KR102001614B1 - The amphiphilic polymer - Google Patents

Abstract

The present application relates to an amphiphilic polymer and a method for producing the same.
The present application also relates to a micelle comprising the amphipathic polymer and a composition comprising the same.
The amphiphilic polymer of the present application has excellent drug encapsulation characteristics and excellent dispersion characteristics.

Description

The amphiphilic polymer < RTI ID = 0.0 >

The present application is directed to amphiphilic polymers, methods for their preparation, micelles comprising amphiphilic polymers and compositions thereof.

In the fields of pharmacy and cosmetics, there has been a demand for development of formulations capable of stably collecting various substances having efficacy on the skin in the product and effectively acting on the skin to improve the condition of the skin.

However, most of the drugs are poorly soluble or unstable, and there is a problem that they bind to or react with other substances and make the whole system unstable.

Accordingly, various techniques have been developed to more stably and easily trap efficacious drugs in formulations. For example, nanoemulsions prepared by emulsion particles in nano units, liposomes using self-assembly properties of phospholipids, solid lipids Nano-sized solid lipid nanoparticles or polymer nanoparticles stabilized at the interface with a surfactant.

However, these nanoparticles still suffer from the difficulty of improving the transdermal absorption effect depending on the poor solubility and dispersion characteristics of the drug.

Korean Patent Publication No. 2009-155282

The present application provides an amphipathic polymer capable of effectively encapsulating a drug while having excellent dispersion characteristics at the same time, and a method for producing the same.

The present application also provides compositions comprising micelles and micelles comprising an amphipathic polymer that is effectively dispersed in water or water and can exhibit excellent percutaneous absorption properties.

The present application is directed to amphiphilic polymers and micelles. The micelle includes an amphiphilic polymer.

The amphipathic polymer according to the present invention is a block copolymer capable of exhibiting phase separation characteristics, effectively encapsulating a target substance using self-assembly properties, and having a good dispersion property, Cosmetic composition and the like.

The term " amphiphilic polymer " in the present application means a polymer which simultaneously contains regions having different physical properties, for example, solubility parameters different from each other, for example, a hydrophilic region and a hydrophobic region May refer to a polymer that is simultaneously included.

The term " hydrophilic or hydrophobic region " in the present application means a region contained in a polymer, for example, forming a block in such a state as to confirm that each region is phase-separated. , The degree of hydrophilicity or hydrophobicity of each is relative.

As used herein, the term " self asembly characteristic " means a phenomenon in which an amphiphilic polymer spontaneously undergoes fine phase separation in the oil or water and has a regular size of regularity.

The amphiphilic polymer according to the present application comprises a first block (A) and a second block (B) which is phase separated from the first block (A). Also, the second block (B) comprises an acrylic monomer or a vinyl-based monomer having a solubility parameter of less than 10.0 (cal / cm < ³ >) ^1/2 .

The amphipathic polymer of the present application can effectively collect target substances, for example, the following drugs, including two blocks that are phase separated from each other.

The term " phase-separated " in the present application means a state in which the first block and the second block do not mix with each other and form their respective blocks in the absence of an external action.

The amphiphilic polymer of the present application comprises a first block (A) and a second block (B) which is phase separated from the first block (A).

The first block (A) means a hydrophilic region of the amphiphilic polymer, and may include, for example, a polymer having a solubility parameter of 10.0 (cal / cm ³ ) ^1/2 or more.

The method of obtaining the above solubility parameter is not particularly limited and may be a known method in this field. For example, the parameter may be calculated or obtained according to a method known in the art as a so-called Hansen solubility parameter (HSP).

In another example, the first block (A) has a solubility parameter of 13 (cal / cm ^{3) 1/2} or more, 14 (cal / cm ^{3) 1/2} or more, 15 (cal / cm ^{3) 1/2} or more, 16 (cal / cm ³ ) ^1/2 or more, or 17 (cal / cm ³ ) ^1/2 or more. The upper limit of the solubility parameter of the first block (A) is not particularly limited, and may be, for example, 25 (cal / cm ³ ) ^1/2 or less or 23 (cal / cm ³ ) ^1/2 or less.

The first block (A) satisfies the above-described solubility parameter and may include any known polymer as long as it can form a hydrophilic region of the amphiphilic polymer.

In one example, the first block (A) may be any one selected from the group consisting of polyethylene glycol, polyethylene glycol-propylene glycol copolymer, polyvinylpyrrolidone and polyethyleneimine.

Specifically, the first block (A) may be polyethyleneglycol having a number average molecular weight within the range of 500 to 100,000, but is not limited thereto. The term " number average molecular weight " in the present application may mean an analytical value measured by a magnetic resonance apparatus (NMR), and unless otherwise specified, the molecular weight of a polymer may mean the number average molecular weight of the polymer .

