Porous microparticles of biodegradable polymer, and polymer filler comprising same

Abstract

The present invention relates to porous microparticles of a biodegradable polymer, and a polymer filler comprising the same.

Claims

1. Porous microparticle of biodegradable polymer, having i) spherical shape, ii) particle diameter of 10 to 50 μm, iii) pore with a diameter of 0.1 to 10 μm, and iv) porosity ratio of 10 to 20%; and d.sub.10 of greater than 20 μm, d.sub.90 of less than 60 μm, and a span value of less than 0.8; wherein the span value is calculated by the following equation: $\mathrm{span}=\frac{D_{90}-D_{10}}{D_{50}}$ wherein D.sub.10, D.sub.50 and D.sub.90 represent size values corresponding to 10%, 50%, and 90%, respectively, of the maximum value in accumulated distribution of particles, represented as the particle sizes corresponding to 1/10, 5/10, and 9/10, respectively, of the particle size distribution curve showing the relatively accumulated amounts of particles according to the size when it is measured, plotted and divided into 10 fractions; wherein the biodegradable polymer is at least one selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(dioxanone), poly(caprolactone), poly(lactic acid-co-glycolic acid), poly(dioxanone-co-caprolactone), poly(lactic acid-co-caprolactone), derivatives thereof and copolymers thereof.

2. The porous microparticle of biodegradable polymer according to claim 1, wherein the biodegradable polymer has a number average molecular weight (Mn) in a range of 10,000 to 1,000,000 g/mol.

3. Polymer filler comprising: the porous microparticle of biodegradable polymer according to claim 1; and one or more biocompatible carriers.

4. The polymer filler according to claim 3, wherein the biocompatible carrier is selected from carboxymethyl cellulose, hyaluronic acid, dextran, collagen and combinations thereof.

5. The polymer filler according to claim 3, wherein, based on 100% by weight of the polymer filler, the amount of the porous microparticle of biodegradable polymer is 10 to 50% by weight and the amount of the biocompatible carrier is 50 to 90% by weight.

6. The polymer filler according to claim 3, which is prepared in an injection formulation.

7. The polymer filler according to claim 3, which is used for wrinkle improvement, facial plastic procedure or body plastic procedure.

Description

BRIEF EXPLANATION OF THE DRAWINGS

(1) FIG. 1 shows scanning electron microscope (SEM) photographs of an embodiment of the porous microparticle of biodegradable polymer used in the biodegradable polymer filler according to the present invention.

(2) FIG. 2 shows scanning electron microscope (SEM) photographs of the microparticle according to Comparative Example 1 of the present invention.

(3) FIG. 3 shows scanning electron microscope (SEM) photographs of the microparticle according to Comparative Example 2 of the present invention.

(4) FIG. 4 shows the sizes and distributions of the microparticles according to Example 1 and Comparative Example 1 of the present invention.

(5) FIG. 5 shows photographs of injection parts taken after the injection of the polymer filler prepared in Example 1 and the filler of Comparative Example 1 of the present invention into mice.

DETAILED DESCRIPTION

(6) The present invention is explained in more detail below.

(7) The polymer filler of the present invention uses porous microparticle of biodegradable polymer, prepared from a polymer having biocompatibility and biodegradability. In the present invention, the biodegradable polymer, which can be used for preparing the porous microparticle of biodegradable polymer, can be at least one selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(dioxanone), poly(caprolactone), poly(lactic acid-co-glycolic acid), poly(dioxanone-co-caprolactone), poly(lactic acid-co-caprolactone), derivatives thereof and copolymers thereof. Preferably, the biodegradable polymer is poly(lactic acid) or poly(caprolactone), and more preferably poly(caprolactone).

(8) Also, in order to maintain the filler retention period for 2 years or longer, the biodegradable polymer can have a number average molecular weight (Mn) in a range of preferably 10,000 to 1,000,000 g/mol, and more preferably 10,000 to 100,000 g/mol.

