KR20140126441A - Cholesterol-hydrophilic polymer conjugate, a preparation thereof, and the use of the same - Google Patents

Abstract

The present invention relates to a cholesterol-hydrophilic polymer conjugate, a method for preparing the same, and a use thereof. More specifically, the cholesterol-hydrophilic polymer conjugate is made by chemically combining O-methacryloyl cholesterol and poly(2-hydroxyethyl methacrylate) or poly(N-isopropylacrylamide). The conjugate according to the present invention is able to effectively collect active substances and efficiently transfer the active substances through percutaneous absorption and, therefore, can be preferably applied to the pharmaceutical and cosmetic fields.

Description

The present invention relates to a cholesterol-hydrophilic polymer conjugate, a preparation thereof, and the use of the same.

The present invention relates to a cholesterol-hydrophilic polymer conjugate capable of achieving a suitable capsule structure according to the polarity of a skin active ingredient and minimizing contact with water and air, which are the main causes of oxidation, Gate, a method for producing the same, and a use thereof.

Cholesterol acts on the self-association of molecules in living organisms and plays an important role in regulating the fluidity of biological membranes. It is a component that constitutes intercellular lipids of the stratum corneum along with ceramides and free fatty acids. It plays an important role in formation. Also, it has emulsifying function for W / O and O / W. It is one of the three major components of liposome and has moisture retention function, which is widely used in moisturizing, skin barrier strengthening cosmetics and drug delivery.

Such applications of cholesterol have been studied in order to increase the biocompatibility, the collection rate of the hydrophobic drug and the stability of the drug in the field of drug delivery. In particular, in the study of liposome membrane strengthening using cholesterol_PAA, it was confirmed that the captured model drug calcein was captured stably in the capsules even at pH change, and the material in which cholesterol was bound to the polyglycerol dendrimer was found to be a paclitaxel (Science and Technology of Advanced Materials 6 (2005) 452-456).

Although studies on cholesterol-based materials have been continuously conducted in the field of drug delivery system research, efforts to introduce and apply them as cosmetic materials have been lacking, and there have been no studies to improve the function of cosmetic preparations.

Science and Technology of Advanced Materials 6 (2005) 452-456

Accordingly, the present inventors have found that cholesterol and hydrophilic polymers can be chemically synthesized so as to enhance transmission to skin by using cholesterol having similarity to intercellular lipid, structure and compositional components thereof, and to capture active ingredients with high content through microcapsules The present inventors have invented a conjugated conjugate, and confirmed that such a conjugate can effectively capture the active substance and effectively deliver the active ingredient through transdermal absorption, thereby completing the present invention.

Accordingly, an object of the present invention is to provide a cholesterol-hydrophilic polymer conjugate and a method for producing the cholesterol-hydrophilic polymer conjugate which can effectively perform the entrapment and transdermal absorption of an active substance.

Another object of the present invention is to provide the use of the cholesterol-hydrophilic polymer conjugate in pharmaceutical compositions and cosmetic compositions.

To this end,

Hydrophilic polymer conjugate characterized in that O-methacryloylcholesterol is chemically bonded to poly (2-hydroxyethyl methacrylate) or poly (N-isopropylacrylamide).

Also,

Reacting cholesterol and methacryloyl chloride to prepare O-methacryloyl cholesterol,

Reacting the O-methacryloylcholesterol with 2-hydroxyethyl methacrylate or N-isopropylacrylamide

Wherein the cholesterol-hydrophilic polymer conjugate is a cholesterol-hydrophilic polymer conjugate.

The present invention also provides a pharmaceutical composition comprising the cholesterol-hydrophilic polymer conjugate.

In addition, the present invention provides a cosmetic composition comprising the cholesterol-hydrophilic polymer conjugate.

The conjugate according to the present invention can be effectively applied to the fields of pharmacy and cosmetics because it can effectively capture the active substance and efficiently deliver the active substance through transdermal absorption.

Figure 1 is a graph showing the IR analysis results of a cholesterol-poly (2-hydroxyethyl methacrylate) conjugate and a cholesterol-poly (N-isopropyl acrylamide) conjugate.
Fig. 2 shows the results of GPC analysis of the conjugates prepared in Example 1 and Example 2. Fig.
3 is an SEM image of the microcapsules prepared in Experimental Example 3 before freeze-drying (left) and after freeze-drying (right).

