AMPHIPHILIC TRIBLOCK POLYMER

Abstract

The present application relates to an amphiphilic triblock polymer and micelles comprising the amphiphilic triblock polymer. The amphiphilic triblock polymer of the present application can have excellent dispersion properties and excellent water solubility while effectively encapsulating the drug.

Claims

1. An amphiphilic triblock (A-B-C) polymer having: a first block (A); and a second block (B) and a third block (C) which are phase-separated from said first block (A), wherein said first block (A) has a solubility parameter larger than the solubility parameters of the second block (B) and the third block (C), where the first block has a solubility parameter of 10 (cal/cm.sup.3).sup.1/2 or more.

2. The amphiphilic triblock polymer according to claim 1, wherein the first block (A) is any one selected from the group consisting of polyethylene glycol, a polyethylene glycol-propylene glycol copolymer, polyvinyl pyrrolidone and polyethyleneimine.

3. The amphiphilic triblock polymer according to claim 1, wherein the second block (B) is a compound represented by Formula 1 below. ##STR00005## wherein, R is hydrogen or an alkyl group, and Z is a group having an alkylene group, an ether group, an ester group or an amide group.

4. The amphiphilic triblock polymer according to claim 1, wherein the third block (C) comprises a polymerized unit (C1) of an acrylic monomer or vinyl monomer.

5. The amphiphilic triblock polymer according to claim 4, wherein said acrylic monomer is a compound represented by Formula 2 or 3 below. ##STR00006## wherein, Q is hydrogen or an alkyl group, and B in Formula 2 is a linear or branched alkyl group, an alicyclic hydrocarbon group, an aromatic substituent group or a carboxyl group, having at least 1 carbon atom and R.sub.1 and R.sub.2 in Formula 3 are each independently hydrogen, or a linear or branched alkyl group, an alicyclic hydrocarbon group or an aromatic substituent group, having at least 1 carbon atom.

6. The amphiphilic triblock polymer according to claim 5, wherein Q in Formula 2 above is hydrogen or an alkyl group having 1 to 4 carbon atoms, and B is an alkyl group having at least 1 carbon atom or an alicyclic hydrocarbon group having 6 to 12 carbon atoms.

7. The amphiphilic triblock polymer according to claim 4, wherein the vinyl monomer is a compound represented by Formula 4 or 5 below. ##STR00007## wherein, X is a nitrogen atom or an oxygen atom, Y is a carbonyl group or a single bond, R.sub.3 and R.sub.5 are each independently hydrogen or an alkyl group, or R.sub.3 and R.sub.5 are linked together to form an alkylene group, and R.sub.4 is an alkenyl group (provided that when X is an oxygen atom, R.sub.3 is not present); ##STR00008## wherein, R.sub.6, R.sub.7 and R.sub.8 are each independently hydrogen or an alkyl group, and R.sub.9 is a cyano group or an aromatic substituent group.

8. The amphiphilic triblock polymer according to claim 4, wherein the third block (C) further comprises a polymerized unit (C2) of a polymerizable monomer having a functional group capable of forming a hydrogen bond.

9. The amphiphilic triblock polymer according to claim 8, wherein said functional group capable of forming a hydrogen bond is a hydroxyl group, an amine group, a nitro group, an amino group, an imide group, an alkoxysilane group or a cyano group.

10. The amphiphilic triblock polymer according to claim 1, wherein the ratio (A:B+C) of the first block (A) and the sum of the second block (B) and the third block (C) is 1:9 to 9:1.

11. The amphiphilic triblock polymer according to claim 1, wherein the ratio (B:C) of the second block (B) and the third block (C) is 1:9 to 9:1.

12. Micelles comprising the amphiphilic triblock polymer according to claim 1.

13. The micelles according to claim 12, further comprising a drug encapsulated by the amphiphilic triblock polymer.

14. The micelles according to claim 13, wherein said drug is any one selected from the group consisting of genistein, daidzein, prangenidin or a derivative thereof; polyphenols; and a mixture thereof.

15. The micelle according to claim 12, having an average particle diameter in a range of 1 to 10,000 nm.

16. A composition for producing particles, comprising the micelles according to claim 12.

17. A method for producing micelles comprising steps of: producing an amphiphilic triblock polymer of claim 1 and mixing said amphiphilic triblock polymer and a drug.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0099] FIG. 1 is a schematic diagram of a micelle comprising an amphiphilic triblock polymer according to the present application.

[0100] FIG. 2 is images confirming the turbidity of amphiphilic triblock polymers or amphiphilic polymers according to examples and comparative examples in the aqueous solution state depending on the water solubility.

