long-term storage stability test of poly-L-lactic acid filler formulations

[0150] After storing the poly-L-lactic acid fillers manufactured in Example 1 and Comparative Example 1 for 12 weeks, their formulations were confirmed using a microscope (scanning electron microscope).

[0151]

[0152] As a result, in the case of poly-L-lactic acid manufactured by Example 1, it was confirmed that the cross-linked hyaluronic acid gel (cross-linked HA gel) was maintained in a uniformly coated form on the surface of the solid microsphere PLLA particles even after 12 weeks.

[0153] On the other hand, in the case of Comparative Example 1, which did not undergo the step of coating the PLLA particle surface with cross-linked hyaluronic acid, it was confirmed that after 12 weeks, the cross-linked hyaluronic acid gel and solid PLLA microsphere particles separated to form layers, and PLLA aggregation occurred.

[0154]

[0155] In the case of the method for manufacturing the poly-L-lactic acid filler of Example 1, it was confirmed that the cross-linked hyaluronic acid gel (cross-linked HA gel) was uniformly coated on the surface of the solid microsphere PLLA particles even after a long period of time, thereby maintaining an excellent homogenized state for a long period of time before use and during storage of the filler, and thus significantly improving the ease of distribution and use.

[0156]

[0157] Test Example 3. Long-term storage stability test of the formulation of an initial volume-forming poly-L-lactic acid filler.

[0158] An animal efficacy test was conducted using hairless mice on the poly-L-lactic acid filler obtained in Example 1 and the filler containing only poly-L-lactic acid without coating the cross-linked hyaluronic acid gel (Comparative Example 2), and the results are shown in Table 1 below.

[0159]

[0160] Example 1 Comparative Example 2 Volume immediately after the procedure 100% 100% After 1 week 95% 40% After 12 weeks 100% 100%

[0161] In the case of the poly-L-lactic acid filler manufactured by the above Example 1, it was confirmed that the volume reduction in the early stage of the procedure was significantly improved by coating the surface of the poly-L-lactic acid particles with a cross-linked hyaluronic acid gel. That is, in the case of the poly-L-lactic acid filler manufactured by the present invention, the initial volume reduction is improved in the early stage of the procedure by coating the cross-linked hyaluronic acid gel, and thereafter, as PLLA is decomposed in the body, collagen formation factors are continuously released, thereby significantly reducing the time required for collagen formation and volume increase after the filler procedure.

[0162]

[0163] From the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical spirit or essential characteristics. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as encompassing all changes or modifications derived from the meaning and scope of the following claims and their equivalent concepts, rather than the detailed description above.

Claims

1. i) A step of producing a hyaluronic acid solution by mixing sodium hyaluronate with an aqueous NaOH solution; ii) a step of adding a cross-linking agent to the hyaluronic acid solution to form a cross-linked hyaluronic acid gel; iii) a step of passing the cross-linked hyaluronic acid gel through a plunger mill to form a granular microparticle gel; iv) a step of mixing the granular microparticle gel with spherical microsphere-shaped PLLA (poly-L-lactic acid); and v) a step of coating cross-linked hyaluronic acid on the surface of solid microsphere PLLA particles using a vacuum mixer; Method for producing poly-L-lactic acid filler.

2. In paragraph 1, A method for manufacturing a poly-L-lactic acid filler, characterized in that the step of forming the granular microparticle gel comprises forming a granular microparticle gel of 50 to 150 μm in size by passing the gel through a plunger mill equipped with holes of 50 to 150 μm in size and capable of pushing out a drug solution.

3. In paragraph 1, A method for manufacturing a poly-L-lactic acid filler, characterized in that the size of the above microsphere PLLA particles is 30 to 70 μm.

4. In paragraph 1, The step of coating cross-linked hyaluronic acid in a spherical shape on the surface of solid microsphere PLLA particles is performed using a rotary mixer. A method for manufacturing a poly-L-lactic acid filler, characterized in that a) a rotational process is performed on a mixture of the granular fine particle gel and the spherical microsphere PLLA (poly-L-lactic acid) in a chamber vessel of a rotary mixer, and then b) an orbital rotation process is performed.

5. In paragraph 4, The above a) self-rotation process causes the PLLA (poly-L-lactic acid) particles to be densely packed at the edge of the chamber, The above b) process rotation process is a method for manufacturing a poly-L-lactic acid filler, characterized in that PLLA (poly-L-lactic acid) particles rotate on cross-linked hyaluronic acid.

6. In paragraph 5, A method for manufacturing a poly-L-lactic acid filler, characterized in that the above a) self-rotation process is performed at a speed of 100 to 1000 rpm for 0.5 to 2 hours.

7. In paragraph 5, A method for manufacturing a poly-L-lactic acid filler, characterized in that the above b) idle rotation process is performed at a speed of 100 to 1000 rpm for 0.5 to 2 hours.

8. In paragraph 5, A method for manufacturing a poly-L-lactic acid filler, characterized in that the above a) self-rotation process is performed at a speed of 300 to 500 rpm for 0.5 to 1 hour.

9. In paragraph 5, A method for manufacturing a poly-L-lactic acid filler, characterized in that the above b) idle rotation process is performed at a speed of 300 to 500 rpm for 0.5 to 1 hour.

10. In paragraph 1, A method for manufacturing a poly-L-lactic acid filler, characterized in that the poly-L-lactic acid filler has a form in which cross-linked hyaluronic acid is spherically coated on the surface of solid microsphere PLLA particles.

11. A poly-L-lactic acid filler having a shape in which cross-linked hyaluronic acid is spherically coated on the surface of solid microsphere PLLA particles manufactured by the method for manufacturing a poly-L-lactic acid filler according to any one of claims 1 to 10.

12. A filler composition for molding comprising a poly-L-lactic acid filler having a spherical shape in which cross-linked hyaluronic acid is coated on the surface of the solid microsphere PLLA particles described in claim 11.

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