The present invention relates to a pharmaceutical composition comprising cholesterol and cholesterol having similarity in structure and composition to intercellular quality and enhancing transmission to the skin and enabling cholesterol and hydrophilic polymer to chemically bind Lt; / RTI >

Specifically, the cholesterol-hydrophilic polymer conjugate according to the present invention is chemically bonded to O-methacryloylcholesterol with poly (2-hydroxyethyl methacrylate) or poly (N-isopropylacrylamide).

Such a conjugate is capable of realizing a suitable capsule structure according to the polarity of the skin active ingredient and minimizing the contact with water and air which are the main causes of oxidation, And cholesterol having a similar structure to its constituent components, so that the active substance can be efficiently delivered through transdermal absorption. Therefore, it can be effectively applied to fields of pharmacy or cosmetics.

The chemical bond is directly linked through a chemical reaction between O-methacryloyl cholesterol and poly (2-hydroxyethyl methacrylate) or poly (N-isopropylacrylamide), and examples thereof include amide bond, ether bond , A thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond.

The conjugate may vary depending on the application, but has a weight average molecular weight of 4000 to 8000. If the molecular weight is less than the above range, the active ingredient can not be effectively collected. On the contrary, if the molecular weight exceeds the above range, the solubility and the skin permeability are deteriorated.

The conjugate can be made up of O-methacryloyl cholesterol and poly (2-hydroxyethyl methacrylate) or poly (N-isopropylacrylamide) in a weight ratio of 1: 1 to 1: 100, Can be adjusted accordingly.

Such a conjugate of the present invention

Reacting cholesterol and methacryloyl chloride to prepare O-methacryloyl cholesterol,

Reacting the O-methacryloylcholesterol with 2-hydroxyethyl methacrylate or N-isopropylacrylamide

Lt; / RTI >

The reaction of O-methacryloylcholesterol with 2-hydroxyethyl methacrylate or N-isopropylacrylamide can be effected through cationic polymerization, anionic polymerization, ring-opening polymerization, or radical polymerization, , Emulsion polymerization, and suspension polymerization may be used. Preferably an initiator in a solvent, and 2-hydroxyethyl methacrylate or N-isopropylacrylamide as a monomer are reacted with O-methacryloyl cholesterol.

Here, the solvent, initiator, catalyst, etc. used in the reaction are specifically limited in the present invention

And a composition suitable for each monomer can be selected by those skilled in the art. It can be carried out under pressure, if necessary, in a wide temperature range from 0 to 100 ° C.

In the reaction, the content of 2-hydroxyethyl methacrylate or N-isopropylacrylamide as a monomer can be selected in consideration of the molecular weight and degree of polymerization of the conjugate to be finally obtained. And may be appropriately set in accordance with the purpose and function to be expressed.

Also, if necessary, O-methacryloylcholesterol and poly (2-hydroxyethyl methacrylate) or poly (N-isopropylacrylamide) are linked by a chemical bond, which may be connected directly or through a separate linker .

The cholesterol-hydrophilic polymer conjugate prepared by this method can be applied to various fields, i.e., a pharmaceutical composition or a cosmetic composition.

Specifically, the cholesterol-hydrophilic polymer conjugate forms micelles in the form of capsules in a dispersed phase, and when the active ingredient useful in the field of drugs or cosmetics is enclosed in the micelles, the penetration of the active ingredient into the skin is effectively Lt; / RTI >

The active ingredient is not particularly limited in the present invention and may be selected from the group consisting of therapeutic agents, skin antiaging agents, skin wetting agents, anti-wrinkle agents, anti-atrophy agents, skin smoothing agents, antibacterial agents, Anti-inflammatory agents, antifungal agents, antifungal agents, anti-pruriginous agents, external anesthetics, antiviral agents, keratolytic agents, free radical scavengers, antiseborrheic agents, (S), growth or pigmentation regulators and penetration accelerators, desquamating agents, depigmenting or propigmenting agents, antiglycation agents, tightening agents, synthesis of dermis or epidermal macromolecules Accelerators and / or decomposition inhibitors; A growth promoter or keratinocyte differentiation promoter of skin cells and / or keratinocytes; Muscle relaxants; Anti-fouling and / or anti-free radical agents; Slimming agents, anticellulite agents, agents acting on the microcirculation; Agents acting on energy metabolism of cells; Hair conditioning agents, sunscreen and / or sunblock compounds, make-up agents, detergents, medicaments, emulsifiers, softeners, preservatives, Anti-caking agents, anti-foaming agents, antioxidants, binders, biologically active agents, enzymes, enzyme inhibitors, enzyme inducers, coenzymes, plant extracts, plants Derivatives, plant tissue extracts, plant seed extracts, vegetable oils, ceramides, and the like.

