KR101549484B1 - Amphiphilic block copolymer and cosmetic or pharmaceutical composition using the same - Google Patents

Abstract

Provided is an amphiphilic block copolymer including a block A which is polyethylene glycol (PEG) or methoxy polyethylene glycol (MPEG) and a block B which is poly(caprolactone(CL)y1-lactone derivative (LD)y2). The lactone derivative is formed from a unit having any one or more structures selected from chemical formula 1 and chemical formula 2. The total molecular weight of the block A is 500 to 100,000 Da; the molecular weight ratio (block A:block B) of the total block A and the total block B is 0.1-10:1; a molar ratio (y1:y2) of y1 and y2 is 0.1-20:1; and the block B is statistical copolymers of caprolactone and lactone derivatives.

Description

[0001] Amphiphilic block copolymer and cosmetic composition using same [0001]

The present invention relates to an amphiphilic block copolymer and a cosmetic or pharmaceutical composition containing the same, and more particularly to a block copolymer containing both a hydrophobic polymer and a hydrophilic polymer to efficiently collect an oil-soluble or physiologically active substance Amphiphilic block copolymers and cosmetics containing them.

Attempts have been made to produce nanoparticles using amphiphilic block copolymers and capture insoluble drugs such as isoflavones. In the amphiphilic block copolymer, poly (ethylene glycol) (PEG) was frequently used as a hydrophilic block, and poly lactic acid (PLA), poly glycolic acid (PGA) caprolactone (PCL), or their copolymers.

In particular, PLA, P (LA-GA) and the like have excellent biodegradability and have been widely used as drugs for drug delivery. However, in cosmetics and external skin preparations which should be circulated in a liquid state, it is rather unstable and has a problem of precipitation of a poorly soluble drug due to its excellent decomposability.

Recently, attempts have been made to use poorly hydrolyzed PEG-PCL block copolymer, which has a high hydrophobicity and high crystallinity, to collect insoluble drugs and use them in cosmetics and external preparations for skin. However, the PCL has a problem that the collection efficiency of the poorly soluble drug is low due to the high crystallinity, and the collected drug gradually precipitates over time.

Accordingly, the inventors of the present invention have conducted studies to develop a carrier of a poorly soluble substance having excellent collection efficiency of a poorly soluble substance and excellent stability.

SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide an amphiphilic block copolymer capable of solving the above problems, having excellent collection efficiency of a poorly soluble substance, and being stably transported.

And, it is intended to provide a polymer-poor mass transfer material for collecting and stably transferring a poorly soluble substance using such an amphiphilic block copolymer.

The present invention also provides a cosmetic composition or a pharmaceutical composition comprising the poorly soluble substance carrier.

And an excellent emulsion stabilizer using the block copolymer containing both the hydrophobic and hydrophilic polymers.

In order to solve the above problems, the present invention provides an amphiphilic block copolymer having both a hydrophobic polymer and a hydrophilic polymer.

The inventors of the present invention have recognized the problems of conventional techniques for trapping an insoluble drug or a physiologically active substance by an amphiphilic block copolymer and have a problem that the biologically active substances precipitate due to decomposition of the copolymers And to develop a cosmetic or pharmaceutical composition capable of stably transferring a physiologically active substance to the skin.

Polycaprolactone (PCL) hydrophobic blocks, which were developed to solve the problems of biodegradability, had a problem that the drug collection efficiency was deteriorated due to the crystallinity of PCL. Due to such a problem, the drug can not be stably trapped, and there has been a problem in that a poorly soluble substance precipitates over time and is difficult to effectively deliver to the skin.

The hydrophobic block polymerized with the lactone derivative of the present invention may have strong hydrophobicity and may be used to capture an oil-soluble drug or an insoluble drug by forming an amorphous core.

Specifically, the inventors of the present invention have confirmed that, unlike linear PCLs, the polymers of the present invention are hard to form crystals by alkyl groups by using lactones substituted with alkyl groups, thereby forming amorphous cores.

According to one embodiment of the present invention, the polymer of the present invention can be used as a polymer for producing particles including an insoluble substance or the like.

That is, the inventors of the present invention confirmed that when a lactone derivative is contained in a hydrophobic block, it is possible to induce stable collection of a poorly soluble substance, thereby effectively applying an insoluble physiologically active substance to a cosmetic or skin external preparation, It was completed.

The present invention provides a block copolymer comprising two or more monomers and is a block copolymer comprising a polyacrylate, poly vinyl pyrrolidone, poly vinyl alcohol and methoxypolyethylene glycol ( MPEG), and a B block that is a poly (caprolactone (CL) _y1 -lactone derivative (LD) _y2 ).

