Nanoemulsion

FIELD: medicine.

SUBSTANCE: group of inventions refers to a nanoemulsion for active agent delivery, a method for preparing it, compositions containing it, and to using a nanoemulsion for preparing pharmaceutical compositions for local application and cosmetic compositions for skin application. The declared nanoemulstion contains a water ingredient and a carrier which contains a lipophilic ingredient in the amount of 0.1-15 wt %, a surfactant and isopropyl and/or 1-propyl alcohol. The average emulsified particle diameter makes less than 100 nm. The method for preparing the nanoemulsion involves mixing the water ingredient and carrier containing the lipophilic ingredient, surfactant and isopropyl and/or 1-propyl alcohol, for preparing the nanoemulsion at temperature 50-60°C. The invention also refers to the composition for photodynamic therapy containing the above nanoemulsion and the active agent representing 5-aminolevulinic acid, a derivative, a precursor and/or a metabolite thereof. The above composition is applied to prepare the drug substance for photodynamic therapy and to treat senile keratosis. What is also declared is a diagnostic composition for detecting the dividing cells which contains the nanoemulsion and 5-aminolevulinic acid. The invention also refers to a kit for photodynamic therapy which comprises the composition for photodynamic therapy and one ingredient specified in a photoresist coating, an agent for attaching the above coating or an agent for applying the composition.

EFFECT: invention provides better stability and intensified cell and tissue penetration of the nanoemulsion.

25 cl, 6 dwg, 9 tbl, 5 ex

 

The technical field to which the invention relates.

The present invention relates to a nano-emulsion containing at least one aqueous component and a carrier, where the carrier contains at least one lipophilic component, at least one surfactant and at least one alcohol. The present invention also relates to compositions containing the specified nanoemulsion and an active agent. In particular, the composition is presented in the form of a gel and the active agent is 5-aminolevulinic acid (ALA), its derivative, precursor and/or metabolite. Additionally, the invention relates to the production of specified nano-emulsion and/or composition and to its use for the treatment of skin diseases, viral diseases, and diseases associated with cell proliferation, namely, cancer and/or psoriasis. The present invention additionally relates to the use of specified nano-emulsion in cosmetic products.

Prior art

Nano-emulsion represent a colloidal system. Colloidal systems include micelles, liposomes, virosome, nanosuspension, micro-emulsions and polymer solutions. Nano-emulsion based on their physical and chemical characteristics, belong to the group of microemulsions. Micro-emulsions are aqueous dispersions consisting of gomag is the R, micro-size particles particles comprising a lipid core surrounded by Pavol and United with Pavam the monolayers. Nano-emulsion characterized by an average particle size (average diameter) of less than 200 nm, often less than 100 nm, and a narrow monodisperse distribution of particles sizes. Additionally, nano-emulsion transparent and a bit dull. Usually, they are made by mechanical fragmentation of the oil phase in the aqueous phase in the presence of PAVA. Very small oil particles can often be achieved through at least one passage through the high-pressure homogenizer or an ultrasonic device. To obtain nano-emulsion described here do not require the use of such devices with great effort shift. The small size of the globules and their high homogeneity give them properties, suitable for use in cosmetology, which distinguish them from traditional emulsions: they are transparent and show the new texture. Additionally, they can carry active agents more efficiently and, therefore, become extremely important in the field of medicine and pharmacy.

Microemulsions called nanodispersion known from the prior art and contain a) a membrane-forming molecule, e.g., soy lecithin, b) a co-emulsifier, (c) a lipophilic component, e.g., Caprylic and/or capric triglyceride Miglyol 812 or Myritol 318) and, optional, d) alcohol, in particular ethanol (EP 0956853). These nanodispersions are used in pharmaceutical formulations as a carrier for the pharmaceutically active agents.

However, the use of ethanol in nano-emulsions has some drawbacks.

First, the use of ethanol as co-PAVA leads to the formation of larger nanoparticles than with alcohols with longer carbon chains. Larger particles are the cause of reducing the area of intercellular contact between the skin and the nanoemulsion, leading to a reduction in the rate of penetration. Secondly, ethanol has a relatively low viscosity, equal 1,10 cf, which is not optimal for the stability of the microemulsions. Additionally, due to the relatively low hydrophobicity of ethanol, the penetration of nano-emulsions through lipophilic physiological membrane of the skin can slow down. As a result, the stability of nano-emulsions, as well as its bioavailability, i.e. the penetration in the tissue decreases. Additionally, ethanol is very expensive alcohol, compared with other types of alcohol, such as isopropyl alcohol. In addition, ethanol is subject to the imposition of a special tax on alcohol under certain conditions in some countries.

Thus, the aim of the present invention was to provide naeemul is s, which will overcome the disadvantages mentioned in the prior art, and which, in particular, exhibits optimal physical properties, which can improve the stability and penetration into cells and tissues, while at the same time being less expensive than the nanoemulsions of the current level of technology.

This goal is achieved according to the invention, by providing nano-emulsions containing (a) at least one aqueous component and b) a carrier, which contains (i) at least one lipophilic component, (ii) at least one surfactant; and (iii) at least one alcohol, where at least one alcohol has at least three carbon atoms.

The inventors now disclose that the nanoemulsion of the invention is optimally low average particle size with a narrow distribution of particle sizes. The reduction of particle size provides improved stability and better penetration into cells and tissues nanoemulsions.

The content of the component (i) of the carrier, i.e. lipophilic component, is preferably in quantities of from 0.1 mass% to 15 mass%, more preferably from 1 mass% to 8 mass%, and most preferably from 3% by mass to 4% by weight, based on the total weight of the nano-emulsion. The content of component ii) of the carrier, i.e. PAVA or surfactant preferably is a number is a number from 1 mass% to 30 mass%, more preferably from 2 mass% to 15 mass%, and most preferably from 4% by mass to 6% by weight, based on the total weight of the nano-emulsion. The content of component (iii) media, i.e. alcohol, is preferably from 0.1 mass% to 10 mass%, more preferably from 0.5 mass% to 5 mass%, and most preferably from 1% by mass to 2% by weight, based on the total weight of the nano-emulsion.

The aqueous component is preferably present in the nano-emulsion in an amount of 50 mass% to 98 mass%, more preferably from 70 mass% to 95 mass%, and most preferably from 88% by weight to 92% by weight, based on the total weight of the nano-emulsion. Mainly, this specific nano-emulsion composition provides a nanoemulsion, which is well tolerated by skin and does not cause stickiness when applied to the skin, which, among other things, is achieved due to the relatively low content of surfactants and lipophilic components.

In the preferred embodiment of the present invention, the nanoemulsion contains as PAVA membrane-forming surfactants and O/W - emulsio-forming co-surfactant. The mass ratio of the membrane-forming PAVA: O/W - emulsio-forming co-PAVA varies from 0.1:1 to 10:1, preferably from 0.2:1 to 0.8:1, more preferably from 0.4:1 to 0.6:1.

