KR20100026143A - Multi-layered lamellar granule and skin external application composition containing same - Google Patents

Abstract

PURPOSE: A multi-layered lamellar granule and a skin external composition containing the same are provided to stably maintain lamellar structure same as skin keratin layer with high formulation stability. CONSTITUTION: A multi-layered lamellar granule contains a nucleant; a keratin layer-like lipid lamellar containing ceramide and phospholipid; and a polymer layer on the lipid lamellar layer. The nucleant is sugar, salt, hyaluronic acid, algininc acid, chodroitin sulfate, chitosan, chitin, polylysine, collagen, gelatin, stearic acid, cetyl alcohol, stearyl alcohol, or their mixture. The ceramide is natural ceramide or ceramide analogue. The phospholipid is phosphatidylcholine, phosphatidyl ethanolamine, phosphatidylcholine, phosphatidyl glycerol, phosphatidic acid or their mixture.

Description

Multilayer lamellar granules and external composition for skin containing same {MULTI-LAYERED LAMELLAR GRANULE AND SKIN EXTERNAL APPLICATION COMPOSITION CONTAINING SAME}

The present invention relates to multilayer lamellar granules that provide excellent moisturizing effect and barrier function (keratin function) healing effect when applied to the skin, and an external skin composition containing the same.

The skin is divided into three layers of epidermis, dermis and subcutaneous tissue in order from the outside, and it functions to protect organs in the body from temperature and humidity changes, ultraviolet rays and other physical and chemical external stimuli. In particular, the epidermis plays an important role in preventing evaporation of moisture inside the human body. The epidermis is divided into the stratum corneum, granule layer, the polar layer and the basal layer in order from the outside, the cells of the stratum corneum act like a brick and the intercellular lipids between the stratum corneum act as a mortar to form the skin barrier (J. Invest.Drmatol. 80 (Suppl.), 44-49. 1983). In addition, keratinocytes of healthy people have high concentrations of Natural Moisturing Factor (NMF) to help skin retain moisture. For example, because amino acids such as amino acids are water-soluble, they effectively combine with moisture Inhibit drying (J. Invest. Dermatol. 54, 24-31, 1970).

However, these days, the artificial temperature control of air conditioning and heating according to the change of environment and life patterns, the skin stress caused by various stresses and environmental pollution that occur in social life, the frequent face wash and the age increase due to makeup habits Due to various causes such as aging of the skin, the moisture of the stratum corneum decreases, the skin becomes dry, the surface becomes rough, the skin becomes crumbly, loses shine and looks dull, so the need for skin moisturizer is increased. have.

Conventionally, a method of increasing moisture retention in the stratum corneum by using an occlusive moisturizer such as a humectant or oil, wax, etc., which has a property of absorbing water for such a moisturizing function. Examples of the humectants include glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, and 2-pyrrolidone-5-sodium carbonate. However, such a moisturizing raw material has a disadvantage in that the ability to contain water is good but the sustainability of the moisturizing power is poor. Moreover, in a dry environment, the skin can be made dry by absorbing moisture in the skin.

As another approach, there are many methods of incorporating niacinamide into external skin preparations or by introducing ceramide directly into external skin preparations by promoting expression of ceramides and filaggrins, thereby enhancing skin barrier function and maintaining skin homeostasis. Is used. These approaches are a popular technology and are preferred because they help maintain homeostasis and are a fundamental approach to moisturizing (J. Invest. Dermatol. (5), 731-740, 1994). Ceramide is a very soluble poorly soluble substance, and when it is contained in a large amount in cosmetic formulations, the amount of additives such as surfactants and oils is also increased, making it difficult for the stratum corneum components to form a structure similar to the skin stratum corneum. In addition, ceramides are easily gelled to reduce the stability of cosmetic formulations and therefore have limitations on their use in amounts of 1% by weight or more.

Accordingly, an object of the present invention is to provide a multi-layer lamellar granules comprising a pseudo-stratum lipid lamellar layer exhibiting a structure similar to the stratum corneum layer without causing gelation due to excellent formulation stability.

Another object of the present invention is to provide a composition for external application of the skin containing the multilayer lamellar granules and exhibiting excellent moisturizing effect and barrier function healing effect when applied to the skin.

In order to achieve the above object, the present invention provides a multilamellar lamellar granules comprising a nucleating agent, a pseudokeratin lipid lamellar layer present on the nucleating agent and containing ceramide and phospholipid, and a polymer layer on the pseudokeratin lipid lamellar layer. do.

In the multilayer lamellar granules of the present invention, the nucleating agent is a group consisting of sugar, salt, hyaluronic acid, alginic acid, chondroitin sulfate, chitosan, chitin, polylysine, collagen, gelatin, stearic acid, cetyl alcohol, stearyl alcohol, and mixtures thereof. The nucleating agent may be included in an amount of 1 to 99% by weight based on the total weight of the multilayer lamellar granules.

