Nanoliposome with application of etherificated lecitin and method of obtaining such, as well as composition for prevention or treatment of skin diseases including such liposomes

FIELD: medicine.

SUBSTANCE: invention relates to medicine and deals with nanoliposome which includes liposomal membrane, contains ethgerificated lecitin and one or more physiologically active ingredients, incorporated in the internal space of liposomal membrane, method of obtaining such, as well as composition for prevention or treatment of skin diseases, containing nanoliposome.

EFFECT: invention ensures long-term stability and homogenecity of nanoliposomes.

15 cl, 22 ex, 4 dwg, 2 tbl

 

The technical FIELD of the INVENTION

The present invention relates to nanoliposomes, including liposomal membrane containing esterified lecithin, and one or more physiologically active ingredients, prisoners in the interior of the liposomal membrane, method for producing thereof, and to compositions for the prevention or treatment of skin diseases, including such.

The prior art INVENTIONS

Liposome is a microscopic endoplasmic reticulum having a closed lipid bilayer membrane, which has a hydrophilic space. Accordingly liposome differs in that it contains water-soluble materials in the hydrophilic inner space and captures fat-soluble materials in the outer bilayer lipid membrane. The material forming such liposomal membrane, called lipoidal. As lipoid usually use phosphoglycerides and sphingolipids. In the field of cosmetics or food industry often use lecithin or ceramide, because they have excellent moisturizing properties and non-toxic to the human body.

However, these lecithin and ceramide are hydrophobic and trudnozapominaemyj both in alcohol and in aqueous solution. Thus, to use the AMB them as lipids, they need to be atomized when heated to a high temperature of about 70°C or higher, and then add functional materials. Accordingly, a major problem is the incorporation into liposomes functional compounds which are oxidized at high temperatures or are thermally unstable, such as coenzyme Q10 and EGF. In addition, the thus obtained liposomes have disadvantages, which include very low stability and heterogeneity in size. In particular, in the liposome difficult to build together two functional compounds differing from each other in polarity, such as hydrophobic coenzyme Q10 and hydrophilic EGF.

Recently widely used fosfolipidkilde lipoid categories of anionic surface-active compounds obtained by reaction of lecithin with phosphoric acid or other polar compounds, and therefore have a high capacity for dispersion in aqueous solution. However, if lipoid is too hydrophilic, can increase the wettability, but the effect of skin permeability is significantly reduced due to the differences in polarity of ingredients on the skin surface. In addition, if lipoid belongs to the category of anionic salts, it decreases the viscosity of cosmetics, as a result requiring further add to the value of thickeners.

Originally coenzyme Q10 was known as coenzyme, contributing to the generation of energy by the cell of the human body, possessing strong antioxidant ability against active oxygen. Therefore, its absorption or applied to the skin can prevent the oxidation of cells, thereby maintaining skin elasticity and effectively preventing aging. In particular, in the human body like coenzyme Q10 is produced in sufficient quantities up to 20 years of age, however, this amount is reduced from the peak value before or after the age of 20 for various reasons, such as unbalanced diet, stress and the like. Before or after 40 years this decrease is accelerated, and therefore need to replenish its stocks.

Epidermal growth factor (EGF) is a protein that is present in colostrum breast milk and has an excellent effect on reproducibles cells, promoting healing of wounds, but because of EGF used as a biological medicinal product for the treatment of diabetic ulcers of the foot. In addition, EGF is known as an ingredient, having a function of delaying wound in a natural way without scar, and it is known that it has the effect of restoring the skin. Accordingly, it is widely used as raw material for preventing the Arat functional cosmetics, and also as a medicine for tightening wounds in the diabetic foot ulcer, burns, cuts or the like.

In patent publication laid Korea No. 10-2005-0058635 describe the extract ofCamellia japonicapossessing anti-inflammatory and antioxidant activities. In patent publication laid Korea No. 10-2006-0025423 describe the extract ofViscum album L. var. coloratumpossessing anti-inflammatory and antioxidant activities.

Description of the INVENTION

One of the purposes of the present invention is nanoliposomal, including liposomal membrane containing esterified lecithin, and one or more physiologically active ingredients, prisoners in the interior of the liposomal membrane. According to the present invention, if the bilayer lipid membrane is formed with the use of esterified lecithin, which is well dispersed in water or alcohol and has hydrophilicity and hydrophobicity, the solution nanoliposomes containing functional materials, such as coenzyme Q10 or epidermal growth factor, can be obtained at a low temperature, and thus obtained nanoliposomes have long-term stability and homogeneity, and therefore can be used as a raw material composition for the skin, with p voshodyi moisturizing and penetrating properties, such as cosmetic preparations, medicines for the treatment of skin diseases and the like.

Another objective of the present invention is a method of obtaining a stable nanoliposomes by dispersion to the nanometer size of the mixed solution of the esterified lecithin and physiologically active ingredient.

