KR20160030730A - EMULSIFIER COMPRISING POLYGLYCEROL-POLY(ε-CAPROLACTONE) BLOCK COPOLYMER - Google Patents

Abstract

The present invention relates to a semi-solid state polymer emulsifier which can stabilize an oil-in-water emulsion. According to the present invention, a polyglycerol-poly(ε-caprolactone) block copolymer uses little energy for homogenization and can easily form a nano-emulsion. Further, the block copolymer can stabilize the formed nano-emulsion for a long period of time, and thus can be used to a cosmetic product or a medicine.

Description

An emulsifier comprising polyglycerol-poly (epsilon -caprolactone) block copolymer and an emulsifier comprising polyglycerol-poly (epsilon -caprolactone)

The present invention relates to an emulsifier capable of forming a semi-solid polymer membrane capable of stabilizing an oil-in-water emulsion.

Emulsion means a heterogeneous system composed of two liquids which do not mix with each other or have very low miscibility. They are generally used in cosmetics and medicine.

Stabilization of emulsion is important because it is a heterogeneous system. Stabilization of oil-in-water emulsion or oil-in-water emulsion is affected by electrostatic interactions, steric hindrance, Maragoni effect, and mechanical stability at the interface. Surface active molecules such as surfactants and lipids are widely used as emulsifiers because they can predict the distribution at the interface between two phases from their molecular structure and molecular weight. However, the interface stabilized with such a low molecular weight material is highly unstable to external forces.

Polymeric emulsifiers have been studied as an alternative to this and are characterized by their extremely low critical micelle concentration, structural stability and specific structure because they are polymers. In addition, their biocompatibility, easy surface modification, and stimulus-response characteristics make them highly bioavailable.

In an oil-in-water emulsion, generally, the hydrophilic segment serves as a corona which is exposed to the water side, and the hydrophobic segment is attached to or partially penetrates the oil droplet, . Therefore, hydrophobic segments generally tend to have a higher solubility in oil.

However, as disclosed in Korean Patent No. 10-0562434, the present inventors have found that, even though the hydrophobic block in the amphiphilic polymer has a rather low solubility in oil, it can effectively form a solid polymer thin film at the interface between oil and water And the emulsion can be stabilized.

Briefly, the hydrophobic block in the amphiphilic polymer is low in solubility in oil, but when the mixture of amphiphilic polymer / oil is dispersed in water when dissolved at a temperature above the melting point, the amphiphilic polymer The oil droplet can be stabilized by forming a film on the semi-solid phase.

On the other hand, the nano emulsion is required to homogenize at a high pressure as compared with the preparation of a general emulsion, and it is difficult to stabilize the formed nano emulsion. Although the amphipathic polymer disclosed in Korean Patent No. 10-0562434 can form a nanoemulsion, it has a disadvantage in that it requires homogenization at a high energy level.

Therefore, the inventors of the present invention have been studying an amphiphilic polymer capable of easily forming a nano emulsion while using less energy for homogenization and stabilizing a formed nano emulsion for a long period of time. In this study, a polyglycerol-poly (epsilon -caprolactone) The present invention has been accomplished.

The present invention provides a polyglycerol-poly (epsilon -caprolactone) block copolymer and a composition for emulsifying the same.

The present invention also provides a process for preparing a polyglycerol-poly (epsilon -caprolactone) block copolymer.

The present invention also provides a method for producing a nanoemulsion using a polyglycerol-poly (epsilon -caprolactone) block copolymer.

In order to solve the above problems, the present invention provides a polymer represented by the following formula (1) and a composition for emulsifying the same:

[Chemical Formula 1]

In this formula,

m: n is 1: 20 to 10: 1,

The weight average molecular weight of the polymer is 2 kDa to 50 kDa.

The polymer represented by Formula 1 is an amphiphilic block copolymer composed of polyglycerol and poly (? -Caprolactone), and stabilizes an oil-in-water (O / W) emulsion in which particles of an oil component are dispersed in water And can be usefully used as an emulsifier.

In the case of general emulsifiers, hydrophilic and hydrophobic properties of the amphiphilic block copolymer are utilized, and the principle of stabilizing the interface between oil and water by allowing the hydrophobic block to dissolve in oil is used. Also in the formation of the emulsion, the oil, the water and the emulsifier are mixed at the same time. However, the polymer represented by Formula 1 of the present invention is slightly different from the general emulsifier in that the poly (epsilon -caprolactone) portion, which is a hydrophobic block, exhibits low solubility in oil.