The preferred alcohol having at least atoma carbon in the scope of the present invention is an alcohol having 3 to 10 carbon atoms, preferably 3-7 carbon atoms, more preferably 3-5 carbon atoms and most preferably 3 carbon atoms. Particularly suitable alcohols having 5 carbon atoms are 1-pentanol and/or 4-methyl-2-pentanol. Suitable alcohols having 4 carbon atoms are 1-butyl alcohol, tert-butyl alcohol (2-methyl-2-propanol) and/or sec-butyl alcohol (2-butanol). Most preferred are alcohols having 3 carbon atoms, namely, 1-propyl alcohol and isopropyl alcohol, where isopropyl alcohol is preferred. When using C3-alcohol, in particular, isopropyl alcohol, in the inventive nano-emulsion, the present inventors have found that the nanoemulsion shows reduced particle size and a narrow distribution of particle size as well as increased stability and improved penetration into tissues, compared with nano-emulsions the current level of technology, using ethanol as the alcohol. This was unexpected as isopropanol and ethanol are very similar in their physical and chemical characteristics.

If the alcohol in inventive nanoemulsion used isopropanol, the size of the emulsified particles is less compared to the use of the ethanol. Due to the resulting increase of the contact surface of the nano-emulsions with the skin, the ability to increase penetration. The reduction of particle size is also crucial for the increased stability of nano-emulsions, since it is known that the level of agglutination of the particles, ultimately leading to phase separation increases with particle size. Preferred effects isopropanol may be due to its slightly higher hydrophobicity, which may lead to a better ability to penetrate the lipophilic physiological membranes. Additionally, isopropanol has a higher viscosity (CP at 25°C is 2,32) compared to ethanol (viscosity/Wed, 25°C, 1,10). Specified higher viscosity isopropanol can be used for better stabilization mechanism in nano-emulsions, as the viscosity decreases the mobility of the molecules. An additional advantage of isopropanol compared with ethanol is that it is available at relatively low cost, which is about 1/3 of the cost of ethanol, and are not subject to additional taxes on alcohol.

Preferably, at least one lipophilic component carrier inventive nano-emulsions is a fat, vegetable oil and/or butter. Suitable fats, according to Nast is ademu the invention, are physiologically suitable fats, such as ceramide, mono-, di - and triacylglycerol (triglycerides), in particular, Caprylic and/or capric triglyceride and/or a mixture of them, especially preferred Miglyol (such as Miglyol 812 or Myritol 318, available, e.g., from Henkel). Suitable vegetable and animal oils, e.g., are sunflower oil, soybean oil, peanut oil, rapeseed oil, fish oil and/or spermaceti.

Suitable membrane-forming Pavon is a phospholipid, lysophospholipid, ceramide and/or a mixture of them. Preferably, the phospholipid is lecithin or cephalin from soybeans or eggs, more preferably lecithin is a soy lecithin.

Preferably, the lecithin contains phosphatidylcholine share in the amount of at least 80% by weight, more preferably at least 90% by weight, and most preferably at least 94% by weight. The inventors have found that the quality of lecithin, namely its phosphatidylcholine content plays an important role for the particle size of the nano-emulsion. The more the content of phosphatidylcholine in lecithin, the smaller the particle size of the nano-emulsion.

As co-PAVA, forming an emulsion O/W (i.e. oil-in-water), are suitable anionic, nonionic, cationic and/or amphoteric PAVA, as well as block copolymers. Fit nionymi Awami are soap, alkylbenzene sulphonate the sulfonates, alkanesulfonyl, alkyl sulphates and/or sulfates Olkiluoto ether. Suitable cationic Awami are Quaternary ammonium compounds, preferably having one or two hydrophobic groups (e.g., cetyltrimethylammonium bromide, cetyltrimethylammonium chloride) and/or salts of primary amines with long-chain. Suitable amphoteric Pavam is N-(acylaminoalkyl)betaine, N-alkyl-β-aminopropionic and/or amine-N-oxide. Suitable block copolymer, for example, is propylene oxide. In the scope of the present invention, nonionic surfactants particularly preferably as a co-surfactant, forming an emulsion O/W Suitable nonionic surfactant is selected from the group consisting of polyglycolic ether fatty alcohol, alkylphenol ether, alkylpolyglucoside, glucamine fatty acids, polyglycolide of fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, a complex ester of fatty acids with polyglycerol, alkanolamide fatty acids and (ethoxycarbonyl) ether of sorbitol and fatty acids (sorbitan). Particularly preferred ethoxycarbonyl ether of sorbitol and fatty acids is monooleate sorbitan of polyoxyethylene preferred Polysorbate 80.

The water component of the nano-emulsion of the present invention preferably contains a weak buffer system with low the m salt, more preferably from 5 mm to 30 mm phosphate buffer, and most preferably 10 mm phosphate buffer. The pH of the phosphate buffer preferably ranges from pH 4 to pH 8, more preferably from pH 5 to pH 7, and most preferably from pH 5.5 to pH 6.5. Water used to prepare the phosphate buffer is preferably sterile deionized water and/or water for injection, more preferably water for injection.

The average diameter of emulsified particles in the nano-emulsion (nanosomes) ranges from 5 nm to 500 nm, preferably from 10 nm to 200 nm, more preferably less than 100 nm, especially up to 90 nm, preferably up to 70 nm, even more preferably from 10 nm to 50 nm and most preferably from 15 nm to 35 nm. The distribution of the nanoparticles size is preferably monodisperse and obeys Gaussian distribution. The diameter of the emulsified particles of the invention is determined by means for determining distributions of particle sizes, which are measured using the method of dynamic light scattering (DLS) (also called photon correlation spectroscopy (PCS)). Statistical analysis of the distribution of particles is carried out using a method called the weighted distribution of the particles, in accordance with the present invention.

An additional object of the present image is a shadow is a method for preparing nano-emulsion of the invention, contains the following stages: a) providing a water component, b) providing a carrier containing at least one lipophilic component, at least one surfactant and at least one alcohol, where at least one alcohol has at least three carbon atoms, and (c) mixing the aqueous component from stage a) with a carrier from stage b). In the preparation of nano-emulsion, media components are provided in the water component, and the mixture becomes a nanoemulsion with intensive or light homogenization. The homogenization can be carried out, for example, using commercially available homogenizers. After the preparation of the nano-emulsion, optionally can be entered additives and excipients, the presence of which is not advisable during homogenization.

The process of making nano-emulsion preferably is performed under aseptic conditions, e.g., using the BSC.

The inventors have found that, in addition to composition, some of the stages of the cooking process are important to the final size and distribution of particle size of the emulsified particles in the nano-emulsion. Namely, the temperature and conditions of homogenization during stage c) play a crucial role. Stage c) is carried out at a temperature between 50 and 60°C. All the ingredients are heated to this temperature. To the container and the mixer must also be optimized for very fast homogentisate mixture components (in seconds), avoiding foam formation. Cm. example 1 to illustrate this procedure. Alternatively, homogenization does not require the use of devices with great effort shift, such as ultrasonic devices, or high-pressure homogenizers.