The authors of the present invention found that if the epidermal growth factor obtained in the form of nanoliposomes and is part of the drug together with natural extracts that have anti-inflammatory activity, increased stability and stimulates the penetration of EGF in the skin, making it possible to obtain a composition having excellent healing effect for skin diseases.

Consequently, another objective of the present invention is a composition for prevention or treatment of skin diseases containing nanoliposomes, which include epidermal growth factor, and one or more natural extracts that have anti-inflammatory activity.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 is a graph showing the absorption in the UV-visible region (%) solution nanoliposomes having a two-layer membrane with EGF/coenzyme Q10, which is obtained with the use of esterified lecithin truly izopet the tion.

Figure 2 is a graph showing the transmittance in the UV-visible region (%) solution nanoliposomes having a two-layer membrane with EGF/coenzyme Q10, which is obtained with the use of esterified lecithin of the present invention.

Figure 3 is a graph showing the particle size distribution of nanoliposomes having a two-layer membrane with EGF/coenzyme Q10, which is obtained with the use of esterified lecithin of the present invention.

The figure 4 illustrates therapeutic effect of the present composition containing nanoliposomes, when the composition is administered to a patient with cancer of the oral cavity and the patient with laryngeal cancer who have been diagnosed with dermatitis caused by radiation therapy.

DETAILED description of the INVENTION

One aspect of the present invention relates to nanoliposomes, including liposomal membrane containing esterified lecithin, and one or more physiologically active ingredients, prisoners in the interior of the liposomal membrane.

Another aspect of the present invention relates to a method of obtaining nanoliposomes, including: 1-St stage of obtaining the esterified lecithin by reaction of lecithin with an organic acid, 2-stage dissolution esterified lecithin and one or b is more physiologically active ingredients in a solvent, and 3-phase dispersion of the obtained solution to obtain liposomes nanometer size.

Another aspect of the present invention relates to compositions for the prevention or treatment of skin diseases containing nanoliposomes, including liposomal membrane containing esterified lecithin, and epidermal growth factor enclosed in the inner space of the liposomal membrane, and one or more natural extracts that have anti-inflammatory activity.

The present invention is explained below.

The term "inclusion (enclosed or enclosing)"used herein means the content (contained or contains) a water-soluble material (e.g., epidermal growth factor, ascorbic acid, and the like) in the hydrophilic space in the center of liposomes or absorption (absorbed or absorbing) a fat-soluble material (e.g., coenzyme Q10, retinol, retinilpalmitat, ascorbyl palmitate, and so on) bilayer lipid membrane of the liposomes.

The term "nanoliposomal", as used herein, means a liposome with a diameter of approximately 100 to 200 nm, typically obtained by dispersion of liposomes micron sizes under pressure of about 1000 pounds/square inch or more.

Truly invented the Yu membrane of liposomes contains esterified lecithin. The membrane of liposomes can optionally contain components of the liposomal membrane (i.e. lipids), which are usually used for obtaining liposomes. Lipids include phosphoglyceride or sphingolipids, such as phosphatidylcholine (lecithin), hydrogenated lecithin, phosphatidylethanolamine, phosphatidylinositol, ceramide, cerebrosides (i.e. galactosylceramide), sphingomyelin, gangliosides or the like. As esterified lecithin, lipoid may also have a moisturizing effect. From among the above lipids preferably can be used hydrogenated lecithin and/or ceramide. Hydrogenated lecithin means lecithin consisting of saturated hydrocarbons, obtained by the reduction of all unsaturated hydrocarbons in lecithin.

Esterified lecithin contained in the membrane of liposomes, well-dispersed in water or alcohol and has hydrophilicity and hydrophobicity. Accordingly esterified lecithin has a polarity sufficient for dispersion in an aqueous solvent, but not sufficient for complete dissolution in aqueous solvent. Thus, if the membrane of liposomes obtained with the use of esterified lecithin, stable solution of liposomes can be obtained even with such a low temperature as 20°C-60°C.

E. arificially lecithin can be obtained by reaction of lecithin or hydrogenated lecithin with an organic acid. The process of esterification is the reaction of condensation, in which the alcohol group of lecithin reacts with an organic acid, and the resulting molecule of water is removed therefrom. Thus obtained esterified lecithin in aqueous solution reacts with water and again dissociates on lecithin (alcohol group) and form organic acids. Consequently, when this reaction esterified lecithin, lecithin (or hydrogenated lecithin) and organic acid co-exist with the necessary balance between esterification and dissociation in accordance with the acidity in the following way:

RCOOR' (esterified lecithin) ⇔ RCOOH (organic acid) + R OH (lecithin or hydrogenated lecithin).

The organic acid used in the preparation of esterified lecithin, organic acids, traditionally used in cosmetic and food products, such as acetic acid, malic acid, lactic acid, glycolic acid, citric acid or oxalic acid, preferably anhydrous organic acid, and more preferably anhydrous malic acid or anhydrous acetic acid. When using anhydrous acetic acid, esterified lecithin shows somewhat greater hydrophilicity, the eat in the case of using anhydrous malic acid. As a result, the organic acid can choose accordingly depending on the relative amounts of hydrophilic or hydrophobic functional material to be added, or the degree of polarity of the functional material. When applied to the skin, these organic acids can also show the effect of removing the Horny substance or the effect of softening the skin.