Specifically, poly (epsilon -caprolactone) can be easily mixed with oil at this temperature because it can be easily melted in a semi-solid phase polymer at room temperature or a melting point of about 60 DEG C with slight warming. The polymer represented by the above formula (1) also has such properties and can be mixed well with the oil at a slight temperature. Therefore, not the method of mixing the oil, the water and the emulsifier at the same time, the oil and the polymer represented by the formula (1) are heated to dissolve the polymer in the oil. When the oil / polymer mixture is dispersed in an aqueous phase (for example, water), the oil / polymer mixture is dispersed in the form of an emulsion, wherein the hydrophilic polyglycerol moves the polymer in the emulsion particle to the particle surface , The emulsion particle can be stabilized by forming a polymer film on the semi-solid phase as the temperature is lowered to the melting point or lower.

Unlike the conventional emulsifiers conventionally used, the stabilization of the emulsion particles according to the present invention is attributed to the formation of a semi-hard phase polymer membrane. Theoretically, the polyglycerol portion of the present invention contains a large number of hydroxy groups The polymer film of the semi-insulating film is more stabilized by hydrogen bonding thereof. In the case of a general emulsifier, if the emulsion is formed and then the temperature is raised again, the emulsion disappears and layer separation may occur again with water and oil. However, in the case where the polymer membrane is formed as in the present invention, And the emulsion remains unchanged. Therefore, the stability of the emulsion is superior to that of a common emulsifier.

According to one embodiment of the present invention, the nano emulsion is sufficiently formed even at a low energy after mixing the polymer and the oil according to the present invention. Also, it was confirmed that the nanoemulsion was retained even when it was left at room temperature for 10 days or when it was frozen / thawed five times. As a result, the polymer according to the present invention can be effectively used as an emulsifier in the formation of nanoemulsion.

In the above formula (1), n and m mean the number of repeating units of poly (? -Caprolactone) and polyglycerol, respectively, and the ratio thereof affects that the nano emulsion can be formed and stabilized at low energy. The ratio (m: n) of m to n is 1:20 to 10: 1, more preferably m: n is 1: 3 to 3: 1, and most preferably 1: 3 to 1: 2 .

The weight average molecular weight (Mw) of the polymer represented by Formula 1 is preferably 2 kDa to 50 kDa. In the case of less than 2 kDa, the length of the polymer may be too small to form the semi-solid polymer membrane. When the molecular weight is more than 50 kDa, the polymer may migrate slowly to the surface of the emulsion. More preferably, the polymer represented by Formula 1 has a weight average molecular weight (Mw) of 5 kDa to 20 kDa.

The present invention also provides a process for preparing a polymer represented by the following formula (1)

[Reaction Scheme 1]

The step (a) is a step of preparing a compound represented by the formula (4) by reacting a compound represented by the formula (2) with a compound represented by the formula (3), and preparing a monomer of polyglycerol.

The step (b) is a step of polymerizing a compound represented by the formula (4) to prepare a compound represented by the formula (5), and it is preferable to use potassium tert-butoxide and THF.

Step c) is a step of reacting a compound represented by the formula (5) with? -Caprolactone to prepare a compound represented by the formula (6) in which a poly (? -Caprolactone) Lt; / RTI > is preferably used.

The step d) is preferably a step of reacting oxalic acid with a compound represented by the general formula (6) to produce a compound represented by the general formula (1), wherein acetone is used.

The present invention also relates to a method for producing a polymer electrolyte membrane, which comprises mixing a polymer represented by Formula 1 and an oil; And dispersing the polymer / oil mixture in water. The present invention also provides a method for producing an emulsion using the polymer represented by formula (1). When the polymer and the oil are mixed, the polymerization is preferably carried out at a temperature at which the polymer represented by the above formula (1) can be sufficiently dissolved, preferably about 50 to 70 ° C.

The polyglycerol-poly (epsilon -caprolactone) block copolymer according to the present invention can easily form a nano emulsion while using less energy for homogenization, can stabilize the formed nano emulsion for a long period of time, and can be used for cosmetics or pharmaceuticals .