The terms A block and B block are used to indicate and distinguish the different monomers in the copolymers according to embodiments of the present invention. Preferably, the A block refers to a hydrophilic block of an amphiphilic block copolymer, and the B block refers to a hydrophobic block.

The A block is preferably made of methoxypolyethylene glycol (MPEG). The molecular weight of the MPEG is not particularly limited, but is preferably 500 to 100,000 Da, preferably 500 to 50,000, May have a molecular weight of 500 to 20,000.

The molecular weight ratio of the A block to the B block may be 0.1 to 10: 1, and preferably 0.2 to 5: 1.

The B block may be formed by polymerization of caprolactone and a lactone derivative, and the B block may be formed by simultaneously adding caprolactone and lactone derivatives during the reaction, May be formed from statistical copolymers, that is, random copolymers.

The lactone derivative may include a lactone derivative formed from a unit having any one or more structures selected from the following formulas (1) and (2).

[Chemical Formula 1]

Each of the Rs connected to -CH- in the above formula (1) may independently include H or a straight-chain or branched alkyl group having 1 to 7 carbon atoms, preferably 1 to 5 carbon atoms, more preferably 1 to 3 carbon atoms , ≪ / RTI >

In Formula 1, n may include an integer of 2 to 5.

The lactone derivative may be a linear or branched alkyl group having at least one R linked in an alkyl (-CH-) chain forming a cyclic structure, and may contain 1 to 7 carbon atoms.

Preferably, the lactone derivative of the above formula (1) is at least one selected from the group consisting of δ-hexalactone, δ-valerolactone, γ-valerolactone, γ-caprolactone, Valerolactone,? -Decalactone,? -Dodecalactone,? -Butyrolactone,? -Methyl-? -Butyrolactone,? -Butyrolactone, Butyrolactone, methylene-γ-butyrolactone, and γ-phenyl-γ-butyrolactone.

(2)

In Formula 2, R ₁ and R ₂ may each independently be H or a methyl group.

Preferably, the lactone derivative in the above formula (2) may be D, L-lactide, L-lactide, D-lactide or Glycolide, and caprolactone (Caprolactone) may be used together with at least one selected from the formulas (1) and (2).

The B block may be represented by the following formula

(3)

Poly (caprolactone (CL) _y1 -lactone derivative (LD) _y2 )

Y1 and y2 may each represent the molar ratio of caprolactone to lactone derivative in the B block, and the molar ratio of y1: y2 may be 0.1 to 20: 1, preferably 0.2 to 10: 1.

The amphiphilic block copolymer of the present invention is not limited to a diblock copolymer and may have, for example, a triblock form.

The amphiphilic block copolymer is poly-MPEG- (CL -LD _{y1 y2)} may be, MPEG- poly (CL -LD _{y1 y2)} a poly-MPEG- connected by a linking group (CL -LD _{y1 y2)} - linking group -poly (CL _y1 -LD _y2 ) -MPEG. ≪ / RTI >

Preferably, the linker may be a diisocyanate.

According to one embodiment of the present invention, when the amphiphilic block copolymer is a triblock block, it may further include PEG as a hydrophilic block.

According to another embodiment of the present invention, the amphiphilic block copolymer is a poly (CL _y1 -LD _y2 ) -PEG-poly (CL _y1 -LD _y2 ) copolymer of PEG and caprolactone and lactone derivatives of the BAB type A triple block.

According to another embodiment of the present invention, there is provided a composition for producing particles comprising the amphiphilic block copolymer as a polymer for producing particles.

The particles may have various sizes depending on the intended use, and preferably have a nano size.

In addition, the present invention can provide a composition comprising the amphiphilic block copolymer and a physiologically active substance.

The physiologically active substance is an insoluble physiologically active substance, and such an insoluble physiologically active substance can be preferably captured in the amphiphilic block copolymer.

The term trap as used herein means that a poorly soluble substance is contained in the block copolymer, and there is no particular limitation on the method of collecting the block copolymer.

The kind of the poorly soluble physiologically active substance to be collected in the amphiphilic block copolymer is not particularly limited as long as it is a hydrophobic substance, and examples thereof include genistein, daidzein, cucurbitacin, francidin, poly Phenol or mixtures thereof may be used.

Preferably, as the poorly soluble physiologically active substance, genistein can be used.