The ceramide of the pseudokeratin lipid lamellar layer may be selected from the group consisting of natural ceramide and pseudoceramide.

The phospholipid of the pseudokeratin lipid lamellar layer may be selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidyl isocitol, phosphatidic acid and mixtures thereof.

The pseudo-keratin lipid lamellar layer may include ceramide and phospholipid in a weight ratio of 1: 0.1 to 1: 1.

In addition, the pseudokeratin lipid lamellar layer may be included in an amount of 0.00001 to 99% by weight based on the total weight of the multilayer lamellar granules.

The pseudo keratin lipid lamellar layer may further comprise fatty acids, cholesterol or derivatives thereof, alcohols, molecular anchoring agents, or mixtures thereof, wherein the fatty acids are unsaturated or saturated fatty acids having 8 to 30 carbon atoms. And the cholesterol or derivative thereof is a group consisting of cholesterol, cholesteryl chloride, cholesteryl octanoate, cholesteryl nonanoate, cholesteryl oleyl carbonate, cholesteryl isostearyl carbonate and mixtures thereof Wherein the alcohol is an unsaturated or saturated alcohol having 8 to 30 carbon atoms, and the molecular fixing agent is a substance having an alkyl or alkenyl group having 12 to 20 carbon atoms as a hydrophobic group and a succinimidyl ester as a hydrophilic group. , Preferably [oleyloxy-poly (ethylene glycol) _n -succinyl-N- under Hydroxysuccinimidyl ester] (n is an integer from 2 to 100). Preferably, the pseudo-keratin lipid lamellar layer comprises 1 to 50 parts by weight, 1 to 50 parts by weight, 1 to 50 parts by weight of fatty acid, cholesterol or derivatives thereof, alcohol and molecular fixative, respectively, based on 100 parts by weight of the ceramide; It may be included in an amount of 1 to 50 parts by weight.

In the multilayer lamellar granules of the present invention, the polymer layer may be included in an amount of 0.01 to 90% by weight based on the total weight of the multilayer lamellar granules.

The multilayer lamellar granules of the present invention can be prepared in a fluidized bed coater.

According to another object of the present invention, the present invention provides a topical skin composition comprising the multi-layer lamellar granules as described above.

In the external preparation composition for skin of the present invention, the granules may be contained in an amount of 0.01 to 99% by weight based on the total weight of the composition.

The external skin composition may be a cosmetic composition or a pharmaceutical composition.

The multi-layer lamellar granules according to the present invention contain a stratum corneous lipid lamellae that mimics the components of the skin's outermost lipid layer (stratum corneum) in the granules, so that even when formulated later, the contact with oil and surfactants is blocked, thereby preventing the skin. The lamellar structure similar to the stratum corneum can be stably maintained. Therefore, the external composition for skin containing the multi-layer lamellar granules of the present invention is excellent in formulation stability and does not cause gelation phenomenon, and shows excellent moisturizing effect and barrier function healing effect when applied to the skin, and thus may be usefully used in cosmetics and drugs.

The present invention provides a multilamellar lamellar granule comprising a nucleating agent, a pseudokeratin lipid lamellar layer present on the nucleator and containing ceramide and phospholipid and a polymer layer on the pseudokeratin lipid lamellar layer.

The nucleating agent used in the present invention is an inert, easily collapsing to external stimuli, such as sugar, salt, hyaluronic acid, alginic acid, chondroitin sulfate, chitosan, chitin, polylysine, collagen, gelatin, stearic acid, Cetyl alcohol, stearyl alcohol and mixtures thereof.

Such nucleating agents can be used in amounts of from 1 to 99% by weight, based on the total weight of the multilayer lamellar granules. When the amount of the nucleating agent is used in the above range, it is possible not only to reduce the aggregation phenomenon that may occur in the process of coating the keratinous lipid lamellar layer, the polymer layer, etc. on the surface of the nucleating agent, but also to increase the coating rate, resulting in a multilayer The structural stability of lamellar granules can be improved.

On the nucleating agent as described above is a layer of pseudokeratin lipid lamellar. The stratum corneum of human skin is composed of keratinocytes and intercellular keratinocytes, acting as a barrier unique to the skin. The most important role in this barrier function is keratinocyte lipid, which has a multi-lamellar lamellar structure. Similar to the structure of the keratinocyte lipid having a lamellar structure corresponds to the pseudokeratin lipid lamellar layer.

Such pseudokeratin lipid lamellar layer essentially includes ceramides and phospholipids, and may preferably further comprise fatty acids, cholesterol or derivatives thereof, alcohols, molecular anchoring agents or mixtures thereof in addition to the ceramides and phospholipids. have.

The ceramides included in the pseudokeratin lipid lamellar layer as described above encompass both natural ceramides and pseudoceramides.