The second block (B) comprises an acrylic monomer having a solubility parameter of the single polymer of less than 10.0 (cal / cm ³ ) ^1/2 or a polymerization unit (B1) of a vinyl monomer.

The term " acrylic monomer " in the present application means (meth) acrylic acid or a derivative thereof. In addition, the term "(meth) acrylic acid" means acrylic acid or methacrylic acid.

The second block (B) of the amphiphilic polymer of the present application is a site adjacent to the drug and surrounding the drug as described later, and plays a role of forming a micelle shape as a whole.

Thus, the second block (B) refers to a relatively hydrophobic region in the amphiphilic polymer.

In another example, the second block (B) has a solubility parameter of a single polymer 9.8 (cal / cm ^{3) 1/2} or less than 9.5 (cal / cm ^{3) 1/2} is less than the acrylic monomer or polymerized units of a vinyl-based monomer (B1). The lower limit of the solubility parameter of the acrylic monomer or vinyl monomer is not particularly limited and may be, for example, 2 (cal / cm ³ ) ^1/2 or more, or 4 (cal / cm ³ ) ^1/2 or more.

The acrylic monomer may be a compound represented by the following general formula (1) or (2), but is not limited thereto.

[Chemical Formula 1]

(2)

In the general formulas (1) and (2), Q is hydrogen or an alkyl group, and B is a linear or branched alkyl group, an alicyclic hydrocarbon group, an aromatic substituent or a carboxyl group having at least 1 carbon atom, and R ₁ and R ₂ are each independently hydrogen , A linear or branched alkyl group having 1 or more carbon atoms, an alicyclic hydrocarbon group, or an aromatic substituent group.

The alkyl group present in Q in formulas (1) and (2) may be an alkyl group having 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms. The alkyl group may be linear, branched or cyclic. In addition, the alkyl group may be optionally substituted with one or more substituents.

In the general formulas (1) and (2), B, R ₁ and R- ₂ each independently may be a linear or branched alkyl group having at least 1 carbon atom, at least 3 carbon atoms, at least 5 carbon atoms, at least 7 carbon atoms or at least 9 carbon atoms, Or may be in an unsubstituted state. Such a compound containing a relatively long alkyl group is known as a hydrophobic compound. The upper limit of the number of carbon atoms of the linear or branched alkyl group is not particularly limited. For example, the alkyl group may be an alkyl group having 20 or less carbon atoms.

B, R ₁ and R-2 in the general formulas (1) and ( ₂₎ may be alicyclic hydrocarbon groups in another example, for example, an alicyclic hydrocarbon group having 3 to 20 carbon atoms, 3 to 16 carbon atoms or 6 to 12 carbon atoms, Examples of the groups include an alicyclic alkyl group having 3 to 20 carbon atoms, 3 to 16 carbon atoms, or 6 to 12 carbon atoms, such as a cyclohexyl group or an isobornyl group. Compounds having an alicyclic hydrocarbon group are also known as relatively hydrophobic compounds.

B, R ₁ and R-2 in formulas (1) and ( ₂₎ may be aromatic substituents, such as aryl groups or arylalkyl groups, in other examples.

The aryl group in the above may be, for example, an aryl group having 6 to 24 carbon atoms, 6 to 18 carbon atoms, or 6 to 12 carbon atoms. The alkyl group of the arylalkyl may be, for example, an alkyl group having 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms. Examples of the aryl group or arylalkyl group include, but are not limited to, a phenyl group, a phenylethyl group, a phenylpropyl group or a naphthyl group.

Examples of substituents which may optionally be substituted in the alkyl group, aryl group or hydrocarbon group in the above formulas 1 and 2 in the present application include halogen such as chlorine or fluorine, glycidyl group, epoxy alkyl group, glycidoxyalkyl group, or alicyclic epoxy group An acryloyl group, a methacryloyl group, an isocyanate group, a thiol group, an alkyl group, an alkenyl group, an alkynyl group or an aryl group, but the present invention is not limited thereto.

The compound represented by Formula 1 may be, for example, alkyl (meth) acrylate. In the above, the term "(meth) acrylate" means acrylate or methacrylate. The alkyl (meth) acrylate may be, for example, methyl (meth) acrylate, ethyl (meth) acrylate, n-propyl (meth) acrylate, isopropyl (meth) Butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, 2-ethylbutyl (meth) acrylate, (Meth) acrylate, n-octyl (meth) acrylate, isobornyl (meth) acrylate, isooctyl (meth) acrylate, isononyl However, the present invention is not limited thereto.

In this application, an appropriate type may be selected and used in consideration of the physical properties of the desired amphiphilic polymer among the monomers described above.

In one example, Q in the formula (1) is hydrogen or an alkyl group having 1 to 4 carbon atoms, and B is an alkyl group having 7 or more carbon atoms or an alicyclic hydrocarbon group having 6 to 12 carbon atoms, but is not limited thereto.