The genistein is one of the isoflavone compounds isolated from soybeans and is known to exhibit estrogen-like activity. In addition, it has been known that genistein effectively inhibits the keratinocyte migration of melanosomes from melanocytes by inhibiting the phagocytosis of keratinocyte cells, but there are restrictions on the development of products due to their low solubility in aqueous solutions.

According to one embodiment of the present invention, the amphiphilic block copolymer can be used as a polymer carrier that stably captures such genistein and delivers it to the skin.

According to one embodiment of the present invention, a composition comprising an amphiphilic block copolymer and a physiologically active substance may comprise a pharmaceutical composition or a cosmetic composition.

The pharmaceutical composition or the cosmetic composition may further contain components commonly used in the art, and the kind of the component to be further used is not particularly limited.

According to another embodiment of the present invention, there is provided a method for producing a particle containing an insoluble physiologically active substance using an amphiphilic block copolymer.

A) an amphiphilic block copolymer comprising an A block which is polyethylene glycol (PEG) or methoxypolyethylene glycol (MPEG) and a B block which is a poly (caprolactone (CL) _y1 -lactone derivative (LD) _y2 ) Dissolving;

B) mixing an insoluble physiologically active substance with the block copolymer solution;

(C) collecting the poorly soluble physiologically active substance by adding a solution containing the poorly soluble physiologically active substance into an aqueous solution and stirring the mixture; And

D) removing the organic solvent. The present invention also provides a method for producing particles containing an insoluble physiologically active substance using an amphiphilic block copolymer.

Examples of the method for producing particles containing an insoluble physiologically active substance using an amphiphilic block copolymer in the present invention include a method of dispersing the copolymer polymer immediately in an aqueous solution and then applying ultrasonic waves, a method of dispersing or dissolving the polymer in an organic solvent A method of dispersing or dissolving the polymer in an organic solvent and then stirring with a homogenizer or a high-pressure emulsifier to evaporate the solvent; a method of dispersing or dissolving the polymer in an organic solvent A method of dialyzing with excessive excess of water, a method of slowly adding water after dispersing or dissolving the polymer in an organic solvent, and the like.

When an amphiphilic block copolymer is used in an aqueous solution and an amphiphilic block copolymer is used to make particles containing an insoluble physiologically active substance, the organic solvent that can be used is acetone, dimethylsulfoxide, dimethyl form One kind selected from amide, N-methylpyrrolidone, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, methyl ethyl ketone, methylene chloride, chloroform, methanol, ethanol, ethyl ether, diethyl ether, hexane, Or a mixed solvent thereof may be used.

When the particles of the present invention are contained, the poorly soluble physiologically active substance does not directly contact the emulsified product or the skin product, so that the product itself is stable and can be used in various forms of cosmetic composition such as cream, milky lotion, . ≪ / RTI > As described above, it was confirmed that the external preparation for skin containing a large amount of particles in which the physiologically active substance was collected had the skin improvement effect of the physiologically active ingredient as it was, and was excellent in stability.

The composition for external application of the present invention is not particularly limited in its formulation, and it can be used as a general ointment, a cream for external use such as a cream, a softening longevity, a convergent lotion, a nutritional lotion, an eye cream, a nutritional cream, , A cleansing foam, a cleansing water, a powder, an essence, a pack, a body lotion, a body cream, a body oil, a body essence, a makeup base, a foundation, .

The amphiphilic block copolymer of the present invention can effectively capture an insoluble physiologically active substance and provides excellent stability as a carrier of a poorly soluble substance.

The particles containing the amphiphilic block copolymer and the poorly soluble substance using the amphiphilic block copolymer of the present invention can be used as a cosmetic composition or a pharmaceutical composition because they can stably collect a poorly soluble substance unlike an amphiphilic block copolymer having excellent decomposability , And is suitable for use as an external preparation for skin.

1 is an analysis of H-NMR and proton peaks of an MPEG-P (CL-HL) block copolymer.
2 is a GPC graph of MPEG and MPEG-P (CL-HL) block copolymers.
3 is a graph showing a DSC curve of an MPEG-P (CL-HL) block copolymer. (second heating run, heating rate: 10 DEG C / min)
FIG. 4 is a polarizing microscope photograph showing the stability of the cream containing Genistein-Block copolymer particles. FIG. 4 is a comparison of the result after 2 weeks from the preparation of the cream.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the above-described embodiments. The embodiments of the present invention are provided by way of example to facilitate a specific understanding of the present invention.

Example  1. Synthesis of block copolymer

Methoxy polyethylene glycol-poly (ε-caprolactone-co-lactone derivatives) (MPEG-P (CL-LD)) block copolymers were synthesized by ring-opening polymerization using MPEG (molecular weight 5,000 Da) as an initiator. Δ-Hexalactone (HL) was used as the lactone derivative.

