KR20150050500A - Spherical hydrogel particles using MPC and water-soluble crosslinking agent PEG-diacrylate - Google Patents

Abstract

The present invention relates to a methacryloyl phosphoryl choline (MPC) spherical hydrogel particle, and more particularly, to a hydrogel particle made of an aqueous solution of a water-in-oil (w / o) emulsion using MPC and a water- Gel particles and a method for producing the same.

Description

Spherical hydrogel particles using MPC and a water-soluble crosslinking agent (MPC and water-soluble crosslinking agent PEG-diacrylate)

The present invention relates to a methacryloyl phosphoryl choline (MPC) spherical hydrogel particle, and more particularly, to a hydrogel particle made of an aqueous solution of a water-in-oil (w / o) emulsion using MPC and a water- Gel particles and a method for producing the same.

Studies of hydrogel particles from the late 1980s to the 1990s have shown that the polymer material can be micro-sized and chemically modified on the surface and inside to form embolization, enzyme immobilization, drug delivery, etc. Has been applied in the field of. With the development of nanotechnology in the 2000s, studies on the manufacture and application of nano-sized particles using water-soluble polymers are underway. Most studies on hydrogel particles to date have used biodegradable polymers for applications in biopharmaceuticals and bio-organs, and they have been made into injectable structures for non-invasive procedures Is focused on. The field includes drug delivery systems, embolization, scaffolds for tissue engineering, bulking agents and implants, and the like. In addition, it is widely used in the fields of protein separation, concentration and stabilization, immunoassay, bioreactor, sensor, biospecific chromatography, and cosmetic filler. These hydrogel particles are made by chemical methods such as physical methods such as emulsification, coacervation, spray drying, and heterogeneous polymerization. One example is the preparation of microcapsules with walls composed of polysaccharides through a cross-linking reaction at the interface using a w / o emulsion (MC Levy et al., Int. J. Pharm., 62, 1990, 27 -35; PCT / FR93 / 00237). This method is a method for obtaining a microcapsule having a size of several microns or more in which only the interface portion is crosslinked through an interfacial crosslinking reaction occurring at the interface between the oily phase containing a crosslinking agent and the polysaccharide-containing interface in the w / o emulsion to be.

It has been found that a hydrogel can be prepared by cross-linking MPC with PEG-diacrylate using a carbodiimide crosslinker. However, a method for producing a hydrogel in an aqueous solution of a water- (International Patent Publication No. WO2011 / 038485), a polymer network using MPC crosslinked with PEG-diacrylate has been studied, but no method for producing a hydrogel in an aqueous solution of w / o emulsion has been disclosed Collagen-phosphorylcholine interpenetrating network hydrogels as corneal substitutes ", Wenguang Liu et al., Biomaterials 30 (2009) 1551-1559). The MPC hydrogels formed by these conventional methods are limited to the form of amorphous hydrogel having a large volume, which is difficult to use for cosmetic applications.

The inventors of the present invention conducted studies to prepare MPC spherical hydrogel particles by chemically crosslinking MPC present in the aqueous solution of the w / o emulsion while adjusting various parameters in manufacturing to solve the conventional problems. Specifically, the type of oil, the ratio of the oily solution to the aqueous solution of the w / o emulsion, the kind and concentration of the surfactant, and the like were determined as manufacturing parameters.

As a result, it was found that when the spherical hydrogel particles were prepared using MPC and a specific water-soluble crosslinking agent, the moisture sensitivity was much improved than that of the MPC hydrogels formed by the conventional manufacturing methods and that they could be easily dispersed on the emulsion phase without the surfactant And completed the present invention.

Accordingly, it is an object of the present invention to provide an MPC spherical hydrogel particle having an improved moisture sensitivity and being easily dispersed in an emulsion, and a method for producing the same.

In order to achieve the above object, the present invention provides a hydrogel particle made from an aqueous solution of a w / o emulsion using MPC and a water-soluble crosslinking agent and a method for producing the same.

The present invention relates to a hydrogel particle made from an aqueous solution of a w / o emulsion using MPC and a specific water-soluble crosslinking agent and a method for producing the same. The MPC spherical hydrogel is in the form of a spherical gel particle of the same size, (30 to 50 μm), the moisture sensitivity of the present invention is significantly improved compared with that of conventional MPC hydrogels, and it can be dispersed on an emulsion without a surfactant, and thus can be easily used in cosmetics and the like.