1 shows an NMR spectrum (FIG. 1A), an FT-IR spectrum (FIG. 1B) and a DSC diagram (FIG. 1C) of PG-b-PCL prepared in an embodiment of the present invention.
FIG. 2 is a graph showing the relationship between the critical micelle concentration (FIG. 2A) of PG-b-PCL prepared in one embodiment of the present invention, the size distribution of PG-b-PCL in aqueous solution (Fig. 2C) and a photograph thereof (Fig. 2D).
FIG. 3A shows TEM images of PG-b-PCL O / W nanoemulsion of ODO, and FIG. 3B shows TEM images of PG-b-PCL O / W nanoemulsion of CEH. FIG. 3C shows a change in the size of the nanoemulsion with time, and FIG. 3D shows a change in size of the nanoemulsion according to the freezing / thawing.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example : Polyglycerol - Poly (竜 - Caprolactone ) Preparation of block copolymer

Materials Used

Glycidol (96%), p-toluenesulfonic acid monohydrate (98.5%), glycerol (99.5%), ethyl vinyl ether (98% ), 2-ethylhexanoate (tin (II) 2-ethylhexanoate, Sn (Oct) ₂ , 95%), epsilon -caprolactone (97%), dichloromethane (anhydrous, 99.8% , And potassium tert-butoxide (98%) were purchased from Sigma-Aldrich (St. Louis, Mo., USA). For polymerization, glycerol was directly distilled and purified by using CaH ₂ before use, and the others were used as they were.

How to identify the properties of the prepared polymer

The polymers prepared in the following examples were confirmed by Fourier transform-infrared spectroscopy (ALPHA FT-IR spectrometer with a diamond ATR probe, Bruker, Billerica, MA, USA). The molecular weight of the synthesized polymer was determined by gel permeation chromatography (GPC). An HPLC system with an Agilent 110 series (Agilent Technologies, Palo Alto, Calif., USA) and a refractive index detector was run with three PLgel columns (300 × 7.5 mm, pore sizes = 103, 104, 105 Å) SEC (size exclusion columns) at 1.0 mL / min. THF was used as the isocratic mobile phase and monodisperse polystyrenes (Polysciences, Inc., Warrington, Pa., USA) were used as calibration standards. The thermal properties of the prepared polymer were analyzed by DSC 204 F1 Phoenix (Netzsch-Geratebau GmbH, Selb, Germany). Two scans of heating and cooling were obtained at a scan rate of -50 ° C to 200 ° C at 10 ° C / min. The enthalpy of the endothermic reaction was analyzed by the second heating data.

Step 1: Ethoxyethyl  Glycerol ether ( Ethoxyethyl Glycerol Ether , EEGE )

70.0 g (0.945 mol) of glycidol and 225.9 g (3.821 mol) of ethyl vinyl ether were placed in a 500 mL flask, stirred for 3 minutes and then cooled to -30 ° C. 0.75 g (3.94 mmol) of TsOH monohydrate was slowly added thereto, followed by stirring at 25 DEG C for 3 hours. 75 g of saturated NaHCO ₃ solution (68 mL, 75 g) was added and the product was extracted twice with ether acetate (84 mL x 2). The organic layer was separated and dried over MgSO _4. After filtration, the residual ethyl vinyl ether was removed at 40 < 0 > C under reduced pressure (65 cmHg). The residue was distilled under vacuum at 65 캜 to recover ethoxyethyl glycerol ether as a colorless liquid product (yield: 75.6%).

Step 2: Ethoxyethyl  Polymerization of Glycerol Ether PEEGE )

The 500 mL flask was heated to dryness under a stream of nitrogen gas. A solution of potassium tert-butoxide in anhydrous THF (6.75 mL, 3 M) was placed in the dried flask under a nitrogen atmosphere. After cooling to -50 占 폚, 40 g of the EEGE prepared in step 1 above was added to the solution. The temperature was slowly raised to 65 占 폚 and the same temperature was maintained during the polymerization. After the polymerization reaction for 24 hours, the flask was cooled again to room temperature, cold methanol (10 DEG C) was added, and the mixture was kept at room temperature for 2 hours. The solvent was evaporated at 20 占 폚, and the resulting polymer was dissolved in hexane and centrifuged at 3,500 rpm for 10 minutes to remove precipitated potassium chloride and then dried in vacuum for 24 hours. The weight average molecular weight (Mw) of the prepared PEEGE was 3.7 kDa and the PDI (polydispersity index) was 1.46 (yield: about 90%).