The natural ceramide may be, for example, at least one selected from the group consisting of ceramide 1, ceramide 2, ceramide 3, ceramide 4, ceramide 5, ceramide 6, ceramide 7, and ceramide 8.

The pseudo ceramide is a synthetic material having properties similar to those of natural ceramide, such as skin protection, water retention ability, and the like. For example, the ceramide may be selected from the group consisting of compounds represented by the following Chemical Formulas 1 to 6, and the like. It is not.

(Wherein

R is C _{9 -} a saturated or unsaturated aliphatic chain of C _21),

(Wherein

n is 1 or 2;

R and R 'are C _{9 -} a saturated or unsaturated aliphatic chain of C _21),.

(Wherein

m and n are the same or different and are an integer from 1 to 3;

k and l are the same or different and are 1 or 2;

j is 0 or 1;

R and R 'are the same or different, which does not contain or contains a hydroxy group, C _{1 -} C ₃₁ straight chain or a branched-chain saturated or unsaturated alkyl group;

A ¹ , A ² and A ³ are the same or different and are hydrogen or any of substituents of the following structure, except that A ¹ , A ² and A ³ are simultaneously hydrogen:

[Wherein M, M ¹ and M ² are alkali metal, lysine, arginine, histidine, triethanolamine, ammonia, polyquaternium-4, polyquaternium-6, polyquaternium-7, polyquaternium-10 , Polyquaternium-11, polyquaternium-16, lauryldimethylbenzylammonium chloride and stearyldimethylbenzylammonium chloride, L is an alkaline earth metal.]),

(Wherein

R and R 'are the same or different, which does not contain or contains a hydroxy group, C _{10 -} C ₃₂ linear or branched and saturated or unsaturated alkyl group;

R ³ and R ⁴ are the same or different, hydrogen or a C _{1 -} C ₄ alkyl group or hydroxy alkyl group of;

R ⁵ is either -CH ₂ CH ₂ OA or a substituent of the following structure:

,

,

,

,

및

,

,

,

,

And

[Wherein M, M ¹ and M ² are alkali metal, lysine, arginine, histidine, triethanolamine, ammonia, polyquaternium-4, polyquaternium-6, polyquaternium-7, polyquaternium-10, Polyquaternium-11, polyquaternium-16, lauryldimethylbenzylammonium chloride and stearyldimethylbenzylammonium chloride, L is an alkaline earth metal.]),

(Wherein

m and n are the same or different and are an integer from 1 to 4;

R and R 'are the same or different and are C ₁ -C ₃₁ straight or branched chain saturated or unsaturated alkyl groups, with or without hydroxy groups;

A ₁ and A ₂ are the same or different and are either hydrogen or a substituent of the following structure:

,

,

,

,

및

,

,

,

,

And

[Wherein M, M ¹ and M ² are an alkali metal or an organic base containing nitrogen and L is an alkaline earth metal]),

(Wherein

m and n are the same or different and are an integer from 1 to 3;

k and l are the same or different and are 1 or 2;

j is 0 or 1;

A ¹ , A ² and A ³ are the same or different and are either hydrogen or a substituent of the following structure:

,

,

및

,

,

And

[Wherein M, M ¹ and M ² are an alkali metal or an organic base containing nitrogen and L is an alkaline earth metal];

R is a substituent having the structure:

[Wherein B is a methyl group in the 5-, 7- or 8- position of tocopherol, m is an integer from 1 to 3, D is -CH ₂ (CH ₃ ) -CH- or -CH (CH ₃ ) = C-].

The compounds of Formulas 1 to 6 have excellent effects on skin moisturizing and skin barrier function recovery, and are sold as ceramides PC104, PC102, PC107 and the like.

In addition, the phospholipid contained in the pseudo-keratin lipid lamellar layer greatly contributes to the stabilization of ceramides and serves to inhibit gelation of ceramides. Phospholipids used in the present invention are prepared by extracting from plants, soybeans, eggs, or the like, or by further purifying them. Specific examples thereof include phosphatidylcholine, phosphatidylethanolamine, Phosphatidylserine, phosphatidylglycerol, phosphatidyl isocitol, phosphatidic acid and mixtures thereof. Preferably, the phospholipid used in the present invention is extracted from soybean, it may be a mixture of saturated lecithin and unsaturated lecithin containing 20-99% by weight of unsaturated lecithin corresponding to 10-99% by weight of phosphatidylcholine.

The pseudo-keratin lipid lamellar layer may include ceramide and phospholipid in a weight ratio of 1: 0.1 to 1: 1.

In addition, as the fatty acid included in the pseudo keratin lipid lamellar layer, for example, unsaturated or saturated fatty acids having 8 to 30 carbon atoms may be used, and for example, unsaturated or saturated alcohols having 8 to 30 carbon atoms may be used as the alcohol.