FIG. 1 is a photograph showing that when the MPC spherical hydrogel according to the present invention is dispersed in an oily phase solution, it is dispersed stably without using a surfactant.
Figure 2 is a micrograph showing that the MPC spherical hydrogel according to the present invention is stably dispersed in both w / o and o / w formulations.
3 is a photomicrograph showing the size change of the MPC spherical hydrogel before drying and after drying.
FIG. 4 is a graph showing changes in moisture change rate according to the addition of the MPC spherical hydrogel according to the present invention to w / o.

The present invention relates to spherical hydrogel particles made in an aqueous solution of a w / o emulsion using MPC and a specific water-soluble crosslinking agent and a method for producing the same.

Hereinafter, the present invention will be described more specifically.

The method for producing spherical hydrogel particles using MPC and the water-soluble crosslinking agent according to the present invention

a) dissolving a surfactant in an oil component to prepare an oily phase solution;

b) dissolving MPC and a water-soluble crosslinking agent in a solvent to prepare an aqueous solution;

c) adding the solution of b) to the solution of a) to form a w / o emulsion;

d) heating the w / o emulsion of c) at 40 to 150 캜 to proceed a crosslinking reaction between the crosslinking agent and the MPC on the aqueous solution; And

e) recovering the MPC spherical hydrogel particles from the w / o emulsion of d).

The oil component used for preparing the MPC spherical hydrogel particles according to the present invention may be selected from the group consisting of vegetable, mineral, silicone oil and synthetic oil, preferably cetyl ethylhexanoate ethyl hexanoate, CEH, dodecane, heptane and the like.

As the surfactant used for preparing the MPC spherical hydrogel particles according to the present invention, at least one surfactant capable of stabilizing the w / o emulsion can be generally used, and preferably cetyl PEG / PPG (PEG / PPG-10/1 dimethicone (ABIL EM-90)), sorbitan sesquioleate (ARLACEL 83), polyethylene glycol dipolyhydroxy stearate stearate (ARLACEL P135)) can be used.

In the present invention, the content of the surfactant is 1 to 10% by weight, preferably 2 to 6% by weight based on the total weight of the mixture of the oil phase and water phase of the w / o emulsion. The concentration of the surfactant influences the size and stability of the w / o emulsion particle. If the concentration is less than 1% by weight, the particle size increases and the stability of the particle becomes unstable. If the concentration exceeds 10% by weight, The particles are stabilized, but the purity is lowered because the surfactant becomes an impurity component which is not necessary in the finally obtained particles.

In the production of the MPC spherical hydrogel particles according to the present invention, the solvent used for preparing the aqueous solution is not particularly limited, but is preferably purified water.

In the present invention, MPC (Methacryloyl phosphoryl choline) is used in an amount of 0.1 to 20% by weight based on the total weight of the mixture of oil phase and water phase.

The water-soluble crosslinking agent used for preparing the MPC spherical hydrogel particles according to the present invention may be selected from at least one crosslinking agent having a characteristic of forming a crosslinking with a natural high-molecular polysaccharide. When bis epoxide is used as the cross-linking agent, an ether bond is formed rather than an ester bond, which is a cross-linkage which is conventionally used through esterification. Considering the use of a PEG chain as a main chain of a cross-linking agent in order to make the components forming the cross-linking structure more closely related to water when the cross-linked structure is dispersed in water, in the present invention, especially, polypropylene glycol di Polypropylene glycol diacrylate (PPG-DA) or polyethylene glycol diacrylate (PEG-DA) is preferable, and polyethylene glycol diacrylate is more preferably used. The MPC spherical hydrogel particles crosslinked with the above material exhibit a fast and high swelling in the water phase.

In the present invention, the water-soluble crosslinking agent is used in an amount of 0.1 to 10% by weight based on the total weight of the mixed liquid of oil phase and water phase.

In the present invention, it is preferable that the MPC and the water-soluble cross-linking agent are mixed in a weight ratio of 1: 9.

In the present invention, the mixing ratio of the oily phase solution in which the surfactant used to constitute the w / o emulsion is dissolved and the aqueous solution in which the MPC and the water soluble crosslinking agent are dissolved is in the range of 1: 7: 3.

