KR101572216B1 - Solubilized formulation containing micelle of intercellular lipid ingredients - Google Patents

Abstract

The present invention relates to a solubilization formulation characterized by containing intercellular lipid ceramide and / or derivatives thereof, phospholipids and cholesterol-formed micelles, and a process for producing the same.

Intercellular lipids, micelles, solubilization, ceramide

Description

[0001] The present invention relates to solubilized formulations containing micelles of intercellular lipid components,

The present invention relates to solubilized formulations containing micelles formed by intracellular lipid components.

Skin barriers that prevent primary penetration of external harmful substances are present in the stratum corneum of the epidermis. The function of the stratum corneum acts as a barrier to suppress the loss of water and electrolytes outside the skin, thereby preventing the epidermis from drying out, providing an environment in which the epidermis can perform normal biochemical metabolism, Protects, and prevents bacteria, fungi, and viruses from invading the skin.

The structure of the stratum corneum is composed of keratinocyte rich in protein and lipid filling between them. Elias et al. In the mid 1970s formed a lamellar structure between the cornified cells and the lipid component in the stratum corneum. And this is the origin of skin barrier function ( J. Invest . Dermatol . 69: 535-546 (1977)).

These interstitial lipids are composed of 50% ceramide, 20-25% cholesterol, 20-25% self-fatty acid, 10% cholesterol ester, 1-2% cholesterol sulfate and a small amount of phospholipids have.

These intercellular lipids are insoluble and do not readily hydrate in water.

On the other hand, Korean Patent Laid-Open Publication No. 10-2005-0026778 (cosmetic composition for skin irritation alleviation containing an intercellular lipid component of nanoliposome) is a study on a composition containing intercellular lipid. However, the above-mentioned technology requires the use of a surfactant that stimulates skin, and it is inconvenient that a high-pressure homogenizer process which is useful for manufacturing nano-sized particles for use in a cosmetic formulation of a liposome having a lamellar structure is required, The lamellar structure forming the liposome has a considerably large size and thus it is difficult to use it in a cosmetic formulation in which formulation stability is required.

Accordingly, the technical object of the present invention is to provide a formulation superior to conventional nanoliposome cosmetic compositions containing intracellular lipids in terms of improvement of damaged skin, increase in moisturizing and softening effect, and storage stability.

In order to achieve the above object, the present invention provides a solubilized pharmaceutical composition containing micelles of an intercellular lipid component, preferably a ceramide and / or a derivative thereof; Phospholipids; And a micelle formed from an intercellular lipid component including cholesterol.

Micelles are generally defined as thermodynamically stable, homogeneous, spherical structures formed by low molecular weight materials that have both affinity, for example, hydrophilic and hydrophobic groups at the same time.

In general, amphiphilic substances constituting micelles are typically surfactants, and polymer materials having a specific molecular structure are also present. When such an amphipathic substance is dissolved in water or other solvent, the hydrophilic property on the surface of the solvent tends to be hydrated toward the water and the hydrophobic chain toward the surface of the solvent due to thermodynamic stability. When the concentration is continuously increased, the surface of the solution is saturated with the surfactant, so that the surface tension is not further reduced. In the aqueous solution, the hydrophilic group of the surfactant is collected outside and the hydrophobic group is collected into the micelle.

The intracellular lipid component of the present invention also has a hydrophilic group and a hydrophobic group, which are characteristics of an amphipathic molecule, together in one molecule, so that they play a role similar to a surfactant below a certain concentration. However, when a certain concentration is exceeded, micelles are formed, And when they contain more intercellular lipid components, they form a double lipid form of lamellar. Bilayer lamellar structures, such as liposomes, can be used in formulations such as creams, but there is a limit to the problem of opacification due to floating due to use in solubilization formulations such as lotion.

