WO2010090502A2 - External use composition containing cholecalciferol or its derivative for treating skin disorders - Google Patents

Abstract

The prevent invention relates to an external use composition containing cholecalciferol or a derivative thereof for treating skin disorders. More specifically, the present invention relates to an external preparation composition for treating skin disorders such as atopic dermatitis and a method for manufacturing a liposome. The composition and method increase skin penetration by enclosing cholecalciferol (vitamin D3) or a derivative thereof as an active ingredient in a nanoscopic liposome so that skin penetration time can be minimized when applied to a lesion. Therefore, variations in drug effects due to light are reduced and drug effects are quickly expressed.

Description

External preparation composition for treating skin diseases containing cholecalciferol or derivatives thereof

The present invention relates to an external preparation composition for treating skin diseases containing cholecalciferol or derivatives thereof, and more particularly, having nanoparticle size of cholecalciferol (vitamin D ₃ ) or a derivative thereof as an active ingredient. By encapsulating and administering to liposomes, the skin permeation effect is improved, and the skin penetration time can be minimized when applying the affected area, thereby reducing the change in the active ingredient caused by light and treating skin diseases such as atopic dermatitis, which is characterized by rapid drug expression. The external preparation composition and the manufacturing method of a liposome are related.

The composition is provided as a pharmaceutical composition that is effective in the alleviation and treatment of symptoms caused by skin diseases such as atopic dermatitis during transdermal application.

<Cause and Status of Dermatitis-Atopic Diseases>

Dermatitis is an inflammatory response of the skin to various external and internal factors, usually used in the same sense as eczema and usually includes atopic dermatitis, contact dermatitis and seborrheic dermatitis. Although atopic dermatitis is thought to be caused by an allergic reaction involving atopy, that is, immunoglobulin (IgE), the cause of the onset is still unclear. In particular, atopic dermatitis is a recurrent chronic dermatitis with severe itching, and because there is a genetic predisposition, the individual has an oversensitized atopic matrix for a particular substance, so that an atopic dermatitis, allergens caused by various antigens Symptoms include asthma, allergic rhinitis and allergic conjunctivitis. On the other hand, the symptoms of atopic dermatitis, depending on the patient's genetic predisposition, environment, age, etc., alone or several diseases appear at the same time, in childhood, redness, exudation and abortion of the face is very itchy. In addition, in infancy, it is mainly limited to the face, but gradually expands to the extremities, and the development of pore papules (atopic skin). It is often healed by the age of 12, but when he is an adult, his face, chest, and nape in addition to the limbs are converted. Childhood asthma is often merged, and once improved, recurrence and exacerbation often occur, and it often takes a long time to cure or does not reach complete cure.

In Korea, atopic dermatitis is a very common disease. About 10-15% of children have atopic dermatitis, 75% of patients develop before 1 year of age, and about 10% of the population It is estimated that between 2 and 3 million people. Even in foreign countries, since it was reported as 3 to 5% in the 1950s and 1960s, although the number of patients has been increasing, there is no suitable treatment method with less side effects and rapid onset of effects.

Need for therapeutic development

Currently, antihistamines and steroids have been used as therapeutic agents for dermatitis including atopic dermatitis. Antihistamines are mainly used to suppress itching and include, for example, promethamine hydrochloride, chlorophenylamine maleate, diphenhydramine hydrochloride, mequitazine and the like. Examples of steroids include excellent clinical effects, but at the same time, various side effects include hydrocortisone butyrate, dexamethasone valerate, betamethasone dipropionate, clobetasol propionate, and prednisolone. It is most effective to apply external preparations (such as ointments) of these drugs in the effect of treatment, and no alternative treatment is established. In addition, while the drugs have a therapeutic effect, they cause side effects such as induced infection, secondary corticosteroids, diabetes mellitus, peptic ulcer, hirsutism, alopecia, and pigmentation. Especially, in external preparations such as ointments, skin thinning or atrophy, Direct adverse effects on the skin, such as flushing, cause significant side effects. Therefore, there is an urgent need for a drug that can be used safely and with less side effects and higher stability than conventional dermatitis treatments.

<Effect of cholecalciferol on dermatitis>

Cholecalciferol, well known as a fat-soluble vitamin that contributes to maintaining homeostasis through calcium regulation in the body, depends on the similarity of structure and similar therapeutic properties described below, and calcitriol, calcipotriol, talcalcitol, maximal calcicol and flies. Calcitol, theocalcitol and the like are treated as derivatives or homologues thereof.

On the other hand, the known techniques for the preparation method of the composition containing the cholecalciferol and its derivatives or the therapeutic application thereof are as follows.

In US Pat. Nos. 4,610,978 and RE33,107 one of the derivatives of cholecalciferol is 1α-hydroxycholecalciferol or 1α, 25-dihydroxycholecalciferol. It is mentioned that it is effective in improving symptoms of general dermatitis, psoriasis, eczema, skin drying, wrinkles, and skin elasticity as dermatological diseases, and Japanese Patent 62/169711 and US Patent 5,459,136 also improve the skin diseases of cholecalciferol and its derivatives. Is specified.

However, despite many reports of improved efficacy and therapeutic effects of cholecalciferol and its derivatives on skin diseases as described above, the application and improvement of atopic diseases has been reported, despite the attempt to apply them as external application for skin application. Repeated topical challenge with chemical antigen elicits sustained dermatitis in NC / Nga mice in Specific-pathogen-free condition: Yoshiaki Tomimori, The Society for Investigative Dermatology (2004), Development of new atopic dermatitis models characterized by not only itching but also inflammatory skin in mice: European Journal of Pharmacy: Accepted 28 February 2007, A method to induce stable atopic dermatitis-like symptoms in NC / Nga mice housed with skin-lesioned mice: N.Takano, British Journal of Dermatology 2006 154, pp 426-430] Cholecalciferol and its derivatives through various experiments This has been found by having a significant effect on atopic dermatitis in addition to the known effects of skin diseases and set out the invention in a pharmaceutical composition that maximizes it.

Conventional Formulation Techniques

In US Pat. No. 5,459,136, examples of creams, ointments, and lotions have been mentioned as preparations for improving skin diseases using cholecalciferol, and in Korean Patent Application No. 2003-7005809, one or more vitamin D or vitamin D A topical composition containing a homologue and one or more corticosteroids is a gel formulation with improved applicability.

However, the prior art of preparing cholecalciferol and its derivatives as a therapeutic agent for dermatitis has some aspects that do not maximize the effect. First, cholecalciferol is unstable in light and heat, and the effect in the formulation itself is reduced. Second, due to the nature of the formulation with adhesive properties, the skin permeability is low, a problem has been raised to maximize the treatment efficiency.