The recovery of the MPC spherical hydrogel particles in e) is carried out by washing the emulsion after completion of the crosslinking reaction with an organic solvent, and then obtaining MPC spherical hydrogel particles on the aqueous solution, drying it at 70 to 90 ° C under vacuum, .

The organic solvent is not limited as long as it can be mixed with water, but is preferably selected from ethanol, methanol, isopropyl alcohol, acetone, and tetrahydrofuran.

Alternatively, in order to completely remove impurities such as oils, surfactants, and unreacted crosslinking agents that may be present in the MPC spherical hydrogel particles washed with an organic solvent, an aqueous solution in which washed MPC spherical hydrogel particles are dispersed And then washing it with an organic solvent.

The MPC spherical hydrogel particles obtained through the above-mentioned production method can be obtained by various methods such as the type and concentration of the crosslinking agent, the ratio of the aqueous solution and oily solution of the w / o emulsion, the kind of the oil used for the w / o emulsion, The particle size can be in the range of tens to hundreds of nanometers in the dry state.

The MPC spherical hydrogel particles prepared according to the present invention can be stably dispersed in an emulsified composition such as oil, w / o or o / w without a surfactant, and thus can be efficiently used in a composition for skin external application such as a cosmetic composition have.

When the MPC spherical hydrogel particles of the present invention are used in a composition for external application for skin, they may be used in an amount of about 20% by weight based on the total weight of the composition, although the content may vary depending on the intended purpose and use.

The present invention will be described in more detail with reference to the following examples and test examples. However, the following examples and test examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited in any way by these examples and test examples.

[Referential Example 1] Preparation of MPC hydrogel

The hydrogels of Examples 1 and 2 and Comparative Example 1 were prepared in the composition shown in Table 1 below (parts by weight). Specifically, Examples 1 and 2 are prepared in an aqueous solution of a w / o emulsion according to the present invention, and Comparative Example 1 is a hydrogel prepared in an aqueous phase.

number ingredient Example 1 Example 2 Comparative Example 1 Daily life One Hexane 98 98 - 2 PEG-30 dipolyhydroxystearate 2 2 - Sum 100 100 - Awards 3 PEG-DA 9 - 9 4 PPG-DA - 9 - 5 MPC One One One 6 Purified water 90 90 90 Sum 100 100 100

≪ Preparation method-Examples 1 and 2 >

1) An oily solution was prepared by mixing hexane with PEG-30 dipolyhydroxy stearate, a surfactant.

2) MPG, and PEG-DA or PPG-DA are mixed with purified water to prepare an aqueous solution.

3) To the solution of 1), the emulsion is prepared by slowly stirring the solution of 2) and mixing and stirring for 10 minutes at a speed of 1800 to 2000 rpm in an emulsifier.

4) The crosslinking reaction is carried out by heating at 70 ° C with stirring at 1800 to 2000 rpm so as to keep the emulsion.

5) After the reaction, the precipitated emulsion is precipitated in isopropyl alcohol and the precipitated MPC spherical hydrogel particles are separated.

6) 5) are separated and precipitated in isopropyl alcohol to remove impurities such as residual oil, surfactant, and unreacted crosslinking agent.

7) The obtained MPC spherical hydrogel particles are vacuum-dried at 70 to 90 ° C for 24 hours to completely remove the residual solvent.

<Manufacturing method-Comparative example 1>

MPC and PEG-DA are dissolved in water and heated at 70 ° C.

[Reference Example 2] Preparation of a composition containing MPC hydrogel

Hydrogels of Formulation Examples 1 to 4 and Comparative Formulation Examples 1 and 2 were prepared (wt%) in the compositions shown in Tables 2 and 3 below. Specifically, Formulation Examples 1 and 2 include the hydrogels of Examples 1 and 2 as w / o formulations, respectively, and Formulations 3 and 4 contain the hydrogels of Examples 1 and 2 as o / w formulations, respectively . In addition, Comparative Formulation Examples 1 and 2 are compositions of the w / o and o / w formulations containing the hydrogel of Comparative Example 1.