Accordingly, the present invention confirms that ceramide, its derivatives and phospholipids constituting intercellular lipids are structurally amphipathic, and forms micelles with these components. Thus, cholesterol, free Fatty acids, other poorly soluble substances, and the like. Furthermore, the present invention is based on the surprising discovery that such micelles can be stably maintained in the solubilized formulations such as lotion and the like, while retaining the micelle structure when certain ingredients are contained at specific concentrations.

Accordingly, it is preferable that the content of each raw material for forming the micelle is 0.1-5 wt%, the phospholipid 0.1-5 wt% and the cholesterol 0.01-2 wt%, based on the total weight of the composition, More preferably, the total weight of the ceramide and the derivative thereof is 0.1 to 2 wt%, the phospholipid is 0.1 to 2 wt%, and the cholesterol is 0.01 to 0.5 wt%. The total weight of the ceramide and the derivative thereof is 0.1 to 1 wt% 0.01 to 0.2% by weight of cholesterol is most preferable in terms of the formation and stabilization of micelles.

In addition, the content of the micelle in the present invention is preferably 0.1-15% by weight based on the total weight of the composition, for the formation of micelles and the stabilization of micelles.

In the present invention, micelles having an average particle diameter of 1-200 nm are preferred, and more preferred are micelles having an average particle diameter of 100-150 nm. If the mean particle diameter of the micelle is more than 200 nm, the formulation stability may be dangerous.

The intercellular lipid component used in the formation of the micelle of the present invention may be various intercellular lipid components known in the art, preferably ceramide type 1-type 6, galactosyl ceramide, phytosphingosine, sphingosine and non-ping's and such switch pinggo cannabinoid lipids, saturated lecithin, unsaturated lecithin, a lipid component liver cells with a phospholipid and a glyceride can be contained in micelles are cholesterol, sitosterol, cholesteryl sulfate, C _{10 -40} And fatty alcohols.

The micelle of the present invention may further contain a free fatty acid, and the free fatty acid is a C _10-40 fatty alcohol, and the content thereof is preferably 0.01-2% by weight based on the total weight of the solubilizing raw material.

The micelle of the present invention may also collect oil, flavor or mixture thereof, and the content thereof is preferably 0.01-1% by weight based on the total weight of the solubilizing raw material. Such ounces and fragrances may be selected from the group consisting of ester-based synthetic oils, silicone oils such as dimethicone and cyclomethicone-based oils, animal-derived vegetable oils such as jojoba oil and squalane, synthetic perfumes and natural perfumes, Raw materials known to the cosmetically useful poorly soluble materials in the industry can be selected.

More preferably, the present invention also provides a composition for solubilization of micelles, characterized in that the micelle is dispersed in a polyol, that is, a micelle dispersed in a polyol. The micelle formed by dispersing the micelle in the polyol stabilizes the stability of the formulation in the formulation for a longer period of time and also helps prevent it from growing into a lamellar structure.

As such polyols, propylene glycol, dipropylene glycol, 1,3-butylene glycol, pentylene glycol, 1,2-hexanediol, etc. may be used singly or in combination, and the amount thereof is preferably 85 -99% by weight.

The components included in the solubilization formulations of the present invention may include components commonly used in solubilization formulations other than the micelles formed by intercellular lipid components, and include conventional adjuvants such as stabilizers, solubilizers, vitamins, pigments and the like can do.

The composition for solubilization of micelles according to the present invention is characterized in that cholesterol, which is an intercellular lipid component contained in micelles and a phospholipid and a derivative of ceramide, which is an intercellular lipid component constituting micelles, is added to the polyol at about 40 to 70 ° C, The mixture is heated to 60 ° C and mixed and dissolved to prepare a solubilized raw material and the aqueous raw material prepared by mixing and dissolving the water-based raw material of purified water, purified water, polyol or the like is mixed and stirred.