In addition, cholesterol or derivatives thereof included in the pseudo-keratin lipid lamellar layer may include, for example, cholesterol, cholesteryl chloride, cholesteryl octanoate, cholesteryl nonanoate, cholesteryl oleyl carbonate, and cholesteryl. Isostearyl carbonate and mixtures thereof.

Molecular anchoring agent included in the stratum corneum lipid lamellar layer serves to chemically bind the lipid structure and the protein on the skin to maintain the lipid structure on the skin for a long time. Molecular fixatives usable in the present invention are those having 12 to 20 carbon atoms or alkenyl groups as hydrophobic groups and succinimidyl esters as hydrophilic groups, preferably [oleyloxy-poly (ethylene glycol) _n- succinyl -N-hydroxysuccinimidyl ester] (n is an integer of 2 to 100, more preferably an integer of 10 to 80).

Preferably, the pseudo-keratin lipid lamellar layer comprises 1 to 50 parts by weight, 1 to 50 parts by weight, 1 to 50 parts by weight of fatty acid, cholesterol or derivatives thereof, alcohol and molecular fixative, respectively, based on 100 parts by weight of the ceramide; It may be included in an amount of 1 to 50 parts by weight.

These keratin The lipid lamella layer can be used, for example, in an amount of from 0.00001 to 99% by weight, based on the total weight of the multilayer lamella granules of the present invention.

The polymer layer is located on the pseudo-keratin lipid lamellar layer as described above. The polymer layer protects the pseudokeratin lipid lamellar layer by enclosing the outer surface of the pseudokeratin lipid lamellar layer, and plays a role of greatly improving the structural stability of the multilayer lamellar granules.

The polymer layer is not particularly limited as long as it is not easily dissolved in a solvent, for example, water or an organic solvent having a polarity, and can be evenly coated on the surface of the keratinous lipid lamella layer. The polymer layer may be a natural polymer or a synthetic polymer. It may also be a mixed type of natural polymer and synthetic polymer.

Natural polymers constituting the polymer layer include, for example, hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, chitosan, chitin, polylysine, collagen, and fibrin.

As the synthetic polymer constituting the polymer layer, for example, polyethylene glycol-polylactic acid-polyethylene glycol (PEG-PLA-PEG), polyethylene glycol-poly (lactic coglycolic acid)-polyethylene glycol (PEG-PLGA-PEG) , Polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-PCL-PEG), polyethylene-bis- (polylactic acid-acrylate) and phosphorus (isopropylacrylamide-co-acrylic acid) Etc.

Moreover, as a mixed type of the natural polymer and the synthetic polymer which comprise a polymer layer, phosphorus (polyethylene glycol-co-peptide), alginate-g- (polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO), for example ), Phosphorus (poly (lacticcoglycolic acid) -co-serine), collagen-acrylate, alginate and the like. Biodegradable hydrophobic aliphatic polyesters can also be used as the polymers, examples of which include poly-L-lactic acid, poly-D, L-glycolic acid, poly-L-lactic acid-co-glycolic acid, poly-D, L Copolymers prepared from -lactic acid-co-glycolic acid, polycaprolactone, polyvalerolactone, polyhydroxybutyrate, polyhydroxyvalrate, polyorsteresters and monomers thereof, and mixtures thereof. .

In addition, polymers usable in the present invention include polystyrene, poly p- or m-methylstyrene, poly p- or m-ethylstyrene, poly p- or m-chlorostyrene, poly p- or m-chloromethylstyrene, poly Styrenesulfonic acid, poly p- or m- or t-butoxystyrene, polymethyl (meth) acrylate, polyethyl (meth) acrylate, polypropyl (meth) acrylate, poly n-butyl (meth) acrylate , Polyisobutyl (meth) acrylate, poly t-butyl (meth) acrylate, poly 2-ethylhexyl (meth) acrylate, poly n-octyl (meth) acrylate, polylauryl (meth) acrylate, Polystearyl (meth) acrylate, poly 2-hydroxyethyl (meth) acrylate, polyethylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) acrylate, polyglycidyl (meth) acrylate, Polydimethylaminoethyl (meth) arc Latex, polydiethylaminoethyl (meth) acrylate, polyvinylacetate, polyvinylpropionate, polyvinylbutyrate, polyvinylether, polyallylbutyl ether, polyallylglycidyl ether, poly (meth) acrylic acid, poly Unsaturated carboxylic acids such as maleic acid, polyalkyl (meth) acrylamide, poly (meth) acrylonitrile and the like can be used in combination.

The polymer layer may be used in an amount of 0.01 to 90% by weight based on the total weight of the multilayer lamellar granules. When the amount of the polymer layer is used in the above range, the stability of the multi-layer lamellar granules can be increased, and when the multi-layer lamellar granules, which are the final result, are applied to external skin preparations such as cosmetics, foreign matter does not appear.

The multilayer lamellar granules according to the present invention can be prepared through various coating methods, and preferably can be prepared using, for example, a fluidized bed coating method using a fluidized bed coater.

