KR101443180B1 - Novel Drug Delivery System for Percutaneous Absorption, Composition for External Preparation Preventing Hair Loss, and Cosmetics Using the Same - Google Patents

Abstract

The present invention provides a new transdermal drug delivery system which is produced by dispersing lecithin in an alcohol mixture containing propylene glycol, and is capable of effectively delivering the active ingredient of hair loss prevention / wool promotion through the skin to the dermis in a transdermal manner, A composition for external use and a cosmetic composition.
When the drug delivery system of the present invention was used to test mice in a manner of transdermal administration, the extract of natural product, which is an effective ingredient of anti-hair loss / wool promotion, was superior to conventional liposomes or ethosomes Effect can be obtained.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel transdermal drug delivery system, a composition for preventing hair loss, and a cosmetic composition using the same. BACKGROUND ART [0002]

The present invention relates to a novel drug delivery system for percutaneous absorption, a composition for preventing and treating hair loss, and a cosmetic preparation using the same. More particularly, the present invention relates to an active ingredient for hair loss prevention / To a dermis by passing through a percutaneous epithelium in the manner of transdermal administration, a composition for external application using the same, and a cosmetic composition.

In recent years, in order to cope with the need for development of a natural product safe for humans, the effect is excellent in a situation where the stress is increased and the hair loss population is increasing due to environmental genetic factors.

The hair is removed through the growth phase, the stage of growth of the hair, the regenerative phase of the growth of the hair, and the rest period, which is the preparation stage before the hair is eliminated. Hair loss is basically around the hair follicles distributed around the 5 alpha allyduthase action of testosterone, a kind of male hormone known to cause hair loss will turn into DHT. This activated DHT binds to the androgen receptor to shorten the growth period of the hair and shrinks the size of the hair follicle, so that the number of hair in the growing period decreases and the number of hair in the rest period increases, thereby causing hair loss. Formulations that have been developed, produced and sold in the past are minoxidil preparations, and propecia as a preservative for the active ingredient. In the case of minoxidil, these ingredients have side effects such as inducing seborrheic dermatitis during long-term application. In the case of propecia, there are problems such as deterioration of sexual function when taking it, and therefore, they have fundamentally problems requiring doctor's prescription. In order to solve this problem, there have been investigated anti-hair-loss preparations and hair-growth preparations which have no adverse effects even when they are applied over a long period of time using natural extracts.

Natural extracts are usually delivered to scalp using a solvent such as alcohol or a drug delivery system such as liposome. However, when an excessive amount of a solvent such as alcohol is used, the penetration efficiency of the hair is not good, Drying, stimulation, and the like. Even when liposomes are used, the thick scalp is covered with thick stratum corneum and sebum, which makes it difficult to infiltrate the liposome.

Recently, studies on DDS system for effectively delivering drugs to the scalp have been carried out. Representative examples include surfactants such as sodium cholate, which is referred to as an edge activator for existing liposomes, surfactants such as lysophosphatidyl choline), and Transfersome, which is made by mixing an appropriate amount of single chain phospholipids. It is possible to ultratradefomation of the phospholipid membrane of the scalp or skin. However, this is good for skin penetration, but it is not suitable for cosmetics applied directly to the scalp due to problems such as stimulation due to extreme deformation.

Recently, attention has been focused on ethosome. Ethanol is a preparation containing a large amount of ethanol. Ethanol itself weakens the intercellular lipid membrane of the skin stratum corneum, thereby increasing the skin absorption rate of the active ingredient. Also, the structural membrane of the lecithin is softened by ethanol, It is known that it is possible to pass through the minute keratinocyte cells more easily and to transfer the drug deep into the skin (Korean Patent Laid-Open Publication No. 2010-0060754).

However, in the case of the above-mentioned ethosomes, problems still arise such as keratinization caused by drying of the scalp, coalescence of particles due to curing of nanoparticles, separation of layers, separation phenomenon due to disappearance of particles (Oswald's lifing phenomenon) . Accordingly, the present inventors have made extensive efforts to develop a drug delivery system capable of delivering a hair-loss preventing / wool-promoting preparation to the scalp more safely and effectively, and as a result, it has been confirmed that lecithin is more efficiently dispersed in lecithin than propylene glycol ethanol, It came to the following.

