KR20190132113A - Dermal filler composition comprising porous microparticles of biodegradable polymer - Google Patents

Abstract

Provided is a dermal filler composition, comprising porous microparticles of biodegradable polymer. The present invention can provide the effect of maintaining the volume due to the volume of the polymer even immediately after the procedure.

Description

Dermal filler composition comprising porous microparticles of biodegradable polymer

The present invention relates to a molding filler composition comprising porous fine particles of a biodegradable polymer.

In the past, many people wanted a healthy life, but as the age of population approaches, people want a healthy life and a beautiful life. As more people want a beautiful life, a variety of related products are on the market.

Products for preventing and treating aging have been released in various fields such as food, medicine and cosmetics. Among them, botulinum toxin and facial fillers are typical products in the medical field. Botulinum toxin, which was initially used for muscle relaxation, is now more often used in the form of facial wrinkles for cosmetic purposes. In addition, the filler market, which can be used as a volume filler for skin by being safe and bioabsorbed, such as collagen and hyaluronic acid, is also rapidly growing.

Filler products are divided into four generations according to the development process.

First-generation fillers used collagen components extracted from animals. However, due to a collagen allergic reaction and a short maintenance period of 1 to 3 months, it is rarely used today.

The second-generation filler is a hyaluronic acid-based filler and currently occupies 90% of the market. Hyaluronic acid is a safe ingredient present in joint fluid, cartilage, and skin in the human body. However, non-crosslinked hyaluronic acid is ineffective in one day after injection into the skin. Therefore, many companies cross-link hyaluronic acid to make fillers that have a 1-1.5 year effect. At this time, the more crosslinking agents used for crosslinking, the more important is the technology to completely remove the crosslinking agent used because it may cause toxicity in the human body.

Third generation fillers are calcium fillers made of materials that do not readily degrade in vivo and polymethylmethacrylate (PMMA) fillers that do not permanently degrade. Calcium fillers do not decompose well, so the effect is long lasting if the procedure is good, but if you do not like the results after the procedure, you have to wait a long time until the raw material is completely biodegraded have. PMMA fillers can be expected to have a permanent effect, but it is difficult to remove if the procedure is wrong. In addition, the raw material remains in the human body for a long time, so the side effects are high, and the market is in danger of exiting the market.

Fourth-generation fillers are currently attracting much attention in the market as fillers using biodegradable polymers. Biodegradable polymer fillers, unlike hyaluronic acid fillers that maintain the volume of the skin in the volume of the product itself, are fillers that naturally restore and maintain the volume by inducing the production of collagen as the polymer biodegrades. The maintenance period can be controlled by the molecular weight of the polymer, and currently released products can maintain the volume for various periods of 1 to 4 years. However, there is a disadvantage that the initial volume decreases significantly within one week after the procedure, and the volume gradually rises over four weeks to six months.

Korean Patent No. 1572256 discloses solubilizing a polycaprolactone polymer in a solvent and then mixing the solubilized polycaprolactone polymer with a liquid containing a surfactant and having a viscosity ranging from 20 to approximately 10,000 cP; A process for preparing polycaprolactone-comprising microparticles comprising forming polycaprolactone-comprising microparticles from a solution obtained, and at least i) a diameter in the range of from 5 to 200 μm, ii) uniformity obtained by said process Homogenous density, morphology and content, iii) essentially spherical microspheres, iv) soft particles characterized by a smooth surface. However, these microparticles have a smooth and smooth surface, and the prepared filler has a disadvantage in that the initial volume decreases significantly within one week after the procedure, and then gradually increases in volume over 4 weeks to 6 months.

Korean Patent No. 1142234 includes a porous biodegradable polymer microparticle used as a bulking agent or filler for urinary incontinence after incorporation, and a temperature-sensitive phase-transfer biocompatible polymer aqueous solution, which is converted into a gel form in vitro and then introduced into the body. Injectables are disclosed. The biodegradable polymer microparticles have a porosity of 80 to 96%, the pore diameter of 25 to 500㎛, the diameter of the particle ranges from 100 to 5,000㎛, the size of the particles is too large, significant difficulty in injection injection Not only that, but it is almost impossible to use for facial use.