This will be described in more detail as follows.

First, the nucleating agent is placed in a fluidized bed coater and vortexed.

Subsequently, the surface of the vortex nucleating agent is first spray-coated with a solution of a pseudo keratin lipid lamellar blend containing ceramide and phospholipid under room temperature and reduced pressure, followed by drying to form a pseudokeratin lipid lamellar layer on the nucleating agent surface. In this case, other optional components may be added together to the spray coating, and the ceramide and the phospholipid may be made into separate solutions, respectively, and spray coating may be performed sequentially. If separate ceramide and phosphorus lipid solutions are used, the optional components can be added in any solution.

The solvent for dissolving the pseudo keratin lipid lamellar blend is volatile and is not particularly limited as long as it can dissolve the pseudo keratin lipid components.

The solvent used in the above process may be any chemicals capable of dissolving the selected keratin lipid components, specifically, linear alkanes such as hexane, heptane, octane, nonane, decane and the like; Linear or branched alcohols such as methanol, ethanol, propanol, butanol and the like; Alcohols having 4 to 10 carbon atoms such as pentanol, hexanol, heptanol, octanol, nonanol, decanol and the like; alkyl esters of 7 or more carbon atoms such as n-hexyl acetate, 2-ethylhexyl acetate, methyl oleate, dibutyl sebacate, dibutyl adipate, 2-butyl carbamate and the like; Aliphatic ketones such as methyl isobutyl ketone, isobutyl ketone and the like; Aromatic hydrocarbons such as benzene, toluene, o- or p-xylene and the like; Chlorine compounds such as methylene chloride, chloroform, carbon tetrachloride, and the like may be used, but are not limited thereto.

Preferably, it is preferable to use methanol, ethanol, methylene chloride, chloroform, acetone, or the like, which has a low boiling point and easily evaporates to facilitate the coating.

The amount of the solvent may be 10 to 99 parts by weight based on 100 parts by weight of the pseudokeratin lipid lamellar blend. When the amount of the solvent is used in the above range, it is possible to effectively dissolve the active ingredient, the spray time is not long when spray coating can increase the efficiency of the process.

Next, the surface of the pseudo-keratin lipid lamellar layer on the nucleating agent may be secondarily spray-coated with a solution of a polymer under room temperature under reduced pressure, followed by drying to prepare a multilayer lamellar granule according to the present invention.

At this time, the solvent for dissolving the polymer is all chemicals that are volatile and have similar solubility parameters for the polymer selected, and the specific example is substantially the same as the solvents for the quaternary lipid lamellae formulations described above.

The amount of the solvent may be 10 to 99 parts by weight based on 100 parts by weight of the polymer. When the amount of the solvent is used in the above range, it is possible to prevent the gelation of the polymer, the spraying time is not long when spray coating can increase the process efficiency.

In addition, the present invention also provides a topical skin composition comprising the multilayer lamellar granules.

The topical skin composition of the present invention may comprise the multilayer lamellar granules in an amount of, for example, about 0.01 to 99% by weight, preferably about 0.01 to 5% by weight, based on the total weight of the composition. Satisfying the above range has advantages in better formulation stability, usability, skin moisturizing and barrier repair effects.

The external preparation composition for skin of the present invention is not particularly limited in its formulation, and may be, for example, a cosmetic composition having a formulation of a softening lotion, a nourishing lotion, a massage cream, a nourishing cream, a pack, a gel, or a skin adhesive cosmetic. Preferably, the cosmetic composition may be an oil-in-water emulsion, solubilizing gel formulation having excellent phase stability.

In addition, the pharmaceutical composition may be a pharmaceutical composition in which the multilayer lamellar granules of the present invention are present in a pharmaceutically acceptable carrier in a dispersed or dissolved state, and may be used for transdermal administration such as lotions, solutions, gels, creams, emollient creams, ointments, patches, or sprays. It may be a formulation. In the case of such pharmaceutical compositions, for example, atopic dermatitis, sweat bands, erosion, frostbite, dermatitis caused by diapers, contact dermatitis, seborrheic dermatitis, vidal thyroiditis, molar eczema, housewives eczema, sun dermatitis, hyperemia, skin exhaustion , Yangjin, weakness, addiction, psoriasis, psoriasis, palmar erythematosus, squamous planar, glossy thyroid, follicular erythematosus, gibbert rosaceous narcosis, erythematosis, erythematosis, disc erythematous lupus, systemic lupus erythematosus Can be used for the treatment and prevention of swelling, swelling, herpes dermatitis, alopecia areata, vulgaris, sarcoidosis, skin amyloidosis, keloids, hypertrophic reunion, wounds, bedsores, skin ulcers, hair loss, wool or hair growth have.