As described in detail above, the solubilization formulation of the present invention using a specific component and a specific amount of intercellular lipid component as a component of micelle formation is excellent in storage stability, moisturizing power and elasticity improvement, Which is superior to the comparative example formulation. In addition, by using the intercellular lipid component as a constituent element of micelles, various difficulties in the manufacturing process can be solved, and since micelles formed by intercellular lipid components are contained, It can be solubilized without the use of a surfactant which gives a stimulus.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. 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 following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

≪ Preparation of Examples and Comparative Examples >

A composition containing micelles (Example) and a composition without micelles (Comparative Example) in which the intercellular lipid component of the present invention was stabilized was prepared with the following composition. Specifically, the A-phase was heated to 50-60 占 폚 and mixed and dissolved. Then, the mixture was stirred while slowly added to the B-phase, and then cooled to prepare respective formulations.

Raw material (unit:% by weight) Example 1 Example 2 Comparative Example 1 Comparative Example 2 A Ceramide 0.1 0.1 - - Galactosyl ceramide 0.3 0.6 - - Phospholipids 0.2 0.4 - - cholesterol 0.1 0.2 0.1 Cetearyl alcohol - 0.2 0.2 - Spices 0.03 0.03 0.03 0.03 PIGGY-40 Hydrogenated Castor Oil - - 0.1 0.1 Dipropylene glycol 8.0 8.0 8.0 8.0 B Purified water Balance Balance Balance Balance glycerin 5.0 5.0 5.0 5.0

≪ Experimental Example 1 >

Stability tests for the solubilized formulations containing micelles stabilizing intracellular lipid components and comparative examples were carried out by the following methods.

In order to test the stability of the formulation, the formulations were stored in a transparent glass container at 25 ° C., 45 ° C. and 40 ° C. in a thermostatic chamber and subjected to a cyclic cycling test to evaluate stability. Storage stability observations of the formulations were evaluated according to the following criteria, and the results are summarized in Table 2. The cycling test means that the storage temperature is changed in a cycle of 1 day. The specific conditions for the change are as follows: 6 hours at 1 -10 ° C, 6 hours at 25 ° C for 2 hours, 6 hours at 3 ° C at 45 ° C, 6 hours at 25 ° C.

?: Good,?: Difference from the beginning, X: Suspended or transparent

Experiment Item Example 1 Example 2 Comparative Example 1 Comparative Example 2 25 ℃ 3 days ○ ○ ○ ○ 1 week ○ ○ X ○ 3 months ○ ○ X ○ 45 ° C 3 days ○ ○ X ○ 1 week ○ ○ X ○ 3 months △ ○ X ○ 40 ℃ 3 days ○ ○ X ○ 1 week ○ ○ X ○ 3 months ○ ○ X ○ Cycling Test 3 days ○ ○ ○ ○ 1 week ○ ○ X ○ 3 months ○ ○ X ○

As can be seen in Table 2 above, the Example is stable under all temperature conditions, but Comparative Example 1, in which the solubilized raw material was directly applied to the formulation without forming micelles as an intercellular lipid component, is unstable at all temperature conditions Could know.

≪ Experimental Example 2 >

The water retention capacity of each of the formulations prepared in Examples 1 and 2 and Comparative Example 2 was evaluated as follows.

The water retention capacity was measured by measuring the electrical conductivity of the skin surface using SKICON-200 (IBS). Resistance value (water loss) was measured after application of 0.03 g of sample per 16 cm ² of skin in a constant temperature and humidity room maintained at 25 ° C and 40% relative humidity. However, the average micros before application of the sample was 50.

Experiment Items (Unit:%) Example 1 Example 2 Comparative Example 2 Short-term moisturizing 1.5 hours after application 617 691 204 3 hours after application 378 358 167 Long-term moisturizing Two doses per day for 5 days 25.7 25.2 4.2

As can be seen from the results of Table 3, it can be seen that the formulation containing micelles stabilizing the intercellular lipid component of the present invention is much better than the formulation of the comparative example in terms of moisture retention over time.

<Experimental Example 3> Elasticity improvement evaluation

The degree of improvement in elasticity of each of the formulations prepared in Examples 1 and 2 and Comparative Example 2 was evaluated in the following manner.