An additional aspect of the present invention is a pharmaceutical and/or cosmetic composition comprising the inventive nanoemulsion. The inventive nanoemulsion suitable in the field of cosmetology, e.g., as an agent against skin aging, because it provides an elegant, translucent and transparent media that can be used for different kinds of products. Nanoemulsion provides the system with a very precise balance, which has a relatively low content of emulsifiers, which are believed to be irritants. The inventive nanoemulsion supports the desired transparency and light transmission, it is capable of providing a reasonable amount of additives, such as flavorings or moisturizers, while remaining stable, light and soft on the skin of the user, due to the low content of emulsifiers. For the intended use of the final product in the case of cosmetics, is it possible to add a non-therapeutic or inactive agents such as softeners, fragrances, is the like, fragrances, thickening agents, thickeners, sunscreen agents, and the like, which extend end-use product, especially for local cosmetic purposes, and particular attention is paid to the prevention of feature selection, which will hurt the purity of the product. The final product may take the form of milk, cream, lotion, gel, serum or liquid spray, among others. In the case of funds from the sun nanoemulsions of the invention can include one or more sunscreen agents such as benzophenone, avobenzone, cinnamates, salicylates and the like.

Nanoemulsions can also be used in pharmaceutical compositions, in particular, they can be used for local production of medicines for the treatment of dermatological diseases, such as not intermatic, psoriasis, keratosis, in particular, senile keratosis, and diseases associated with cell proliferation, such as cancer. Preferably, the cancer is selected from the group consisting of basal cell carcinoma, squamous cell cancer, disease Bowen, intraepithelial neoplasia of the vulva (VIN) or cancer of nodes and subcutaneous tissue. Additionally, the nanoemulsion is suitable for treatment of diseases associated with viral infection caused by the s the human papilloma virus, such as Genital warts. By incorporation of a lipophilic component nanoemulsions, transdermal water loss can have a predominant influence, i.e. the barrier function of the skin can be enhanced and, as a consequence, skin diseases such as dermatitis, can hit mostly.

An additional aspect of the present invention relates to compositions containing the inventive nanoemulsion and an active agent. This song in particular is suitable as pharmaceutical and/or cosmetic compositions, e.g., for application to the skin or hair. Nano-emulsion of the invention, in the above-mentioned compositions, provide a very efficient delivery system for a wide range of active agents. Examples of active agents that may be suitable include agents to eliminate age spots, keratoses and wrinkles, analgesics, anesthetics, anti-acne agents, antimicrobial agents, enterosgelya agents, antifungal agents, antiviral agents, agents dandruff agents against dermatitis, antipruritic agents, antiemetics, and agents against motion sickness, anti-inflammatory agents, agents against keratolysis, agents against skin dryness, antiperspirant agents against psoriasis, agents against seborrhea, hair conditioners and Agen the s treatment for hair loss, agents from aging agents, anti-wrinkle, Antiasthmatic agents and bronchodilators, agents from the sun, antihistamine agents, skin whitening agents, depigmenting agents, vitamins, corticosteroids, hormones, retinoids, such as retinoic acid and retinol, local cardiovascular agents, clotrimazole, ketoconazole, miconazole, griseofulvin, hydroxyzine, diphenhydramine, pramoxine, lidocaine, procaine, mepivacaine, monobenzone, erythromycin, tetracycline, clindamycin, kanamycin, meclocycline, hydroquinone, minocycline, naproxen, ibuprofen, theophylline, kromolin, albuterol, steroids for topical use, such as hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate and hydrocortisone 17-butyrate, betamethasone valerate, betamethasone dipropionate, triamcinolone acetonide, fluocinonide, clobetasol propionate, benzoyl peroxide, crotamiton, propranolol, promethazine, vitamin A palmitate, vitamin E acetate and mixtures of them.

In the preferred embodiment of the present invention the active agent is selected from the group consisting of 5-aminolevulinic acid, its derivative, precursor and/or metabolite. Under "derivative" should be understood in particular that has been subjected to the esterification of the amino group of 5-aminolevulinic acid, substituted by one or two alkyl GRU is the groups, particularly preferably the same metal group. The most preferred derivative is methylaminoethanol acid. Obtaining derivatives can also be understood as complexes of salts and additional compounds, and alkyl compounds. Under the "predecessor" and "metabolite" refers to a substance that is converted in the cell to protoporphyrin IX. The active agent 5-aminolevulinic acid or its derivative are particularly preferred.

5-Aminolevulinic acid is administered as a prodrug in the field of photodynamic therapy. Photodynamic therapy is a promising treatment for a variety of precancerous and cancerous diseases associated with cell proliferation (Taylor EL and Brown SB, 2002, Journal of Dermatological treatment, 13, Suppl. 1, S3-11 and Q. Peng et al., 1997, Cancer, 79, S2282 - 2308). The principle of photodynamic therapy is based on the introduction of so-called photosensitizing agent into the affected tissue and subsequent irradiation with radiation of an appropriate wavelength to convert the cytotoxic agent in the active agent, which, in turn, causes the destruction of cells. The selectivity of this method is due to increased content of the sensitizing agent in the rapidly-proliferating or diseased cells compared to normal t is the sand. In addition, the irradiation of the photosensitizer causes a characteristic fluorescent radiation, which can be used for diagnostic purposes, for example, to detect proliferating cells.

5-Aminolevulinate acid is an endogenous substance that is synthesized from glycine and succinyl-CoA in cells. In the scope of the biosynthesis of heme, protoporphyrin IX, which photoactive in a high degree, is formed from 5-aminolevulinic acid (5-ALA) and then turns into a gem. This control mechanism is disturbed by exogenous introduction of synthetically derived 5-aminolevulinic acid, thereby leading to increased production of photoprotein IX. Since the destruction of photoprotein IX additionally inhibited natural control mechanism, this compound accumulates in the cells. When exposed to light, photoprotein IX undergoes photochemical reactions of oxidation and as a result acts as a photosensitizer for photodynamic therapy.

Systemic application of 5-aminolevulinic acid associated with a number of side effects that can be avoided if the local application of drugs. A number of studies using topically applied compositions of 5-aminolevulinic acid known from the prior art. Although these studies have in common that 5-aminolevulic the new acid is used in the form of an emulsion of oil-in-water, differences exist with respect to other parameters such as the period of penetration, the period of treatment, the type of radiation and the dose of the applied radiation.

B.Thiele et al. (H+G, Vol.69, No.3, pp.161-164 (1994)) describe studies that include the use of 20% 5-aminolevulinic acid in the form of an emulsion oil-in-water, with a period of penetration from 5 to 6 h and further irradiation of the argon-ion laser dye (peak emission 630 nm), providing a total accumulated dose from 50 to 100 j/cm2.

Wolf et al. (Journal of the American Academy of Dermatology, Vol.28, pp.17-21, 1993) describes studies that include the use of 20% 5-aminolevulinic acid in the form of an emulsion oil-in-water, with a period of penetration from 4, 6 or 8 h, and exposure to unfiltered light or red light, providing a small dose of 30 j/cm2up to 100 j/cm2.