Korean Patent Publication No. 2017-0126416 An injection composition for molding fillers comprising porous biodegradable microparticles and water-soluble natural polymers, the composition comprising a combination of content of porous biodegradable microparticles, crosslinking rate of hyaluronic acid, crosslinked hyaluronic acid, and purified water. Although it can be described that the collagen content can be improved, according to the description, it is impossible to prepare porous microparticles per se, and the tissue resilience after 8 weeks of injection is still insufficient at only 38 to 76%.

Therefore, it is biocompatible, biodegradable polymer material that can induce collagen production, control the maintenance period for a long time, and maintain the volume right after the procedure like the existing hyaluronic acid filler, and can also be injected with needles with small particle size. There is a continuing need for polymer fillers that can minimize pain and foreign body feeling after injection.

The present invention is to solve the problems of the above-mentioned conventional filler products, induce collagen generation after injection into the human body, and is a biodegradable polymer material with a long maintenance period, as well as maintaining the volume immediately after the procedure, like conventional hyaluronic acid fillers, It is a technical problem to provide a molded filler composition which can be injected with a needle having a smaller size to minimize the pain and foreign body feeling felt after the injection.

One aspect of the present invention

Porous fine particles of a biodegradable polymer; And

Provided is a molded filler composition comprising a biocompatible carrier.

In an embodiment, the porous microparticles of the biodegradable polymer can be one or more of the following i) to i), for example all of i) to i) below:

Iii) spherical;

Ii) particle diameter 10 to 200 μm;

Iii) have pores with a diameter of 0.1-20 μm;

Iii) 5-50% porosity.

Molding filler composition according to the present invention may have a larger volume compared to the same mass as the existing product due to the porous polymer particles, it can provide an effect of maintaining the volume due to the volume of the polymer immediately after the procedure.

The molded filler composition of the present invention is mixed with the polymer particles and the carrier similarly to the conventional polymer filler, and like the conventional products, the carrier is absorbed first and the remaining polymer is slowly biodegraded to induce self collagen production of surrounding tissues for a long time, thereby making hyaluronic acid Longer retention period than the filler. In addition, the molding filler composition according to the present invention has almost no volume reduction effect because the volume of the polymer itself is larger than that of the existing polymer filler even when the carrier is absorbed first. In addition, by adjusting the porosity of the porous particles can be adjusted to provide a volume as desired by adjusting the degree of volume reduction immediately after the procedure. In one embodiment, the molding filler composition of the present invention may be one or more weeks after the injection to maintain at least 80%, for example at least 85%, for example at least 90%, for example at least 95% of the initial volume.

Therefore, the molded filler composition according to the present invention can be used in various parts of the body including the face as a filler used in humans depending on the particle size and porosity. In addition, the particle size can be injected with a needle that is small in size to minimize the pain and foreign body feeling after the injection.

1 is a scanning electron microscope (SEM) photograph of an embodiment of porous fine particles of a biodegradable polymer, which is used in the molding filler composition according to the present invention.
2 is a scanning electron microscope (SEM) photograph of the fine particles according to Comparative Example 1 of the present invention.
3 is a scanning electron microscope (SEM) photograph of the fine particles according to Comparative Example 2 of the present invention.
4 is a view showing the particle size and distribution of the fine particles according to Example 1 and Comparative Example 1 of the present invention.
5 is a photograph of the injection site after injecting the molded filler composition prepared in Example 1 of the present invention and the filler of Comparative Example 1 into the rat.

Hereinafter, the present invention will be described in more detail.