As such, cholecalciferol and its derivatives are used for the purpose of improving atopic dermatological diseases, and a technique for improving the treatment efficiency by enhancing skin absorption rate has not been established.

Meanwhile, a technique for preparing liposomes in a form favorable for skin permeation and absorption is generally a method of dissolving phospholipids in volatile organic solvents, obtaining a thin film through a reduced pressure drying process, and then obtaining a multilayer liposome as an aqueous solution and further processing them. [Liposomal Technology third edition: Gregory Gregoriadis: 1 ~ 19].

U.S. Patent No. 5,834,016 has attempted to develop an external preparation composition in liposome form so that the active ingredient can be immediately absorbed into the skin, but by using the conventional manufacturing method as described above, 1) drying the dried lipid membrane with a reduced pressure drying process As a result, the production time is long and complicated, and it is practically difficult to expand from a small scale laboratory production to a commercial production unit and thus a large production. 2) The obtained lipid membrane is again hydrated through an aqueous solution, It takes a long time to form liposomes, and 3) to formulate afterwards, the excess aqueous solution in the solution containing liposomes obtained through hydration must be concentrated again and removed. The loss of is inevitably accompanied.

The present invention, in spite of the pharmacological advantages of liposome structure itself against atopic dermatitis, includes not only the preparation method which can overcome the above technical limitations, which is a limitation of mass production and commercialization, but also as an active ingredient. Liposomes comprising cholecalciferol or derivatives thereof were processed to a specific particle size to achieve a formulation that maximizes skin permeability.

Accordingly, the present inventors prepared various types of preparations including gels, ointments, and creams including liposome particles containing cholecalciferol or derivatives thereof as an active ingredient, and a simple and efficient manufacturing process rather than a conventional liposome preparation method. The present invention was completed by developing a formulation that facilitates skin permeation by processing the particle size of the liposome obtained at this level to a nano level.

In addition, the liposomes according to the present invention are nano-level, which itself has a skin permeability, and proved a significant improvement effect on atopic dermatitis through a test example using an experimental animal model.

Accordingly, an object of the present invention is to provide an external preparation for treating skin diseases with improved liposome-containing skin permeation effect, including cholecalciferol and its derivatives encapsulated in nano-scale liposomes as an active ingredient.

The present invention is characterized by an external preparation for treating skin diseases in which at least one active ingredient selected from cholecalciferol and derivatives thereof is encapsulated in liposomes.

The present invention will be described in more detail as follows.

The present invention is to provide an external preparation for treating skin diseases as a preparation for improving absorption by encapsulating a pharmacologically active ingredient in liposomes in order to improve the disadvantage that it is difficult to expect a rapid medicinal effect due to the nature of general transdermal administration. The present invention relates to an external preparation composition and a method for preparing liposomes effective for the treatment of dermatitis.

Currently, cholecalciferol or derivatives thereof used for the treatment of dermatitis are unstable in light, and thus the effect on the agent itself is reduced when exposed to sunlight, and due to the nature of the formulation with adhesive properties, the problem of maximizing the treatment efficiency is low. Is being raised. Thus, the present invention by encapsulating and administering the active ingredient in liposomes having a nano-sized particle size, the skin penetration effect is improved, thereby minimizing the skin penetration time when the affected area is applied, thereby reducing the change in the active ingredient caused by light and rapid drug efficacy It is possible to express and can be provided as a composition excellent in the therapeutic effect on atopic dermatitis and diseases.

In addition, as well as the therapeutic effect described above, the commercial use value may be increased by manufacturing through a simple and optimized manufacturing process than the conventional liposome preparation technology.

1 is a graph showing the results of edema inhibition reaction experiment through the embodiment according to the present invention.

2 is a graph showing the water retention capacity evaluation through the embodiment according to the present invention.

3 is a graph showing the light stability evaluation through the embodiment according to the present invention.

Specifically, the method for preparing a cholecalciferol or a derivative-containing composition thereof according to the present invention may be prepared by preparing a liposome solution containing the active ingredient, and gels, creams, ointments, solutions, and suspensions so as to be appropriately applied to the affected areas. Can be roughly divided into two stages, formulated into a patch, a functional patch, a lotion and a lotion.

The preparation method of cholecalciferol or its derivative-containing liposome solution according to the present invention is as follows.

First, sterols such as cholesterol are added to polyols such as propylene glycol, glycerol or polyethylene glycol, and then dissolved by heating to 75-95 ° C., and then cooled to 50-70 ° C. while cholestericol or its phospholipids and active ingredients are dissolved. Dissolve the derivative.

After that, a polyol solution in which sterols, phospholipids, and active ingredients are dissolved is added separately to distilled water heated to 50 to 70 ° C, and stirred to form a multi-film liposome.

The formed liposome is subjected to reduced pressure extrusion to form liposomes having a particle size of 30 to 400 nm, preferably 90 to 150 nm.

At this time, the encapsulation efficiency of cholecalciferol in the liposome is in the range of 30 to 100%, more preferably in the range of 50 to 100%.

At least one phospholipid selected from the phospholipids forming the liposomes and sterols are mixed and used in a ratio of 1 to 10: 1 (w / w). In this case, sterols are used for strengthening hydrophobic bonds, and when the mixing ratio of the lipid is out of the range, there is a problem in that aggregation and fusion between liposome particles occur. In addition, the concentration of the mixed phospholipid is preferably maintained at 0.1 ~ 10 mM, if the concentration is out of the above range, the sealing rate of the drug is lowered, there is a problem in the stability of liposomes.

Examples of the sterols include cholesterol, cholesterol hexasuccinate, 3β- [N- (N ', N'-dimethylaminoethane) carbamoyl] cholesterol, ergosterol, and lanosterol.

On the other hand, as a phospholipid to form liposomes, the phospholipid constituting the liposome of the present invention is also not particularly limited and may be a known phospholipid. In addition, such phospholipids may be substituted with glycolipids having similar properties, that is, weakly lipophilic properties, and common fatty acid derivatives, and fatty acid derivatives include glycerol alkyl ethers, polyoxyethylene alkyl ethers, and the like, alkyl glycosides, and alkyl methyl glucamides. Long-chain alkylamines or long-chain fatty acid hydrazides such as amphiphilic block copolymers such as polyoxyethylene-polylactic acid such as alkyl sucrose ester, dialkyl polyoxyethylene ether and dialkyl polyglycerol ether.