Although the research described in the prior art technique, clearly demonstrate the promising potential of photodynamic therapy using 5-aminolevulinic acid, a known emulsion oil-in-water still suffer from several disadvantages.

For example, M.Novo Rodriguez et al. (SPIE, Vol.2371, pp.204-209) showed that high concentrations required for clinical use, aminolevulinate acid is not stable in aqueous solutions at pH values from neutral to basic. During the 25-hour periodicidad, satisfactory results were obtained only for concentrations of 3% and at pH 5, which are specific conditions for aqueous solutions of 5-aminolevulinic acid. For clinical application, however, in General it will be necessary to provide the composition in a larger range of concentrations. In addition, for commercial purposes, a solution of 5-ALA should be resistant to the time that is measured in weeks and months.

V.von Arx et al. (J. Pharm. Pharmacol. 49: 652-656, 1997) described research related to local application of 5-aminolevulinic acid composition of different gels. In this publication it is stated, that the best structure for maintaining the stability of 5-aminolevulinic acid is a combination of Novion AA-1, polyacrylic acid, at pH<6.

Hurlimann et al. (Dermatology, Vol.197, No.3, 1998, pp.248-254) describes nanocolloids lotions containing 5-aminolevulinic acid, and their use in photodynamic therapy, without further definition of the emulsion.

WO 00/28971 describes a composition comprising a nanoemulsion and 5-aminolevulinate acid, where the nanoemulsion consists of egg lecithin (83% phosphatidylcholine), Miglyol 812 (triglyceride) and Polysorbate 80 in 20 mm phosphate buffer (see example 1 of WO 00/28971), but alcohol is not used as a solvent. Nanocolloids compositions containing egg lecithin in image quality is as emulsifier, nevertheless, suffer from the drawback, namely, they are much stronger painted than nanoemulsions of 5-aminolevulinic acid, soy lecithin as an emulsifier. The change of color in the composition correlates with the formation of the degradation product of an active agent 5-aminolevulinic acid. From this we must conclude that nanoemulsion compositions containing egg lecithin, include significantly reduced the stability of 5-aminolevulinic acid in comparison with compositions containing soy lecithin as an emulsifier.

Another disadvantage of the known emulsions oil-in-water with 5-aminolevulinic acid is the depth of penetration of the photosensitizer in the tissue is not optimal. As a result, diseased tissue susceptible to photodynamic therapy only in its upper layers, although the penetration depth of the radiation used to activate the photosensitizer, will also allow the processing of more deep-lying layers.

Thus, an additional aim of the present invention was to provide compositions containing 5-aminolevulinic acid, which, at least partially, overcome the known shortcomings of the current level of technology.

According to the present invention, this objective is achieved by providing a composition containing the image is matelskiy the nanoemulsion and 5-aminolevulinate acid, its derivative, precursor and/or metabolite as the active agent. In these compositions, the above preferred properties regarding stability, penetration and the cost of the inventive nano-emulsions can be used for delivery of 5-aminolevulinic acid to the object tissue sections.

Specific interaction was found between aminolevulinic acid and nanoparticles emulsion. Namely, 5-aminolevulinic acid, its derivative, precursor and/or a metabolite, is attached on the outer side of the monolayer of nanoparticles nano-emulsions. Thus, aminolevulinate acid is transferred particles is not contained in the core particles. More precisely, aminolevulinate acid is located outside the nucleus particles due to interactions between aminolevulinic acid and the external monolayer. In the traditional nano-emulsions, in contrast, the drug is contained within the lipid core of the particles of the nano-emulsions.

Surprisingly it was found that the stability of 5-aminolevulinic acid may rise significantly if 5-aminolevulinate acid is prepared from the inventive nanoemulsion containing at least one alcohol which has at least three carbon atoms. Although the reasons for this are not known but it is assumed that h is of the microenvironment created by nanosome, has a particularly appropriate action on the stability of 5-aminolevulinic acid.

Also found, unexpectedly, that the improved cell and tissue penetration can be achieved by using the nano-emulsion of the invention, penetrating to the deeper lesions and/or lesions with the thickness of the upper layers, are also becoming available for treatment. Large penetration depth was surprised, especially because before that it was considered, due to their small size, 5-aminolevulinate acid will in any case quickly penetrate the affected epidermis, which is present, for example, in tissues associated with inflammation and precancerous stages and tumors.

The third unexpected advantage was that when compiling with nanosome of the invention, 5-aminolevulinate acid is absorbed obviously very efficiently from cells. First of all it improves targeting; secondly, it means the period of penetration, i.e. the time between the application of the composition and exposure of the affected tissue with light, can be reduced, which means the apparent relief for the patient. As you can see from example 4, 5, 5-aminolevulinate acid is absorbed by the cultured cells, and conversion of aminolevulinic acid in PpIX in the cells increases with the increase of the concentrations developed in the agriculture nano-emulsion with a constant concentration of aminolevulinic acid.

Stability during storage, also, can rise through the application of nano-emulsion of the invention, which contains an alcohol having at least 3 carbon atoms as a solvent in the media.

According to the invention, the composition preferably contains an active agent which is selected from 5-aminolevulinic acid or its derivative, precursor and/or metabolite. Under "derivative" should be understood in particular that has been subjected to the esterification of the amino group of 5-aminolevulinic acid, substituted by one or two alkyl groups, particularly preferably a single metal band. Most preferred is 5-aminolevulinic acid or 5-methylaminoethanol acid. Obtaining derivatives can also be understood as complexes of salts and additional compounds, and alkyl compounds.

Under the "predecessor" and "metabolite" refers to a substance that is converted in the cell to protoporphyrin IX. The active agent 5-aminolevulinic acid or its derivative are particularly preferred.

The size of the emulsified particles in the nano-emulsion (nanosolar) presented above. The size of the particles, which, in each case, the optimal depends on additional parameters such as the viscosity of the composition. For example, a good re ulitity were obtained nanoemulsion, having a viscosity of from 1 to 10 mPas with an average particle diameter of less than 100 nm.

The amount of active agent, preferably 5-aminolevulinic acid in the composition mainly depends on the intended use. In the preferred embodiment, is about 1 to 30 wt.% active agent, based on the total weight of the composition. Higher and lower doses, however, are also suitable. It is proved that the number is preferably from 3 to 15 wt.% suitable for use in combination with photodynamic therapy.

The inventive composition preferably may further comprise at least one stabilizer and at least one solvent.

In a particularly preferred embodiment, the composition is made up in the form of a gel. The agents forming the gel, are forming the matrix agents, preferably xanthan gum. If the particle size of nano-emulsions in the form of a gel is preferably less than 100 nm, the viscosity will be much higher, e.g., 500-2000 mPas.