MODE FOR INVENTION

[0101] Hereinafter, the present application will be described in more detail by way of examples, but the examples are merely examples limited to the gist of the present application. Furthermore, it is obvious to those skilled in the art that the present application is not limited to the process conditions set forth in the following examples and they may be optionally selected within the scope of the conditions necessary for achieving the object of the present application.

Example 1

[0102] Production of Amphiphilic Triblock Polymer (P1)

[0103] After removing moisture from polyethyleneglycol monomethyl ether (mPEG-OH) forming the first block (A), 20 equivalents of -caprolactone and 0.05 equivalents of tin (II) ethylhexanoate, relative to the OH functional group, are added thereto, and reacted at 140 C. for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, dissolved in dichloromethane (DCM) at a concentration of 30%, precipitated in diethyl ether to remove impurities and dried to obtain a white powdery form of PEG-PCL (polyethylene glycol monomethyl ether-poly(-caprolactone)) polymer (A-B).

[0104] 3 equivalents of triethylamine (TEA) and 2 equivalents of 2-bromoisobutyryl bromide, relative to the OH functional group of the prepared block polymer, are added thereto and reacted to produce an initiator for ATRP. Then, a bromine-terminal PEG-PCL polymer from which impurities are removed by repeating a process of precipitation in a solvent of diethyl ether twice and drying, is dissolved in a reaction solvent (ethanol) and methyl methacrylate (MMA) is introduced in a molar ratio to be produced. After the flask was sealed with a rubber stopper, the dissolved oxygen was removed by nitrogen purging and stirring for 30 minutes at room temperature, and then the flask was immersed in an oil bath set at 60 C., the catalyst solution and the catalyst reducing agent were introduced thereto, and the reaction was carried out for 24 hours to produce an amphiphilic triblock polymer (A-B-C). The catalyst was used by dissolving CuBr.sub.2 100 ppm (mole)/TPMA 2 equivalents (vs. Cu) in ACN, and as the catalyst reducing agent, 6 equivalents (vs. Cu) of V-65 was used.

Example 2

[0105] Production of Amphiphilic Triblock Polymer (P2)

[0106] An amphiphilic triblock polymer (A-B-C) was produced by carrying out the same manner as in Example 1, except that the bromine-terminal PEG-PCL polymer produced in the same manner as in Example 1 was dissolved in a reaction solvent (ethanol) and MMA and N,N-dimethylaminoethyl methacrylate (DMAEMA) were introduced in a molar ratio to be produced.

Example 3

[0107] Production of Amphiphilic Triblock Polymer (P3)

[0108] An amphiphilic triblock polymer (A-B-C) was produced by carrying out the same manner as in Example 1, except that the bromine-terminal PEG-PCL polymer produced in the same manner as in Example 1 was dissolved in a reaction solvent (ethanol) and MMA and hydroxyl ethyl methacrylate (HEMA) were introduced in a molar ratio to be produced.

Example 4

[0109] Production of Amphiphilic Triblock Polymer (P4)

[0110] An amphiphilic triblock polymer (A-B-C) was produced by carrying out the same manner as in Example 1, except that the bromine-terminal PEG-PCL polymer produced in the same manner as in Example 1 was dissolved in a reaction solvent (ethanol) and MMA and 3-methacryloxypropyl methyl dimethoxy silane were introduced in a molar ratio to be produced.

Comparative Example 1

[0111] Production of Amphiphilic Triblock Polymer (P5)

[0112] The bromine-terminal PEG-PCL polymer produced in the same manner as in Example 1 is dissolved in a reaction solvent (ethanol) and MMA and DMAEMA (N,N-dimethylaminoethyl methacrylate) are introduced in a molar ratio to be produced. After sealing the flask with a rubber stopper, the dissolved oxygen was removed by nitrogen purging and stirring at room temperature for 30 minutes, and then the flask was immersed in an oil bath set at 60 C., and the catalyst solution and the catalyst reducing agent were introduced and the reaction was carried out for 24 hours to produce an amphiphilic triblock polymer (A-B-C). The catalyst was used by dissolving CuBr.sub.2 100 ppm (mole)/TPMA 2 equivalents (vs. Cu) in ACN, and as the catalyst reducing agent, 6 equivalents (vs. Cu) of V-65 was used.