The molding filler composition of the present invention comprises porous fine particles of a biodegradable polymer made of a polymer having biocompatibility and biodegradability. In the present invention, biodegradable polymers that can be used in the preparation of porous fine particles of biodegradable polymers are polylactic acid (Poly (lactic acid)), polyglycolic acid (Poly (glycolic acid)), polydioxanone (Poly (dioxanone) )), Poly (caprolactone), lactic acid-glycolic acid copolymer (Poly (lactic acid-co-glycolic acid)), dioxanone-caprolactone copolymer (Poly (dioxanone-co-caprolactone) And lactic acid-caprolactone copolymers (Poly (lactic acid-co-caprolactone)), derivatives thereof, and copolymers thereof. Preferably, they are polylactic acid or polycaprolactone, particularly preferably polycaprolactone.

In addition, the biodegradable polymer may have a number average molecular weight (Mn) of preferably 10,000 to 1,000,000 g / mol, more preferably 10,000 to 100,000 g / mol in order to maintain the filler retention period for 2 years or more. .

The particle size of the porous microparticles of the biodegradable polymer should be smaller than the diameter of the needle used to enable injection, and the shape of the particles is substantially spherical in shape so as not to cause pain and feel to the patient. to be.

In one embodiment, the particle size (particle diameter) of the porous fine particles of the biodegradable polymer may be typically 200 μm or less, and preferably has a diameter of 10 μm or more so as not to be phagocytized by macrophages in biological tissues. In a preferred embodiment, the porous microparticles of the biodegradable polymer have a diameter of less than 10-100 μm, more preferably 10-80 μm, even more preferably 10-50 μm, most preferably 20-40 μm.

In a preferred embodiment, the porous fine particles of the biodegradable polymer have d _{10, which} is the basis of the particle size distribution, larger than 20 μm, d ₉₀ smaller than 100 μm, preferably d ₁₀ larger than 20 μm, and d ₉₀ is 60 μm. Smaller, more preferably d ₁₀ is larger than 25 μm and d ₉₀ is smaller than 40 μm.

Also in a preferred embodiment, the porous microparticles of the biodegradable polymer should have a span value of less than 1 indicating an even distribution of the particles, preferably less than 0.8, and more preferably less than 0.6. The span value is larger when the particle distribution is wider, and becomes closer to zero when the distribution is narrower. The span value is calculated by the following equation.

[D ₁₀ , D ₅₀ , D ₉₀ Definition: A particle size distribution curve representing the relative cumulative amount of particles by size, corresponding to 10%, 50%, and 90% of the maximum value in the cumulative distribution of the particles. Measured, plotted, and divided into 10 pieces, showing the size of particles corresponding to 1/10, 5/10, 9/10 respectively.]

The porous fine particles of the biodegradable polymer used in the present invention have pores, and thus have more volume to the same mass depending on the porosity.

In one embodiment, the porosity of the porous fine particles of the biodegradable polymer may be 5 to 50%, preferably 10 to 50%, more preferably 10 to 30%.

In the present invention, the "porosity" is obtained by the following formula.

Porosity = (volume of porous polymeric microparticles-volume of nonporous polymeric microparticles) / volume of porous polymeric microparticles x 100

The pore size (diameter) of the porous fine particles of the biodegradable polymer according to the present invention may be 0.1㎛ ~ 20㎛, preferably 0.1 ~ 10㎛.

The method for preparing porous microparticles of such biodegradable polymers may be emulsification, solvent evaporation, precipitation, or other methods generally used in the art, and the present invention is not limited by the method for preparing porous microparticles.

The amount of the porous microparticles of the biodegradable polymer included in the molding filler composition of the present invention may be 10 to 50% by weight, more specifically 10 to 30% by weight, based on 100% by weight of the composition. It can be adjusted according to the desired volume effect of the injection site.

The molded filler composition of the present invention also includes one or more biocompatible carriers. Such carriers are usually absorbed into the body within one to six months after injection.