The second block (B) may comprise polymerized units (B1) of vinyl monomers whose solubility parameter of the single polymer is less than 10 (cal / cm ³ ) ^1/2 .

The vinyl monomer may be, for example, a compound represented by the following formula (3) or (4).

(3)

Wherein X is a nitrogen atom or an oxygen atom, Y is a carbonyl group or a single bond, R ₃ and R ₅ are each independently hydrogen or an alkyl group, or R ₃ and R ₅ are linked together to form an alkylene group, R ₄ is an alkenyl group (provided that when X is an oxygen atom, R ₃ is not present);

[Chemical Formula 4]

In the general formula (4), R ₆ , R ₇ and R ₈ are each independently hydrogen or an alkyl group, and R ₉ is a cyano group or an aromatic substituent.

When Y is a single bond in formula (3), a structure in which R ₅ and X are directly connected can be realized without a separate atom in the part denoted by Y.

In formula (3), R ₄ may be, for example, a straight chain, branched chain or cyclic alkenyl group having 2 to 20 carbon atoms, 2 to 16 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms or 2 to 4 carbon atoms, Which may be optionally substituted or unsubstituted. As the alkenyl group, a vinyl group or an allyl group may be used.

R ₃ and R ₅ in Formula 3 are each independently hydrogen or a straight, branched or cyclic alkyl group having 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, To form an alkylene group having 1 to 20 carbon atoms, 2 to 16 carbon atoms, 2 to 12 carbon atoms, or 2 to 8 carbon atoms. In the above, when R ₃ and R ₅ form an alkylene group, the compound of formula (3) may be a cyclic compound.

Examples of the vinyl monomer represented by the above formula (3) or (4) include styrene monomers such as styrene and methyl styrene; Acrylonitrile; Amide-based monomers such as N-vinylamide compounds; Ester monomers such as vinyl ester compounds; Ether-based monomers such as vinyl ether compounds; And the like, but it is not limited thereto and can be used as a vinyl-based monomer contained in polymerization unit of the amphipathic polymer of the present application without limitation, as long as it satisfies the solubility parameter of the single polymer described above.

The second block (B) may further comprise a polymerized unit (B2) of a polymerizable monomer having a functional group capable of forming a hydrogen bond, in addition to the polymerized units (B1) of the acrylic monomer or vinyl monomer have.

The amphiphilic polymer of the present application is obtained by polymerizing a polymerization unit (B2) of a polymerizable monomer having a functional group capable of forming a hydrogen bond with the polymerization unit (B1) of the acrylic monomer or vinyl monomer described above in the second block (B) By including them at the same time, it is possible to improve the collection ability of the drug to be a target and to position the drug more stably in the micelle core.

The polymerizable monomer having a functional group capable of forming a hydrogen bond as described above may be a polymerizable monomer other than the acrylic monomers and the vinyl monomers described above and may mean a monomer having a functional group capable of forming a hydrogen bond.

In one example, the functional group of the polymerizable monomer may be exemplified by a hydroxyl group, an amine group, a nitro group, an amino group, an imide group, an alkoxysilane group, or a cyano group, but the present invention is not limited thereto. It is a functional group that plays a role of an electron donor capable of interacting, specifically forming a hydrogen bond to improve the trapping ability of a drug, and more stably positioning a drug in a micelle core, There are no restrictions.

Examples of the polymerizable monomer containing an amine group include 2-aminoethyl (meth) acrylate, 3-aminopropyl (meth) acrylate, N, N-dimethylaminoethyl (meth) acrylate or N, Aminopropyl (meth) acrylate, and the like, but are not limited thereto.

Examples of the polymerizable monomer containing an alkoxysilane group include vinylalkoxysilane, allylalkoxysilane, (meth) acryloxyalkylalkoxysilane, vinyl acryloxysilane, and the like. The (meth) acryloxyalkylalkoxysilane may be, for example, 3- (meth) acryloxypropylmethyldimethoxysilane, 3- (meth) acryloxypropylmethyldiethoxysilane, 3- (Meth) acryloxypropyltriethoxysilane, (meth) acryloxymethyltriethoxysilane or (meth) acryloxymethyltris (trimethylsiloxy) silane can be exemplified, But is not limited thereto.

Examples of the polymerizable monomer containing a cyano group include, but are not limited to, cyanomethyl (meth) acrylate, cyanoethyl (meth) acrylate or cyanopropyl (meth) acrylate .

Such a polymerizable monomer having a functional group capable of forming a hydrogen bond forms a polymerized unit (B2) in the second block (B), and the polymerized unit (B2) is, for example, located outside the polymer , And can capture the drug.