An additional aspect of the present invention consists in a pharmaceutical, cosmetic and/or diagnostic compositions containing the inventive composition. In this case, the composition may further comprise cosmetically and/or pharmaceutically suitable additives and/or excipients, in which W is STI, substance, usually used in cosmetics and pharmacy. Examples of such substances are buffers, stabilizers, additional emulsifiers, thickeners, etc. Additionally, the composition does not contain components that are pharmaceutically or diagnostically unusable, and preferably does not contain components that, for example, provoke radiation and/or distort the diagnosis. In addition to the media that mentioned, pharmaceutical and/or diagnostic drug may contain additional adjuvants and/or additives which are suitable and preferably well tolerated.

Preferably, the composition is presented in the form of liquid or semi-solid substances. Suitable fluid volume present invention are selected from the group consisting of solution, preferably drops, spray, aerosol, emulsion or lotion. Suitable semi-solid substances in the scope of the present invention are selected from the group consisting of ointments, creams (O/W emulsion), fatty cream (W/O emulsion, gel, lotion, foam, paste, and/or suspension.

For dermatological and gynecological applications, the preferred drug in a form that is suitable for topical application, in particular gel. The properties possessed by the drug, e.g., the viscosity and rheology, which is favorable DL the appropriate form of application, necessary to ensure that after drug application, nanosomes, loaded with 5-aminolevulinic acid, penetrate in sufficient volume to the target tissue. The specified properties of viscosity and rheology can be adjusted by adding thickeners such as esters of polyethylene glycol and stearyl alcohol, polyethylene glycol stearates and/or polysaccharides, such as polysaccharide B-1459, for example.

In a particularly preferred embodiment, the inventive composition is presented in the form of a gel. Gels are superior medical properties compared with the above compositions. The inventive gel composition shows improved adhesiveness, resistance, release of the active agent and the portability of the skin and mucous membranes. The inventive gel preferably contains from 0.01 mass% to 50 mass%, more preferably from 0.5 mass% to 30 mass%, and most preferably from 1% by mass to 20% by weight of active agent, from 1 mass% to 60 mass%, more preferably from 15 mass% to 50 mass%, most preferably from 10 mass% to 30 mass% nano-emulsion, from 0.01% by mass to 4% by weight, more preferably from 1 mass% to 3% by weight, of at least one filler, from 1 mass% to 3 mass% of at least one stabilizer based on the total weight of the compositions is AI, and the balance of supports, at least one solvent.

An additional aspect of the present invention consists in a method of preparation of the inventive composition comprising the following stages:

a) providing a water component,

b) providing a carrier containing at least one lipophilic component, at least one surfactant and at least one alcohol, where at least one alcohol has at least three carbon atoms,

c) mixing the aqueous component from stage a) with a carrier from stage b), for forming a nano-emulsion,

d) adding the active agent before and/or after the formation of the mentioned nano-emulsion from stage c), and

e) optionally adding additional additives and/or excipients in stage d).

Particularly preferably, the active agent in stage d) is added after the formation of the mentioned nano-emulsion from stage c).

The method preferably is carried out under aseptic conditions, e.g., when using the Cabinet. Water component carrier and an active agent used in the above method, have the same preferred and suitable values, as described above. Mixing water component with the carrier preferably is carried out with intensive homogenization. 5-aminolevulinate acid and NeoMaster is but the presence of additives and/or excipients may be added before and/or after homogenization, preferably after homogenization.

Preferably, the air is excluded when performing the method, for example, by applying a vacuum and/or protective gas atmosphere. In addition, it is preferable to carry out the method with the exception of light.

The method is carried out at a temperature, which may be formed in the desired nanoemulsion, as mentioned above, and, until the last stages, components, in particular, the active substance, are fairly stable. In General, it was found that the temperature range of from about 5 to 30°C is suitable. However, processing additives and/or excipients, in which, for example, are first mixed and homogenized, if necessary, in a separate mixtures, and only after that add to the composition, can also be carried out at higher temperatures, up to about 70°C. Particularly for pharmaceutical applications, you must be sure that the final product is sterile, e.g., by application of sterile source materials and maintaining sterile conditions and/or by sterilizing stage after cooking.

In the field of cosmetology, the inventive composition is preferably used as an agent on aging, e.g., to eliminate age spots, wrinkles and/or against dry skin.

The importance of the second field of application of the compositions of the invention lies in the field of photodynamic therapy, special preference should be given to local application of nanoemulsions. The nanoemulsion of the invention can be used in the case of all diseases, the control of which includes the inhibition of proliferation or destruction of cells or tissues by photoactivation of the photosensitizer, which is formed from 5-aminolevulinic acid. Diseases, in particular, include diseases associated with viral infection, viruses, preferably selected from the group of human papilloma virus (HPV). Most preferably, the disease associated with viral infection is genital warts. Genital warts are defined as benign epithelioma viral origin, which is almost always located genitale, the pathogen which is the human papilloma virus (HPV) types 6, 11, and 42. In the course of the disease, papules size of a pinhead into a papillary proliferation of the type of cauliflower and the cock's comb.

The composition of the invention is also suitable for the treatment of dermatological diseases, such as diseases associated with keratosis, senile keratosis particularly preferable. Senile keratosis is a squamous cell carcinoma of the epidermis in situ. Senile keratosis is a proliferation of transformed the s keratinocytes, which are limited to the epidermis. Senile keratosis develops predominance with prolonged exposure to ultraviolet light, especially the sun (also called solar keratosis). Senile keratosis is detected independently in the form of a coarse removable spots, papules or ulcers with a diameter from 1 mm to about 2 cm

Additionally, the inventive composition is preferably intended for the treatment of diseases associated with increased cell proliferation, since, in this case, the photosensitizer is concentrated especially in greater extent in increased cellular metabolism in infected cells

Thus, compositions of the invention suitable for the treatment of cancers, such as basal cell adenoma, squamous cell carcinoma, disease Bowen, intraepithelial neoplasia of the vulva (VIN) and/or cancer disease sites and/or skin. Psoriasis is an example of non-oncological diseases associated with increased cell proliferation.

Compositions of the invention particularly preferred for the treatment of basal cell adenoma. Basal cell adenoma is characterized as epithelial tumor that grows locally invasive and destructive, however, spreads very rare and, therefore, is poluslona the natural enemy. It is mainly located (80%) in the head and neck region, especially in the forehead, kantusa and nose. In case of unfavorable development, followed by destruction of the tissue and even death, e.g., due to bone and vascular erosion and bleeding associated with it, and also due to CNS invasion. Basal cell adenoma comes from the transformed cells of the germinal layer (basal cell layer) of the epidermis and/or the outer root sheaths of hair follicles. Unlike healthy basal cells, which lose their ability to divide when passing through the epidermis, disintegrate and transform the stratum corneum, basal cell carcinoma cells retain the ability to divide and not able to form the stratum corneum of the skin.

The invention additionally relates to the use of nano-emulsion of the invention for the preparation of drugs in photodynamic therapy.