Skin elasticity was measured by measuring skin elasticity using Cutometer MPA 580 (CK electronic). After applying 30 μl of sample per 4 cm ^{2 of} skin, elasticity was measured before treatment and after treatment.

Experiment Items (Unit:%) Example 1 Example 2 Comparative Example 2 Improved elasticity Day 1 1.04 1.05 1.01 Day 5 6.03 5.99 1.05

As shown in Table 4, it can be seen that the formulation of Example of the present invention containing micelles stabilizing the intercellular lipid component is more excellent in the elasticity improvement than the formulation of the comparative example.

<Experimental Example 4> Human skin patch test

The degree of irritation of each formulation prepared in Examples 1 and 2 and Comparative Example 2 was evaluated as follows in 20 men and women who did not have any skin disease in Forearm or Back.

15 μl of sample was applied to a pin chamber (Finn chamber, 100 × 10, EPITEST, Finland), and the test site was hermetically sealed. After 24 hours of exposure, the patches were removed and marked with the marking pen. Two hours after removal of the patches, the test site was observed to observe erythema and edema.

Skin reactions were determined according to the International Contact Dermatitis Research Group (ICDRG), and the results are shown in Table 5.

- Criteria and scoring criteria for skin reactions

sign score Evaluation standard - 0 No response ± 0.5 Weak erythema + 1.0 Clear erythema ++ 2.0 Severe erythema with edema +++ 3.0 Severe erythema, blisters, edema

Experiment Item Example 1 Example 2 Comparative Example 2 Skin Reversal Index (PII) 0.05 0.06 0.08

As shown in Table 5, it can be seen that the formulation of Example of the present invention containing micelles stabilizing the intercellular lipid component has less skin irritation than the formulation of the comparative example.

Claims (9)

As solubilization formulations containing micelles of intracellular lipid components, The micelle may be a ceramide, a derivative thereof or a mixture thereof; Phospholipids; &Lt; / RTI &gt; and cholesterol, The content thereof is 0.1-2 wt% of the total weight of the ceramide and the derivative thereof, 0.1-2 wt% of the phospholipid and 0.01-2 wt% of the cholesterol, Wherein the micelle has an average particle diameter of 1-200 nm. [Claim 3] The composition according to claim 1, wherein the content of the ceramide and its derivative, phospholipid and cholesterol is 0.1-2% by weight of the ceramide and the derivative thereof, 0.1-2% by weight of the phospholipid and 0.01-0.5% Lt; / RTI &gt; solubilization formulation. [3] The composition of claim 1, wherein the content of the micelle is 0.1-15% by weight based on the total weight of the composition. The composition of claim 1, wherein the micelle contains a free fatty acid, the free fatty acid is a C _10-40 fatty alcohol, and the content thereof is 0.01-2% by weight based on the total weight of the solubilizing raw material. [3] The composition of claim 1, wherein the micelle collects an oil, a perfume or a mixture thereof, and the content thereof is 0.01-1% by weight based on the total weight of the solubilizing raw material. [3] The composition of claim 1, wherein the micelle is dispersed in a polyol, and the content of the polyol is 85-99% by weight based on the total weight of the solubilizing raw material. The method of claim 1, wherein the intercellular lipid component is selected from the group consisting of ceramide type 1-type 6, galactosyl ceramide, sphingosine, sipingosine, sphinganine, sphingoid lipids, saturated lecithin, unsaturated lecithin, glycerophospholipid , Cholesterol, sitosterol, cholesteryl sulfate, and mixtures thereof. 6. The composition of claim 5, wherein the oil and fragrance is selected from the group consisting of ester-based synthetic oils, silicone oils such as dimethicone and cyclomethicone-based oils, eastern vegetable oils such as jojoba oil and squalane, &Lt; / RTI &gt; The composition according to claim 6, wherein the polyol is at least one selected from the group consisting of propylene glycol, dipropylene glycol, 1,3-butylene glycol, pentylene glycol and 1,2-hexanediol. .