w / o formulation number ingredient Formulation Example 1 Formulation Example 2 compare
Formulation Example 1 compare
Formulation Example 2 Daily life One Decamethylcyclosenta siloxane 14.00 14.00 14.00 14.00 2 Dimethicone 1.00 1.00 1.00 1.00 3 PEG-10 Dimethicone 3.00 3.00 3.00 3.00 4 Cyclocentasiloxane / Polyethylene / Dimethicone / PEG.PPG 20,15 Dimethicone / Phenyl methicone 1.50 1.50 1.50 1.50 Awards 5 Purified water To 100 To 100 To 100 To 100 6 Sodium chloride 0.50 0.50 0.50 0.50 7 Butylene glycol 8.00 8.00 8.00 8.00 8 Phenoxyethanol 0.30 0.30 0.30 0.30 9 Hydrogel (Example 1 20.00 - - - 10 Hydrogel (Example 2) - 20.00 - - 11 Hydrogel (Comparative Example 1) - - 20.00 -

o / w Formulation number ingredient Formulation Example 3 Formulation Example 4 compare
Formulation Example 3 Daily life One Cetyl octanoate 7.00 7.00 7.00 2 Hydrogenated polyisobutene 3.00 3.00 3.00 3 Glycerol stearate 3.40 3.40 3.40 4 Cetyl alcohol / glyceryl stearate / PEG-5 stearate / Ceteth-20 / Steareth-20 1.00 1.00 1.00 5 Glyceryl stearate / PEG-100 stearate 1.20 1.20 1.20 Awards 6 Purified water To 100 To 100 To 100 7 Butylene glycol 6.00 6.00 6.00 8 Phenoxyethanol 0.05 0.05 0.05 9 Polyacrylate-13, polyisobutene, polysorbate 20 0.48 0.48 0.48 10 Hydrogel (Example 1 20.00 - - 11 Hydrogel (Example 2) - 20.00 - 12 Hydrogel (Comparative Example 1) - - 20.00

[Test Example 1] Properties of MPC spherical hydrogel

The MPC hydrogel of Examples 1 to 2 or Comparative Example 1, or the same amount of water as that of the hydrogel was dispersed in a single oil phase (using a hydrogenated polydecene), and then the dispersion state was observed. A micrograph and a photograph of the comparative example 1 observed with naked eyes are shown in Fig. In addition, the dispersion states of Formulation Examples 1 to 4 and Comparative Formulation Examples 1 and 3 in which the hydrogel particles according to the present invention were dispersed in the composition of w / o or o / w formulation were measured, and Formulation Examples 1 and 3 2 is a micrograph of the sample.

When Example 1 or Example 2 was dispersed on a single oil, the hydrogel particles were stably dispersed in both cases. 1 showing the dispersion state of the hydrogel particles of Example 1, the MPC spherical hydrogel prepared according to the present invention was stably dispersed in the oily phase without the surfactant, but the same amount of water It can be confirmed that the separation occurs. In addition, it can be confirmed that, when the MPC hydrogel of Comparative Example 1 is dispersed, it is not dispersed unless a surfactant is used.

2, the formulation in which the MPC spherical hydrogel particles prepared according to the present invention are dispersed can be prepared by dispersing all of the dispersions in a state in which the separation is not performed without using a surfactant, whether it is a w / o formulation or an o / w formulation .

[Test Example 2] Measurement of water content of MPC spherical hydrogel

In order to measure the water content of the MPC spherical hydrogel particles according to the present invention, the weight change before and after drying of the hydrogel particles of Example 1 was measured using a halogen humidity analyzer (Mettler Toledo) after the MPC spherical hydrogel was dried, Lt; 0 &gt; C for 60 minutes. Changes in particle size were observed with a microscope (Olympus, x200) and are shown in Fig.

The MPC spherical hydrogel particles remained 8.19 ± 0.16% after drying, indicating that the MPC spherical hydrogel bound to about 11.2 times the moisture. 3, it can be seen that the size of the MPC spherical hydrogel after drying is remarkably reduced, which is a result of a decrease in the amount of water bound to the MPC spherical hydrogel while being dried.

[Test Example 3] Measurement of moisture of MPC spherical hydrogel

In order to measure the moisture resistance of the MPC spherical hydrogel particles according to the present invention, Formulation Example 1 and Comparative Formulation Example 2 were applied to the skin to measure moisture change. For the measurement of water content, the subjects were aged 20 to 50 years old, and then they were cleaned with soap, and the skin was adapted for about 15 minutes under constant temperature and humidity conditions (20 ° C, RH 40%). The water content before coating was measured using a moisture meter (Corneometer® CM825, C + K, Germany), and then ² μl per 1 cm ² was used to prepare Formulation 1 on one side and Comparative Formulation 2 on the other side After the application, the water content was measured immediately after the application, 1 hour and 3 hours after the application, and the increase / decrease rate was calculated and shown in Table 4.