As the phospholipid, for example, phosphatidylcholine (soy phosphatidylcholine, egg yolk phosphatidylcholine, bovine phosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine or distearoylphosphatidylcholine, etc.), phosphatidylethanolamine Lauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine or distearoylphosphatidylethanolamine, dioreoylphosphatidylethanolamine, etc.), phosphatidylserine (dilauroylphosphatidylserine, diureo Myristoylphosphatidylserine, dipalmitoylphosphatidylserine or distearoylphosphatidylserine, etc.), phosphatidic acid, phosphatidylglycerol (dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol or distea in Ylphosphatidylglycerol, etc.), phosphatidyl inositol (dilauroylphosphatidyl inositol, dimyristoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol or distearoyl phosphatidyl inositol, etc.), risphophosphidyl choline, sphingomyelin, yolk lecithin, soybean lecithin Or natural or synthetic phospholipids such as hydrogenated phospholipids. In particular, one or two or more selected from phosphocholines having 3 to 24 carbon atoms in the diacyl group is preferable, and specifically 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1 , 2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero -3-phosphocholine and the like are suitable.

Examples of the glycolipid include glycerol glycolipid, sphingolipid glycolipid, and the like, and glycerol glycolipid may include digalactosyldiglycerides (digalactosyldilauroylglycerides, digalactosyldimyristoylglycerides, digalactosyldipalmitoylglycerides, or the like). Digalactosyl distearoyl glycerides, etc.) or galactosyl diglycerides (galactosyl dilauroyl glycerides, galactosyl dimyristoyl glycerides, galactosyl palmitoyl glycerides or galactosyl distearoyl glycerides, etc.) Examples of sphingoglycolipids include galactosyl selecbroside, lactosyl selecbroside, and gangloside.

As said fatty acid derivative, polyglycerol alkyl ether, polyoxyethylene alkyl ether, alkyl glycoside, alkyl methyl glucamide, alkyl sucrose ester, dialkyl polyoxyethylene ether, dialkyl polyglycerol ether, polyoxyethylene polylactic acid Etc. can be mentioned.

The liposome solution obtained by the above production method is added to a coating formulation composition such as gels, creams, ointments, solutions, suspensions, patches, water-containing patches, lotions and lotions prepared in a conventional manner, and stirred homogeneously. It can be obtained simply by, and described in detail as follows.

The preparation of cholecalciferol or a derivative-containing gel according to the present invention firstly gradually adds a water-soluble coating-forming base to purified water at a concentration of 3 to 10% by weight of the whole to completely dissolve and prepare a uniform aqueous solution. The aqueous solution was added by mixing 0.5 to 2% by weight of the emulsifier in the total composition and 5 to 20% by weight of the solvent in the total composition, followed by addition of liposome solution containing the prepared cholecalciferol or derivatives thereof Prepare a uniform aqueous solution. Thereafter, purified water is added according to the total amount of the preparation, and the mixed solution is stirred with a homogeneous mixer until it is homogeneous at 3,000 to 6,000 rpm to prepare a gel.

In the composition, the water-soluble film-forming base is carbomer, polyethylene glycol, polypropylene glycol, polyoxyethylene-polyoxypropylene copolymer, polyacrylic acid, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl One or two or more selected from cellulose, polyvinylpyrrolidone, gelatin (Gelatine), alginate salts, chitin and chitosan derivatives may be used, but the present invention is not limited thereto.

In addition, it is preferable to use a nonionic surfactant as the emulsifier which can be used in the gel formulation, and polyoxyethylene fatty acid ester, polyoxyethylene glycerine fatty acid ester, polyoxy Ethylene sorbitan fatty acid ester (Polyoxyethylene sorbitan fatty acid ester), glyceryl fatty acid ester (Glyceryl fatty acid ester), or a mixture thereof, but the present invention is not limited thereto. Solvents usable in the gel preparation include glycerin, ethanol, isopropanol, ethyl acetate, propylene glycol and ethoxydiglycol, and preferably propylene glycol and glycerin.

Meanwhile, the method for preparing cholecalciferol or its derivative-containing cream according to the present invention will be described in detail.

First, sodium hydroxide is added to purified water so as to have a total concentration of 0.1 to 2.0% by weight, followed by stirring using a stirrer until complete dissolution. The base forming the oil phase is added so as to have a concentration of 5.0 to 15.0% by weight, and the emulsifier is added to a concentration of 2.0 to 10.0% by weight, and then mixed, and all components are completely dissolved at a temperature of 60 to 90 ° C. The oil phase is prepared using a magnetic stirrer until

The aqueous phase and oil phase prepared above were slowly mixed at a temperature of 60 to 90 ° C., stirred for 20 minutes with a paddle mixer, and then cooled slowly to 20 to 40 ° C. using a thermostat until a homogeneous state was reached. A homogenized mixer (Homomixer) is stirred at 3,000 to 10,000 rpm to prepare an emulsified cream, and the resulting bubbles are completely removed by vacuum.

Thereafter, separately prepared liposome solution containing cholecalciferol or a derivative thereof is added to the homogeneously mixed creamy base and stirred until it becomes homogeneous again.

In the composition, the base forming the oil phase may be any of saturated hydrocarbon oil or unsaturated hydrocarbon oil, and mixtures thereof may be used, and as the pharmaceutically acceptable oil base in the present invention, There is no restriction on use. The saturated hydrocarbon-based oils include liquid paraffin, paraffin wax, squalene, petrolatum, and other branched hydrocarbon-based oils, and unsaturated hydrocarbon-based oils may include natural oils such as animal oils and vegetable oils. All can be used in the present invention.

In the case of an external preparation containing cholecalciferol or a derivative thereof according to the present invention, the active ingredient is preferably contained in an amount of 0.001 to 0.1 wt% based on the total external preparation composition. If the content of the active ingredient is less than 0.001% by weight, there is a problem in that atopic dermatitis treatment effect is low, and when it exceeds 0.1% by weight, there is a problem of causing skin irritation.

In addition, in addition to the cholecalciferol according to the invention it is confirmed that the effect is similar or improved even if one or two or more additionally selected from among the previously known cholecalciferol derivatives such as calcipotriol, calcitriol, tacalcitol It was. In addition to the above-mentioned active ingredient, steroidal agents such as dexamethasone, betamethasone, hydrocortisone, prednisolone, clobetasol, immunosuppressants such as tacrolimus, pimecrolimus, cyclosporine or tretinoin, vitamin E-acetate, vitamin B5, vitamin B12, etc. It was confirmed that the effect is increased when a combination of vitamins and the like. More specifically, vitamin B12 may include adenosyl cobalamin, cyanocobalamin, hydroxylcobalamin, methylcobalamin, and the like, and experimentally confirmed that the effect is increased by using adenosyl cobalamin as the vitamin B12. On the other hand, in addition to the emulsions and gels according to the present invention, by using an active ingredient and a pharmaceutically acceptable carrier or excipient, medicines such as ointments, solutions, suspensions, patches, and functional patches and emulsions, lotions, creams, packs, lotions It can be used as a skin external preparation of cosmetics, such as soap, and the manufacturing method of these follows a well-known method. The effective amount of the active ingredient may vary depending on the degree, site, age, etc. of the dermatitis, but is generally applied within the range of 0.1 g to 5.0 g twice or several times a day.

