AMPHIPHILIC POLYMER

Abstract

The present application relates to an amphiphilic polymer and a method of preparing the same.

Furthermore, the present application relates to a micelle including a drug encapsulated by the amphiphilic polymer and a composition including the same.

The amphiphilic polymer according to the present application has excellent drug encapsulation properties as well as good dispersion properties in an aqueous solution.

Claims

1. An amphiphilic polymer, comprising: a first block (A); and a second block (B) which is phase-separated from the first block (A) and includes a polymerization unit (B1) of an acrylic monomer or vinyl-based monomer of which a homopolymer has a solubility parameter of less than 10.0 (cal/cm.sup.3).sup.1/2 and a polymerization unit (B2) of a polymerizable monomer having a functional group which is capable of forming a hydrogen bond, wherein a weight ratio (B1:B2) of the polymerization unit (B1) of an acrylic monomer or vinyl-based monomer of which a homopolymer has a solubility parameter of less than 10.0 (cal/cm.sup.3).sup.1/2 to the polymerization unit (B2) of a polymerizable monomer having a functional group which is capable of forming a hydrogen bond in the second block (B) is in a range of 1:9 to 9:1.

2. The amphiphilic polymer of claim 1, wherein the first block (A) includes a polymer having a solubility parameter of 10.0 (cal/cm.sup.3).sup.1/2 or more.

3. The amphiphilic polymer of claim 1, wherein the first block (A) is one or more selected from the group consisting of a polyethylene glycol, a polyethylene glycol-propylene glycol copolymer, a polyvinylpyrrolidone and a polyethyleneimine.

4. The amphiphilic polymer of claim 1, wherein the acrylic monomer is a compound represented by the following Formula 1 or 2: ##STR00004## where, in Formulas 1 and 2, Q is hydrogen or an alkyl group, in Formula 1, B is a linear or branched alkyl group with one or more carbon atoms, an alicyclic hydrocarbon group, an aromatic substituent or a carboxyl group, and in Formula 2, R.sub.1 and R.sub.2 each independently represent hydrogen, a linear or branched alkyl group with one or more carbon atoms, an alicyclic hydrocarbon group, or an aromatic substituent.

5. The amphiphilic polymer of claim 4, wherein, in Formula 1, Q is hydrogen or an alkyl group with 1 to 4 carbon atoms, and B is an alkyl group with one or more carbon atoms or an alicyclic hydrocarbon group with 6 to 12 carbon atoms.

6. The amphiphilic polymer of claim 1, wherein the vinyl-based monomer is a compound represented by the following Formula 3 or 4: ##STR00005## where, in Formula 3, 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 each independently represent hydrogen or an alkyl group, R.sub.3 and R.sub.5 are connected to each other to form an alkylene group, and R.sub.4 is an alkenyl group (but, when X is an oxygen atom, R.sub.3 is not present); ##STR00006## where, in Formula 4, R.sub.6, R.sub.7 and R.sub.8 each independently represent hydrogen or an alkyl group, and R.sub.9 is a cyano group or an aromatic substituent.

7. The amphiphilic polymer of claim 1, wherein the functional group is a hydroxyl group, an amine group, a nitro group, an amino group, an imide group, an alkoxysilane group or a cyano group.

8. The amphiphilic polymer of claim 1, wherein a block ratio (A:B) of the first block (A) and the second block (B) is different.

9. The amphiphilic polymer of claim 8, wherein a block ratio (A:B) of the first block (A) to the second block (B) is in a range of 1:9 to 9:1.

10. The amphiphilic polymer of claim 8, wherein a block ratio (A:B) of the first block (A) to the second block (B) is in a range of 3:7 to 7:3.

11. A micelle comprising the amphiphilic polymer of claim 1.

12. The micelle of claim 11, further comprising a drug encapsulated by the amphiphilic polymer, wherein a second block of the amphiphilic polymer is adjacent to the drug.

13. (canceled)

14. The micelle of claim 11, wherein an average particle size is in a range of 1 to 10,000 nm.

15. The micelle of claim 12, wherein the drug includes an insoluble biologically active substance.

16. (canceled)

17. The micelle of claim 14, wherein the insoluble biologically active substance is one or more selected from the group consisting of genistein, daidzein, cucurbitacin, prangenidin or a derivative thereof; a polyphenol; and a mixture thereof.

18. A composition for preparing a particle, comprising the micelle of claim 11, wherein the micelle preferably further includes a drug encapsulated by the amphiphilic polymer.

19. (canceled)

20. A pharmaceutical or cosmetic composition, comprising the micelle of claim 11.

21. The pharmaceutical or cosmetic composition of claim 20, wherein the micelle further includes a drug encapsulated by the amphiphilic polymer.