Esterified lecithin can be used in quantities sufficient for the formation of liposomes, without special restrictions, preferably from 1 to 5 weight share, per 1 weight proportion of physiologically active ingredient.

Physiologically active ingredient enclosed in the inner space of the liposomal membrane of the present invention, can be represented as, but not limited to, water-soluble drug, a fat-soluble drug, thermally unstable functional material or the like. Preferably, the physiologically active ingredient is one or more than one selected from the group consisting of coenzyme Q10 and epidermal growth factor.

Nanoliposomal of the present invention may further comprise any one or more selected from the group consisting of organic compounds of ovarian cancer is and triglycerides, preferably Caprylic/capric triglyceride, anionic surface-active compounds, preferably of diethylaminoacetate, ascorbylpalmitate sodium, phosphatidylcholine or triethylenephosphoramide sodium, hydrogenated lecithin with saturated hydrocarbons, softening means, preferably butylated benzyl alcohol, amphiphilic surfactants betainovuyu number, preferably such as laurylamidopropyl, laurylether, laurylamine or cocamidopropylbetaine and chelating means, preferably sodium salts of ethylenediaminetetraacetic acid.

The present invention also relates to a method of obtaining nanoliposomes, including: 1-St stage of obtaining the esterified lecithin by reaction of lecithin with an organic acid, 2-stage dissolution esterified lecithin and one or more physiologically active ingredients in a solvent, and 3-stage dispersing the resulting solution to obtain liposomes nanometer size.

On the 1st stage esterified lecithin is produced by condensation reaction of lecithin with an organic acid. The organic acid preferably selected from the group consisting of acetic acid, malic acid, lactic acid, glycolic sour is s, citric acid or oxalic acid, and their anhydrides.

On the 2nd stage of the physiologically active ingredient is, but not limited to, water-soluble drug, a fat-soluble drug or thermally unstable functional material. More preferably, the physiologically active ingredient is one or more than one selected from the group consisting of coenzyme Q10 and epidermal growth factor. Also, if necessary, as a physiologically active ingredient can optionally be used antioxidants such as coenzyme Q10, retinol, retinal, retinilpalmitat, retinoic acid, ascorbic acid, ascorbyl phosphate or its salt, or ascorbyl palmitate.

If you use both hydrophobic ingredient, such as coenzyme Q10, and hydrophilic ingredient, such as EGF, 2nd stage preferably includes the following stages: obtaining a solution of an oil phase by dissolving the esterified lecithin and hydrophobic active ingredient, such as coenzyme Q10, in an organic solvent; obtaining a solution of the aqueous phase by dissolving a hydrophilic active ingredient, such as EGF, in an aqueous solvent; and mixing the oil phase solution and the aqueous solution phase.

On this to enter the stage of obtaining the solution of oil phase esterified lecithin and hydrophobic active ingredient, such as coenzyme Q10, is dissolved in an organic solvent, such as ethanol. Preferably, the organic solvent can optionally be added hydrogenated lecithin with saturated hydrocarbons, hydrophilic organic compound of a number of triglycerides, such as Caprylic/capric triglyceride, anionic surface-active compound, such as diethylaminoacetate, sodium ascorbyl phosphate, phosphatidylcholine or triethylammonium sodium, or emollient, such as equivalent.

In the above process of getting solution of the aqueous phase the aqueous solution phase is obtained by dissolving a hydrophilic active ingredient, such as EGF, clean water. Preferably, the solution of the aqueous phase can optionally be added anionic surface-active compound, such as diethylaminoacetate, sodium ascorbyl phosphate, phosphatidylcholine or triethylammonium sodium, or chelating agent, such as sodium salt of ethylenediaminetetraacetic acid.

The procedure of dissolving the esterified lecithin and physiologically active ingredient in the solvent is preferably carried out at a temperature from 20°C to 60°C. If the temperature is below 20°C, the dissolution can be carried out, but the dissolution will be long, and after races is the its can be stability problems. If the temperature is above 60°C, coenzyme Q10 and/or EGF or similar physiologically active ingredients can be unstable.

After received the above method, the solution of oil phase and water phase are mixed, the mixture is homogenized using a mixer-homogenizer. At this point liposomes in gomogenizirovannom liposomal solution have a particle size within the micron scale.

On the 3rd stage solution nanoliposomes receive, passing the homogenized solution of 2-th stage through microfluidizer (M/f) at a pressure equal to 1000 pounds/square inch or higher, one or more times to disperse different liposomes to nanometer size. At pressures below 1000 psi will be difficult to obtain liposomes of nanometer sizes. Preferably, the homogenized solution is passed through microfluidizer (M/f) two or more times.