Hereinafter, the present invention will be described in more detail based on the following examples, test examples and preparation examples, but the present invention is not limited thereto.

EXAMPLE

Example 1 Preparation of Nano Liposome-Containing Solution

In order to prepare the cholecalciferol nano liposome-containing solution of the present invention it was carried out under the condition that the light is blocked.

First, 1,2-distearoyl-sn-glycero-3-phosphocholine (distearoylphosphatidylcholine) was dissolved in 0.5 g of cholesterol in 75 g of propylene glycol at a temperature of 80 ° C. and then cooled to 60 ° C. 1.595 g and 0.05 g of cholecalciferol were added and dissolved.

Next, while separately stirring purified water heated to 60 ℃ using a stirrer, a solution of an oily phase containing the active ingredient prepared first was gradually added to prepare a multilayer membrane liposome solution. The prepared liposome solution was passed five times through a polycarbonate membrane having a pore of 200 nm and five times through a polycarbonate membrane having a pore of 100 nm using a pressure extruder to prepare a nano liposome solution composed of a single membrane liposome.

Example 2 Preparation of Nanoliposome-Containing Gel Formulations

In order to prepare the cholecalciferol nano liposome-containing gel of the present invention it was carried out under the condition that the light is blocked by the following method.

A small amount of 6 g Carbomer 940 was added to the purified water as a base and dissolved completely with gentle stirring.

0.5 g of hydroxyethyl cellulose as a thickener, 100 g of glycerin as a wetting agent, 0.5 g of sodium edate as a stabilizer, and 3 g of polyoxyl 40 hydrogenated castor oil as an emulsifier were added to the solution, and the mixture was warmed and stirred. Cool to 40 ° C, add 1 g of methylparaben and 0.5 g of propylparaben as preservatives, add 5 g of triethanolamine as a pH adjuster so that the pH of the entire base is 7.0 ± 0.5, and stir until homogeneous. To complete.

A gel preparation 1000 containing 0.005% by weight of cholecalciferol nano liposomes was added to the finished gel base by adding a cholecalciferol liposome-containing solution prepared in the same manner as in Example 1 and stirring until homogeneous. g was completed.

Example 3: Preparation of Nano Liposomal Containing Cream Formulations

In order to prepare the cholecalciferol nano liposome-containing cream of the present invention it was carried out under the condition that the light is blocked.

40 g of stearic acid, 40 g of cetyl alcohol, 20 g of glycerine, 50 g of liquid paraffin, and 25 g of polysorbate 80 as emulsifier are mixed together until all components are completely dissolved at a temperature of 80 ° C. An oil phase was prepared using a stirrer.

Separately, 0.5 g of sodium dihydrogen phosphate was added to 700 mL of purified water to completely dissolve the aqueous and oil phases, which were slowly mixed at a temperature of 80 ° C. and stirred for 20 minutes with a paddle mixer, and then slowly to 40 ° C. using a thermostat. While cooling, the homogenized mixer was stirred at 3,000 rpm until it reached a homogeneous state to prepare an emulsified cream, and the resulting bubbles were completely removed by vacuum.

To the finished cream base was added a solution of cholecalciferol liposomes prepared in the same manner as in Example 1 and stirred until homogeneous, to complete 1000 g of 0.005% by weight of cholecalciferol nanoliposome-containing cream preparation It was.

Example 4 Preparation of Nanoliposome-Containing Ointment

The externally prepared meat preparation was prepared with the composition and content according to the following prescription, and the manufacturing process is as follows.

Prescription (based on a total amount of 1000 g): (a) stearic acid (10 g), monostearic acid (100 g), monostearic acid polyoxyethylene glycol (40 g), polyoxyethylene cetostearyl ether (20 ethylene oxide) (15 g), polyoxyethylenecetostearyl ether (12 g), cetanol (30 g), liquid paraffin (100 g); (b) 1, 3- butylene glycol (100 g), glycerin (60 g), purified water (residual amount).

Preparation Method: Oil Phase (Oil Phase) The raw material (composition (a)) was accurately weighed and dissolved in an oil phase auxiliary tank by heating to 75 ° C. The raw material (composition (b)) of the water phase was weighed and poured into an emulsification tank, heated and dissolved at 75 DEG C, and then the composition (a) was added thereto. After pouring the oily raw material into the emulsion tank under vacuum pressure, the mixture was cooled to a temperature of about 25 ° C. while stirring at 3500 rpm of a homogenizer and 100 rpm of a pedal mixer. .

On the other hand, prepared in the same manner as in Example 1, 1,2-dipalmitoyl-sn-glycero-3 instead of 1,2- distearoyl-sn-glycero-3-phosphocholine as phospholipids Prepare a solution of cholecalciferol liposome using phosphocholine, add it to the finished meat preparation, stir until homogeneous, and then add 1000g of 0.005 wt% cholecalciferol nano liposome ointment. Completed.

Example 5 Preparation of Nanoliposome-Containing External Solution

The external solution was prepared with the composition and content according to the following prescription, and the manufacturing process is as follows.

Formulation (based on a total amount of 1000 g): isopropanol (5 g), cetanol (5 g), 1,3-butylene glycol (2 g), sodium carboxymethyl cellulose (5 g), purified water (remaining amount).

Preparation Method: Cetaneol was accurately weighed and placed in an auxiliary tank and heated and dissolved at a temperature of 70 ° C. Sodium carboxymethylcellulose, 1,3-butylene glycol and adenosyl cobalamin were stirred and distilled in distilled water, and then poured into a main tank, and heated and dissolved at a temperature of 70 ° C. After slowly adding the liquid from the auxiliary tank to the main tank, cool it to a temperature of 40 ° C, add isopropanol, cool it to a temperature of about 25 ° C with stirring at a pedal mixer of 50 rpm, and terminate the work and mature. Was prepared.

A cholecalciferol liposome-containing solution prepared in the same manner as in Example 1 was added to the finished external solution and stirred until it became a homogeneous state to complete 1000 g of a 0.005 wt% cholecalciferol nanoliposome-containing external solution. It was.

Example 6 Preparation of Nanoliposome-Containing External Suspension

The external suspension was prepared with the composition and content according to the following prescription, and the manufacturing process is as follows.

Prescription (based on 1000g total):; (a) stearic acid (15 g), cetanol (10 g), white petrolatum (30 g), squalene (30 g), tri (caprylic acid / capronic acid) glycerin (15 g), monoolefin sorbitan (17 g), polyethylene glycol (40 g) (b) dipropylene glycol (40 g), triethanolamine (5 g), purified water (500 g); (c) isopropanol (85 g) and purified water (residual amount).