22. The pharmaceutical or cosmetic composition of claim 21, which is in the form of water-in-oil or oil-in-water emulsion.

23. A method of preparing the amphiphilic polymer of claim 1 comprising a step of polymerizing a polymer which forms a first block (A) with an acrylic monomer or vinyl-based monomer of which a homopolymer having a solubility parameter of less than 10.0 (cal/cm.sup.3).sup.1/2 and a polymerizable monomer having a functional group which is capable of forming a hydrogen bond.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0107] The above and other objects, features and advantages of the present invention will become more apparent to those of ordinary skill in the art by describing in detail exemplary embodiments thereof with reference to the accompanying drawings, in which:

[0108] FIG. 1 is a schematic view of a micelle including the amphiphilic polymer according to the present application;

[0109] FIG. 2 shows images for determining precipitation of amphiphilic polymers according to examples and comparative examples and drugs encapsulated by the amphiphilic polymers; and

[0110] FIG. 3 is a schematic view of a Franz cell for a percutaneous absorption test.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0111] Hereinafter, the present application will be described in detail with reference to examples, but the following examples are only examples within the gist of the present application. Meanwhile, it is apparent to those skilled in the art that the present application is not limited to process conditions proposed by the following examples but may be arbitrarily selected within a range required to achieve the objects of the present application.

EXAMPLE 1

Preparation of Amphiphilic Polymer P1

[0112] After a polyethyleneglycol monomethyl ether polymer (molecular weight:

[0113] 5000, purchased from Sigma-Aldrich Co. Llc) forming a first block was dissolved in dichloromethane at a concentration of 30%, 3 equivalent weights of triethylamine and 2 equivalent weights of 2-bromo isobutyryl bromide were introduced with respect to a —OH group to perform a reaction, thereby preparing an initiator for ATRP. Then, a process of precipitation and loading of the initiator in a diethyl ether solvent was repeated twice and drying was performed to remove impurities and obtain a polyethylene glycol polymer at bromine end groups. 100 parts by weight of the polyethylene glycol polymer with bromine end groups thus obtained was dissolved in 250 parts by weight of an anisole-containing reaction solvent in a flask, methyl methacrylate with a solubility parameter of 9.5 (cal/cm.sup.3).sup.1/2) and N,N-dimethylarninoethyl methacrylate with a solubility parameter of 9.6 (cal/cm.sup.3).sup.1/2 were added thereto in the weight ratio of 80:20, and a flask was sealed with a rubber stopper. Thereafter, nitrogen purging and stirring were carried out at room temperature for 30 minutes to remove dissolved oxygen, the flask was dipped in an oil bath with a temperature set to 60° C., and a copper (II) bromide complex and a catalytic reducing agent were introduced thereinto to perform a reaction. When a desired molecular weight was obtained, the reaction was completed, thereby preparing an amphiphilic polymer P1 with a B-A-B triblock structure. The molecular weight and the ratio B:A:B of each block of the triblock of the amphiphilic polymer P1 are shown below in Table 1.

EXAMPLE 2

Preparation of Amphiphilic Polymer P2

[0114] An amphiphilic polymer P2 with a triblock structure (B-A-B) was prepared in the same manner as in Example 1 except that methyl methacrylate with a solubility parameter of 9.5 (cal/cm.sup.3).sup.1/2) and N,N-dimethylaminoethyl methacrylate with a solubility parameter of 9.6 (cal/cm.sup.3).sup.1/2 were added thereto in the weight ratio of 60:40. The molecular weight, the ratio B:A:B of each block of the triblock and the weight ratio B1:B2 of polymerization units in the second block (B) of the amphiphilic polymer P2 are shown below in Table 1.

COMPARATIVE EXAMPLE 1

[0115] A polycaprolactone (B)-polyethylene glycol (A)-polycaprolactone (B) copolymer P4, in which a polycaprolactone with a solubility parameter of approximately 10 (cal/cm.sup.3).sup.1/2 which is a polyester-based polymer was used, was prepared by the following method.