Comparative Example 2

[0113] Production of Amphiphilic Polymer (P6)

[0114] mPEG-OH forming the first block (A), 3 equivalents of TEA and 2 equivalents of 2-bromoisobutyryl bromide, relative to the OH functional group, are added thereto, and reacted to produce an initiator for ATRP. Impurities are removed by repeating a process of precipitating in a solvent of diethyl ether twice and drying. The prepared bromine-terminal PEG polymer is dissolved in a reaction solvent (ethanol) and MMA and DMAEMA are introduced in a molar ratio to be produced. After the flask was sealed with a rubber stopper, the dissolved oxygen was removed by nitrogen purging and stirring for 30 minutes at room temperature, and then the flask was immersed in an oil bath set at 60 C., the catalyst solution and the catalyst reducing agent were introduced thereto, and the reaction was carried out for 24 hours to produce an amphiphilic polymer (A-C). The catalyst was used by dissolving CuBr.sub.2 100 ppm (mole)/TPMA 2 equivalents (vs. Cu) in ACN, and as the catalyst reducing agent, 6 equivalents (vs. Cu) of V-65 was used.

Comparative Example 3

[0115] Production of Amphiphilic Polymer (P7)

[0116] After removing moisture from mPEG-OH forming the first block (A), 20 equivalents of -caprolactone and 0.05 equivalents of tin (II) ethylhexanoate, relative to the OH functional group, are added thereto and reacted at 140 C. for 4 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature, dissolved in DCM (dichloromethane) at a concentration of 30%, precipitated in diethyl ether to remove impurities and dried to obtain a white powdery PEG-PCL amphiphilic polymer (A-B).

Experimental Example 1Evaluation of Block Ratio and Molecular Weight of the Produced Amphiphilic Polymer

[0117] The block ratio and molecular weight of the produced amphiphilic triblock polymers (P1-P5) and amphiphilic polymer (P6-P7) were evaluated by the following methods and shown in Table 1.

[0118] Specifically, the polymer solution was solidified through a purification step of the polymer solution in which the catalyst was completely removed and then the block ratio of the amphiphilic polymer was confirmed through .sup.1H NMR analysis. In the purification of the polymer solution, the polymer solution is solidified by passing it through an alumina column to remove the copper complex catalyst and then dropping it to the excess amount of diethyl ether under stirring to remove the residual monomers. The solidified polymer is dried in a vacuum oven for 24 hours. The amphiphilic polymer purified by the above method is dissolved in a solvent of CDCl.sub.3 and measured with a .sup.1H NMR analysis instrument.

[0119] As an analytical result of Examples 1 to 4, no 1H peak derived from CH.sub.2C(CH.sub.3) of the double bond terminal was confirmed, and accordingly, it can be confirmed that no unreacted monomer is present.

[0120] Also, in the case of Examples 1 to 4 and Comparative Examples 1 to 3, since 3H peaks derived from OCH.sub.3 of the ethylene glycol block terminal were confirmed at around 3.2 ppm, and the ratio and molecular weight of each polymer block were calculated, based on the above. Since peaks of about 450 H (4H X repeating units: 113) derived from CH.sub.2CH.sub.2O of ethylene glycol formed into the polymer appeared in the region of 3.6-3.8 ppm, and in the case of Examples 1 to 4 and Comparative Examples 1 and 2, 3H peaks derived from CH.sub.3 adjacent to the main chain of methyl methacrylate formed into the polymer appeared in the region of 3.5-3.6 ppm, the content of each constituent monomer was calculated as a mass fraction through an area ratio thereof.

[0121] In the case of Examples 2 to 4 and Comparative Examples 1 and 2, since 2H peaks derived from OCH.sub.2 adjacent to COO of dimethylaminoethyl methacrylate, hydroxyethyl methacrylate, and 3-methacryloxypropylmethyl dimethoxysilane side chains formed into the polymer appeared in the region of 4.0-4.2 ppm, the content of each constituent monomer was calculated as a mass fraction through an area ratio thereof. In the case of Comparative Examples 1 and 3, since 2H peaks derived from the first CH.sub.2 on the right of CO in (COCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)n-, which is a chain of caprolactone formed into the polymer, appeared in the region of 2.3-2.4 ppm, the molecular weight was confirmed through the 3H peak area derived from OCH.sub.3 of the ethylene glycol terminal and the 2H peak area derived from the first CH.sub.2 on the right of CO of caprolactone.