Liposomes contained in the obtained by the above method the solution nanoliposomes form in an aqueous solution of double liposomes type of water phase/oil phase and thus can stabilize functional material that lies deep within the aqueous phase, such as EGF and incremental water-soluble antioxidant, and can further stabilize the hydrophilic active ingredients such as EGF, and hydrophobic the active ingredients, such as coenzyme Q10, at the same time.

These nanoliposomes with the use of esterified lecithin containing coenzyme Q10 and EGF, you can apply for traditional methods of composition for the skin, such as cosmetics, medicines for the treatment of skin diseases or the like.

The preferred quantity of raw materials used in the preparation of this composition is described in detail in the examples. In addition, the above additives can be substituted by other similar additives and quantity of these supplements can accordingly be adjusted in accordance with the number of functional material to optimize production conditions.

According to one variant of implementation of the present invention relates to compositions for the prevention or treatment of skin diseases containing nanoliposomes, including liposomal membrane containing esterified lecithin, and epidermal growth factor enclosed in the inner space of the liposomal membrane, and one or more natural extracts that have anti-inflammatory activity.

In this composition, use of epidermal growth factor in the form of inclusions in nanoliposomes which can be enhanced pharmaceutical stability-high volt the medicinal product and its penetration into the skin. In addition, the esterified lecithin used to produce liposomes, can provide additional moisturizing effect, which is advantageous for the treatment of skin diseases. The usual cause of skin diseases are injured due to burns, cuts or the like, or radiation therapy of the patient with cancer. Therefore, esterified lecithin, which provides a moisturizing effect in the field injured, you may have the best effect in the treatment of skin diseases. In addition, the esterified lecithin has the effect of softening the skin and stimulate skin permeability, thereby enhancing penetration of the skin epidermal growth factor and natural extract.

In addition, since the present composition contains nanoliposomes obtained so that in the liposomal membrane contains esterified lecithin, can be solved the conventional problems, and heating the dispersion of active ingredients at high temperature (70°C or above), low stability, uniformity, or the like.

The present composition of the epidermal growth factor can be used in a quantity sufficient to treat skin diseases, and effective for the treatment amount can vary depending on the condition of the patient, age, sex, individual senses the activity or the like. The content of epidermal growth factor in the present compositions can comprise from 1 to 50% by weight, calculated on the total weight of nanoliposomes.

In this composition nanoliposomal comprising EGF, may optionally contain an antioxidant. The antioxidant may include, but not limited to, coenzyme Q10, retinol, retinal, retinilpalmitat, retinoic acid, ascorbic acid, ascorbyl phosphate or its salt, or ascorbyl palmitate. Coenzyme Q10 plays the role of the coenzyme to stimulate the generation of energy by the cell in the human body and has powerful antioxidant ability against active oxygen, and because it is known that its ingestion or application to the skin effective to prevent oxidation of cells, thereby effectively maintaining skin elasticity and preventing skin aging. The amount of antioxidant in the present composition may be from 0.1 to 10% by weight, calculated on the total weight of nanoliposomes.

Natural extract that has anti-inflammatory activity includes, without limitation extract from natural sources raw materials known to contain anti-inflammatory ingredient. Natural extract that has anti-inflammatory activity, suitable for the present compositions may include an extract of one or more natural sources in the earth with the total amount such asCamellia japonica, Viscum album L. var. coloratum, Ulmi cortex, Lillium brownii F. E., Pimellia ternate Thunb Breit, Bletilla striata Reichb. fil., Paeonia lactiflora Pall, Boswellia carterii Birdw, Anemarrhena a rhizome, Aralia cortex, Rehmaniae radix, Dioscoreae Radix, Corni Fructus, Hoelen, Moutan Cortex Radicis, Schizandrae Fructus, Tuber Asparagi, Liriopsis Tuber, Bulbus Fritillariae, Armeniacae Semen, Pinelliae Tuber, Platicodi Radix, Scutellariae Radix, Coptidis Rhizomaor like them. Natural extract can be applied individually or in combination of two or more extracts. Preferably, a natural extract derived fromCamellia japonicaand/orViscum album L. var. coloratumand more preferably, the extract is obtained fromCamellia japonicaas disclosed in patent publication laid Korea No. 10-2005-0058635, orViscum album L. var. Coloratum,as disclosed in patent publication laid Korea No. 10-2006-0025423.

Natural extract can be used in varying amounts depending on the use of natural raw materials, extraction or the like. As a rule, the content of natural extract in the present compositions may comprise from 0.01 to 10% by weight, calculated on the total weight of the composition.

This composition for the prevention or treatment of skin diseases can be obtained by making the drug nanoliposomes obtained in the aforementioned manner so that they include liposomal membrane containing esterified lecithin, and epidermal growth factor enclosed in the inside of the it space liposomal membrane, together with natural extracts that have anti-inflammatory activity. The drug can be obtained dispersive and/or dissolving a natural extract that has anti-inflammatory activity in solution by nanoliposomes obtained above. The dispersion and/or dissolution is preferably carried out at room temperature.