Production method: The raw material of the composition (a) was accurately weighed and poured into the main tank, and heated and dissolved at a temperature of 70 ° C. The raw material of the composition (b) is accurately weighed and introduced into the main tank, heated and dissolved at a temperature of 70 ° C., and stirred at a 2000 rpm of a homogenizer. Subsequently, the main tank was cooled to a temperature of 40 ° C. while stirring at 100 rpm of a Pedal Mixer, and then (c) was added and cooled to a temperature of 25 ° C. while stirring at 50 rpm of a Pedal Mixer. Termination and ripening to prepare an external suspension.

Into the finished external suspension, a solution of cholecalciferol liposomes prepared in the same manner as in Example 1 was added and stirred until it became homogeneous, and then 1000 g of an external suspension containing 0.005% by weight of cholecalciferol nanoliposomes was added. Completed.

Example 7 Preparation of Nanoliposome-Containing Patches

The patch (Plaster) was prepared with the composition and content according to the following prescription, and the manufacturing process is as follows.

Prescriptions: (a) isopropyl myristic acid (30 g), liquid paraffin (50 g), polybutene (200 g), 1,3-pentadiene copolymer resin (250 g); (b) titanium oxide (20 g), dibutylhydroxytoluene (1 g), polyoxyethylene sorbitan stearate (10 g), zinc oxide (20 g); (c) kaolin (70 g); (d) solid natural rubber latex (180 g), solid SBR synthetic rubber (150 g); (e) Sodium polyacrylate (0.7 g), purified water (residual amount), glycerin (5 g).

Manufacturing method: The raw material of the composition (a) was accurately weighed, injected into the main tank, heated and dissolved at a temperature of 115 ° C, and adjusted to a temperature of 90 ° C. The raw materials of the compositions (b) and (c) were mixed in the auxiliary tank and then injected into the main tank. In addition, after injecting the raw material of the composition (e) into the main tank, the raw material of the composition (d) was injected at a temperature of 70 ℃ to produce an ointment. To the finished ointment, the solution of cholecalciferol liposomes prepared in the same manner as in Example 1 was added and stirred until it became a homogeneous state to complete 1000 g of 0.005 wt% cholecalciferol nanoliposome-containing ointment. It was. The resulting ointment was spread on a nonwoven fabric or a woven fabric, and cut into a size of 10 cm x 14 cm to prepare a patch.

Example 8 Preparation of Nanoliposome-Containing Waterborne Patches

The functional patch was prepared by the composition and content according to the following prescription, and the manufacturing process is as follows.

Prescription: (a) D-sorbitol (250 g), purified water (100 g), kaolin (150 g), titanium oxide (10 g); (b) gelatin (10 g), purified water (50 g); (c) sodium metaphosphate (2 g), purified water (10 g); (d) Magnesium alumina hydroxide (2 g), sodium polyacrylate (60 g), propylene glycol (40 g), starch acrylic acid (5 g), castor oil (10 g), monoolefinic polyoxyethylene sorbitan (5 g), monoolefinic acid sorbitan (5 g); (e) D-sorbitol (150 g), dibutylhydroxytoluene (1 g); (g) methacrylic acid / n-butyl acrylate copolymer (30 g); (f) D-sorbitol (50 g), tartaric acid (12 g).

Production method: The raw material of the composition (a) was accurately weighed and poured into the main tank, and heated and dissolved at a temperature of 40 ° C. In addition, while stirring the composition of the main tank at 100 rpm with a Pedal Mixer, the raw material of composition (c) was heated and dissolved at a temperature of 40 ° C. in the auxiliary tank, and the compositions (b) and (f) were sequentially injected. It was. After mixing the raw material of composition (d), it injected into a tank, and then injected the raw material of composition (e), and injected the raw material of composition (f) little by little to produce the ointment. To the finished ointment, the solution of cholecalciferol liposomes prepared in the same manner as in Example 1 was added and stirred until it became a homogeneous state to complete 1000 g of 0.005 wt% cholecalciferol nanoliposome-containing ointment. It was. The resulting ointment was spread on a nonwoven fabric or a woven fabric or the like, and cut into a size of 10 cm x 14 cm to prepare a functional patch.

Example 9 Preparation of Nano Liposomal Containing Lotion

The lotion was prepared with the composition and content according to the following prescription, and the manufacturing process is as follows.

Prescription (based on a total amount of 1000 g): (a) sodium carboxymethyl cellulose (5 g), polyethylene glycol (60 g), propylene glycol (40 g); (b) polyoxyethylene oleincetyl ether (10 g), jojoba oil (5 g); (c) perfume (suitable), ethanol (100 g); (d) Purified water (remaining amount).

Manufacturing method: After accurately weighing and mixing the raw materials of the compositions (d) and (a), they were injected into a main tank and heated and dissolved at a temperature of 45 ° C. In addition, the composition of the main tank was cooled to room temperature while stirring at 100 rpm of a Pedal Mixer. The raw material of the composition (c) was injected into the auxiliary tank, and the raw material of the composition (b) was further injected and dispersed, and then injected into the main tank and homogenized while stirring at 300 rpm of a pedal mixer (Pedal Mixer) to prepare a lotion.

On the other hand, prepared in the same manner as in Example 1, 1,2-dimyristoyl-sn-glycero-3 instead of 1,2- distearoyl-sn-glycero-3-phosphocholine as phospholipids A solution of cholecalciferol liposomes was prepared using phosphocholine, and added to the finished lotion and stirred until it became homogeneous to complete 1000 g of 0.005 wt% cholecalciferol nanoliposome-containing lotion. .

Example 10 Preparation of Calcitriol Nano Liposomal Containing Lotion Formulations

A lotion formulation was prepared according to the following formulation and content, and the manufacturing process is as follows.

Formulation (based on a total amount of 1000 g): glycerin (50 g), isopropanol (100 g), cetanol (10 g), polyoxyethylenecetostearyl ether (5 g), triethanolamine (5 g), stearic acid (30 g), purified water (remaining amount).

Preparation Method: Cetanol, polyoxyethylenecetostearyl ether and stearic acid were accurately weighed and injected into the main tank and heated and dissolved at a temperature of 70 ° C. while stirring at 2000 rpm of an emulsifier. In addition, triethanolamine, distilled water, adenosyl cobalamin and glycerin were injected into the auxiliary tank and heated and dissolved at a temperature of 70 ° C. while stirring at 50 rpm with a Pedal mixer. The composition of the auxiliary tank was slowly injected into the main tank and cooled to a temperature of 40 ° C., followed by quenching and ripening at 25 ° C. while continuously stirring with the addition of isopropyl alcohol to prepare a lotion base.