In the second block (B), the polymerization unit (B1) of the above-mentioned acrylic monomer or vinyl monomer and the polymerization unit (B2) of the polymerizable monomer having a functional group capable of forming a hydrogen bond are contained in a predetermined weight ratio .

For example, it is preferable that the solubility parameter of the single polymer in the second block (B) is less than 10.0 (cal / cm < ³ >) ^1/2 , The weight ratio (B1: B2) of the polymerized units (B2) of the polymerizable monomer having a functional group may be the same or different. For example, the weight ratio (B1: B2) may be in the range of 1: 9 to 9: 1. In another example, the weight ratio (B1: B2) may be in the range of from 2: 8 to 8: 2, from 3: 7 to 7: 3, or from 4: 6 to 6: 4. Within the range of the weight ratio (B1: B2), the drug can be effectively trapped and the amphiphilic polymer safely dispersed in the aqueous solution can be formed.

The second block (B) may for example have a number average molecular weight within the range of 500 to 100,000. Within this range, desired hydrophobic properties and ability to collect drugs can be secured.

The amphiphilic polymer of the present application may have the same or different block ratio (A: B) of the first block (A) and the second block (B).

In one example, the block ratio (A: B) of the first block (A) and the second block (B) may be different from that of the amphipathic polymer.

Specifically, the amphiphilic polymer of the present application can adjust the block ratio (A: B) of the first block (A) and the second block (B) within the range of 1: 9 to 9: 1. In the above, the term "block ratio (A: B)" means a mass ratio between blocks.

In another example, the block ratio (A: B) of the first block A and the second block B is 2: 8 to 8: 2, 3: 7 to 7: 3, or 4: : May be four.

The amphiphilic polymer may have a number average molecular weight (Mn) in the range of 1,000 to 500,000.

The present application is also directed to a micelle comprising the above-described amphiphilic polymer.

As used herein, the term " micelle " may refer to particles of from several nanometers to tens of thousands of nanometers having a core / shell structure by self-assembling properties of amphiphilic polymers.

The micelle comprising the amphiphilic polymer of the present application can have excellent dispersion characteristics in water or in water and can also have excellent stability.

Such a micelle may further comprise, for example, a drug encapsulated by an amphipathic polymer.

In one example, as shown in FIG. 1, the micelle of the present application may be a structure comprising a drug 100 and an amphiphilic polymer 200 encapsulating the drug 100. The amphiphilic polymer 200 includes a first block 201 and a second block 202 and a second block 202 of the amphipathic polymer 200 is disposed adjacent to the drug 100 Lt; / RTI > As used herein, encapsulation refers to a structure in which an amphiphilic polymer surrounds a drug, as in Fig. 1, and is used in the present application in the same sense as " collection ".

Typically, the drug is poorly soluble, but the drug of the present application is encapsulated by an amphiphilic polymer having both a hydrophobic region and a hydrophilic region, thereby ensuring excellent dispersion characteristics of the drug in water or water.

In the case of the micelle of the present application, the amorphous polymer containing the amphiphilic polymer having the same or different block ratio (A: B) of the first block (A) and the second block (B) It is possible to further secure the superiority of the dispersing property and further to have a good encapsulation property including a functional group capable of a predetermined interaction with the drug.

The drug contained in the micelle of the present application is not particularly limited, but may include, for example, a physiologically active substance.

In one example, the bioactive material may be sparingly soluble.

Such physiologically active substances include, for example, genistein, daidzein, cucurbitacin, francidin and derivatives thereof; Polyphenols; Or a mixture thereof.

As an example of the physiologically active substance, the term " genistein, daidzein, cucurbitacin, francidin, or derivatives thereof refers to a phenolic compound or its glycoside contained in soybean, and female hormone is similar to estrogen Structure, and has excellent antioxidative effect, and is used in a variety of fields from skin beauty to chemotherapy.

Specifically, the isoflavone may be a glycoside of genistein or genistein such as acetyl genistein or malonyl genistein, but is not limited thereto. .

Isoflavone such as genistein, daidzein, cucurbitacin, francidinine, or derivatives thereof is a phenolic compound, and includes -H in the molecule, and -H in the molecule is an amphipathic polymer 2 block (B) to hydrogen bond with a functional group capable of hydrogen bonding, thereby improving the stability of the drug located in the micelle.

The drug contained in the micelle may be included in the micelle in such an amount as to express the physiological activity when the micelle is manufactured into a formulation.

In one example, the content of the drug may be in the range of 1 to 60 wt%, 1 to 50 wt%, 1 to 40 wt%, or 1 to 20 wt%, based on the total weight of the micelle. If the content of the drug is more than 60% by weight, effective collection may not be obtained, and the drug may flow out of the micelle and be aggregated or denatured in a crystalline form.