(9) The particle size of the porous microparticle of biodegradable polymer should be smaller than the diameter of the injection needle so that it can be injected, and the shape of the particle is substantially in spherical form so as not to cause pain to the patient and not to be felt by touch.

(10) In an embodiment, the particle size (particle diameter) of the porous microparticle of biodegradable polymer can be typically 200 μm or less, and it preferably has a diameter of 10 μm or greater in order not to be eaten by macrophage in living tissues. In a preferable embodiment, the porous microparticle of biodegradable polymer has a diameter of 10 to less than 100 μm, more preferably 10 to 80 μm, still more preferably 10 to 50 μm, and most preferably 20 to 40 μm.

(11) In a preferable embodiment, as the standard of particle size distribution, the porous microparticle of biodegradable polymer has d.sub.10 of greater than 20 μm and d.sub.90 of less than 100 μm, preferably d.sub.10 of greater than 20 μm and d.sub.90 of less than 60 μm, and more preferably d.sub.10 of greater than 25 μm and d.sub.90 of less than 40 μm.

(12) Also, in a preferable embodiment, the porous microparticle of biodegradable polymer should have a span value, which shows uniform distribution of particles, of less than 1, preferably less than 0.8, and more preferably less than 0.6. The span value becomes greater as the particle size distribution becomes broad, and it becomes close to 0 as the particle size distribution becomes narrow. The span value is calculated by the following equation:

(13) $\mathrm{span}=\frac{D_{90}-D_{10}}{D_{50}}$

(14) [Definitions of D.sub.10, D.sub.50 and D.sub.90: Size values corresponding to 10%, 50% and 90%, respectively, of the maximum value in accumulated distribution of particles, represented as the particle sizes corresponding to 1/10, 5/10 and 9/10, respectively, of the particle size distribution curve showing the relatively accumulated amounts of particles according to the size) when it is measured, plotted and divided into 10 fractions.]

(15) Since the porous microparticle of biodegradable polymer used in the present invention has pores, it has a larger volume per the same mass according to the porosity ratio.

(16) In an embodiment, the porosity ratio of the porous microparticle of biodegradable polymer can be 5 to 50%, preferably 10 to 50%, and more preferably 10 to 30%.

(17) In the present invention, the “porosity ratio” is obtained according to the following equation:
Porosity ratio=(Volume of porous polymer microparticle−Volume of non-porous polymer microparticle)/Volume of porous polymer microparticle×100

(18) The pore size (diameter) of the porous microparticle of biodegradable polymer according to the present invention can be 0.1 μm to 20 μm, and preferably 0.1 to 10 μm.

(19) As a method for preparing such porous microparticle of biodegradable polymer, an emulsification method, a solvent evaporation method, a precipitation method or other generally used in this field of art can be used, and the present invention is not limited by any method for preparing porous microparticle.

(20) The amount of the porous microparticle of biodegradable polymer contained in the polymer filler of the present invention can be typically 10 to 50% by weight, and more concretely 10 to 30% by weight, based on 100% by weight of the polymer filler, and it can be adjusted according to the desired volume effect of the desired injection part.

(21) The polymer filler of the present invention also comprises one or more biocompatible carriers. Such a carrier is absorbed in body typically within 1 day to 6 months after the injection.

(22) In an embodiment, a carrier selected from carboxymethyl cellulose, hyaluronic acid, dextran, collagen and combinations thereof can be used as the biocompatible carrier.

(23) The amount of the biocompatible carrier contained in the polymer filler of the present invention can be typically 50 to 90% by weight, and more concretely 70 to 90% by weight, based on 100% by weight of the polymer filler.

(24) As well as the ingredients explained above, additive ingredients—for example, a lubricant such as glycerin, phosphate buffer or the like conventionally comprised in an injection formulation—can be further comprised in the biocompatible carrier.

(25) The polymer filler of the present invention can be an injection formulation preferably. An injection formulation of the polymer filler of the present invention can be provided as being contained in a sterilized injection syringe or a sterilized vial, and it has high use convenience since no pretreatment is needed, it is safe since 100% thereof is biodegraded over a predetermined time after the injection leaving no foreign substance in living tissues, and it does not cause allergic reaction since it contains no substances derived from animal at all.