If necessary, the present composition may further contain a stabilizing agent, such as amino acid, sodium bisulfite, sodium metabisulfite, sodium sulfite, disodium salt of ethylenediaminetetraacetic acid, bisulfite sodium, formaldehydeinduced sodium, thiourea, acetone sodium bisulfite, or the like; humectants, such as ceramide, glycerin, propylene glycol, ammonium alginate, cyclomethicone, Dimethicone, Polydextrose, sodium hyaluronate, sodium lactate, sorbitol, triacetyluridine, triethanolamine, xylitol, or the like; emulsifiers, such as simple alkilany ether of polyoxyethylene, polyoxyethylene derivative of castor oil, ester of fatty acid and sorbitan of polyoxyethylene, polyoxyethylene stearate or the like; or pharmaceutically acceptable additive, such as sodium benzoate, methylparahydroxybenzoate, metilparagidroksibenzoat, (ISO)propylparabens, (ISO)butylperoxybenzoate, sorbic acid is, potassium sorbate, sodium sorbate, dehydroacetic acid, dehydroacetic sodium, benzalconi chloride, basantani chloride, phenol, cresol, chlorocresol, benzyl alcohol or the like. The present composition may be prepared in the form of a medicinal product for external use, such as ointment, cream, lotion, and so forth.

Additionally, this composition may be in the form of various cosmetic products such as skin lotion, nourishing lotion, nourishing cream, massage cream, nourishing essence, mask, Foundation makeup, concealer, oil for body care, hair oil, shampoo, mouthwash, and so on.

The present invention will be explained more specifically by the following examples. However, it should be understood that the following examples are intended to illustrate the present invention and can not in any way limit the scope of the present invention.

EXAMPLES

Synthesis of esterified lecithin

Example 1

When heated to 200 g tertrahydrofuran ring of the solvent to a temperature of 70°C, was added 31 g of hydrogenated lecithin with saturated hydrocarbons and dissolved. After dissolution of lecithin to transparency to the mixture was added 3 g of anhydrous malic acid and dissolved. After the dissolution of anhydrous malic acid to which prozracnosti, there was added as catalyst, 0.5 g of triethylamine, and the reaction was conducted under reflux for more than 3 hours. Upon completion of the reaction the mixture was dried in vacuum at 45°C, receiving esterified lecithin in the form of white powder.

Example 2

Esterified lecithin was synthesized in the same manner as in example 1, except for using 2.5 g of anhydrous acetic acid instead of anhydrous malic acid.

Obtaining solution nanoliposomes

Example 3

1) preparation of the oil phase solution

15 g of esterified lecithin, 15 g of hydrogenated lecithin with saturated hydrocarbons, 200 g of Caprylic/capric triglycerides (MCT), 10 g diethylaminoacetate and 0.5 g of bottled hydroxytoluene (BHT) were added to 110 g of ethanol, and the mixture was heated to approximately 40°C, stirred and dissolved. Then the dissolved mixture was cooled to room temperature, obtaining a solution of the oil phase.

2) obtaining the solution of the aqueous phase

0.5 g Na-EDTA, 1 g ascorbylpalmitate sodium (NAP) and 2 g of EGF was dissolved with stirring in 650 g of water at room temperature, obtaining the solution of the aqueous phase.

3) Mixing the oil phase solution and the aqueous solution phase

The solution of the aqueous phase obtained in the above manner, was added to the obtained solution Maslenitsa, and the mixture was thoroughly which using a homogenizer for more than 5 minutes, getting a homogeneous mixture.

4) Receiving nanoliposomes

Solution nanoliposomes was obtained by passing the obtained homogeneous mixture through microfluidizer under pressure more than 1000 pounds/square inch or above one or more times to disperse different liposomes to nanometer size. Temperature conditions procedures bandwidth was reduced to values below room temperature by means of cooling water.

Example 3'

Solution nanoliposomes was obtained in the same manner as in example 3, except that used 2.4 g EGF.

Example 4

Solution nanoliposomes was obtained in the same manner as in example 3, except that used 30 g of esterified lecithin.

Example 5

Solution nanoliposomes was obtained in the same manner as in example 3, except that he used 10 g of laurelbethany (amphiphilic surface-active compound betainovuyu number) instead of diethylaminoacetate (anionic surface-active connection).

Example 6

Solution nanoliposomes was obtained in the same manner as in example 3, except that used 50 g of esterified lecithin and did not use any hydrogenated lecithin with saturated hydrocarbons or diethylaminosulfur is so

Example 7

1) preparation of the oil phase solution

15 g of esterified lecithin, 15 g of hydrogenated lecithin with saturated hydrocarbons, 200 g of Caprylic/capric triglycerides (MCT), 10 g diethylaminoacetate, 0.5 g of bottled hydroxytoluene (BHT) and 10 g of coenzyme Q10 was added to 110 g of ethanol, and the mixture was heated to approximately 40°C, stirred and dissolved. Then the dissolved mixture was cooled to room temperature, obtaining a solution of the oil phase.