Thus, the treatment of the above diseases is, for example, by local application of nano-emulsions containing the active agent, e.g., 5-aminolevulinate acid, and subsequent storage in order to enable a sufficient amount of 5-aminolevulinic acid to penetrate into the fabric, which is then subjected to treatment. During curing, it is preferable to avoid the effects of light on the workpiece about the region, for example, by covering it, in order to prevent any unwanted premature activation. After a period of aging, which is usually from about 1 to 8 hours, and typically about 4 h, the tissue is exposed to a sufficient dose of radiation using a light source. Suitable light sources include lamps emitting white light and monochromatic light sources. Radiation doses are typically in the range from about 20 j/cm2up to several 100 j/cm2to use.

Another area of application of the gel with 5-aminolevulinic acid of the invention relates to the detection of proliferative cells in the sample, e.g. a tissue sample. The detection is based on the selective accumulation of a photosensitizer, which is produced by the metabolism of the active agent, in proliferating cells compared with normal cells. Preferably, the active agent is a 5-aminolevulinate acid and photosensitizer - fetoprotein IX. The amount of the photosensitizer accumulates, can be defined photodiagnostic ways, for example, by applying light radiation having a wavelength of 405 nm, and the measurement of fluorescent radiation generated by the photosensitizer. Nanoemulsions of the invention in pH and suitable for use in the diagnosis of tumors.

Additionally, the invention relates to a kit, which contains a composition of the invention, which contains the inventive nanoemulsion and 5-aminolevulinic acid, its derivative, precursor and/or a metabolite, which is suitable for application topically, and one or more auxiliary substances. Examples of these auxiliary substances are the main photoresistant material to cover, such as a polymer film, which is applied to the plot, which is processed after the application of nano-emulsions in a specified area to prevent premature activation of the radiation, and means for attaching material to cover, or other means for the application of nano-emulsions in the area that is being treated.

Additionally, the invention relates to a method for the treatment of diseases associated with viral infection, dermatological diseases and/or diseases associated with cell proliferation, containing the application pharmaceutically effective amount of the inventive composition to a subject in need of it. Preferably, the subject is a mammal, more preferably human.

An additional aspect of the present invention relates to compositions containing an active agent selected from the group consisting of 5-amino is evelyneva acid, its derivative, precursor and/or metabolite, and nano-emulsion, where the nanoemulsion contains alcohol.

Preferably, the composition and, in particular, the nanoemulsion additionally contain at least one aqueous component, preferably water, and at least one lipophilic component and/or at least one surfactant.

Apply 5-aminolevulinic acid, its derivative, precursor and/or a metabolite, which is suitable for topical application. Under "derivative" should be understood in particular that has been subjected to the esterification of the amino group of 5-aminolevulinic acid, substituted by one or two alkyl groups, particularly preferably a single metal band. Most preferred is 5-aminolevulinic acid or 5-methylaminoethanol acid. Obtaining derivatives can also be understood as complexes of salts and additional compounds, and alkyl compounds. Under the "predecessor" and "metabolite" refers to a substance that is converted in the cell to protoporphyrin IX. The active agent 5-aminolevulinic acid or its derivative are particularly preferred.

As the alcohol, it is preferable to C2-C8alcohol, in particular, C3-C8alcohol and isopropanolamine and/or 1-impregnated the new alcohol is more preferred for the reasons above.

Preferably, aminolevulinic acid, its derivative, precursor and/or metabolite attached to the outer monolayer of the particles of the nano-emulsion. Aminolevulinate acid, therefore, is located outside of the nucleus particles, which is caused by the interaction of aminolevulinic acid and outer part of the monolayer.

Preferably, at least one lipophilic component is a Miglyol, at least one surfactant is a phospholipid, preferably soy lecithin and/or surfactant type polyoxyethylene, preferably Polysorbate 80.

An additional aspect of the invention relates to pharmaceutical and/or diagnostic composition comprising the above composition.

An additional aspect of the present invention relates to the application specified nanoemulsions in pharmaceutical compositions, in particular for the preparation of drugs for the treatment of skin diseases such as psoriasis, keratosis, and in particular, senile keratosis. Additionally, the composition is suitable for diseases associated with cell proliferation, such as cancer, e.g., basal cell carcinoma, squamous cell carcinoma, Bowen's disease, intraepithelial neoplasia of the vulva (VIN) and/or node and/or skin cancer disease is selected. Additionally, the composition is suitable for treatment of diseases associated with viral infection, such as genital warts.

Another aspect of the invention relates to a composition comprising a nanoemulsion and an active agent, where the active agent is attached to the outer side of the monolayer of particles of nano-emulsions. It is particularly suitable for improving the chemical properties (e.g., sustainability and pharmaceutical properties (e.g., the depth of penetration into the skin and the biological availability of the active agent.

Preferably, the nanoemulsion and/or active agent are defined as compositions described above (see page 9 for details).

An additional aspect relates to pharmaceutical and/or cosmetic compositions containing a composition in which the active agent is attached to the outer side of the monolayer of particles of nano-emulsions.

Covered by the present invention is also the use of a composition comprising a nanoemulsion and an active agent in which the active agent is attached to the outer side of the monolayer of particles of nano-emulsions, for preparing a medicinal product for the treatment associated with viral infection, dermatological associated with cellular proliferation diseases and/or photodynamic therapy. Preferred embodiments of these diseases and photo dynamic therapy I have are those above.

The figures and the following examples are intended to further illustrate the invention.

Figure 1 shows the distribution of particle sizes exemplary party Nanoemulsions BF-200, measured by photon-correlation spectroscopy.

Figure 2 shows an electron micrograph of cristaliana Nanoemulsions BF-200. (A) an increase in 1200000 times, (B) increase of 250,000 times.

Figure 3 shows an electron micrograph of negative staining Nanoemulsions BF-200. (A) an increase in 1200000 times, (B) increase of 250,000 times.

Figure 4 shows UV-induced PpIX fluorescence measured in Hela cells, incubated for three hours with ALA and various concentrations of BF-200. Fluorescence was measured two hours after laundering from the environment.

Figure 5 shows an electron micrograph of cristaliana gel with aminolevulinic acid with increasing 50,000 times.

6 shows an electron micrograph of cristaliana gel with aminolevulinic acid. (A) an increase of 250,000 times, (B) increase in 1200000 times.

Information confirming the possibility of carrying out the invention

Example 1. Preparation of nano-emulsion BF200

Quantitative and qualitative composition of the nano-emulsion BF200 presented in the table below.

Table 1
The composition contained in the nano-emulsion BF200
Ingredient% (weight/weight)FunctionQuality
Soy lecithin1,73PAV>94% Phosphatidylcholine, for pharmaceutical applications, USP
Polysorbate 80 (monooleate sorbitan of polyoxyethylene)3,40Co-surfactantsHeb. Pharmacop.
Caprylic/capric triglycerides3,45The lipid coreHeb. Pharmacop.
Isopropyl alcohol1,42SolventHeb. Pharmacop.
10 mm Phosphate buffer, pH 6ad 100,00SolventWater for injection: Heb. Pharmacop.
Disodium phosphate and sodium phosphate: Heb. Pharmacop.