Block copolymers were synthesized according to the weight ratios of MPEG, CL and HL in Table 1 below.

Stannous 2-ethyl-hexanoate (Sn (Oct) ₂ ) was used as a reaction catalyst.

All of the raw materials were purchased from Sigma-Aldrich.

MPEG and Sn (Oct) ₂ were dried in a 2-neck round flask at 110 ° C under vacuum for 4 hours to remove moisture, and then the reactor was cooled to room temperature. A certain amount of CL and HL was added to the reactor in a nitrogen atmosphere, followed by vacuum drying at 60 ° C for 1 hour. The reactor was gradually heated to 130 캜 in a nitrogen atmosphere, reacted for 18 hours, and cooled to room temperature to terminate the reaction. The reaction mixture was cooled to room temperature and methylene chloride was added to dissolve the reaction product. The reaction mixture was slowly added to excess cold ethyl ether to precipitate the block copolymer. The precipitated block copolymer was filtered and vacuum-dried at 40 ° C for 48 hours. Finally, a block copolymer of MPEG-P (CL-HL) was obtained. The yield of the block copolymer was more than 85%.

a: Measured by GPC, relative to poly (ethylene glycol) standards

The number average molecular weight and composition ratio were calculated from H-NMR (Nuclear Magnetic Resonance) and Equation 1, and the molecular weight distribution was confirmed by GPC (Gel Permeation Chromatography). The crystallinity of the hydrophobic block was confirmed by DSC (Differential Scanning Calorimeter) thermal analysis.

[Equation 1]

As a result of 1 H-NMR analysis, it was confirmed that the monomer was successfully synthesized according to the monomer feed ratio (FIG. 1), and a block copolymer having a uniform molecular weight was synthesized from GPC. (Fig. 2)

Also, from the DSC results shown in FIG. 3, it was confirmed that the crystallinity of the ε-caprolactone chain sharply decreases as the δ-hexalactone content having a methyl side group increases, and amorphous at a degree of about 30% or more. That is, it was confirmed that D-3 to D-5 were amorphous.

From the above results, it was confirmed that the degrees of decrease in crystallinity were different depending on the molar ratio of CL and HL.

Example  2. Insoluble drugs Capture

Genistien, a poorly soluble substance, was captured using the synthesized block copolymer. First, 10 g of block copolymer was dissolved in 40 mL of ethanol and mixed with 20 g of PEG 400 and 2 g of Genistein. The solution was slowly added to 100 mL of a 0.5% aqueous solution of polyvinyl alcohol while stirring. The ethanol solution was left to stir for a certain period of time to allow the ethanol solvent to evaporate, and the remaining ethanol was removed using a rotary evaporator to prepare a solution having a genistein content of 2%. The precipitated genistein was removed by filtering the prepared solution.

The particle size of the prepared block copolymer was measured using a Malvern Zetasizer 3000, and the content of genistein captured in the block copolymer particle was measured by liquid chromatography (HPLC). The drug loading capacity and drug loading efficiency of the block copolymer were calculated by the following equation.

&Quot; (2) "

&Quot; (3) "

Table 2 shows the result of measurement of the particle size of the block copolymer, and the drug collection capacity and the drug collection efficiency according to the result.

As shown in Table 2, the block copolymer containing a hydrophobic block polymerized with a lactone derivative exhibited a drug collection efficiency of about 5 times or more, even though it had a similar particle size.

That is, D-1 is a block copolymer containing a polycaprolactone hydrophobic block in which lactone derivative HL is not polymerized, D-3 contains a hydrophobic block having a molar ratio of CL and HL of about 7: 3 Block copolymer. Although D-1 and D-3 had the same particle size (130 ㎛), the drug collection capacity of D-3 was about 4 times larger than that of D-3 and the drug collection efficiency was about 4 times higher . As can be seen from the DSC results, as the hydrophobic block involved in drug inclusion is composed of CL only in the case of D-1, the crystallinity of the core is high and the inclusion efficiency is low, while the content of HL increases The amorphous form of the core of the particle is increased, and the inclusion efficiency of the poorly soluble drug is increased.

From the above results, it was confirmed that the amphiphilic block copolymer of the present invention, that is, the hydrophobic block, is more excellent in the collecting efficiency of the insoluble matter than the block copolymer composed of the caprolactone and the lactone derivative.