2) Getting nanoliposomes

Solution the aqueous phase was obtained in the same manner as in example 3, thus obtained solution of the aqueous phase obtained was mixed with the above-described method, the oil phase solution, and the mixture was dispersively to nanometer size, to obtain a solution nanoliposomes.

Example 8

Solution nanoliposomes was obtained in the same manner as in example 7, except that used 30 g of esterified lecithin and did not use hydrogenated lecithin with saturated hydrocarbons.

Example 9

Solution nanoliposomes was obtained in the same manner as in example 7, except that he used 10 g of laurelbethany (amphiphilic surface-active compound betainovuyu number) instead of diethylaminoethylamine.

Example 10

Solution nanoliposomes received the same way is, as in example 7, except that used 50 g of esterified lecithin and did not use any hydrogenated lecithin with saturated hydrocarbons, neither diethylaminoacetate.

Example 11

1) 15 g of esterified lecithin, 15 g of hydrogenated lecithin with saturated hydrocarbons, 200 g of Caprylic/capric triglycerides (MCT), 0.5 g of bottled hydroxytoluene (BHT) and 10 g of coenzyme Q10 was added to 110 g of ethanol, and the mixture was heated to approximately 50°C, stirred and dissolved. Then the dissolved mixture was cooled to room temperature.

2) 2.4 g EGF was dissolved in 10 g of distilled water. Thus obtained solution was added to the solution obtained in the above step 1).

3) a Mixed solution obtained in the above step 2), was carefully which using a homogenizer for 10 minutes.

4) the Solution obtained in the above step 3)was passed through microfluidizer under pressure over 1000 pounds/square inch.

5) the Solution obtained in the above step 4)was added to 650 g of water containing 0.5 g Na-EDTA and 1 g of ascorbylpalmitate sodium with stirring in a homogenizer.

6) After adding the mixture was carefully which for more than 10 minutes.

7) the Solution obtained in the above step 6)was passed through microfluid the ATOR one or more times, to obtain the solution of two-layer nanoliposomes.

Example 12

Solution nanoliposomes was obtained in the same manner as in example 11, except that used 35 g esterified lecithin and did not use hydrogenated lecithin with saturated hydrocarbons.

Example 13

Solution nanoliposomes was obtained in the same manner as in example 11, except that used 50 g of esterified lecithin and did not use hydrogenated lecithin with saturated hydrocarbons.

Example 14

1) 1 g diethylaminoacetate, 200 g of Caprylic/capric triglycerides (MCT), 10 g of esterified lecithin, 0.5 g of bottled hydroxytoluene (BHT) and 10 g of coenzyme Q10 was added to 110 g of ethanol, and the mixture was intensively stirred and dissolved at room temperature to obtain a solution of the oil phase.

2) 2.3 g EGF was dissolved in 10 g of distilled water. Thus obtained solution was added to the solution obtained in the above step 1).

3) a Mixed solution obtained in the above step 2), was carefully which using a homogenizer for 10 minutes.

4) the Solution obtained in the above step 3)was passed through microfluidizer under pressure over 1000 pounds/square inch.

5) the Solution obtained in the above step 4), it is time to relax is whether to 650 g of water, containing 0.5 g Na-EDTA and 1 g of ascorbylpalmitate sodium with stirring in a homogenizer.

6) After adding the mixture was carefully which for more than 10 minutes.

7) the Solution obtained in the above step 6)was passed through microfluidizer one or more times to obtain the solution of two-layer nanoliposomes.

Example 15

Solution nanoliposomes was obtained in the same manner as in example 14, except that used 1 g ascorbylpalmitate sodium instead of diethylaminoethylamine.

Example 16

Solution nanoliposomes was obtained in the same manner as in example 14, except that used 1 g triethylenephosphoramide sodium (MIAMI CT130, anionic surface-active connection) instead of diethylaminoethylamine.

Example 17

Solution nanoliposomes was obtained in the same manner as in example 14, except that used 1 g of laurylamidopropyl (amphiphilic surface-active compound betainovuyu number) instead of diethylaminoethylamine.

Comparative example

Solution nanoliposomes was obtained in the same manner as in example 7, except that used 30 g of hydrogenated lecithin with saturated hydrocarbons and used the esterified lecithin.

Receiving the drug for external use

Example 18

5 ml Rast is ora-nanoliposomes, obtained in example 3 was added to 95 g of basic nutritional lotion containing extract ofCamellia japonicaobtained in accordance with example 2 of the patent publication laid Korea No. 10-2005-0058635. Then the mixture was stirred at room temperature for 20 minutes to obtain a composition for prevention or treatment of skin diseases.

Example 19

5 ml of solution nanoliposomes obtained in example 3 was added to 95 g of basic nutritional lotion containing extract ofViscum album L. var. coloratumobtained in accordance with example 1 drug from patent publication laid Korea No. 10-2006-0025423. Then the mixture was stirred at room temperature for 20 minutes to obtain a composition for prevention or treatment of skin diseases.