In one embodiment, the biocompatible carrier may be other than hyaluronic acid, such as crosslinked hyaluronic acid.

In another embodiment, the biocompatible carrier is a temperature sensitive sol-gel phase transfer biocompatible polymer such as polyethylene oxide (PEO) -polypropylene oxide (PPO) copolymer, polyethylene oxide (PEO) -polylactic acid (PLA) copolymer At least one temperature sensitive sol-gel phase change not selected from the group consisting of polyethylene oxide (PEO) -polyglycolic acid (PLGA) copolymer and polyethylene oxide (PEO) -polycaprolactone (PCL) copolymer It may be.

In another embodiment, the biocompatible carrier may be selected from carboxymethyl cellulose, hyaluronic acid, dextran, collagen, and combinations thereof.

The amount of the biocompatible carrier included in the molding filler composition of the present invention may be 50 to 90% by weight, and more specifically 70 to 90% by weight, based on 100% by weight of the composition.

In addition to the above components, the biocompatible carrier may further include additive components normally included in the injection formulation, for example, a lubricant such as glycerin, a phosphate buffer, and the like.

The molding filler composition of the present invention may be for use as an injection. The molded filler injectable composition of the present invention can be provided in a sterile syringe or a sterile vial, and is easy to use because it does not require pretreatment, and is 100% biodegradable over a predetermined time after injection, so that it does not leave foreign substances in biological tissues and is safe and animal. It does not cause allergies because it does not contain any derived material.

In one embodiment, the molded filler injection of the present invention comprises from 23 gauge (nominal outer diameter 0.635 mm, nominal inner diameter 0.318 mm) to 30 gauge (nominal outer diameter 0.305 mm, nominal inner diameter 0.140 mm), for example 25 gauge (nominal outer diameter 0.508 mm) , Nominal inner diameter 0.241 mm) to 29 gauge (nominal outer diameter 0.330 mm, nominal inner diameter 0.165 mm) can be injected into the needle. The molding filler injection composition according to the present invention can be injected with a thinner needle than a conventional product, and thus can be used more safely and effectively for face molding. In addition, the molding filler composition of the present invention can produce more volume effect with the same amount of polymer compared to existing polymer products (eg, polymer ratio of 30%), so that the volume effect can be maintained even if the carrier is absorbed. Therefore, the molding filler composition of the present invention can be preferably used for wrinkle improvement, face molding or body molding.

Hereinafter, the present invention will be described in more detail based on Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention should not be construed as being limited by these examples.

[ Example ]

Example  One

Polycaprolactone (PCL) having a number average molecular weight of 50,000 g / mol was used to prepare porous fine particles (porosity: 10%) of a biodegradable polymer having a diameter of 20 to 40 µm by membrane emulsification. That is, 1 g of a biodegradable polymer and 0.2 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in an aqueous PVA solution to prepare porous fine particles of a biodegradable polymer having a porosity of 10%.

The porous fine particles of the biodegradable polymer thus prepared were mixed with a carrier made of 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At this time, the mixing ratio was 30% by weight of the porous fine particles and 70% by weight of the carrier based on 100% by weight of the mixture.

Example  2

Using polycaprolactone (PCL) having a number average molecular weight of 50,000 g / mol, porous fine particles (porosity: 20%) of a biodegradable polymer having a diameter of 20 to 40 µm were prepared by membrane emulsification. That is, 1 g of biodegradable polymer and 0.3 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in PVA aqueous solution to prepare porous microparticles of biodegradable polymer having a porosity of 20%.

Porous microparticles of the prepared biodegradable polymer were mixed with a carrier made of 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At this time, the mixing ratio was 30% by weight of the porous fine particles and 70% by weight of the carrier based on 100% by weight of the mixture.

Example  3

Polycaprolactone (PCL) having a number average molecular weight of 50,000 g / mol was used to prepare porous fine particles (porosity: 10%) of a biodegradable polymer having a diameter of 20 to 40 µm by membrane emulsification. That is, 1 g of a biodegradable polymer and 0.2 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in an aqueous PVA solution to prepare porous fine particles of a biodegradable polymer having a porosity of 10%.