(26) In addition, as compared with the existing polymer product (for example, polymer content of 30%), the polymer filler of the present invention can provide a greater volume effect with the same amount of polymer, and thus the volume effect can be maintained even if the carrier is absorbed. Therefore, the polymer filler of the present invention can be used preferably for wrinkle improvement, facial plastic procedure or body plastic procedure.

(27) The present invention is explained in more detail by the following examples. However, the following examples are intended only to illustrate the present invention, and should not be interpreted as limiting the scope of the present invention in any manner.

EXAMPLE

Example 1

(28) By using polycarprolactone (PCL) with a number average molecular weight of 50,000 g/mol, porous microparticles of biodegradable polymer (porosity ratio: 10%) in 20 to 40 μm diameter were prepared through a membrane emulsification method. That is, 1 g of the biodegradable polymer PCL and 0.2 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in a PVA aqueous solution to prepare porous microparticles of biodegradable polymer with porosity ratio of 10%.

(29) The prepared porous microparticles of biodegradable polymer was mixed with a carrier prepared from 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At that time, the mixing ratio was, based on 100% by weight of the mixture, 30% by weight of the porous microparticles and 70% by weight of the carrier.

Example 2

(30) By using polycarprolactone (PCL) with a number average molecular weight of 50,000 g/mol, porous microparticles of biodegradable polymer (porosity ratio: 20%) in 20 to 40 pan diameter were prepared through a membrane emulsification method. That is, 1 g of the biodegradable polymer PCL and 0.3 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in a PVA aqueous solution to prepare porous microparticles of biodegradable polymer with porosity ratio of 20%.

(31) The prepared porous microparticles of biodegradable polymer was mixed with a carrier prepared from 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At that time, the mixing ratio was, based on 100% by weight of the mixture, 30% by weight of the porous microparticles and 70% by weight of the carrier.

Example 3

(32) By using polycarprolactone (PCL) with a number average molecular weight of 50,000 g/mol, porous microparticles of biodegradable polymer (porosity ratio: 10%) in 20 to 40 μm diameter were prepared through a membrane emulsification method. That is, 1 g of the biodegradable polymer PCL and 0.2 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in a PVA aqueous solution to prepare porous microparticles of biodegradable polymer with porosity ratio of 10%.

(33) The prepared porous microparticles of biodegradable polymer was mixed with a carrier prepared from 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At that time, the mixing ratio was, based on 100% by weight of the mixture, 40% by weight of the porous microparticles and 60% by weight of the carrier.

Example 4

(34) By using polycarprolactone (PCL) with a number average molecular weight of 50,000 g/mol, porous microparticles of biodegradable polymer (porosity ratio: 20%) in 20 to 40 μm diameter were prepared through a membrane emulsification method. That is, 1 g of the biodegradable polymer PCL and 0.3 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and homogeneously mixed in a PVA aqueous solution to prepare porous microparticles of biodegradable polymer with porosity ratio of 20%.

(35) The prepared porous microparticles of biodegradable polymer was mixed with a carrier prepared from 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At that time, the mixing ratio was based on 100% by weight of the mixture, 40% by weight of the porous microparticles and 60% by weight of the carrier.

Example 5

(36) By using polycarprolactone (PCL) with a number average molecular weight of 50,000 g/mol, porous microparticles of biodegradable polymer (porosity ratio: 10%) in 20 to 40 μm diameter were prepared through a microfluidic method. That is, 1 g of the biodegradable polymer PCL and 0.2 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and uniformly fed into a PVA aqueous solution by using a microfluidic device to prepare porous microparticles of biodegradable polymer with porosity ratio of 10%.

(37) The prepared porous microparticles of biodegradable polymer was mixed with a carrier prepared from 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At that time, the mixing ratio was, based on 100% by weight of the mixture, 30% by weight of the porous microparticles and 70% by weight of the carrier.