The present invention provides a drug delivery system for percutaneous absorption of hair loss-inhibiting / wool-promoting active ingredient, which is prepared by dispersing lecithin in an alcohol mixture containing propylene glycol.

The content of propylene glycol in the alcohol mixture is preferably 50% by weight or more.

The mixing ratio of the alcohol mixture to the lecithin is preferably in a ratio of 5 to 50 parts by weight of lecithin to 100 parts by weight of the alcohol mixture.

The particle diameter of the carrier is preferably 10-200 nm.

The present invention also provides a composition for external use for hair loss prevention / wool, comprising a composite in which an effective ingredient of hair loss prevention / wool promotion is collected in a drug delivery vehicle for percutaneous absorption prepared by dispersing lecithin in an alcohol mixture containing propylene glycol.

The hair growth promoting active ingredient may be one comprising a nettle extract, a walnut extract, a tsunami extract, and a persimmon leaf extract.

Also, the present invention provides a cosmetic comprising 1 to 50% by weight of the composition.

When the drug delivery system of the present invention was used to test mice in a manner of transdermal administration, the extract of natural product, which is an effective ingredient of anti-hair loss / wool promotion, was superior to conventional liposomes or ethosomes Effect can be obtained.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram illustrating the mechanism of action of the drug substance of the present invention. FIG.
2A, 2B, 2C, and 2D are photographs taken on day 18 after application of the composition prepared in Example, Comparative Example 1, Comparative Example 2, and Comparative Example 3 to skin of depilated mice in order.
3A, 3B, 3C and 3 D, in order, the compositions prepared in Examples, Comparative Example 1, Comparative Example 2 and Comparative Example 3 were applied to skin of depilated mice, and on day 18, .

The present invention provides a drug delivery system for percutaneous absorption of hair loss-inhibiting / wool-promoting active ingredient, which is prepared by dispersing lecithin in an alcohol mixture containing propylene glycol.

The term " percutaneous absorption " in the present invention means that external substances are absorbed through the skin of an animal and then introduced into the deep part of skin and blood vessels. The drug delivery system of the present invention is particularly designed to allow the skin to penetrate the stratum corneum to reach the dermis.

The term " lecithin " used in the preparation of the drug delivery system of the present invention refers to a generic term of phospholipids containing glycerophosphoric acid. The lecithin may be extracted from plant or animal skin tissue, yolk, soybean oil, liver, brain, and the like. Chemically phosphoric acid, choline. (Such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatic acid, etc.), and the like, or a mixture thereof.

The transdermal drug delivery system of the present invention is prepared by dispersing the above-mentioned lecithin in an alcohol mixture containing propylene glycol as a main component. The drug delivery system prepared by dispersing lecithin in an alcohol mixture containing propylene glycol as a main component is a drug delivery system prepared by dispersing lecithin in water or a conventional alcohol such as methanol, propanol, and butanol, for example, a liposome or an ethosome The phospholipid membrane forming the external shape of the drug delivery system is soft and has a merit that the transdermal administration of the drug contained in the carrier is effective since the shape of the drug is easily deformed to pass through the keratin. In addition, the drug delivery system of the present invention can be manufactured in a small size of 10-200 nm, and is characterized in that it is smaller in size than conventional liposomes or ethosomes. This additional feature may serve as another advantage for transdermal administration of the drug.

In the present invention, propylene glycol as a main component means that the proportion of propylene glycol in the alcohol mixture is 50% by weight or more. Components that can be added to the alcohol mixture in addition to propylene glycol include water, C1-C5 monoalcohols, and the like. When the content of propylene glycol in the alcohol mixture is less than 50% by weight, the compatibility of the drug with lecithin increases, resulting in an excessively large drug carrier and an increased strength, which is disadvantageous for the drug carrier to pass through the keratin.