Step 3: PEEGE -b- PCL Manufacturing

22 g (144.5 mmol) of the PEEGE (Mw = 3.7 kDa, determined by GPC) prepared in the step 2 and 16.5 g of? -Caprolactone were placed in a flask containing a Teflon-coated magnetic stirrer. The flask was degassed under vacuum and purged with argon gas. The mixture was dissolved in an oil bath preheated to 125 DEG C, and 1.15 g of tin (II) 2-ethylhexanoate was immediately added thereto and reacted at the same temperature for 20 hours. After cooling the flask to room temperature, the resulting polymer was dissolved in 200 mL of methylene chloride and centrifuged at 3,500 rpm for 10 minutes to remove undissolved impurities. The methylene chloride was removed with a rotary evaporator, and the block copolymer was precipitated in a 10-fold excess of cold hexane. The precipitate was filtered with a glass filter, washed with hexane more than 2 times, and then placed under reduced pressure to give a dried product. The weight average molecular weight (Mw) of the PEEGE-b-PCL prepared was 13.5 kDa and the PDI (polydispersity index) was 2.48.

Step 4: PG -b- PCL Manufacturing

8 g of the PEEGE-b-PCL prepared in the above step 3 was dissolved in 50 g of acetone. A solution of 2.46 g of oxalic acid in 16.5 g of water was prepared and placed in a PEEGE-b-PCL solution and stirred at ambient temperature for 5 hours. Next, the mixture was dialyzed overnight at room temperature (MWCO = 1 kDa) with excess water. The water in the dialyzed product mixture was removed with a rotary evaporator at 75 ° C for 40 minutes and the evaporation procedure with acetone was repeated three times to remove water.

¹ H-NMR (ppm, 300 MHz, CDCl ₃ ): 1.37 (m, 2H); 1.63 (m, 4 H); 2.30 (t, 2 H); 3.41-3.78 (m, 2H); 4.05 (t, 2H)

The ¹ H-NMR spectrum is shown in FIG. 1A. As shown in FIG. 1A, peak numbers 1-5 represent hydrogen of the PCL segment, and peak numbers 6-8 represent hydrogen of the PG segment. Further, as a result of FT-IR (Fig. 1B), the presence of a hydroxyl group was confirmed.

The molar ratio (PCL: PG) of PCL to PG in the PG-b-PCL was 2.44: 1, which was 3.85: 1 in terms of mass ratio. The weight average molecular weight (Mw) of the prepared PG-b-PCL was 17 kDa and the PDI (polydispersity index) was 1.51.

The thermal properties of PG-b-PCL are shown in Figure 1C and the thermal properties of PCL were also evaluated for comparison. Separation of the endothermic melting peak is found in both polymers, indicating that two types of crystalline phases are present in the PCL block. The melting point of PG-b-PCL was significantly lower than PCL (1st: 58.3 ℃ vs 68.4 ℃, 2nd: 51.6 ℃ vs 54.2 ℃). In addition, the enthalpy was also significantly lower (1st: -93.04 J / g vs -102.2 J / g, 2nd: -70.59 J / g vs -75.15 J / g) and these results indicate that the PG block is effectively involved in the PCL decision do.

Experimental Example

One) PG -b- PCL Micelle - like Aggregates Manufacturing

To prepare the polymeric micelle, the polymer powder (10 mg) prepared in the above example was dissolved in acetone at a concentration of 10 mg / mL, and the polymer solution was diluted with 10 mL of deionized water. The prepared solution was left overnight to completely evaporate the organic solvent to a final concentration of 1 mg / mL.

2 mg of pyrene was dissolved in 20 mL of ethanol and diluted with deionized water to a final concentration of 0.5 mM. 2 mL of the solution was diluted with 8 mL of deionized water, and 1 mL thereof was diluted with 49 mL of deionized water. Then, 100 μL (2 μM) of the pyrene solution was added to 900 μL of PG-b-PCL solution. Fluorescence intensity was measured by a fluorescence spectrophotometer F7000 (Hitachi, Tokyo, Japan) using a quartz cell. Fluorescence spectra were recorded at 350 nm to 450 nm at 332 nm excitation. The scan speed was 240 nm / min, and the slit width was 5 nm for both excitation and emission. The peak intensities at 372 nm and 384 nm were recorded and the ratio thereof (I ₃₇₂ / I ₃₈₄ ) was recorded as a function of the concentration of the block copolymer. The critical micelle concentration (cmc) value was calculated by sigmoidal (Boltzmann type) fitting curve.