Example 6

(38) By using polycarprolactone (PCL) with a number average molecular weight of 50,000 g/mol, porous microparticles of biodegradable polymer (porosity ratio: 20%) in 20 to 40 μm diameter were prepared through a microfluidic method. That is, 1 g of the biodegradable polymer PCL and 0.3 g of tetradecane for pore formation were dissolved in 20 g of methylene chloride, and uniformly fed into a PVA aqueous solution by using a microfluidic device to prepare porous microparticles of biodegradable polymer with porosity ratio of 20%.

(39) The prepared porous microparticles of biodegradable polymer was mixed with a carrier prepared from 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At that time, the mixing ratio was, based on 100% by weight of the mixture, 30% by weight of the porous microparticles and 70% by weight of the carrier.

Example 7

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

(41) The prepared porous microparticles of biodegradable polymer was mixed with a carrier prepared from 3% by weight of carboxymethyl cellulose, 27% by weight of glycerin and 70% by weight of phosphate buffer. At that time, the mixing ratio was, based on 100% by weight of the mixture, 30% by weight of the porous microparticles and 70% by weight of the carrier.

Comparative Example 1

(42) Commercially available facial filler (Ellanse®) using PCL as the raw material was purchased.

Comparative Example 2

(43) Commercially available facial filler (Sculptra®) using polylactic acid (PLA) as the raw material was purchased.

Experimental Example 1

(44) The porous microparticles of biodegradable polymer obtained in the above Example 1 and the microparticles of Comparative Examples 1 and 2 were observed with scanning electron microscope (SEM). The results are shown in FIG. 1, FIG. 2 and FIG. 3, respectively. As shown in FIG. 1, the porous microparticles of biodegradable polymer according to the present invention had particle diameter of 20 to 40 μm and pore diameter of 0.1 to 6 μm, that is, smaller particle size and uniform pores with smaller diameter as compared with the existing products.

Experimental Example 2

(45) The particle sizes and distributions of porous microparticles of biodegradable polymer prepared in the above Example 1 and the microparticles of Comparative Example 1 were measured. The results are shown in FIG. 4. As shown in FIG. 4, it can be confirmed that as compared with the microparticles of Comparative Example 1, the porous microparticles of biodegradable polymer according to the present invention were generally smaller (Example 1: 20 to 40 μm, Comparative Example 1: 30 to 50 μm) and more uniform in light of the average value, and showed narrower distribution. The results are shown in Table 1.

(46) TABLE-US-00001 TABLE 1 D.sub.10 D.sub.50 D.sub.90 C.V..sup.1) span Example 1 24.92 μm 29.82 μm 36.59 μm 19.1% 0.391 Comparative 31.06 μm 38.83 μm 51.01 μm 24.3% 0.514 Example 1 .sup.1)C.V. (coefficient of variation): The value of dividing standard deviation by average, and the standard for measuring the degree of relative dispersion. As the calculated value is closer to 0, it means that the particles are populated on the average and the degree of dispersion is small.

Experimental Example 3

(47) The mixed formulation was filled within a syringe and 200 μl thereof was injected into the back of a hairless mouse. The polymer fillers prepared in Examples 1 to 7 and the polymer fillers of Comparative Examples 1 and 2 were injected into the mice, and the photographs of the injection parts were taken for 2 weeks and are shown in FIG. 5. The sizes of the injection parts were measured, and the size changes were periodically checked continuously. The results are shown in Table 2.

(48) As shown in Table 2, as for the filler formulation comprising the porous microparticles of biodegradable polymer according to the present invention, it can be confirmed that the initial volume reduction after the procedure was improved remarkably.

(49) TABLE-US-00002 TABLE 2 Comp. Comp. Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 1 Example 2 Volume 100% 100% 100% 100% 100% 100% 100% 100% 100% immediately after the procedure Volume 90% 95% 95% 100% 90% 95% 85% 50% 10% after 1 week Volume 100% 105% 100% 110% 100% 100% 95% 80% 60% after 3 months