Meanwhile, the drug delivery system of the present invention preferably has a size of 10-200 nm. If it does not reach 10 nm, the size is too small, which causes problems in trapping the drug to be delivered. If it exceeds 200 nm, it is disadvantageous to passage of keratin in the transdermal administration process. For reference, it is known that liposomes prepared by using water as a dispersion medium have a typical size of 100-300 nm, and ethosomes prepared using ethanol as a dispersion medium have a size of 60-200 nm have.

The drug delivery vehicle can be prepared by dispersing lecithin in an alcohol mixture by a known method. For example, an oil phase prepared by mixing an alcohol mixture containing propylene glycol, lecithin, and the like is mixed with an aqueous phase containing purified water as a main component, and then the mixture is stirred at an appropriate temperature and a suitable means such as a homogenizer And then dispersing the mixture. In this case, for the purpose of solubilizing lecithin in the oily phase, triglyceride (MIDDLE CHAIN TRIGLYCERIDE, MTC) having a medium-chain fatty acid group having 8 to 10 carbon atoms (C) having similar function to triglyceride in the living body, Can be added. The oil phase and / or water phase may contain additives known in the art, for example, antioxidants, surfactants, vegetable oils, ester oils, cholesterol, anhydrous or hydrous lower alcohols having 1 to 4 carbon atoms, polyols such as glycerin The drug delivery vehicle of the present invention can be prepared by adding components according to the purpose of use.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram illustrating the mechanism of action of the drug substance of the present invention. FIG. By way of non-limiting intention, it is understood that the drug delivery system of the present invention increases the efficiency of drug delivery by simultaneously fusing the stratum corneum composed of the phospholipid bilayer and the outer wall of the drug delivery system through the mechanism as illustrated in Fig. That is, when lecithin is contacted with propylene glycol, a film of a carrier formed of a phospholipid bilayer is formed, and the formed film has greater flexibility than a film of ordinary liposome or etosome. Therefore, even when the diameter of the stratum corneum formed by propylene glycol (represented by "PG" in FIG. 1) is smaller than the diameter of the transporter itself, the smoothly deformed transporter membrane changes shape and passes through a small space formed in the stratum corneum . As a result, the efficiency of drug delivery is increased.

The present invention provides a composition for external use for hair loss prevention / wool, comprising a composite in which an effective ingredient of hair loss prevention / wool promotion is collected in a drug delivery vehicle for percutaneous absorption prepared by dispersing lecithin in an alcohol mixture containing propylene glycol.

The drug delivery vehicle of the present invention is an effective ingredient for hair loss prevention / wool promotion, particularly, an active ingredient for hair loss prevention / wool promotion including at least one natural product extract such as nettle extract, walnut extract, It will be sufficiently demonstrated in the following examples and comparative examples that it is particularly suitable for delivering to hair follicles in the manner described above. However, the drugs to which the drug delivery system of the present invention can be delivered are not limited thereto. For example, synthetic raw materials such as minoxidil, PDO, pinasteride, aminecil and other natural extracts such as saw palmetto, jojoba, Synthetic medicines and the like.

The above-mentioned composition for external application may be manufactured into various formulations such as shampoo, rinse, tonic, essence, etc. and used as a cosmetic. In the cosmetic, the external preparation composition is usually 1 to 50% by weight.

Hereinafter, preferred embodiments and comparative examples of the present invention will be described. The following examples are intended to illustrate the invention and should not be construed as limiting the scope of the invention.

Manufacturing example  : New  Drug delivery, Ethosome  And Liposomal  Produce

Table 1 below summarizes the drug carriers used in the examples and the comparative examples and the manufacturing prescription of conventional ethosomes and liposomes.

division Component (parts by weight) Production Example 1
(Novel drug delivery system) Production Example 2
(Ethosomes) Production Example 3
Liposome

Floating Propylene glycol 40.0 _ _ MCT (MIDDLE CHAIN TRIGLYCERIDE) 10.0 10.0 10.0 lecithin 4.0 4.0 4.0 Ceramide 1.7 1.7 1.7 cholesterol 1.3 1.3 1.3 BHT 0.02 0.02 0.02 Active material part Natural Products Extract * 20.0 20.0 20.0 Above 1 Purified water To 100 To 100  To 100 SMS (SODIUM METABI SULFATE) 0.05 0.05 0.05 Above 2 ethanol 10 10 _

* Natural product extract: a mixture of 30% by weight of nettle extract, 30% by weight of walnut extract, 30% of citrus extract, and 10% by weight of persimmon leaf extract

The process for preparing the novel drug delivery system / etosome / liposome is as follows.