 Porous microparticles of the prepared biodegradable polymer were mixed with a carrier made of 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At this time, the mixing ratio was 40% by weight of the porous fine particles and 60% by weight of the carrier based on 100% by weight of the mixture.

Example  4

Using polycaprolactone (PCL) having a number average molecular weight of 50,000 g / mol, porous fine particles (porosity: 20%) of a biodegradable polymer having a diameter of 20 to 40 µm were prepared by membrane emulsification. That is, 1 g of biodegradable polymer and 0.3 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in PVA aqueous solution to prepare porous microparticles of biodegradable polymer having a porosity of 20%.

Porous microparticles of the prepared biodegradable polymer were mixed with a carrier made of 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At this time, the mixing ratio was 40% by weight of the porous fine particles and 60% by weight of the carrier based on 100% by weight of the mixture.

Example  5

Using polycaprolactone (PCL) having a number average molecular weight of 50,000 g / mol, porous microparticles (porosity: 10%) of a biodegradable polymer having a diameter of 20 to 40 µm were prepared by the Microfluidic method. In other words, 1 g of biodegradable polymer PCL and 0.2 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and microfluidic devices were used to uniformly add PVA aqueous solution to prepare porous microparticles of biodegradable polymer having a porosity of 10%. .

The porous fine particles of the biodegradable polymer thus prepared were mixed with a carrier made of 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At this time, the mixing ratio was 30% by weight of the porous fine particles and 70% by weight of the carrier based on 100% by weight of the mixture.

Example  6

Using polycaprolactone (PCL) having a number average molecular weight of 50,000 g / mol, porous microparticles (porosity: 10%) of a biodegradable polymer having a diameter of 20 to 40 µm were prepared by the Microfluidic method. That is, 1 g of biodegradable polymer PCL and 0.3 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and microfluidic devices were used to uniformly add PVA aqueous solution to prepare porous microparticles of biodegradable polymer having a porosity of 20%. .

Porous microparticles of the prepared biodegradable polymer were mixed with a carrier made of 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At this time, the mixing ratio was 30% by weight of the porous fine particles and 70% by weight of the carrier based on 100% by weight of the mixture.

Example  7

Using polylactic acid (PLA) having a number average molecular weight of 80,000 g / mol, porous fine particles (porosity: 10%) of a biodegradable polymer having a diameter of 20 to 40 µm were prepared by membrane emulsification. That is, 1 g of biodegradable polymer PLA and 0.2 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in an aqueous PVA solution to prepare porous microparticles of biodegradable polymer having a porosity of 10%.

The porous fine particles of the biodegradable polymer thus prepared were mixed with a carrier made of 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At this time, the mixing ratio was 30% by weight of the porous fine particles and 70% by weight of the carrier based on 100% by weight of the mixture.

Comparative example  One

We purchased a facial filler (Ellanse®) from PCL.

Comparative example  2

Facial fillers (Sculptra®) were purchased from existing polylactic acid (PLA).

Experimental Example  One

The porous fine particles of the biodegradable polymer obtained in Example 1 and the fine particles of Comparative Examples 1 and 2 were observed by scanning electron microscope (SEM). The results are shown in FIGS. 1, 2 and 3, respectively. As shown in FIG. 1, the porous fine particles of the biodegradable polymer according to the present invention have a particle diameter of 20 to 40 μm and a pore diameter of 0.1 to 6 μm, and thus have a smaller size and a smaller diameter uniformity than conventional products. Has one pore

Experimental Example  2

Particle sizes and distributions of the porous microparticles of the biodegradable polymer prepared in Example 1 and the microparticles of Comparative Example 1 were measured. The results are shown in FIG. As shown in FIG. 4, the porous fine particles of the biodegradable polymer according to the present invention have a smaller overall size than the fine particles of Comparative Example 1 (Example 1: 20 to 40 μm, Comparative Example 1: 30 to 50 μm), and an average value. It can be seen that it is more uniform and shows a narrower distribution. The results are shown in Table 1.