Such a micelle may have an average particle diameter of, for example, in the range of 1 nm to 10,000 nm. The average particle diameter of the micelle is a value measured by a dynamic light scattering method and is a range covering a particle size of a single micelle or a micelle aggregate itself .

The present application is also directed to compositions comprising such micelles.

In one example, the present application is directed to a composition for making particles comprising a micelle comprising the amphipathic polymer.

The composition for particle production of the present application includes a micelle formed due to self-assembling properties of an amphipathic polymer. In addition, the amphiphilic polymer forming such a micelle may be encapsulating, for example, a drug.

For example, the micelle contained in the composition for particle production may further comprise a drug encapsulated by an amphipathic polymer.

The present application is also directed to a pharmaceutical or cosmetic composition comprising a micelle comprising the amphipathic polymer.

Specifically, the micelle contained in the pharmaceutical or cosmetic composition may include an amphipathic polymer and a drug encapsulated by the amphipathic polymer.

In one example, when the composition is a pharmaceutical composition, the drug in the micelle may be included in the composition in a pharmaceutically acceptable form. In addition, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

In addition, the pharmaceutical composition may be of various oral or parenteral formulations.

When the pharmaceutical composition is formulated, it may be prepared by using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient.

In one example, solid formulations for oral administration include tablets, pills, powders, granules, or capsules, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose, lactose, gelatin and the like.

In one example, the liquid preparation for oral administration includes suspensions, solutions, emulsions or syrups. In addition to water or liquid paraffin, which is a simple diluent commonly used, various excipients such as wetting agents, sweeteners, , Preservatives, and the like. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, or suppositories.

The pharmaceutical compositions may be formulated into oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups or aerosols according to conventional methods; External preparations such as ointments and creams; Suppository; Or sterile injectable solutions, and the like, may be formulated and used in any form suitable for pharmaceutical preparations.

In another example, the composition may be a cosmetic composition that may be included in an external preparation for skin having a formulation such as a soft lotion, a convergent lotion, a nutritional lotion, a nutritional cream, a cleansing foam, an essence, or a pack.

The cosmetic composition and the external preparation for skin may contain a known additive component such as a powdery base or a carrier (such as a binder, a disintegrant, an excipient or a lubricant), an oily base or a carrier (such as animal and vegetable oils, wax, petroleum jelly, A chelating agent, an antioxidant, a cooling agent, a stabilizing agent, a fluidizing agent, an emulsifier, a viscosifying agent, a buffering agent, an antioxidant, a preservative, Dispersant, adsorbent, humectant, wetting agent, desiccant, antistatic agent, or other resin (olefin resin such as polyamide resin hydrogenated polybutene), and the like.

Such a pharmaceutical or cosmetic composition may be in the form of an oil-in-water or water-in-oil emulsion.

Micelles within the composition may, for example, form aggregates. Such micelle aggregates may be formed due to van der Waals forces, etc. between hydrophobic regions. The size of such micelle aggregates may be in the range of, for example, 10 nm to 10,000 nm.

The present application also relates to a method for producing the above-described amphipathic polymer.

That is, the production method of the present application includes a step of polymerizing an acrylic monomer or a vinyl monomer having a solubility parameter of less than 10.0 (cal / cm ³ ) ^1/2 of a polymer forming the first block (A) and a single polymer.

Specifically, in the method for producing the amphiphilic polymer of the present application, the method of polymerizing the polymer forming the first block (A) and the above-mentioned monomer is not particularly limited, but a narrow molecular weight distribution and an effective attainment of a desired molecular weight , Living radical polymerization, for example, atom transfer radical polymerization (ATRP), may be used.

More specifically, the amphiphilic polymer of the present application is produced by reacting a polymer forming the first block (A) containing a halogen atom with a transition metal complex catalyst to produce radicals, and the radicals are reacted with the acrylic block (B) having a polymerization unit (B1) of an acrylic monomer or a vinyl-based monomer by accepting a double bond site electron of a monomer or a vinyl monomer and forming the second block (B) having a polymerization unit (B1) of an acrylic monomer or a vinyl monomer.

The polymer forming the first block is, for example, a polymer having a solubility parameter of 10.0 (cal / cm < ³ >) ^1/2 or more with or without a halogen atom, When a polymer is used, it may further include a step of preparing an initiator for ATRP through reaction with a compound containing a halogen atom.

The present application also relates to a process for preparing a micelle comprising the step of mixing the drug with the amphipathic polymer prepared as described above.

The method of mixing the amphiphilic polymer and the drug for preparing the micelle is not particularly limited. For example, after the amphiphilic polymer is dissolved in a predetermined organic solvent such as ethanol and the like, And a solution comprising the drug.

Further, the method may include a step of removing the solvent in a subsequent step after the step. However, the present invention is not limited to this.

The temperature in the step of removing the solvent differs depending on the boiling point of each solvent. For example, the solvent may be removed at a temperature of 50 ° C or higher, but the present invention is not limited thereto.