First, the oil phase was heated to 80 DEG C to completely dissolve the oil phase, and then the aqueous phase 1, which had been heated to 80 DEG C, was well mixed with the active material and homogenized and cooled to 35 DEG C. After mixing again, the ethanol was added to the upper part of the flask and the upper part of the flask, and the flask was mixed well and treated with a high pressure homogenizer such as microfluidizer three times.

In this case, since the active material part should be located in the inside of the multi-structure, it must be mixed first and then ethanol should be treated after cooling. When ethanol is added at high temperature, the composition ratio is changed due to the volatilization of ethanol, none.

Example  1: composition for external application prepared with new drug delivery vehicle

The composition prepared with the novel drug delivery vehicle contains 20% by weight of the drug carrier obtained in Preparation Example 1 in a conventional hair tonic. The novel drug delivery system is an endoplasmic reticulum having a particle size of 100 to 200 nm and has a low viscosity. In addition to the general tonicity, there is no problem of separation and sedimentation by simply stirring any formulation easily. Therefore, . The active ingredient of the novel drug delivery system is 20% contained in the drug delivery system and 20% is actually used in the drug delivery system. Therefore, it actually contains 4.0%. Butyleneglycol is used to impart moisturizing function, and raffinose and betaine are derived from plant seeds and are used to impart moisturizing function to cosmetics. Citric acid and sodium citrate were used as pH regulators.

Comparative Example  One : Into the etosome  The prepared external preparation composition

The composition for external application was prepared in the same manner as in Example 1, except that the ethosome obtained in Preparation Example 2 was used as the drug delivery vehicle.

Comparative Example  2 : With liposomes  The prepared external preparation composition

An external preparation composition was prepared in the same manner as in Example 1, except that the liposome obtained in Preparation Example 3 was used as the drug delivery vehicle.

Comparative Example  3: composition containing no active ingredient

A typical hair tonic composition was prepared by containing nettles, tsunami seeds, walnuts, and persimmon leaves as an active ingredient in an amount of 20% by weight.

The prescriptions of the examples and comparative examples are summarized in Table 2 below.

division Component (parts by weight) Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3
Water top Butylene glycol 4.0 4.0 4.0 4.0 Raffinos 1.0 1.0 1.0 1.0 Betaine 2.0 2.0 2.0 2.0 Purified water To 100 To 100 To 100 To 100 Active material part New drug delivery vehicle 20.0 _ _ _ Ethosome 20 Liposome _ _ 20 _ pH adjuster Citric acid 0.04 0.04 0.04 0.04 Sodium citrate 0.1 0.1 0.1 0.1

Hair Score Test

For comparison of efficacy of Example 1 and Comparative Examples 1, 2 and 3, a hair score test using a mouse was performed. The animals used in the test were purchased from a 5-week-old SPF (specific pathogen member) C57 / BL6 mouse with an average body weight of about 23g in a central laboratory animal and adapted for about 1 week. After selecting healthy animals, 50 ± 10%, 10-12 times of exhaust, 12 hr cycle of fluorescent light and 150 ~ 160 Lux of light intensity. To evaluate the gross appearance of the skin, the hairy area was photographed using a digital camera to observe the hair-related characteristics of the skin on the 18th day, the end of the test.

Figures 2a, 2b, 2c and 2d are photographs taken on day 18 after application of the composition prepared in Examples, Comparative Example 1, Comparative Example 2 and Comparative Example 3 to skin of depilated mice in order. As can be seen from FIG. 2A, in the group to which the composition of Example 1 was applied to the skin, all four of them observed hair growth of about 100% in the entire skin area deprived of hair.

On the other hand, in the group to which the composition of Comparative Example 1 was applied to the skin, 3/4 hairs were observed in the entire back, and a hair growth phenomenon of about 75% was observed as a whole (see Fig. 2B).