Water increase / decrease rate (%) Immediately after application After 1 hour of application After 3 hours of application Comparative Formulation Example 2 95.0 * 74.4 * 66.1 * Formulation Example 1 144.0 * 124.0 * 96.0 * * p < 0.05

As can be seen from Table 4, Formulation Example 1 containing the MPC spherical hydrogel prepared according to the present invention was compared with Comparative Formulation Example 2 containing no MPC spherical hydrogel. Immediately after application, 1 hour after application, After 144 hours, the water content was increased to 144.0%, 124.0% and 96.0%, respectively. This means that the MPC spherical hydrogel according to the present invention has a high water retention ability and thus can realize a high moisture holding ability when applied to various formulations.

Claims (14)

i) an oil phase solution in which a surfactant is dissolved in an oil component; And ii) an MPC spherical hydrogel particle crosslinked in a w / o emulsion mixed with an aqueous solution in which methacryloyl phosphoryl choline (MPC) and a water-soluble crosslinking agent are dissolved. The method according to claim 1, wherein the mixing ratio of the oily phase solution in which the surfactant is dissolved and the aqueous solution in which the methacryloylphosphorylcholine (MPC) and the water soluble crosslinking agent are dissolved is in an oil phase solution: aqueous solution = 1: 1 to 7: 3. The MPC spherical hydrogel particle according to claim 1, wherein the oil component is at least one selected from the group consisting of cetyl ethylhexanoate (CEH), dodecane, and heptane. The composition of claim 1, wherein the surfactant is selected from the group consisting of cetyl PEG / PPG-10/1 dimethicone, sorbitan sesquioleate and polyethylene glycol dipolyhydroxystearate (Polyethylene glycol dipolyhydroxy stearate). The MPC spherical hydrogel particles are at least one selected from the group consisting of polyethylene glycol dipolyhydroxy stearate. The MPC spherical hydrogel particle according to claim 1, wherein the content of the surfactant is 1 to 10% by weight based on the total weight of the mixed solution of the oily phase and the aqueous solution of the w / o emulsion. [3] The MPC spherical hydrogel particle according to claim 1, wherein the content of MPC is 0.1 to 20% by weight based on the total weight of the mixture of oil phase and water phase. The MPC spherical hydrogel particle according to claim 1, wherein the water soluble crosslinking agent is at least one selected from the group consisting of polypropylene glycol diacrylate and polyethylene glycol diacrylate. [3] The MPC spherical hydrogel particle according to claim 1, wherein the content of the water soluble crosslinking agent is 0.1 to 10% by weight based on the total weight of the mixture of oil phase and water phase. The MPC spherical hydrogel particles according to claim 1, wherein the particles have a size of 30 to 50 占 퐉. a step of crosslinking in a w / o emulsion obtained by mixing i) an oil phase solution in which a surfactant is dissolved in an oil component and ii) an aqueous phase solution in which methacryloyl phosphoryl choline (MPC) and a water soluble crosslinking agent are dissolved; Wherein the MPC spherical hydrogel particles are dispersed in water. [Claim 11] The method according to claim 10, wherein the MPC spherical hydrogel particles are prepared by the following steps:
a) preparing an oily phase solution in which a surfactant is dissolved in an oil component;
b) preparing an aqueous solution in which MPC and a water-soluble crosslinking agent are dissolved;
c) adding the solution of b) to the solution of a) to form a w / o emulsion;
d) heating the w / o emulsion of c) at 40 to 150 캜 to proceed a crosslinking reaction between the crosslinking agent and the MPC on the aqueous solution; And
e) recovering the MPC spherical hydrogel particles from the w / o emulsion of d) above. A cosmetic composition comprising MPC spherical hydrogel particles according to any one of claims 1 to 9. 13. The cosmetic composition according to claim 12, wherein the composition is an oily phase, or a w / o or o / w emulsion type composition. 14. The cosmetic composition according to claim 13, wherein the composition does not comprise a surfactant.

Images