On the other hand, prepared in the same manner as in Example 1, using a calcitriol as a main component, to prepare a liposome solution, and added to the finished lotion base and stirred until a homogeneous state containing 0.005% by weight of calcitriol nanoliposomes 1000 g of lotion formulation was completed.

Example 11 Preparation of Calcipotriol Nano Liposomal Containing Gel Formulations

In the same manner as in Example 1, without adding cholecalciferol, a nanoliposome containing calcipotriol was prepared.

Gel formulation containing 0.005% by weight of calcipotriol was prepared by the same prescription and preparation method as in Example 2.

Example 12 Preparation of Nanoliposome-Containing Composite Gel Formulations

A nanoliposome containing gel formulation of 0.005 wt% cholecalciferol and 0.05 wt% (as dexamethasone) dexamethasone propionate was prepared in the same manner as in Examples 1 and 2.

Example 13: Preparation of Nanoliposome-Containing Composite Gel Formulations

In the same manner as in Example 1 and Example 2, but was prepared nano liposome-containing gel formulation of 0.005% by weight of cholecalciferol and 0.1% by weight of tacrolimus hydrate.

Example 14 Preparation of Nanoliposome-Containing Composite Gel Formulations

In the same manner as in Example 1 and Example 2, but prepared a nano liposome-containing gel formulation of 0.005% by weight of cholecalciferol and 0.25% by weight of tretinoin.

Example 15 Preparation of Nanoliposome-Containing Vitamin Complex Gel Formulations

In the same manner as in Example 1 and Example 2, a nano liposome-containing gel formulation of 0.005 wt% cholecalciferol and 1.0 wt% tocopherol acetate was prepared.

Example 16 Preparation of Nanoliposome-Containing Vitamin Complex Gel Formulations

In the same manner as in Example 1 and Example 2, a nano liposome-containing gel formulation of 0.005 wt% cholecalciferol and 1.0 wt% adenosyl cobalamin (vitamin B12) was prepared.

Example 17 Preparation of Nanoliposome-Containing Vitamin Complex Gel Formulations

In the same manner as in Example 1 and Example 2, a nano liposome-containing gel formulation of 0.005 wt% cholecalciferol and 0.005 wt% calcidiol was prepared.

Comparative Example 1

In the same manner as in Example 1, without adding cholecalciferol as an active ingredient, after preparing a liposome solution, it is added to the gel base prepared by the method of Example 2 until the homogeneous state Stirred.

Comparative Example 2

In the same manner as in Example 1, without adding cholecalciferol as an active ingredient, after preparing a liposome solution, it is added to the cream base prepared by the method of Example 3 until the homogeneous state Stirred.

Comparative Example 3

In the same manner as in Example 2, the gel preparation was prepared by directly adding and stirring the main component of cholecalciferol, which is the main component, without adding the liposome solution prepared in Example 1.

Comparative Example 4

In the same manner as in Example 3, the cream formulation was prepared by directly adding and stirring cholecalciferol, which is a main component, without adding the liposome solution prepared in Example 1.

Experimental Example

Test Example 1: Determination of anti-inflammatory efficacy of external skin preparations

Observing the dermatitis treatment efficacy of the cholecalciferol or the derivative-containing test drug prepared in Examples 1 to 4, the test drug prepared in Comparative Examples 1 to 4, and the test ingredient containing the composite ingredient prepared in Examples 11 to 17 In order to evaluate the effect of inhibiting edema and redness reaction by making a dermatitis animal model as follows. In addition, commercially available 0.1% tacrolimus ointment and 0.1% dexamethasone cream were prepared as positive controls.

1. Production of atopic dermatitis animal model

Repeated topical challenge with chemical antigen elicits sustained dermatitis in NC / Nga mice in Specific-pathogen-free condition: Yoshiaki Tomimori, The Society for Investigative Dermatology with reference to Tomimori et al. (2004), Development of new atopic dermatitis models characterized by not only itching but also inflammatory skin in mice: European Journal of Pharmacy: Accepted 28 February 2007, Amethod to induce stable atopic dermatitis-like symptoms in NC / Nga mice housed with skin- lesioned mice: N. Takano, British Journal of Dermatology 2006 154, pp 426-430].

Male 7-week-old Nc / Nga mice were used as experimental animals. A 1 wt% solution was prepared by dissolving 2,4-dinitrochlorobenzene (DNCB) in a solution of acetone and olive oil in a 4: 1 ratio. 100 μl of 1 wt% 2,4-dinitrochlorobenzene solution was applied to the back of the mouse to induce sensitization, and then 100 μl of 0.4 wt% 2,4-dinitrochlorobenzene solution was applied for 5 weeks once a week. Atopic dermatitis was repeatedly induced.

2. Evaluate the effect of suppressing edema reaction

Examples, comparative examples, and positive control drugs were applied at a dose of 100 µg per 10 cm 2 of skin area, respectively, 1 hour before and 4 hours after edema induction. The back thickness was measured with a dial thickness gauge over time after induction. The increase in the thickness of the back skin was expressed by subtracting the thickness of the back before inducing edema from the thickness of the back after inducing edema. Inhibition rate was calculated by the following equation 1 and the results are shown in Table 1 and FIG.

division	Number of test animals	% Inhibition after 4 hours of induction	% Inhibition after 24 hours of induction	% Inhibition after 48 hours of induction
Base Control (Edema-Inducing Group)	5	1.2	2.6	5.2
Positive control (0.1% tacrolimus ointment)	5	38.2	57.2	70.1
Positive Control (0.1% Dexamethasone Cream)	5	42.1	50.2	65.8
Example 2	5	36.8	51.0	69.0
Example 3	5	40.5	51.2	68.4
Comparative Example 1	5	8.8	14.4	48.9
Comparative Example 2	5	10.7	12.3	46.2
Comparative Example 3	5	11.0	16.7	50.7
Comparative Example 4	5	15.3	18.5	51.2
Example 11	5	32.6	50.7	67.9
Example 5	5	33.4	42.2	69.8
Example 7	5	31.2	49.4	66.6
Example 12	5	38.8	49.6	72.7
Example 13	5	38.6	52.7	74.2
Example 14	5	40.2	48.7	72.2
Example 15	5	40.5	53.7	70.0
Example 16	5	43.8	50.0	72.4
Example 17	5	49.0	48.9	68.7

As shown in Table 1 and Figure 1, the test drug containing the nanoliposomes of cholecalciferol or derivatives thereof prepared in Examples 2, 3, 11 according to the present invention, the drug efficacy of Comparative Examples 1, 2 Compared with the formulation containing no component, it showed an effect of suppressing edema effectively.

In addition, the composite component-containing formulations of Examples 12 to 17 were superior to the preparations of Examples 2, 3, 5, 7, 11 containing only cholecalciferol and one derivative thereof as active ingredients.