TABLE-US-00001 TABLE 1 Weight Ratio of Third Polymerized Molecular Weight Block Ratio Units (Mn, A:B:C) (A:B:C) (C1:C2) Example 1 12,000 (5000:2000:5000) 41.5:16.5:42 100:0 Example 2 12,000 (5000:2000:5000) 41.5:16.5:42 80:20 Example 3 12,000 (5000:2000:5000) 41.5:16.5:42 80:20 Example 4 12,000 (5000:2000:5000) 41.5:16.5:42 80:20 Comparative 12,000 (5000:2000:5000) 41.5:16.5:42 50:50 Example 1 Comparative 12,000 (5000:0:7000) 41.6:0:58.4 80:20 Example 2 Comparative 9,900 (5000:4900:0) 50.5:49.5:0 Example 3 C2 of Example 2, Comparative Example 1 and Comparative Example 2: DMAEMA C2 of Example 3: HEMA C2 of Example 4: 3-methacryloxypropyl methyldimethoxysilane

Experimental Example 2Confirmation of Turbidity of Micelles

[0122] For confirming water solubility of the produced amphiphilic triblock polymers (P1-P5) and amphiphilic polymers (P6-P7), the turbidity was evaluated by the following method and shown in Table 2.

[0123] Specifically, a solution in which 1 g of the polymer was dissolved in 100 mL of distilled water was prepared. The solution was stirred at 50 C. for about 1 hour and then stabilized at room temperature for 3 hours. The light transmittance of this solution at 600 nm was measured using a UV/VIS spectrometer from Agilent, and then the turbidity (ABS) was calculated from Equation 1 below.

[00001]$\begin{array}{cc}\mathrm{Turbidity}.Math..Math.\left(\mathrm{Absorbance},\mathrm{ABS}\right)=\mathrm{Log}\left(\frac{1}{\mathrm{Transmittance}\left(T\right)}\right)& \left[\mathrm{Equation}.Math..Math.1\right]\end{array}$

TABLE-US-00002 TABLE 2 Example Comparative Example 1 2 3 4 1 2 3 Turbidity (ABS) 0.12 0.02 0.02 0.02 0.33 2.25 0.46

Experimental Example 3Preparation of Micelle and Confirmation of Drug Dissolution Concentration

[0124] Using the synthesized amphiphilic triblock polymers (P1-P5) and amphiphilic polymers (P6-P7), umbelliferone, as a poorly soluble material and a similar structure of the above-mentioned drugs, was encapsulated. First, a solution, in which 3 g of the polymer and 3 g of umbelliferone were dissolved in 100 mL of ethanol, was prepared. The solution was slowly added to 300 mL of distilled water under stirring, and then left to stand for a certain period of time for evaporation of the ethanol solvent. The prepared solution was diluted with 10 times of distilled water and stored at room temperature (25 C.) for 7 days to allow precipitation of non-encapsulated umbelliferone. The precipitated umbelliferone was removed by filtration with a syringe filter (pore size: 0.45 m) and then the content of umbelliferone was measured using a UV/VIS spectrometer. The drug loading capacity and drug loading efficiency were calculated by the following equations and the particle size of the micelles comprising the drug-collecting amphiphilic triblock polymer or amphiphilic polymer was measured using Zetasizer 3000 from Malvern.

[00002]$\begin{array}{cc}\mathrm{Loadin}.Math..Math.\mathrm{capacity}.Math..Math.\left(\%\right)=\frac{\mathrm{Dye}.Math..Math.\mathrm{capacity}}{\mathrm{Polymer}.Math..Math.\mathrm{capacity}+\mathrm{Dye}.Math..Math.\mathrm{capacity}}100& \left[\mathrm{Equation}.Math..Math.2\right]\\ \mathrm{Loading}.Math..Math.\mathrm{efficieny}.Math..Math.\left(\%\right)=\frac{\mathrm{Residual}.Math..Math.\mathrm{dye}.Math..Math.\mathrm{concentration}.Math..Math.\mathrm{after}.Math..Math.\mathrm{wash}}{\mathrm{Initial}.Math..Math.\mathrm{input}.Math..Math.\mathrm{dye}.Math..Math.\mathrm{concentration}}100& \left[\mathrm{Equation}.Math..Math.3\right]\end{array}$

[0125] The results of measuring the size of micelle particles and the resulting drug loading capacity and drug loading efficiency were shown in Table 3 below.

TABLE-US-00003 TABLE 3 Example Comparative Example 1 2 3 4 1 2 3 Particle size 131 125 121 124 230 125 100 (diameter, nm) Loading capacity (%) 6 16 15 11 5 10.7 1 Loading efficiency (%) 32 80 75 68 43 60 6

EXPLANATION OF REFERENCE NUMERALS

[0126] 100: drug [0127] 200: amphiphilic triblock polymer [0128] 201: first block (A) [0129] 202: second block (B) [0130] 203: third block (C)