The topical dermatological composition of the present invention may also serve as a substrate for delivery of other agents to enhance clinical response to the agents. Examples of such agents include anti-inflammatory agents such as corticosteroids, colchicine, sulfasalazine and sulfones; Antibiotics such as quinolone, macrolide, penicillin, cephalosporin, sulfonamide and tetracycline; Antiviral agents (eg, acyclobit, idoxuridine, zidovudine, 2 ', 3'-dideoxyinosine (ddI), vidaribin, and trifluidine); Antifungal agents (eg, ketoconazole, econazol, griseofulvin, cycloprix and naphtidine); Antihistamines (eg, diphenhydramine, astemizol, hydroxyzine, doxepin, amitriptyline, ciproheptadine and sodium chromoline); Antipruritic agents such as campo, menthol, phenol, benzocaine, benzyl alcohol, salicylic acid, diclonin and pramoxin; Anti-neoplastic agents (eg methotrexate, pyritrexime, cisplatin, 5-fluorouracil, bleomycin, carmustine, hydroxyurea, azathioprine, and nitrogen mustard); Carboxylic acid analogs such as 1-monolaurin, azeraic acid and dodecanedioic acid; Natural or synthetic vitamins and analogues thereof, such as vitamin D, calcitritriol, 1,25-dihydroxy cholecalciferol, retinol, retinyl palmitate, retinyl ascorbate, isotretinoin, estretinate and reti Nonsan); And artemisinin analogues (eg, artesate, arteether, artemeter, dihydroartemisinin and artelenic acid).

The composition of the present invention is not limited to the above-mentioned components, and may contain other components to be blended into a conventional cosmetic composition or a pharmaceutical composition, if necessary. For example, fats and oils, moisturizers, emollients, surfactants, organic or inorganic pigments, organic powders, ultraviolet absorbers, preservatives, fungicides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, flavorings, blood circulation promoters, And a cooling agent, a restriction | limiting agent, purified water, etc. can be included.

Although an Example and a comparative example are given to the following and this invention is demonstrated to it further more concretely, this invention is not limited only to these examples.

Example 1 Preparation of Multi-Layered Lamellar Granules Containing Similar Ceramides (1)

Similar ceramide, ceramide PC104 (Macrocare, Korea) was used, and granules were prepared by the following procedure.

First, 500 g of sugar nucleating agent having an average size of 200 mm was placed in a fluidized bed coater (Glatt, Germany) and vortexed. Subsequently, 1000 g of ceramide PC104 was completely dissolved in 5 kg of methylene chloride, and then the surface of the nucleating agent was spray coated with this solution at room temperature under reduced pressure. Subsequently, 100 g of phosphatidylcholine, 10 g of [oleyloxy-poly (ethylene glycol) _20- succinyl-N-hydroxysuccinimidyl ester] as a molecular fixative, and 50 g of stearic acid were dissolved in 500 g of methylene chloride in the same manner as described above. The surface of the coating was spray coated at room temperature under reduced pressure. Subsequently, the surface of the coating obtained above was spray-coated under a room temperature reduced pressure condition with a solution of 50 g of chitin dissolved in 95 g of water. The spray rates were all 10 ml / min and all processes were run at room temperature. The final recovered multi-lamellar granules were sifted to remove fine residues and kept airtight in aluminum packs.

Example 2: Preparation of Multilayer Lamellar Granules Containing Natural Ceramides

Multilayer lamellar granules were prepared in the same manner as in Example 1, except that Ceramide 1 (Doosan, Korea), which is a natural ceramide, was used instead of pseudoceramide.

Example 3: Preparation of Multi-Layered Lamellar Granules Containing Similar Ceramides-(2)

The multilayer lamellar granules were prepared in the same manner as in Example 1 except that no molecular fixative was used.

Test Example 1: Structural Analysis of Multilayer Lamellar Granules

The shape of the multilayer lamellar granules prepared in Examples 1 and 2 was observed with an optical microscope, a polarizing microscope, and an electron microscope, and the electron micrographs of the granules prepared in Example 1 are shown in FIG. 1. From the photograph of FIG. 1, it can be seen that in the case of the multilayer lamellar granules prepared in Example 1, a nucleating agent is present therein, and the lamellar layer and the polymer layer are continuously surrounded around the nucleating agent. It can be seen from the polarization micrograph that the lamellar layer shows a strong crystal phase image, indicating that the ceramide and the phospholipid coating layer form a lamellar structure.

In addition, the multilayer lamellar granules prepared in Example 2 also showed the same shape as the microscopic image shown in FIG. 1, indicating that the ceramides, molecular fixatives and fatty acids were arranged in a lamellar structure and immobilized together with the phospholipids.

Formulation Example 1: Preparation of Solubilized Formulations-Formulation Stability Test

A solubilized formulation in the form of a transparent gel (viscosity about 3,500 cps) having the composition of Table 1 was prepared. At this time, the viscosity was measured at 12 ℃ at 30 ℃ using Brookfield (Brookfield, LVDVII +). In addition, the granules were all added at 5% by weight, and ceramide PC104 or ceramide 1 was added separately to compare formulation stability. The formulation thus prepared was stored in an oven at 25 ° C. and 45 ° C., respectively, and samples were taken after 2, 4 and 8 weeks to observe the degree of gelation. The results are shown in Table 2 below.