The results of I ₃₇₂ / I ₃₈₄ are plotted in Figure 2A. cmc values were calculated by the baseline and slope lines shown in the graph. The measured cmc value was very small at 1.29 × 10 ^-4 g / L due to high molecular weight (Mw: 17 kDa) and high PCL: PC mass ratio (3.85). This is smaller than the other nonionic surfactants Tween 20 (7.4 × 10 ^-2 g / L), Triton X-100 (2.0 × 10 ^-1 g / L) and Brij 35 (1.1 g / L) (2.6 ~ 8 g / L), which is a coagulant, Pluoronic F127.

2) DLS  And TEM ( Dynamic Light Scattering and Transmission Electron Microscopy )

The size distribution was measured by DLS using a zeta-potential & particle size analyzer ELSZ-1000 (Otsuka Electronics Co., Ltd., Osaka, Japan) at 25 ° C. The hydrodynamic diameter was determined by the CONTIN algorithm. Second order polydispersity index (μ ₂ / Γ ² ) was determined by the cumulants method. Transmission electron microscopy (TEM) was also used to observe particle morphology. 5 μL of the nanoemulsion was mixed with 10 μL of 1% uranyl acetate and the mixture was placed on a carbon-coated copper grid and incubated at room temperature for 20 minutes. The drop was removed with a filter paper, the grid was dried for 20 minutes and observed with a Electron Microscope JEM 3010 (JEOL, Akishima, Japan) operated at 300 kV.

As a result, the average diameter of the particles was about 111 nm (FIG. 2B), and the second order polydispersity index (μ ₂ / Γ ² ) was 0.18, which means narrow particle distribution.

3) O / W Nano-emulsion  Produce

10 mg of PG-b-PCL and 100 mg of oil (ODO, CEH and DC345, respectively) were completely dissolved in 1 mL of ethanol in a 70 DEG C ultrasonic bath for 15 minutes. The solution was slowly added to deionized water at 70 占 폚 using a Wise Tis HG-15A homogenizer (witeg Labortechnik GmbH, Wertheim, Germany) at atmospheric pressure at 10,000 rpm for 5 minutes with high speed homogenization. The mixture was then stirred under ambient atmosphere until cooled to ambient temperature.

As a result, the nano emulsion was successfully produced regardless of the kind of oil. The hydrodynamic diameters of each nanoemulsion were 246 nm (ODO), 278 nm (CEH), 226 nm (DC345) (FIG. 2C). As a result of visual observation, phase separation was not observed (Fig. 2D).

After incubation at room temperature overnight, the cells were observed under a microscope. As a result, fine CEH nanoemulsion was observed for creaming, and homogenization was still observed in ODO and DC345 nanoemulsion (FIGS. 3A and 3B).

In addition, ODO and DC345 nanoemulsion were tested at room temperature for 10 days (Fig. 3C). Although slight variations were observed, the size of the nanoemulsion did not substantially change, and phase separation was not observed.

In addition, ODO and DC345 nanoemulsion were tested for freezing / thawing circulation (Figure 3D), and homogenization was still observed. Thus, it was confirmed that the PG-b-PCL according to the present invention can effectively form a nano emulsion and maintain its homogenization.

Claims (7)

A polymer represented by the following formula (1):
[Chemical Formula 1]

In this formula,
m: n is 1:20 to 10: 1,
The weight average molecular weight of the polymer is 2 kDa to 50 kDa.
The polymer according to claim 1, wherein m: n is 1: 3 to 3: 1.
The polymer according to claim 1, wherein the polymer has a weight average molecular weight of 5 kDa to 20 kDa.
A composition for emulsification, comprising the polymer of any one of claims 1 to 3.
The composition for emulsification according to claim 4, wherein the composition for emulsification is a composition for emulsifying a nano emulsion.
The composition for emulsification according to claim 4, wherein the polymer represented by Formula (1) forms a polymer film at an interface between oil and water to stabilize the emulsion.
The composition for emulsification according to claim 6, wherein the polymer membrane is semi-solid.

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