The present application can provide an amphiphilic polymer capable of effectively encapsulating a drug and having excellent dispersion characteristics in an aqueous solution, and a process for producing the same.

The present application is also able to provide micelles and compositions containing them that are effectively dispersed in water or water and can exhibit excellent percutaneous absorption properties upon manufacture as a formulation.

1 is a schematic diagram of a micelle comprising an amphipathic polymer according to the present application.
FIG. 2 is an image obtained by observing the precipitation of the amphiphilic polymer and the drug encapsulated therein according to the examples and the comparative examples through an optical microscope.
Figure 3 is a schematic diagram of Franz cell for percutaneous absorption experiment.

Hereinafter, the present application will be described in more detail by way of examples, but is merely an example limited to the gist of the present application. It will be understood by those skilled in the art that this application is not limited to the process conditions set forth in the following examples, but may be optionally selected within the scope of the conditions necessary to accomplish the object of the present application Do.

Example One.

Amphibian  Preparation of Polymers (P1)

After the polyethylene glycol monomethyl ether polymer (molecular weight: 5,000, manufacturer: Aldrich) forming the first block was dissolved in dichloromethane at a concentration of 30%, a solution of triethylamine 3 equivalents of triethylamine and 2 equivalents of 2-bromo isobutyryl bromide are reacted to prepare an initiator for ATRP. Thereafter, the precipitating and collecting steps in the diethyl ether solvent are repeated twice and dried to obtain a bromine-endbrominated polyethylene glycol polymer from which the impurities have been removed. 100 parts by weight of the obtained bromine-terminated polyethylene glycol polymer was dissolved in 250 parts by weight of anisole reaction solvent in a flask, and methyl methacrylate (solubility parameter: 9.5 (cal / cm ³ ) ^1/2 ) 150 parts by weight was put into the flask, and the flask was sealed with a rubber stopper. Thereafter, dissolved oxygen was removed by nitrogen purging and stirring at room temperature for 30 minutes, immersed in an oil bath set at 60 ° C, and the reaction was carried out by adding a second copper bromide complex and a catalyst reducing agent. When the desired molecular weight was prepared, the reaction was terminated to prepare an amphiphilic polymer (P1). The molecular weight and the block ratio (A: B) of the amphiphilic polymer (P1) are shown in Table 1 below.

Example  2. - Amphibian  Preparation of Polymers (P2)

The bromine-terminated polyethylene glycol monomethyl ether polymer prepared in the same manner as in Example 1 was dissolved in an anisole reaction solvent and methyl methacrylate (solubility parameter: 9.5 (cal / cm ³ ) ^{1 / 2} ): N, N-dimethylaminoethyl methacrylate (solubility parameter: 9.6 (cal / cm ³ ) ^1/2 ) was added at a weight ratio of 80:20 The amphiphilic polymer (P2) was prepared in the same manner as in (1). The molecular weight and the block ratio (A: B) of the amphiphilic polymer (P2) and the weight ratio (B1: B2) of the polymerization unit in the second block (B) are shown in Table 1 below.

Example  3. - Amphibian  Preparation of Polymer (P3)

The bromine-terminated polyethylene glycol monomethyl ether polymer prepared in the same manner as in Example 1 was dissolved in an anisole reaction solvent and methyl methacrylate (solubility parameter: 9.5 (cal / cm ³ ) ^{1 / 2} ): N, N-dimethylaminoethyl methacrylate (solubility parameter: 9.6 (cal / cm ³ ) ^1/2 ) was added at a weight ratio of 60:40 The amphiphilic polymer (P3) was prepared in the same manner as in Example 1. The molecular weight and the block ratio (A: B) of the amphiphilic polymer (P2) and the weight ratio (B1: B2) of the polymerization unit in the second block (B) are shown in Table 1 below.

Comparative Example  One - Amphibian  Preparation of Polymer (P4)

(A) -polycaprolactone (B) copolymer (P4) to which a polyester-based polymer, polycaprolactone (solubility parameter: about 10 (cal / cm ³ ) ^1/2 ) Respectively.

Specifically, it was synthesized through ring-opening polymerization using polyethyleneglycol monomethyl ether polymer (molecular weight: 5000, manufacturer: Aldrich) as an initiator. Stannous 2-ethyl-hexanoate (Sn (Oct) ₂ ) was used as a reaction catalyst. Polyethylene glycol monomethyl ether 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. Polyethylene glycol monomethyl ether and the same amount of? -Caprolactone were 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. To the reactor cooled to room temperature, methylene chloride was added to dissolve the reaction product, and the copolymer was precipitated by adding slowly to excess cold ethyl ether. The precipitated block copolymer was filtered and vacuum-dried at 40 DEG C for 48 hours to finally obtain a polyethylene glycol (A) -polycaprolactone (B) copolymer (P4).