D ₁₀ D ₅₀ D ₉₀ CV ¹⁾ span Example 1 24.92 μm 29.82 μm 36.59 μm 19.1% 0.391 Comparative Example 1 31.06㎛ 38.83 μm 51.01 μm 24.3% 0.514

1) C.V. (coefficient of variation): The standard deviation divided by the mean value, which is a measure of the degree of relative scattering, and the closer the calculated value is to 0, the denser the particle is and the less scatter it means.

Experimental Example  3

The mixed formulation was filled in a syringe and then 200 μl injected into the back of the hairless mice. The molded filler compositions prepared in Examples 1 to 7 and the polymer fillers of Comparative Examples 1 and 2 were injected into mice, and photographs of the injection sites for 2 weeks are shown in FIG. 5. The size of the injection-injected site was measured, and the size change was continuously measured at regular intervals. The results are shown in Table 2.

As shown in Table 2, in the case of the filler formulation including the porous fine particles of the biodegradable polymer according to the present invention it can be seen that the initial volume reduction is significantly improved.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Comparative Example 1 Comparative Example 2 Volume immediately after the procedure 100% 100% 100% 100% 100% 100% 100% 100% 100% Volume after 1 week 90% 95% 95% 100% 90% 95% 85% 50% 10% Volume after 3 weeks 100% 105% 100% 110% 100% 100% 95% 80% 60%

Claims (15)

Porous fine particles of a biodegradable polymer; And
A molded filler composition comprising a biocompatible carrier. The molding filler composition of claim 1, wherein the porous microparticles of the biodegradable polymer satisfy at least one of the following i) to iv):
Iii) spherical;
Ii) particle diameter from 10 to 200 mu m;
Iii) pores with a diameter of 0.1-20 탆;
Iii) 5 to 50% porosity. The molding filler composition according to claim 2, wherein the porous fine particles of the biodegradable polymer satisfy all of i) to iv). The method of claim 1, wherein the biodegradable polymer is polylactic acid, polyglycolic acid, polydioxanone, polycaprolactone, lactic acid-glycolic acid copolymer, dioxanone-caprolactone copolymer, lactic acid-caprolactone copolymer, Molding filler composition, characterized in that at least one selected from the group consisting of derivatives and copolymers thereof. The molding filler composition according to claim 1, wherein the number-average molecular weight (Mn) of the biodegradable polymer is 10,000 to 1,000,000 g / mol. The molding filler composition according to claim 2, wherein the porous fine particles of the biodegradable polymer have a diameter of less than 10 to 100 μm. The molding filler composition according to claim 2, wherein the porous fine particles d ₁₀ of the biodegradable polymer are larger than 20 μm, and d ₉₀ is smaller than 100 μm. The molded filler composition of claim 2, wherein the porous fine particle span value of the biodegradable polymer is less than one. The molding filler composition of claim 1, wherein the biocompatible carrier is not hyaluronic acid. The molding filler composition of claim 1, wherein the biocompatible carrier is not a temperature sensitive sol-gel phase change biocompatible polymer. The molded filler composition of claim 1, wherein the biocompatible carrier is selected from carboxymethylcellulose, dextran, collagen, and combinations thereof. The molded filler composition according to any one of claims 1 to 8, wherein the content of the porous fine particles of the biodegradable polymer is 10 to 50% by weight, and the content of the biocompatible carrier is 50 to 90% by weight. The molding filler composition according to any one of claims 1 to 8 for use as an injection. The molding filler composition according to claim 13, which is injected with a needle of 23 to 30 gauge. The molding filler composition according to any one of claims 1 to 8, for use for face molding.

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