[0116] Specifically, the synthesis was conducted through ring-opening polymerization with a polyethylene glycol polymer (molecular weight: 2000, purchased from Daejung Chemical & Metal Co.) as an initiator. Stannous 2-ethyl-hexanoate (Sn(Oct).sub.2) was used as a catalyst. The polyethylene glycol and Sn(Oct).sub.2 were dried at 110° C. under vacuum conditions for 4 hours in a 2-neck round flask to eliminate moisture, and a reactor was cooled to room temperature. ε-Caprolactone was added in the same amount as polyethyleneglycol monoethyl ether to the reactor in a nitrogen atmosphere and vacuum-dried at 60° C. for 1 hour. The reactor was gradually cooled to 130° C. in a nitrogen atmosphere to perform a reaction for 18 hours, and cooled to room temperature again to complete the reaction. Methylene chloride was added to the reactor cooled to room temperature to dissolve a reactant, and an excess amount of cold ethyl ether was gradually added to precipitate a copolymer. The precipitated block copolymer was filtered and vacuum-dried at 40° C. for 48 hours to finally obtain a polycaprolactone (B)-polyethylene glycol (A)-polycaprolactone (B) copolymer P4.

COMPARATIVE EXAMPLE 2

Preparation of Amphiphilic Polymer P4

[0117] The amphiphilic polymer P4 was prepared in the same manner as in Comparative Example 1 except that the amount of added ε-caprolactone was twice the amount of polyethyleneglycol monoethyl ether during the synthesis of a polyethylene glycol (A)-polycaprolactone (B) copolymer in which a polycaprolactone with a solubility parameter of approximately 10 (cal/cm.sup.3).sup.1/2 which is a polyester-based polymer was used.

EXPERIMENTAL EXAMPLE 1

Evaluation of Block Ratio B:A:B of Prepared Amphiphilic Polymer

[0118] The block ratio of the prepared amphiphilic polymers P1 to P5 was evaluated by the following method and the results are shown in Table 1.

[0119] Specifically, the polymer solution from which the catalyst was completely removed underwent a purification process to be solidified, and the block ratio of the amphiphilic polymer was determined by 1H NMR analysis. The purification of the polymer solution was carried out by having the polymer solution pass through an alumina column to eliminate a copper complex catalyst, and adding the polymer solution dropwise into an excess amount of diethyl ether with stirring to remove the remaining monomer to be solidified. The solidified polymer was dried in a vacuum oven for 24 hours. The amphiphilic polymer purified by the aforementioned method was dissolved in a CDCl.sub.3 solvent and measured using 1H-NMR analysis equipment. In the case of Examples 1 and 2 and Comparative Examples 1 and 2, as the analysis result, a 1H peak derived from CH.sub.2═C(CH.sub.3)— at double-bond end groups was not deteiniined, from which it can be seen that no unreacted monomer existed. Moreover, 3H peaks derived from —OCH.sub.3 of ethylene glycol block end groups were confirmed at around 3.2 ppm, and thus the ratio and molecular weight of each copolymer block was calculated based on this. Approximately 450 of H peaks (4H×113 repeat units) derived from —CH.sub.2CH.sub.2O— of ethylene glycol formed of the polymer were shown in a 3.6 to 3.8 ppm region, and in the case of Examples 1 and 2, 3H peaks derived from —CH.sub.3 adjacent to a main chain of methyl methacrylate formed of the polymer were shown in a 3.5 to 3.6 ppm region, 2H peaks derived from —OCH.sub.2— adjacent to —COO— of a side chain of dimethylaminoethyl methacrylate formed of the polymer were shown in a 4.0 to 4.2 ppm region, and thus the content of each constituent monomer was calculated as a mass fraction through the area ratio thereof. In the case of Comparative Examples 1 and 2, 2H peaks derived from the first —CH.sub.2— from the right of —CO— in—(CO—CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2—O—).sub.n which is a chain of caprolactone formed of the polymer were shown in a 2.3 to 2.4 ppm region, and thus the molecular weight was confirmed by the area of 3H peaks derived from —OCH.sub.3 of ethylene glycol block end groups and the area of 2H peaks derived from the first —CH.sub.2— from the right of —CO— of caprolactone.

TABLE-US-00001 TABLE 1 Molecular weight Weight ratio (B1:B2) (Mn, second Block of polymerization block:first ratio units of second block block:second block) (A:B:A) (B) (B1:B2).sup.a Example 1 11,000 (5,000:6,000) 4.55:5.45 80:20 Example 2 11,000 (5,000:6,000) 4.55:5.45 60:40 Comparative  9,900 (5,000:4,900) 5.05:4.95 — Example 1 Comparative 14,700 (5,000:9,700) 0.34:0.66 — Example 2 .sup.aMass ratio of methyl methacrylate (B1):N,N-dimethylaminoethyl methacrylate (B2)