Comparative Example  2 - Amphibian  Preparation of Polymer (P5)

Polyester-based polymer, a polycaprolactone (solubility parameter: about ^{10 (cal / cm 3) 1/2} ) is applied to the polyethylene glycol (A) - polycaprolactone (B) during synthetic co-polymer of polyethylene glycol monomethyl ether (polyethyleneglycol monomethyl ether was prepared in the same manner as in Comparative Example 1, except that 2-fold amount of epsilon -caprolactone was added to prepare an amphipathic polymer (P5).

Experimental Example  1- Prepared Amphibian  Polymeric The block ratio (A: B) and  Molecular weight evaluation

The block ratio and molecular weight of the prepared amphiphilic polymers (P1 to P5) were evaluated by the following methods and shown in Table 1.

Specifically, the solid solution was solidified after purification of the polymer solution completely removed from the catalyst, and the block ratio of the amphiphilic polymer was confirmed by 1H NMR analysis. Purification of the polymer solution is carried out by passing through an alumina column to remove the copper complex catalyst and then adding dropwise with stirring to excess diethyl ether to remove residual monomer and solidify. 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 ₃ and measured by 1 H-NMR analysis equipment. As a result of the analysis of Examples 1 to 3, 1H peak derived from CH ₂ ═C (CH ₃ ) - at the double bond end was not confirmed, confirming that no unreacted monomer was present. Also, in Examples 1 to 3 and Comparative Examples 1 and 2, the 3H peak derived from -OCH ₃ at the end of the ethylene glycol block was confirmed at around 3.2 ppm, and the ratio and molecular weight of each polymer block were calculated based on this. 450 H-peaks (4H x repeating units: 113) derived from -CH ₂ CH ₂ O- of ethylene glycol formed of a polymer appeared in the range of 3.6 to 3.8 ppm. In Examples 1 to 3, methyl methacrylate A 3H peak derived from -CH ₃ adjacent to the main chain of the acrylate appears in the range of 3.5-3.6 ppm and a 2H peak derived from -OCH ₂ - adjacent to -COO- of the dimethylaminoethyl methacrylate side chain formed of the polymer is 4.0 -4.2 ppm, the content of each constituent monomer was calculated as a mass fraction based on its area ratio. Comparative Examples 1 to 2 In the case of a chain formed of a polymer of caprolactone _{- (CO-CH 2 CH 2} CH 2 CH 2 CH 2 -O-) n -CO- in the right first -CH ₂ - derived from a 2H peak The molecular weight was confirmed through the 3H peak area derived from -OCH ₃ at the end of the ethylene glycol block and the 2H peak area derived from the -CO- right side first -CH ₂ - of caprolactone.

Molecular weight (Mn, first block: second block) Block ratio (A: B) Second Block (B) Polymerized Unit Weight Ratio (B1: B2) ^a Example 1 11,000 (5,000: 6,000) 4.55: 5.45 100: 0 Example 2 11,000 (5,000: 6,000) 4.55: 5.45 80:20 Example 3 11,000 (5,000: 6,000) 4.55: 5.45 60:40 Comparative Example 1 9,900 (5,000: 4,900) 5.05: 4.95 - Comparative Example 2 14,700 (5,000: 9,700) 0.34: 0.66 -

a: methyl methacrylate (B1): N, N-dimethylaminoethyl methacrylate (B2) mass ratio

Experimental Example  2 - Micelle  Manufacturing and checking the concentration of drug dissolved

Genistin, an insoluble substance, was encapsulated using the synthesized amphiphilic polymer (P1 to P5). First, a solution obtained by dissolving 10 g of amphiphilic polymer in 30 mL of ethanol was mixed with 20 g of diphenylene glycol (DPG)) 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 in order to evaporate the ethanol solvent, and the remaining ethanol was removed using a rotary evaporator to prepare a solution having a content of 2% of the genistein. The prepared solution was diluted with 10 times of purified water and stored at room temperature (25 ° C) for 7 days. The change with time was confirmed by an optical microscope, and it is shown in FIG. The solution was filtered with a syringe filter (pore size: 1 탆) to remove the precipitated genistein, and the content of genistein encapsulated in the amorphous macromolecular micelle particles was measured from liquid chromatography (HPLC). Drug loading capacity and drug loading efficiency of the amphipathic polymer were calculated by the following equation and the particle size of the micelle containing the amphipathic polymer in which the drug was collected was measured by Malvern Gt; Zetasizer 3000 < / RTI >

[Equation 1]

&Quot; (2) "

Table 2 shows the results of measuring the size of micelle particles, the drug collection capacity and the drug collection efficiency.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Particle Size (nm) 110 125 135 100 150 Drug collection capacity (%) 2.4 10.7 16.1 1.2 1.8 Drug collection efficiency (%) 13 60 96 6 9