Test Example 2: Skin irritation test (evaluation of suppression of redness reaction)

Examples and Comparative Examples, a positive control drug was applied to the inflammation site of the mouse twice a day for 4 weeks at a dose of 100 μg per 10 cm ^{2 of} skin area, and then the thickness of the inflammation site was visually observed and flared. The degree of severity of the mice that did not cause inflammation was evaluated by dividing from 0 to 7 points from the baseline, and the results are shown in Table 2 below.

division	Number of test animals	Red Score
		2 weeks after application	4 weeks after application
Base Control (Edema-Inducing Group)	3	4.8 ± 1.2	6.2 ± 1.0
Positive control (0.1% tacrolimus ointment)	5	4.6 ± 0.8	2.8 ± 0.8
Positive Control (0.1% Dexamethasone Cream)	5	5.2 ± 1.0	3.7 ± 1.2
Example 2	5	4.6 ± 1.0	2.5 ± 0.7
Example 3	5	4.8 ± 1.5	3.3 ± 0.4
Comparative Example 1	5	5.6 ± 0.7	5.3 ± 0.8
Comparative Example 2	5	5.8 ± 0.1	5.2 ± 0.1
Comparative Example 3	5	5.2 ± 0.1	3.9 ± 0.1
Comparative Example 4	5	5.1 ± 0.4	4.8 ± 0.3
Example 5	5	4.8 ± 0.8	3.2 ± 0.7
Example 7	5	4.6 ± 1.0	3.3 ± 0.7
Example 11	5	4.2 ± 1.2	2.7 ± 0.2
Example 12	5	5.0 ± 0.8	2.1 ± 0.5
Example 13	5	4.8 ± 0.6	1.6 ± 0.3
Example 14	5	4.7 ± 1.1	2.3 ± 0.7
Example 15	5	4.7 ± 1.3	1.9 ± 0.8
Example 16	5	4.9 ± 0.4	2.2 ± 0.2
Example 17	5	4.9 ± 0.4	2.2 ± 0.2

As shown in Table 2, the cholecalciferol-containing formulation of Example 2 according to the present invention exhibited a redness suppressing effect, and was superior to a preparation that did not include the active ingredient of Comparative Example 1. In addition, the composite component-containing formulations of Examples 12 to 17 exhibited superior anti-fogging activity than the formulations of Examples 2, 3, 5, 7, and 11 containing only one type of cholecalciferol or derivatives thereof as an active ingredient.

On the other hand, in Comparative Example 3 and Comparative Example 4, which does not include liposomes, the degree of improvement of redness after 4 weeks of application was less than that of Example, and similar results were obtained in Comparative Example 1 and Comparative Example 2, which did not contain the active ingredient. As a result, it can be seen that the utilization of high skin-friendly liposomes is a major factor in the expression of efficacy according to the present invention.

Test Example 3 Measurement of Skin Moisture Retention Efficacy of External Skin Agents

Skin moisture of the test drug containing cholecalciferol or derivatives thereof prepared in Examples 2, 3, 5, 7, and 11, the test drug prepared in Comparative Examples 1 to 4, and the test compound of the composite components of Examples 12 to 17 In order to observe the retention effect, the animal model was prepared and skin moisture retention was evaluated as follows. In addition, 0.1% tacrolimus ointment and 0.1% dexamethasone cream were prepared as positive controls.

1. Animal model production

The epidermal water loss (TEWL: transepidermal water loss) animal model was tested by referring to Takano et al. [Contact sensitisation and allergic contact dermatitis: Immunobiological mechanisms: Toxicology Letters 2006 162, pp49-54, A method induce stable atopic dermatitis-like symptoms in NC / Nga mice housed with skin-lesioned mice: British Journal of Dermatology 2006 154, pp 426-430].

As a test animal, 7 weeks old male NC / Nga was used. A 2% by weight solution was prepared by dissolving 2,4-dinitrochlorobenzene (DNCB) in a solution of acetone and olive oil in a 4: 1 ratio. After treating 2 wt% 2,4-dinitrochlorobenzene (DNCB) solution with 100 µl twice a day for 7 days to impair the function of the stratum corneum, epidermal moisture loss using a water evaporation measuring device (Tewameter, Germany) (TEWL: transepidermal water loss) was measured as the measured value before application of the test drugs in Table 3.

2. Water retention capacity evaluation

Test drug, positive control test drug and base were applied twice a day for 4 weeks at a dose of 100 ㎍ per 10 cm 2 of skin area, and TEWL was measured with the moisture evaporation measuring device over time. 2 is shown.

division	Number of test animals	Before application	1 week after application	2 weeks after application	3 weeks after application	4 weeks after application
Positive control (0.1% tacrolimus ointment)	3	8.1 ± 1.0	21.2 ± 1.3	23.7 ± 1.1	24.3 ± 0.7	20.2 ± 1.1
Positive Control (0.1% Dexamethasone Cream)	3	8.4 ± 0.8	25.7 ± 2.2	28.8 ± 1.0	26.8 ± 0.4	22.1 ± 1.8
Example 2	3	7.8 ± 1.2	16.8 ± 0.8	18.1 ± 0.2	16.3 ± 0.4	14.1 ± 1.7
Example 3	3	8.1 ± 0.9	19.2 ± 2.3	18.8 ± 3.3	15.1 ± 0.4	13.7 ± 0.2
Example 5	3	7.6 ± 1.7	20.2 ± 3.3	17.9 ± 2.7	14.0 ± 3.6	10.6 ± 2.5
Example 7	3	8.0 ± 0.7	19.4 ± 2.6	20.7 ± 1.5	15.5 ± 0.5	12.7 ± 1.2
Example 11	3	7.9 ± 1.1	17.4 ± 0.9	18.4 ± 0.3	17.0 ± 0.9	12.2 ± 0.6
Comparative Example 1	3	7.8 ± 0.9	22.3 ± 1.2	23.7 ± 1.1	22.8 ± 1.1	24.7 ± 0.7
Comparative Example 2	3	8.2 ± 0.2	21.4 ± 1.0	25.8 ± 1.1	26.7 ± 0.6	26.9 ± 1.0
Comparative Example 3	3	8.1 ± 0.6	20.3 ± 0.9	21.1 ± 1.0	20.4 ± 1.5	19.7 ± 1.1
Comparative Example 4	3	7.9 ± 0.8	22.3 ± 1.2	22.7 ± 1.1	19.4 ± 1.1	19.9 ± 0.4
Example 12	3	7.9 ± 0.4	18.9 ± 0.7	21.6 ± 0.8	18.2 ± 1.6	14.2 ± 0.8
Example 13	3	8.2 ± 0.7	20.7 ± 1.3	22.4 ± 1.2	20.1 ± 0.2	13.2 ± 1.4
Example 14	3	8.1 ± 0.4	21.8 ± 1.7	22.7 ± 0.6	19.8 ± 1.3	15.7 ± 1.2
Example 15	3	7.9 ± 0.6	20.2 ± 0.5	22.7 ± 0.8	20.1 ± 1.1	19.2 ± 0.7
Example 16	3	8.2 ± 1.3	18.5 ± 0.8	20.3 ± 0.5	20.4 ± 0.6	19.6 ± 0.9
Example 17	3	8.0 ± 1.1	20.4 ± 0.6	22.1 ± 0.9	19.7 ± 0.2	19.5 ± 1.0