The method of preparation of the emulsion BF200 consists of the following stages:

Stage 1: P is the production of 10 mm phosphate buffer, pH 6 (water component).

Stage 2: Preparation of a carrier containing a lipophilic component, a surfactant, and

the alcohol.

Stage 3: Production of nano-emulsion by mixing the water component of the Stage 1 and the media from Stage 2.

Stage 4: Sterilization by filtration and filling the nano-emulsion BF200 in sterile glass vessels in hoods.

Description of methods of making a typical lot sizes:

Stage 1: Prepare a 10 mm phosphate buffer (1000 g), pH 6, and phosphate buffer was sterilized by filtering through 0.2 μm sterile filter.

Stage 2: Preparation of a carrier containing a lipophilic component, a surfactant, and alcohol.

Table 2
Media
IngredientsWeight (g)
Soy lecithin17,30
Polysorbate 8034,00
Caprylic, capric triglyceride34,50
Isopropyl alcohol14,20

Soy lecithin (17,30 g) was weighed in a suitable vessel, was added isopropyl alcohol (14,20 g) and sasunarusasu avoid evaporation of the alcohol. Soy lecithin was dissolved with continuous stirring with a suitable stirrer at room temperature. Weighed Caprylic/capric triglyceride (34,50 g) and Polysorbate 80 (34,00 g) was added to a solution of soy lecithin. The mixture is stirred with a suitable stirrer at room temperature to obtain a homogeneous transparent solution. The solution was concentrate, containing all of the emulsifiers and lipid components Nanoemulsions BF200.

Stage 3: Production of emulsion by mixing 900 g of phosphate buffer (from Stage 1) and 100 g of the carrier (from Stage 2).

First, the water component containing phosphate buffer, heated to approximately 55°C in a suitable vessel. Then, the media (concentrate) from stage 2 was heated to approximately 55°C. subsequently, the medium was poured into phosphate buffer with continuous stirring using a propeller stirrer (700 rpm). The resulting nanoemulsion was mixed for 15 minutes the Temperature was maintained at approximately 55°C throughout the procedure. In the end, the nanoemulsion was cooled to room temperature in a water bath.

Stage 4: the Nanoemulsion were sterilized by filtering through 0.2 μm sterile filter and filled into 100 ml sterile glass jars in a laminar flow Cabinet.

Example 2. Preparation of gels with 1%, 3% and 10% aminolevulinic acid and the ground is Bo

Qualitative and quantitative composition in a gel containing placebo, 1%, 3% or 10% aminolevulinic acid presented in the table below.

Table 3
The composition of the gel containing placebo
IngredientNumber per gram gelFunctionQuality
Xanthan gum20,375 mgFillerHeb. Pharmacop.
Nanoemulsion BF200175,0 mgMediaThe domestic.
Propylene glycol9.0 mgStabilizerHeb. Pharmacop.
Methyl parahydroxybenzoate0.7 mgStabilizerHeb. Pharmacop.
Sodium propyl parahydroxybenzoate0.3 mgStabilizerHeb. Farmak is p.
Water for injections794,625 mgSolventHeb. Pharmacop.

Table 4
The composition is in a gel containing 1% aminolevulinic acid
IngredientNumber per gram gelFunctionQuality
Aminolevulinic acid hydrochloride10.0 mgDrug substanceInt.
Xanthan gum20,125 mgFillerHeb. Pharmacop.
Nanoemulsion BF200175,0 mgMediaInt.
Propylene glycol9.0 mgStabilizerHeb. Pharmacop.
Methyl parahydroxybenzoate0.7 mg StabilizerHeb. Pharmacop.
Propilparagidroksibenzoat0.3 mgStabilizerHeb. Pharmacop.
Water for injections784,875 mgSolventHeb. Pharmacop.

Table 5
The composition is in a gel containing 3% aminolevulinic acid
IngredientNumber per gram gelFunctionQuality
Aminolevulinic acid hydrochloride30.0 mgDrug substanceInt.
Xanthan gum19,625 mgFillerHeb. Pharmacop.
Nanoemulsion BF200175,0 mgMediaInt.
Impregnated Anglican 9.0 mgStabilizerHeb. Pharmacop.
Methyl parahydroxybenzoate0.7 mgStabilizerHeb. Pharmacop.
Sodium propyl parahydroxybenzoate0.3 mgStabilizerHeb. Pharmacop.
Water for injections765,375 mgSolventHeb. Pharmacop.

Table 6
The composition is in a gel containing 10% aminolevulinic acid
IngredientNumber per gram gelFunctionQuality
Aminolevulinic acid hydrochloride100.0 mgDrug substanceInt.
Xanthan gum17,875 mgFiller Heb. Pharmacop.
Nanoemulsion BF200175,0 mgMediaInt.
Propylene glycol9.0 mgStabilizerHeb. Pharmacop.
Methyl parahydroxybenzoate0.7 mgStabilizerHeb. Pharmacop.
Sodium propyl parahydroxybenzoate0.3 mgStabilizerHeb. Pharmacop.
Water for injections697,125 mgSolventHeb. Pharmacop.

A method of manufacturing a gel containing placebo or aminolevulinate acid, consists of the following stages:

- Stage 1: Making a gel base by adding xanthan resin to water for injection, mixing and steam sterilization

- Stage 2: Preparation of concentrated solution of the stabilizers of methylparahydroxybenzoate, propilparagidroksibenzoat in propylene glycol

- Phase 3, placebo: Cooking and ogopogo gel composition by adding a concentrated solution of the stabilizers to the gel base, adding nano-emulsions BF200 to the base gel and the homogenization of the gel.

- Stage 3, for gels containing aminolevulinic acid: Preparation of the final gel composition by adding a concentrated solution of the stabilizers to the gel base. Preparation of a solution of the hydrochloride aminolevulinic acid in Nanoemulsions BF200. The addition of a solution of the hydrochloride aminolevulinic acid in Nanoemulsions BF200 to the base gel and the homogenization of the gel.

Description of manufacturing process:

Stage 1: Preparation of a gel base with xanthan resin

A. the Bowl Stephen disinfected with isopropanol 70%. Water for injection (97,50 units) were placed in the bowl and then distributed it xanthan gum (2.5 units). The mixture was dispersively under vacuum at a pressure of approximately 100 mbar per minute at 600 rpm for 90 minutes. The main result of the gel was filled in a 200 ml flask from Schott, which prior application was rinsed with water for injection (filled 1/3, not more). The main gel flasks were then sterilized under steam in an autoclave for 20 minutes at 121°C.

Stage 2: Preparation Parabeni conc.

Methylparahydroxybenzoate acid (7.0 parts), and

propyltriethoxysilane acid (3,0 parts) was weighed in a suitable vessel. Was added propylene glycol (90 parts) and parahydroxybenzoate was dissolved in propylene is licola. The mixture was heated on a heating plate with stirring using a magnetic stirrer to dissolve the mixture (70°C) to obtain a transparent solution.