EXPERIMENTAL EXAMPLE 2

Preparation of Micelle and Determination of Dissolved Concentration of Drug

[0120] Genistein which is an insoluble substance was loaded using the synthesized amphiphilic polymers P1 to P5. First, a solution obtained by dissolving 10 g of the amphiphilic polymer in 30 mL of ethanol was mixed with a solution obtained by dissolving 20 g of dipropylene glycol (DPG) in 2 g of genistein. After the mixed solution was introduced into 100 mL of a 0.5% polyvinyl alcohol aqueous solution with stirring, the remaining ethanol was eliminated using a rotary evaporator to prepare a solution in which the content of genistein was 2%. The prepared solution was diluted with 10 times as much distilled water and stored at room temperature (25° C.) for 7 days to determine whether property changes of the solution occurred over time using an optical microscope, and the results are shown in FIG. 2. Furthermore, after the solution was filtered using a syringe filter with a pore size of 1 μm to eliminate the precipitated genistein, the content of genistein loaded in an amphiphilic polymer micelle particle was measured by liquid chromatography (HPLC). The drug loading capacity and drug loading efficiency of the amphiphilic polymer were calculated according to the following equations, and the particle size of the amphiphilic polymer micelle in which a drug was loaded was measured using Zetasizer 3000 manufactured by Malvern Instruments, Inc.

[00001]$\begin{array}{cc}\mathrm{Drug}.Math..Math.\mathrm{loading}.Math..Math.\mathrm{capacity}=\frac{\mathrm{Amount}.Math..Math.\mathrm{of}.Math..Math.\mathrm{impregnated}.Math..Math.\mathrm{drug}}{\begin{array}{c}\mathrm{Amount}.Math..Math.\mathrm{of}.Math..Math.\mathrm{impregnated}.Math..Math.\mathrm{drug}+\\ \mathrm{Content}.Math..Math.\mathrm{of}.Math..Math.\mathrm{block}.Math..Math.\mathrm{copolymer}\end{array}}.Math.s.Math..Math.100.Math.\left(\%\right)& \left[\mathrm{Equation}.Math..Math.1\right]\\ \mathrm{Drug}.Math..Math.\mathrm{loading}.Math..Math.\mathrm{efficiency}=\frac{\mathrm{Amount}.Math..Math.\mathrm{of}.Math..Math.\mathrm{impregnated}.Math..Math.\mathrm{drug}}{\mathrm{Initial}.Math..Math.\mathrm{drug}.Math..Math.\mathrm{dose}}.Math.s.Math..Math.100.Math.\left(\%\right)& \left[\mathrm{Equation}.Math..Math.2\right]\end{array}$

[0121] The results of measuring the particle size of the micelle and the resulting drug loading capacity and drug loading efficiency of the micelle are shown in the following Table 2.

TABLE-US-00002 TABLE 2 Comparative Comparative Example 1 Example 2 Example 1 Example 2 Particle size (nm) 125 135 100 150 Drug loading 10.7 16.1 1.2 1.8 capacity (%) Drug loading 60 96 6 9 efficiency (%)

EXPERIMENTAL EXAMPLE 3

Percutaneous Absorption Test

[0122] The percutaneous absorption of genistein of the amphiphilic polymer solution in which genistein was loaded and which was prepared as above was evaluated using porcine skin (2×2 cm, thickness: 1000 μm) and a Franz diffusion cell. A phosphate buffered saline (PBS) solution containing 30 wt % of dipropylene glycol (DPG) was used as an aqueous solution (acceptor solution) to maintain a sink condition with respect to genistein. 0.2 g of the amphiphilic polymer solution on which genistein was loaded was loaded in a Franz diffusion cell on which the porcine skin was mounted, and the test was performed at 32° C. similar to a skin temperature for 24 hours. Skin tissue into which genistein was absorbed was pulverized and extracted to analyze the content of genistein absorbed into the skin tissue and the content of genistein absorbed into the acceptor solution through HPLC, and the results are shown in Table 3.

TABLE-US-00003 TABLE 3 Comparative Comparative Example 1 Example 2 Example 1 Example 2 Skin penetration 1.85 3.70 0.22 0.35 amount (μg/cm.sup.2) Skin penetration 1.05 2.10 0.13 0.20 ratio (%)

[0123] The present application can provide an amphiphilic polymer that can effectively encapsulate a drug and have excellent dispersion properties in an aqueous solution, and a method of preparing the same.

[0124] Furthermore, the present application can provide a micelle that is effectively dispersed in water or oil, and capable of exhibiting excellent percutaneous absorption properties when prepared as a formulation, and a composition including the same.

[0125] The above description of the present invention is merely an example, and it will be apparent to those skilled in the art that various modifications can be made to the above-described exemplary embodiments of the present invention without departing from the spirit or scope of the invention. Thus, the above-described embodiments of the present invention are intended merely to be examples in all aspects and the present invention is not limited thereto.