When the composition is applied as a pharmaceutical composition, it may further include a pharmacologically acceptable carrier or excipient depending on the formulation, method of use, and purpose of use.

Pharmaceutically acceptable carriers or excipients include water, dextrin, calcium carbonate, lactose, propylene glycol, liquid paraffin, physiological saline, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gelatin, calcium phosphate , Calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. These may be used alone or in combination, but are not limited thereto Conventional carriers and excipients are all usable. In addition, when the anti-obesity composition is weakly formulated, it may further contain conventional fillers, extenders, binders, disintegrators, surfactants, anti-coagulants, lubricants, wetting agents, flavorings, emulsifiers or preservatives.

The composition of the present invention can be administered orally or parenterally. The dose is determined in consideration of the administration method, the age, sex and weight of the recipient, health condition, excretion rate, diet, administration time and severity of disease .

In addition, when it is used as a cosmetic product, it may be a cream, a lotion, a gel, a milk, a night, and the like, more preferably a cream formulation. Such a formulated massage cosmetic composition can be used for a body skin care, a face skin care, a baby care, an after sun care, a whitening care, an anti-cellulite care, a cleansing and the like.

In addition, the compositions of each formulation may contain various bases and additives necessary for formulation of the formulation, and may contain non-ionic surfactants, silicone polymers, extender pigments, flavorings, preservatives, But are not limited to, disinfectants, oxidative stabilizers, organic solvents, ionic or nonionic thickeners, plasticizers, antioxidants, free radical scavengers, opacifiers, stabilizers, emollients, silicones, A preservative, a surfactant, an anti-inflammatory agent, a substance P antagonist, a filler, a polymer, a propellant, a basicizing or acidifying agent, or a coloring agent.

Hereinafter, the present invention will be described in more detail with reference to 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 embodiments described below. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Example  1. Cholesterol - poly  ( NIPAM ) Conjugate  Produce

5.17 mmol of cholesterol was added to 60 mL of THF, the temperature of the reactor was lowered to 0 ° C., and the temperature was raised to 25 ° C. for 2.5 hours. The reaction was continued for 12 hours. After filtration and washing, O-methacryloyl cholesterol was recovered by drying in a vacuum oven. 0.66 mmol of the recovered O-methacryloylcholesterol was dissolved in 60 ml of anhydrous tetrahydrofuran, and then 0.3 mmol of azobisisobutyronitrile (AIBN) and N-isopropylacrylamide (NIPAM) monomer was added thereto. For 8 hours. After completion of the reaction, the reaction product was filtered, washed, and dried in a vacuum oven to recover the final product.

Example  2. Cholesterol - poly ( HEMA ) Conjugate  Produce

(HEMA) monomer was used instead of N-isopropylacrylamide (NIPAM) in Example 1, and the same operation was carried out.

Experimental Example  One: IR  analysis

IR analysis was performed to determine whether cholesterol-poly (2-hydroxyethyl methacrylate) conjugate and cholesterol-poly (N-isopropyl acrylamide) conjugate prepared in Example 1 and Example 2 were synthesized And the results are shown in Fig.

Referring to FIG. 1, it was confirmed that hydroxyethyl methacrylate (HEMA) was polymerized through an OH peak which appeared strongly and widely at 3500 cm ^-1 . It is also possible to identify 3292 cm ^-1 (NH), 2970 cm ^-1 (-CH ₃ ), 1650 cm ^-1 and 1550 cm ^-1 (C═O) peaks characteristic of N-isopropylacrylamide (NIPAM) there was.

Experimental Example  2: GPC  analysis

GPC analysis of the cholesterol-poly (2-hydroxyethyl methacrylate) conjugate and the cholesterol-poly (N-isopropylacrylamide) conjugate prepared in Example 1 and Example 2, Respectively.

Fig. 2 shows the results of GPC analysis of the conjugates prepared in Example 1 and Example 2. Fig.

2, the molecular weights of the desired cholesterol-poly (N-isopropyl acrylamide) conjugate and cholesterol-poly (2-hydroxyethyl methacrylate) conjugate were 4,000 and 8,000, respectively, It was confirmed that the synthesis was completed.