From Table 2 above, the solubilized formulations of Formulation Examples 1-1 and 1-2 containing ceramide only as granular keratin lipid lamellar layer do not cause gelation, whereas Formulation Examples 1-3 containing ungranulated ceramide. And 1-4 solubilized formulations were found to gel over time.

Formulation Example 2: Preparation of Emulsified Formulations-Formulation Stability Test

In order to examine the anti-gelling effect in the emulsion formulation, a lotion having a composition of Table 3 was prepared. Each oil phase and water phase were completely dissolved at 70 ° C. and emulsified at 7,000 rpm for 5 minutes to prepare a lotion in the form of an opaque gel. The viscosity of the lotion was about 3,000 cps. The formulation thus prepared was stored in an oven at 25 ° C. and 45 ° C., respectively, and samples were taken after 4 weeks, 8 weeks, and 16 weeks, respectively, and the degree of gelation was observed. The results are shown in Table 4 below.

From Table 4 above, the emulsion formulations of Formulation Examples 2-1 and 2-2 containing ceramide only as granular keratin lipid lamellar layer do not cause gelation, whereas Formulation Example 2-3 comprising ungranulated ceramide. And the emulsion formulation of 2-4 was confirmed to gel over time.

Reference Example 1 Effect of Molecular Fixing Agent

The following test was carried out by verifying the effect of the molecular fixative in the prepared multilayer lamellar granules.

Each of the emulsion formulations prepared in Formulation Examples 2-1 and 2-5 was placed in an amount of 0.2 g on the artificial skin, mixed well by adding 0.01 g of a water soluble pigment No. 227 1/1000, and then mixed well. After washing for 7 minutes using magnetic stirring in water, the amount of adsorbed pigment was observed and the photograph is shown in FIG. 2 (left: formulation of Formulation Example 2-1, right: formulation Example 2-5 Formulation). From the photograph of FIG. 2, the formulation of Formulation Example 2-1 in which the molecular fixative is used mostly remains on the skin, whereas the formulation in Formulation Example 2-5 in which the molecular fixative is not used is mostly washed off. This shows that multilayer lamellar granules can remain on the skin for a longer time through the use of molecular fixatives.

From the above results, it was confirmed that the ceramide present in the multi-layer lamellar granules according to the present invention shows excellent formulation stability despite the high content in the cosmetic formulation. These results show that ceramides, which have been limited in their use, can be used in greater amounts as formulation stability is drastically lowered by the use of ethanol, surfactants, and other cosmetic additives.

1 is an electron micrograph of the granules prepared in Example 1,

Figure 2 is a photograph of comparing and observing the amount of pigment adsorbed after washing the mixture of each of the emulsion formulations prepared in Formulation Examples 2-1 and 2-5 with the pigment for a certain time (left: Formulation Example 2-1 Formulation, right: formulation of Formulation Examples 2-5).

Claims (21)

Nucleating agent; A pseudokeratin lipid lamellae present on the nucleating agent and containing ceramide and phospholipids; And Polymer layer on the pseudo-keratolipid lamellae layer Containing, multilayer lamellar granules. The method of claim 1, The nucleating agent is a multilayer lamellar granules selected from the group consisting of sugar, salt, hyaluronic acid, alginic acid, chondroitin sulfate, chitosan, chitin, polylysine, collagen, gelatin, stearic acid, cetyl alcohol, stearyl alcohol and mixtures thereof. The method of claim 1, Wherein the nucleating agent is included in an amount of 1 to 99% by weight based on the total weight of the multilayer lamella granules. The method of claim 1, The ceramide is a multilayer lamellar granules selected from at least one of natural ceramides and similar ceramides. The method of claim 4, wherein The natural ceramide is a multilayer lamellar granules selected from at least one of the group consisting of ceramides 1 to 8. The method of claim 4, wherein The pseudo ceramide is a multilayer lamellar granules selected from at least one group consisting of the following formulas (1) to (6). [Formula 1]

(Wherein R is a saturated or unsaturated aliphatic chain of C ₉ -C ₂₁ ), [Formula 2]

(Wherein n is 1 or 2; R and R 'are C _9- C ₂₁ saturated or unsaturated aliphatic chains), [Formula 3]

(Wherein m and n are the same or different and are an integer from 1 to 3; k and l are the same or different and are 1 or 2; j is 0 or 1; R and R 'are the same or different and are C ₁ -C ₃₁ straight or branched chain saturated or unsaturated alkyl groups, with or without hydroxy groups; A ¹ , A ² and A ³ are the same or different and are hydrogen or any of substituents of the following structure, except that A ¹ , A ² and A ³ are simultaneously hydrogen:

[Wherein M, M ¹ and M ² are alkali metal, lysine, arginine, histidine, triethanolamine, ammonia, polyquaternium-4, polyquaternium-6, polyquaternium-7, polyquaternium-10, Polyquaternium-11, polyquaternium-16, lauryldimethylbenzylammonium chloride and stearyldimethylbenzylammonium chloride, L is an alkaline earth metal.]), [Formula 4]

(Wherein R and R 'are the same or different and are C ₁₀ -C ₃₂ straight or branched chain saturated or unsaturated alkyl groups, with or without hydroxy groups; R ³ and R ⁴ are the same or different and are hydrogen or a C ₁ -C ₄ alkyl or hydroxyalkyl group; R ⁵ is either -CH ₂ CH ₂ OA or a substituent of the following structure:

,

,

,

,

And

[Wherein M, M ¹ and M ² are alkali metal, lysine, arginine, histidine, triethanolamine, ammonia, polyquaternium-4, polyquaternium-6, polyquaternium-7, polyquaternium-10, Polyquaternium-11, polyquaternium-16, lauryldimethylbenzylammonium chloride and stearyldimethylbenzylammonium chloride, L is an alkaline earth metal.]), [Formula 5]

(Wherein m and n are the same or different and are an integer from 1 to 4; R and R 'are the same or different and are C ₁ -C ₃₁ straight or branched chain saturated or unsaturated alkyl groups, with or without hydroxy groups; A ₁ and A ₂ are the same or different and are either hydrogen or a substituent of the following structure:

,

,

,

,

And

[Wherein M, M ¹ and M ² are an alkali metal or an organic base containing nitrogen and L is an alkaline earth metal]), [Formula 6]

(Wherein m and n are the same or different and are an integer from 1 to 3; k and l are the same or different and are 1 or 2; j is 0 or 1; A ¹ , A ² and A ³ are the same or different and are either hydrogen or a substituent of the following structure:

,

,

And

[Wherein M, M ¹ and M ² are an alkali metal or an organic base containing nitrogen and L is an alkaline earth metal]; R is a substituent having the structure:

[Wherein B is a methyl group in the 5-, 7- or 8- position of tocopherol, m is an integer from 1 to 3, D is -CH ₂ (CH ₃ ) -CH- or -CH (CH ₃ ) = C-]. The method of claim 1, The phospholipid is a multilayer lamellar granules selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidyl isocitol, phosphatidic acid and mixtures thereof. The method of claim 1, Multi-layer lamellar granules of the ceramide and phospholipid are included in a weight ratio of 1: 0.1 to 1: 1. The method of claim 1, Wherein the pseudo-keratolipid lamellae layer is included in an amount of 0.00001 to 99% by weight based on the total weight of the multilayer lamella granules. The method of claim 1, The pseudo keratin lipid lamellar layer further comprises a fatty acid, cholesterol or derivatives thereof, alcohols, molecular fixatives, or mixtures thereof. The method of claim 10, The fatty acid is a multilayer lamellar granules of unsaturated or saturated fatty acids having 8 to 30 carbon atoms. The method of claim 10, The cholesterol or derivative thereof is selected from the group consisting of cholesterol, cholesteryl chloride, cholesteryl octanoate, cholesteryl nonanoate, cholesteryl oleyl carbonate, cholesteryl isostearyl carbonate and mixtures thereof Multilayer lamella granules. The method of claim 10, The alcohol is a multilayer lamellar granules having 8 to 30 carbon atoms of unsaturated or saturated alcohol. The method of claim 10, The molecular fixer is a multi-layer lamellar granules having a alkyl group or alkenyl group having 12 to 20 carbon atoms as a hydrophobic group and a succinimidyl ester as a hydrophilic group. The method of claim 14, The molecular fixer is [oleyloxy-poly (ethylene glycol) _n- succinyl-N-hydroxysuccinimidyl ester] (n is an integer of 2 to 100) multilayer lamellar granules. The method of claim 10, The fatty acid, cholesterol or derivatives thereof, alcohols, and molecular fixatives may be included in amounts of 1 to 50 parts by weight, 1 to 50 parts by weight, 1 to 50 parts by weight, and 1 to 50 parts by weight based on 100 parts by weight of the ceramide, respectively. Lamella granules. The method of claim 1, The polymer layer is a multi-layer lamellar granules in an amount of 0.01 to 90% by weight based on the total weight of the multi-layer lamellar granules. The method of claim 1, The multilayer lamella granules are multilayer lamella granules produced in a fluidized bed coater. A topical skin composition comprising the multilayer lamellar granules according to claim 1. The method of claim 19, A composition containing 0.01 to 99% by weight of the multilayer lamellar granules based on the total weight of the composition. The method of claim 19, The composition is a cosmetic composition or a pharmaceutical composition.

Images