In the group to which the composition of Comparative Example 2 was applied, 2/4 hairs were observed in the entire back, and a hair growth phenomenon of about 50% was observed as a whole (see Fig. 2C).

On the other hand, in the group to which the composition of Comparative Example 3 containing no nettle, millet, walnut and persimmon leaf extract was applied, hair growth in a very small part and grayish spots in part of the dorsal skin were observed and gross hair growth phenomenon could not be observed. In the case of completely hairy hair all over the epilated skin area, it was not observed in one mouse, and the hairy rate was about 2 ~ 3% of the total epilated skin area (see Fig. 2d)

Histological observation

In order to histologically observe the change in the number of hair follicles in the skin, the hairy part of the dorsal skin was cut parallel to the vertebral line and fixed with 4% paraformaldehyde solution. After fixing, a cryostat was prepared by a conventional method, and a 7 μm-thick section was prepared and H & E staining was performed to observe the change of the tissue.

3A, 3B, 3C and 3 D, in order, the compositions prepared in Examples, Comparative Example 1, Comparative Example 2 and Comparative Example 3 were applied to skin of depilated mice, and on the 18th day, (400 times). ≪ / RTI > In the photograph, the part dyed black is hair follicle, and the part dyed red is tissue.

Compared to the skin-applied group of Comparative Example 1, Comparative Example 2 and Comparative Example 3, the number of hair follicles was larger than that of the skin-applied group, and the hair shaft in the hair follicle was the most (Fig. 3A).

On the other hand, in the group to which the composition of Comparative Example 1 and Comparative Example 2 was applied to the skin, the number of hair follicles was observed to be larger than that of the group to which the composition of Comparative Example 3 was applied, A small number of hair follicles were observed (see Figs. 3B and 3C). In particular, microscopic observations showed that the number of hair follicles in the dermis was smaller in the group to which the composition was applied in Comparative Example 3 (see FIG. 3D).

Taking the above results into consideration, it can be seen that the case where the ethosome of Example 1 is selected as the drug delivery system of the active ingredient is superior to the case where the ordinary liposome and extract are directly applied.

Results of clinical trials

In order to confirm the effect through the actual person, a small clinical trial was conducted by selecting a person having female and male alopecia through a basic formulation which can be commercialized with Comparative Example 1 and Comparative Example 2. Subjects were 30 males and 20 females, 20 males and 70 females, respectively.

The experimental period was 3 months and the effect was confirmed every 15 days. As a method, the amount (120 ml) which can be applied every month for one month per patient was prescribed and the progress of the treatment was measured every 15 days.

Tables 3 and 4 below summarize the results of small-scale clinical trials in which the composition of Example 1 of the present invention and the composition of Comparative Example 2 were applied respectively. From the tables, it can be seen that when applying the composition according to the present invention, the hair loss prevention effect, which is about twice as much as that of the composition based on the simple formulation of a general drug, can be obtained.

division 1/2 month 1 month 1/2 month 2 months 1/2 2 months 3 months Reducing hair loss 24% 50% 85% 90% 100% 100% The fluffy beginning 0% 30% 54% 68% 89% 100% Fluffy and old hair thickened 0% 0% 20% 27% 55% 84% New hair begins to grow 0% 0% 0% 8% 23% 48%

division 1/2 month 1 month 1/2 month 2 months 1/2 2 months 3 months Reducing hair loss 12% 24% 52% 58% 62% 62% The fluffy beginning 0% 18% 22% 32% 38% 46% Fluffy and old hair thickened 0% 0% 0% 15% 32% 37% New hair begins to grow 0% 0% 0% 0% 10% 24%

Claims (7)

delete delete delete delete A drug delivery system for percutaneous absorption prepared by dispersing lecithin in an alcohol mixture containing propylene glycol, wherein at least one selected from the group consisting of nettle extract, walnut extract, tsunami extract and persimmon leaf extract is contained as an effective ingredient for preventing hair loss or promoting wool Wherein the composition for preventing hair loss or wool is used. delete A cosmetic comprising 1 to 50% by weight of the composition of claim 5.

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