As shown in Table 3 and FIG. 2, the cholecalciferol-containing formulations of Examples 2, 3, 5, 7, and 11 according to the present invention exhibited water retention and did not include the active ingredient of Comparative Example 1. Moisture retention was superior to the formulation. The decrease in water retention in such a cholecalciferol-free formulation means that the damaged skin barrier was not recovered during the preparation of the animal model of atopic disease. On the other hand, in the comparative example, the liposome-containing preparation containing no main ingredient also exhibited a water retention ability of more than a positive control group, and in the examples, the water retention capacity of Examples 5 and 7 was excellent due to the characteristics of the formulations. The complex component-containing formulation of 17 exhibited better water retention than the formulations of Examples 2, 3, and 11 containing only one type of cholecalciferol or a derivative thereof as an active ingredient.

Test Example 4: Light Stability Test

Using the animal model of Test Example 2, the test drug, the positive control test drug, and the preparations containing the cholecalciferol of Examples 2, 3, 4, and 11 as a single component and the cholecalciums of Examples 12, 13, and 14 A dosage of 100 μg per unit area (10 cm 2) is coated on a 20 cm × 20 cm cut glass plate of a formulation comprising a non-ferrol steroid compound, respectively, and can simulate sunlight irradiation during normal handling and use. After irradiating ultraviolet rays and visible rays using a stability tester (Climacell404, manufacturer: MMM (Germany)), the main component (cholecalciferol) was quantified in the following manner and observed for changes. Shown in

Test temperature: 25 ℃ ± 2

Test condition: After exposure to ultraviolet (irradiation-200 watts · hours / m ² or more),

Expose visible light (light quantity-1.2 million lux · hour or more).

Test Method Basis: ICH guideline Guidance for Industry

-Q1B Photostability Testing of New Drug Substances and Products

Assay of Principal Components

-According to 'Assay' in 'Cholecalciferol' of 31 US Pharmacopoeia.

division	Test	Content at end of test
Positive Control 1 (0.005% Calcipotriol Ointment)	3	78.6
Comparative group 1	3	98.9
Positive Control 2 (0.005% Calcipotriol + 0.05% Betamethasone Ointment)	3	70.4
Comparative group 2	3	99.3
Example 2 (0.005% cholecalciferol gel)	3	92.4
Comparative group 3	3	98.9
Example 4 (0.005% cholecalciferol ointment)	3	98.4
Comparative Group 4	3	99.3
Example 11 (0.005% calcipotriol gel)	3	94.3
Comparative Group 5	3	99.1
Example 12 (0.005% calcipotriol + 0.05% dexamethasone gel)	3	95.5
Comparative Group 6	3	98.8
* The comparison group is a shading test group, each test group of the same test number is completely wrapped in aluminum foil, then left under the same test conditions, and the content (%) was measured after 15 days at the end of the test.

As shown in Table 4 and FIG. 3, the formulations of Examples 2, 4, 11 and 12 according to the present invention proved to have improved stability to light as compared to the positive control. Increasing the content (%) in the preparation containing the cholecalciferol and its derivatives as an active ingredient means that the sensitivity of the active ingredient to light is reduced, which is a major improvement in the present invention by liposome encapsulation.

Thus, the composition provided by the present invention is processed into a liposome having a nano-sized particle size in order to improve the skin penetration effect, thereby improving the light stability by liposomes, as well as improved stability to additional light due to rapid skin penetration Has

As described above, the composition containing the cholecalciferol and its derivatives according to the present invention not only effectively suppressed edema and redness in the atopic dermatitis experimental animal model, but also encapsulated in liposomes by an efficient and simple preparation method. The formulation can improve the skin penetration effect to minimize the skin penetration time when the affected area is applied, thereby reducing the change in the active ingredient caused by light and can be provided as an external preparation for treating atopic skin diseases characterized by rapid drug expression.

In addition, the present invention showed an effect equal to or greater than in the comparative experiments when using the above-mentioned separate effective ingredient and complex use, thereby providing a skin-coated external preparation effective in treating atopic dermatitis containing a complex component.

Claims (11)

1. An external preparation for treating skin diseases, characterized in that one or more active ingredients selected from cholecalciferol and derivatives thereof are encapsulated in liposomes.
   
2. The external preparation for treating skin diseases according to claim 1, wherein the active ingredient is 0.001 to 0.1 wt% based on the total weight of the external preparation.
   
   
3. The external preparation for treating skin diseases according to claim 1, wherein the derivative is selected from calcipotriol, calcitriol, and tacalcitol.
   
   
4. The external preparation for treating skin diseases according to claim 1, wherein the liposome is composed of phospholipids and sterols.
   
   
5. The external preparation for treating skin diseases according to claim 4, wherein the phospholipid and sterols have a weight ratio of 1 to 5: 1.
   
   
6. The external preparation for treating skin diseases according to claim 4, wherein the phospholipid is one or two or more selected from phosphocholines having 3 to 24 carbon atoms in the diacyl group.
   
   
7. The method of claim 4, wherein the sterols are cholesterol, cholesterol hexasuccinate, 3β- [N- (N '(N', N'-dimethylaminoethane) carbamoyl] cholesterol, ergosterol or lanosterol, characterized in that External preparation for the treatment of skin diseases.
   
   
8. The external preparation for treating skin diseases according to claim 1, wherein the external preparation is formulated as a gel, a cream, a liposome-containing hydrated gel, an ointment, a liquid, a suspension, a patch, a water-containing patch, a lotion or a lotion.
   
   
9. The external preparation for treating skin diseases according to any one of claims 1 to 8, further comprising a steroid, a vitamin, and an immunosuppressive agent.
   
   
10. The external preparation for treating skin diseases according to claim 1, wherein the skin disease is atopic dermatitis.
    
    
11. Dissolving phospholipids and cholecalciferol or derivatives thereof by adding sterols to a polyol, warming them to 75-95 ° C., and then cooling them to 50-70 ° C .; Adding a polyol solution in which the sterols, phospholipids and cholecalciferol are dissolved in distilled water heated to 50 to 70 ° C. separately to form a multi-film liposome; And forming a liposome having a particle size of 30 to 400 nm through reduced pressure extrusion of the formed liposome.
    
    

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