Experimental Example  3 - Percutaneous  Absorption experiment

The transdermal absorption of genistein from the ampholytic polymer solution collected from the above-prepared genistein was evaluated using pig skin (2 x 2 cm, thickness 1000 탆) and Franz diffusion cell. PBS (phosphate buffered saline) solution containing 30% by weight of dipropylene glycol (DPG) as an acceptor solution was used to maintain the sink condition for the genistein. After loading 0.2g of amphoteric polymer solution with genistein in Franz diffusion cell equipped with pig skin, it was tested at 32 ℃ similar to skin temperature for 24 hours. Genistein-absorbed skin tissue was pulverized-extracted, and the content of the absorbed genistein in the skin tissue and the content of genistein in the acceptor solution were analyzed by HPLC and shown in Table 3.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Skin permeation (/ / cm ² ) 0.66 1.85 3.70 0.22 0.35 Skin Transmittance (%) 0.38 1.05 2.10 0.13 0.20

100: Drugs
200: amphiphilic polymer
201: first block
202: second block

Claims (25)

An amphipathic polymer and a drug encapsulated by the amphipathic polymer,
Wherein the amphiphilic polymer comprises a first block (A); (B1) of an acrylic monomer or a vinyl monomer having a solubility parameter of the single polymer of less than 10.0 (cal / cm < ³ >) ^{1/2 and} a polymerizable monomer And a second block (B) comprising a polymerized unit (B2) of a polymerizable monomer having a functional group,
Wherein the drug is selected from the group consisting of genistein, daidzein, coccitabathine, francidinine or derivatives thereof; Polyphenols; And a mixture thereof, wherein the physiologically active substance is an insoluble physiologically active substance.
Having a functional group capable of forming a hydrogen bond with a polymerization unit (B1) of an acrylic monomer or a vinyl monomer having a single polymer solubility parameter of less than 10.0 (cal / cm ³ ) ^{1/2 in} the second block (B) (B1: B2) of the polymerized units (B2) is in the range of 1: 9 to 9: 1,
And a second block (B) of the amphiphilic polymer is adjacent to the drug. The method according to claim 1,
The first block (A) comprises a polymer having a solubility parameter of 10 (cal / cm ³ ) ^1/2 or more. The method according to claim 1,
The first block (A) is any one selected from the group consisting of polyethylene glycol, polyethylene glycol-propylene glycol copolymer, polyvinylpyrrolidone and polyethyleneimine. The method according to claim 1,
The acrylic monomer is a compound represented by the following general formula (1) or (2): Micelle:
[Chemical Formula 1]

(2)

In the general formulas (1) and (2), Q is hydrogen or an alkyl group, and B is a linear or branched alkyl group, an alicyclic hydrocarbon group, an aromatic substituent or a carboxyl group having at least 1 carbon atom, and R ₁ and R ₂ are each independently hydrogen , A linear or branched alkyl group having 1 or more carbon atoms, an alicyclic hydrocarbon group, or an aromatic substituent group. 5. The method of claim 4,
Q in the formula (1) is hydrogen or an alkyl group having 1 to 4 carbon atoms; and B is an alkyl group having 1 or more carbon atoms or an alicyclic hydrocarbon group having 6 to 12 carbon atoms. The method according to claim 1,
The vinyl monomer is a compound represented by the following formula 3 or 4:
(3)

Wherein X is a nitrogen atom or an oxygen atom, Y is a carbonyl group or a single bond, R ₃ and R ₅ are each independently hydrogen or an alkyl group, or R ₃ and R ₅ are linked together to form an alkylene group, R ₄ is an alkenyl group (provided that when X is an oxygen atom, R ₃ is not present);
[Chemical Formula 4]

In the general formula (4), R ₆ , R ₇ and R ₈ are each independently hydrogen or an alkyl group, and R ₉ is a cyano group or an aromatic substituent. delete The method according to claim 1,
The 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. delete The method according to claim 1,
Wherein the amphiphilic polymer includes the first block and the second block in a different block ratio (A: B). The method according to claim 1,
Wherein the amphiphilic polymer comprises the first block and the second block in a block ratio (A: B) of 1: 9 to 9: 1. 12. The method of claim 11,
Wherein the amphiphilic polymer comprises the first block and the second block in a block ratio (A: B) of 3: 7 to 7: 3. delete delete delete The method according to claim 1,
Micelles having an average particle diameter in the range of 1 nm to 10,000 nm. delete delete delete A composition for producing particles comprising the micelle of claim 1. delete A pharmaceutical composition comprising the micelle of claim 1. delete 23. The method of claim 22,
Wherein the pharmaceutical composition is in the form of an oil-in-water or water-in-oil emulsion.
delete

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