Test example 1

A stability test

For solutions nanoliposomes obtained in the above example 8 (using only the esterified lecithin), example 7 (using esterified lecithin and hydrogenated lecithin with saturated hydrocarbons) and comparative example (using only the hydrogenated lecithin with saturated hydrocarbons), compared the average particle size and gelation due to prolonged storage at room temperature. The results are presented in nigelle the existing table 1. In addition, conducted surveillance to confirm cases of the effect of Ostwald, which represents a growth mechanism of the particles by the deposition of substances on larger particles due to the difference in size between the particles in solution [Ostwald,Z Phys. Chem.(34), 1900, 495-5031].

If the solution of liposomes is stored for a long time, usually gelation due to coagulation. Therefore, we determined the time to gelation as the time after which generowanie the solution was no longer re-dispergirujutsja or re-dissolve, despite repeated stirring.

Table 1
The test results on stability
The sample solutionThe average size
particles in liposomes
Time to
gelation
Notes
Example 8470 nm25 daysGelation is evolving slowly
Example 7750 nm20 daysTogether with gelation partially develops the effect of Oswald
Comparative the Rymer 1300 nm15 daysGelation and effect Oswald occur simultaneously, and the liposomes are separated from the solution
*Temperature test: room temperature (20°C on average)

The absorption and transmittance of the solution at nanoliposomes in the UV-visible region

For solution nanoliposomes having a two-layer membrane with EGF (aqueous phase)/coenzyme Q10 (oil phase)obtained in the above example 8 using only the esterified lecithin of the present invention, was determined by the absorption and transmittance in the UV-visible region. The results are presented in figures 1 and 2.

As shown in figures 1 and 2, the visible light region from 400 nm to 700 nm does not significantly dissipated and is not absorbed, which means high transparency of the obtained solution nanoliposomes, and the fact that the size of the liposomes were standard.

Measuring the distribution of particle sizes

For solution nanoliposomes having a two-layer membrane obtained in the above example 8, measured the size distribution of particles. The results are presented in figure 3.

As shown in figure 3, the distribution nanoliposomes particles were in a narrow range, which means a high transparency of the obtained rest the RA nanoliposomes and the size of liposomes were standard.

Test example 2

To compare the stability of EGF, when it is enclosed in nanoliposomes and nanoliposomes dispersed in cosmetic preparations, phosphate buffer solution of 10 mm EGF at a pH of 7.4, the solution nanoliposomes with EGF of example 3 and the composition of the dispersion nanoliposomes with EGF of example 18 was kept in harsh conditions at 40°C and a relative humidity of 75% within three months and compared their relative stability. The residual amount was analyzed using ELISA method. The results are presented in the following table 2. As shown in table 2, the stability of EGF, solitary nanoliposomes, is greatly increased as compared to that in buffer solution, and the stability of EGF in the composition increases even more.

Table 2
The test results on the stability - comparison of stabilnosti EGF in phosphate buffer solution of 10 mm EGF at a pH of 7.4, nanoliposomes with EGF and in the composition of the dispersion nanoliposomes with EGF (n=3)
TimeThe content of EGF (%)
phosphate buffer solution with a pH of 7.4solution nanoliposomes with EGFcomposition containing nanoliposomes with EGF
2 weeks72,23 ± 2,395,42 ± 3,096,51 ± 1,0
4 weeks55,82 ± 5,588,57 ± 2,889,95 ± 7,2
8 weeks31,67 ± 4,767,04 ± 4,175,36 ± 2,2
12 weeks23,39 ± 1,251,08 ± 4,264,18 ± 1,6

Test example 3

The patient with oral cancer, which is 33 times received radiation therapy (59,4 Gy) and consequently had a serious inflammation of the skin after radiation therapy (left column in figure 4), the composition obtained in example 18, was carefully applied to the affected area 2 times a day for about 1.5 months (28.02.2006 ~ 17.04.2006). During the period of the introduction of this composition, the affected area was inspected daily. 5 days after the introduction of the inflammation in the affected area decreased significantly. After 10 days the skin color in the affected area began to change after about 1 month the affected area was covered almost normal skin (figure 4).

Two patients with laryngeal cancer who had seriously the second skin inflammation the composition obtained in example 18, was carefully applied to the affected area 2 times a day for approximately 1 month (29.03.2006 ~ 17.04.2006) and for about 1 week (11.04.2006 ~ 18.04.2006). During the period of introduction, the affected area was inspected daily. After about 1 month, and after about 1 week, respectively, the affected area was covered almost normal skin (figure 4).

INDUSTRIAL APPLICABILITY

Nanoliposomal of the present invention forms a liposomal membrane containing esterified lecithin, and could therefore conclude inside liposomes thermally unstable functional materials without risk at low temperature, and also to simultaneously capture and hydrophilic materials, hydrophobic materials. In addition, since the removal of keratinous substances as functional groups using anhydrous organic acid, it has the advantage of showing different functional effects, such as removal of keratinous substances or soften the skin.