Example  3. Oil oil  Creation of cream and stability of cream

In order to confirm the stability of the cream containing particles with poorly soluble drug, a certain amount of Genistein was collected with the block copolymer prepared in Example 1. The drug capturing capacities of the block copolymers of D-1 to D-5 were respectively 2.5%.

The composition of the oil-in-water cream containing genistein-block copolymer particles is shown in Table 3. The compositions in Table 3 are shown in weight percent.

Composition of Oil-in-Water Cream

ingredient Formulation Example C14-22 alcohol, C12-20 alkyl glucoside
Glyceryl stearate, phage-100 stearate
Glyceryl stearate
Cetearyl alcohol
Polyglyceryl-3 methyl glucoside distearate
Hydrogenated polydecene
Cyclohexasiloxane
Carbomer
Tromethamine
glycerin
Dipropylene glycol
1,2-hexanediol
Genistein-block copolymer particle
Purified water 1.5
1.2
0.9
1.5
1.5
4.5
3.5
0.2
0.2
3
3
2
10
Remaining amount (To 100)

The stability of the cream over time was confirmed by a polarizing microscope. As shown in Fig. 4, Genistein, which is a poorly soluble substance, began to precipitate in the D-1 particle for 2 days after the cream production. In the case of D-2, . However, it was confirmed that D-3 to D-5 were stable without precipitation for 3 months.

These results show that the cosmetic composition comprising an amphiphilic block copolymer containing a hydrophobic block composed of caprolactone and a lactone derivative of the present invention can stably contain a poorly soluble substance and effectively deliver it to the skin there was.

Claims (13)

Block A which is polyethylene glycol (PEG) or methoxypolyethylene glycol (MPEG) and
And a B block which is a poly (caprolactone (CL) _y1 -lactone derivative (LD) _y2 )
The lactone derivative is formed from a unit having a structure represented by the following formula (1)
The total molecular weight of the A block is 500 to 100,000 Da,
The molecular weight ratio (A block: B block) of the total A block to the total B block is 0.1 to 10: 1,
The molar ratio (y1: y2) of y1 and y2 is 7: 3 or 1: 1,
Wherein said B block is Statistical copolymers of caprolactone and lactone derivatives.
[Chemical Formula 1]

In the formula (1), each R connected to -CH- is independently H or a linear or branched alkyl group having 1 to 7 carbon atoms, n is an integer of 2 to 5, and the lactone derivative is an alkyl ( -CH-) chain is a linear or branched alkyl group having 1 to 7 carbon atoms. The amphiphilic block copolymer according to claim 1, wherein the amphiphilic block copolymer comprising the A block and the B block comprises at least one of (MPEG) -poly (CL _y1 -LD _y2 ), (MPEG) -poly (CL _y1 -LD _y2 ) Poly (CL _y1 -LD _y2 ) - (MPEG), or poly (CL _y1 -LD _y2 ) -PEG-poly (CL _y1 -LD _y2 ). 3. The amphiphilic block copolymer of claim 2, wherein the linker is a diisocyanate. The method of claim 2, wherein the copolymer (MPEG) - poly (CL -LD _{y1 y2)} an amphiphilic block copolymer, characterized in that. The lactone derivative according to claim 1, wherein the lactone derivative is at least one selected from the group consisting of Hexalactone,? -Valerolactone,? -Valerolactone,? -Caprolactone,? -Methyl- Valerolactone,? -Decalactone,? -Dodecalactone,? -Butyrolactone,? -Methyl-? -Butyrolactone,? -Butyrolactone, Wherein the amphiphilic block copolymer is at least one selected from the group consisting of methylene-γ-butyrolactone, and γ-phenyl-γ-butyrolactone. The amphiphilic block copolymer according to claim 5, wherein the lactone derivative is? -Hexalactone. delete A composition for the production of particles characterized by comprising an amphiphilic block copolymer according to any one of claims 1 to 6 as a polymer for producing particles. 7. An amphiphilic block copolymer according to any one of claims 1 to 6,
A composition comprising a physiologically active substance. The composition according to claim 9, wherein the physiologically active substance is an insoluble physiologically active substance, and the insoluble physiologically active substance is entrapped in an amphiphilic block copolymer. 11. The composition according to claim 10, wherein the poorly soluble physiologically active substance is genistein, daidzein, cucurbitacin, francidin, polyphenol or a mixture thereof. 10. The composition of claim 9, wherein the composition is a pharmaceutical or cosmetic composition. 13. The composition of claim 12, wherein the cosmetic composition is in the form of an oil-in-water or an oil-in-water emulsion.

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