Experimental Example  3. Conjugate  Manufacture of microcapsules using

W / O / W microcapsules were prepared by using the cholesterol conjugate prepared in Example 1 and Example 2 as shells and using Jeju organic plant extract as the core to evaluate the stability of the core material , Feeling of use improvement and transdermal absorption degree were evaluated.

Organic raw materials include ogupi, aloe, broccoli, cabbage, and mandarin orange

After washing with purified water, the water was removed. 50 g of each of the raw materials was prepared and put into 1000 g of 40% 1,3-butylene glycol. The mixture was heated for 96 hours at 60 ° C by ultrasonication, and then extracted with 300 mesh filter plugs. The filtrate was aged at 10 ° C for 8 days The filtrate was filtered through filter paper No. 5 of Hwatman. The filtrate was dried at 70 ° C with a rotary evaporator to obtain respective extracts. These extracts were mixed to obtain an organic complex plant extract.

A W1 phase with PVA at 0.1% w / v in water, an oil phase containing 10% w / v of an organic compound plant extract in CH ₂ Cl ₂ , a cholesterol-poly (2-hydroxyethyl methacrylate) W1 phase containing 0.2% w / v of conjugate or cholesterol-poly (N-isopropylacrylamide) conjugate or polyvinyl alcohol, W1 / O phase of 1:10 with W1: W / O / W emulsion was prepared by adding ultrasonic waves to W1 / O at a ratio of 10: 1 prepared on W2 and stirring at 150 rpm for 12 hours.

SEM analysis of the microcapsules of the W / O / W emulsion thus obtained confirmed the size and morphology of the particles.

3 is an SEM image of the microcapsules prepared in Experimental Example 3 before freeze-drying (left) and after freeze-drying (right).

As shown in FIG. 3, the microcapsules before and after freeze-drying had almost no size change, but cracks occurred on the surface of the particles after freeze-drying. As a result, the stability of the inner core material is expected to be broken after lyophilization, and the prepared material is applied to the formulation in emulsion form.

Experimental Example  4: stability of microcapsule and Brittle  evaluation

The stability and spreadability of the W / O / W emulsion prepared in Experimental Example 3 were measured by the following method. The results are shown in Table 1.

The stability of emulsification was evaluated by observing stability for 2 months at room temperature, 45 ° C thermostatic bath and 7 days cycling condition (-4 ° C to 45 ° C, 1 time / day). In addition, the soft feeling (sensory evaluation) was measured by the average value of the evaluated value (5-point scale) after the feeling test through the expert panel on the next day after manufacture.

<Evaluation Criteria>

⊚: very good, ∘: good, △: slight discoloration, irregularity, ×: discoloration,

Dried sensory evaluation; 1: very bad, 2: bad, 3: normal, 4: good, 5: very good

Comparative Preparation Example 1
(PVA) Production Example 1
(Chol-HEMA) Production Example 2
(Chol-NIPAM) Comparative Example 1 Stability (room temperature) ◎ ◎ ◎ △ Stability (45 ℃) ◎ ◎ ◎ × Stability (Cycle) ◎ ◎ ◎ × Soft hair (sensual) 4.6 4.5 4.6 2.8

Claims (7)

Wherein the O-methacryloyl cholesterol is chemically bonded to poly (2-hydroxyethyl methacrylate) or poly (N-isopropylacrylamide). 2. The conjugate of claim 1, wherein the chemical bond is a cholesterol that binds directly to 2-hydroxyethyl methacrylate (HEMA) or N-isopropyl acrylamide (NIPAM) or through a linker. The conjugate of claim 1, wherein the conjugate is selected from the group consisting of O-methacryloyl cholesterol and poly (2-hydroxyethyl methacrylate) or poly (N-isopropylacrylamide) in a weight ratio of 1: Lt; / RTI &gt;  2. The conjugate of claim 1, wherein the conjugate has a weight average molecular weight of 4000-8000. Reacting cholesterol and methacryloyl chloride to prepare O-methacryloyl cholesterol,
Reacting the O-methacryloylcholesterol with 2-hydroxyethyl methacrylate or N-isopropylacrylamide
Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; A pharmaceutical composition comprising the cholesterol-hydrophilic polymer conjugate of claim 1. A cosmetic composition comprising the cholesterol-hydrophilic polymer conjugate of claim 1.

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