In addition, the present composition for prevention or treatment of skin diseases contains epidermal growth factor, a prisoner in nanoliposomes, thereby exhibiting exceptional effect to stimulate skin permeability and good pharmaceutical stability. More t the th, used in the preparation of liposomes esterified lecithin can provide additional moisturizing effect, which is advantageous for the treatment of skin diseases. Typically, skin diseases occur because of wounds due to burns, cuts or the like, or radiation therapy of the patient with cancer. Thus, esterified lecithin, providing a moisturizing effect on the area injury, you may show a greater effect in the treatment of skin diseases. Next, esterified lecithin has the effect of softening the skin and stimulate skin permeability, thereby increasing the penetration into the skin epidermal growth factor and natural extract. In addition, since the present composition contains nanoliposomes obtained so that in the liposomal membrane contains esterified lecithin, can be solved the conventional problems associated with heating and dispersion of the active ingredients at high temperature (70°C or above), low stability, uniformity, or the like.

1. Nanoliposomes containing liposomal membrane containing esterified lecithin, and one or more physiologically active ingredients, prisoners in the interior of the liposomal membrane, where the esterified lecithin is a reaction product guide is organiziranog lecithin with saturated hydrocarbons and organic acids.

2. Nanoliposomal according to claim 1, where the physiologically active ingredient is one or more substances selected from the group consisting of coenzyme Q10 and epidermal growth factor.

3. Nanoliposomal according to claim 1, where the organic acid is selected from the group consisting of anhydrous acetic acid, anhydrous malic acid, anhydrous lactic acid, glycolic acid anhydrous, anhydrous citric acid or anhydrous oxalic acid.

4. Nanoliposomal according to claim 1, additionally containing one or more substances selected from the group consisting of hydrogenated lecithin with saturated hydrocarbons, anionic surface-active compounds, organic compounds of a number of triglycerides, a cushioning means, chelating means and amphiphilic surfactants betainovuyu series.

5. The method of obtaining nanoliposomes according to claim 1, including:
The 1st step of obtaining esterified lecithin, by the reaction of hydrogenated lecithin with saturated hydrocarbons with an organic acid,
2-stage dissolution esterified lecithin and one or more physiologically active ingredients in a solvent, and 3-stage dispersing the resulting solution to obtain liposomes nanometer size.

6. The method according to claim 5, where the physiologically active ing event represents one or more substances, selected from the group consisting of coenzyme Q10 and epidermal growth factor.

7. The method according to claim 6, where the 2nd stage involves the following stages:
a solution of the oil phase by dissolving the esterified lecithin and coenzyme Q10 in an organic solvent,
a solution of the aqueous phase by dissolving epidermal growth factor in aqueous solvent, and
mixing the oil phase solution and the aqueous solution phase.

8. The method according to claim 5, where the 2nd stage is carried out at a temperature of from 20 to 60°C.

9. Composition for prevention or treatment of skin diseases containing nanoliposomes according to claim 1, and epidermal growth factor enclosed in the inner space of the liposomal membrane, and one or more natural extracts that have anti-inflammatory activity, where the esterified lecithin is a reaction product of hydrogenated lecithin with saturated hydrocarbons and organic acids.

10. The composition according to claim 9, where nanoliposomal further includes one or more antioxidants selected from the group consisting of coenzyme Q10, retinol, retinal, retinilpalmitat, retinoic acid, ascorbic acid, ascorbylpalmitate or their salts, and ascorbyl palmitate.

11. The composition according to claim 9, where the natural extract is an extract of one or more natural the sources of raw materials, selected from the group consisting of Camellia japonica, Viscum album L. var. coloratum, Ulmi cortex, Lillium brownii F.E., Pimellia ternata Thunb Breit, Bletilla striata Reichb. fil, Paeonia lactiflora Pall, Boswellia carterii Birdw, Anemarrhena a rhizome, Aralia cortex, Rehmaniae radix, Dioscoreae Radix, Corni Fructus, Hoelen, Moutan Cortex Radicis, Schizandrae Fructus, Tuber Asparagi, Liriopsis Tuber, Bulbus Fritillariae, Armeniacae Semen, Pinelliae Tuber, Platicodi Radix, Scutellariae Radix and Coptidis Rhizoma.

12. The composition according to claim 9, where the natural extract is an extract of Camellia japonica or Viscum album L. var. coloratum.

13. The composition according to claim 9, where the liposomal membrane contains hydrogenated lecithin, ceramide or their mixture in addition to the esterified lecithin.

14. The composition according to claim 9, where the organic acid is acetic acid, malic acid, lactic acid, glycolic acid, citric acid, oxalic acid or their anhydrides.

15. Composition according to any one of PP-13, where nanoliposomal further comprises one or more selected from the group consisting of anionic surface-active compounds, organic compounds of a number of triglycerides, a cushioning means, chelating means and amphiphilic surfactants.



 

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