Stage 3, part 1: Preparation of gel containing placebo

Table 7
Preparation of gel with placebo from the main gel and Parabeni conc.
ComponentsUnits
AndThe base gel81,50
InNanoemulsion BF20017,50
DParabeni conc. FH1,0
Total100,0

All following steps were carried out in a laminar flow of air under aseptic conditions. 1 unit parabeni conc. (D) and 81.5 core units of gel (A) was added to a suitable vessel. of 17.5 units of nano-emulsion (C) was filtered through 0.2 μm sterile filter and added to the base gel. The mixture was stirred for 10 minutes In the future, 2 units of each gel was filled in Lamy the new aluminum tube.

Stage 3, part 2: Preparation of the gel with 1% aminolevulinic acid

Table 8
Preparation of the gel with 1% aminolevulinic acid
ComponentsUnits
AThe base gel80,50
BNanoemulsion BF20017,50
C5 ALA (hydrochloride aminolevulinic acid)1,00
DParabeni conc. FH1,0
Total100,0

All following steps were carried out in a laminar flow of air under aseptic conditions. 1 unit parabeni conc. (D) and 80.5 core units of gel (A) was added to a suitable vessel. 1 unit ALA (C) was dissolved in 17.5 units of nano-emulsion (B) by mild stirring to obtain a solution. This solution was filtered through a 0.2 μm sterile filter and added to the base gel. The mixture is PE is amasyali for 10 min to obtain a homogeneous gel. Further, 2 g of each gel was filled in laminated aluminum tube.

Stage 3, part 3: Preparation of gel with 3% and 10% aminolevulinic acid

3% and 10% gel was obtained in the same manner described for a 1% gel, using only 78,50 core units of gel and 3 units of ALA or 71,50 core units of gel and 10 units of ALA, respectively.

Example 3. The particle size of nano-emulsion BF-200

The average particle size of the fabricated nano-emulsion, which is defined Photon-Correlation Spectroscopy, PCS (also called dynamic scattering of laser radiation, DLS), is less than 100 nm. Moreover, the nanoemulsion has a very narrow distribution of particle size (see figure 1 below).

The nanoemulsion is stable in a wide temperature range, but can be destroyed by freezing and autoclaving. Nano-emulsion is relatively insensitive to changes in pH and ionic strength, and due to their small size they can be sterilized by filtration through 0.2 μm filter. Nano-emulsion have the opportunity to improve the delivery of active substances into the skin, thus increasing the effectiveness of drugs used topically.

Nanoemulsion BF-200 is prepared using low-energy devices; i.e., the preparation of nano-emulsions does not require devices with large us what Lee shift, such as ultrasound or high-pressure homogenizers.

The study of nanoparticles in nano-emulsions BF-200 was carried out using photon-correlation spectroscopy and two methods of electron microscopy: cristaliana EAT and negative staining.

Photon-correlation spectroscopy confirmed that the BF-200 results in nano-emulsions with a very constant and reliable particle size and narrow particle distribution. These characteristics are stable for a long period of time and at different temperatures (see table 9 below).

Table 9
The results of the study of the stability of nano-emulsion BF-200
Time MonthStorage conditionspHViscosity 20°CThe average size of the nanoparticlesThe distribution of particles sizes
Definitionweak
matte liquid
5,5-6,5information. MPa·s <100 nm90%<200 nm
resultSTD. rejected.
0-> Matt6,2n.t.1590%<21 nmthe 4.7
125°C/60% ov> Matt6,2n.t.1690%<22 nm4,6
40°C/75% ov> Matt6,2n.t.1590%<22 nmthe 5.7
25°C> Matt6,211290%<17 nm4,2
25°C/60% ov> Matt6,21 1590%<21 nmthe 4.7
35°C> Matt6,261490%<20 nmthe 4.7
25°C/60% ov> Matt6,111490%<20 nm4,8
65°C> Matt6,361790%<23 nm5,0
258°C/60% ov> Matt6,361490%<20 nm5,2
125°C> Matt6,22990%<12 nm -
25°C/60% ov> Matt6,121190%<15 nm-
185°C> Matt6,2101390%<18 nm-
25°C/60% ov> Matt6,081190%<15 nm-

So, all the results are presented with the regulatory limits observed during 12 months of storage under different storage conditions.

Electron micrograph of cristaliana nano-emulsion BF-200 with the increase in 1200000 times and 250,000 times are shown in figure 2 below. The most notable features in the micrographs presented a large number of very small spherical vesicles with a diameter of 15 to 50 nm. These values correlate well with the values that are measured using photon correlation spectroscopy (see table 9 above). Vesicles are most likely one is layer, since the thickness of the membrane vesicles is 3-4 nm. This corresponds to the length of the molecule of phosphatidylcholine, which is the main component of lecithin, PAVA in nano-emulsion. Liposomes and other bikinie vesicles have a thickness of about 7 nm.

The structure of the vesicles may well be Obozrevatel on electron micrographs, obtained by negative staining. Nanoparticles in the nano-emulsion BF-200 represent a sphere about a diameter of 20 nm, from about 3 to 4 nm thick hollow and filled with amorphous material (see figure 3 below). Empty particles could not be found.

The study of nanoparticles in the gel containing aminolevulinic acid, was carried out using electron microscopy, using methods cristaliana and negative staining.

Electron micrograph of cristaliana gel with aminolevulinic acid confirmed that the nanoparticles present in the gel, have a size similar to those found in pure nano-emulsion BF-200. The micrograph shows a single particle, and conglomerates (figure 5). The morphology and size of nanoparticles in the gel does not affect storage conditions. Research of BF-200 ALA (10% gel after 4 months storage at 25°C (60% O.V.) using electron microscopy of cristaliana revealed particles with the same size and shape to those found svegesrublennom gel. The study of the stability of the party of BF-200 ALA gel (10% aminolevulinate acid) and placebo for BF-200 ALA gel used in phase III clinical studies in parallel with the clinical study will include the study of particle size using electron microscopy at a later time point.

6 shows an electron micrograph of cristaliana gel with the greatest increase. The fracture surface shows predominantly membrane-covered particles. Break through the particle itself is very rare. It seems that vesicles surrounded by a layer of material that is presented aminolevulinic acid. The resulting image type scrambled eggs (marked by arrow in part 6).

Electron micrograph made by negative staining of the gel with 10% aminolevulinic acid represented nanoparticles with muddy diffuse surface structure, which can confirm the stratification of the material on the nanoparticles that is seen on electron micrographs of cristaliana.

Example 4. Absorption in mammalian cells: studies of cell cultures in vitro on the uptake of ALA: Studies of cell cultures:

The uptake of ALA and turning in fetoprotein IX (PpIX) in the culture cells can be observed by measuring the UV-induced PpIX fluorescence. Experiments on to mocnych cultures were carried out with several neoplastic cell lines: HELA, HepG2 and CCD 106 KERTr (cell line of human keratinocytes). Cells were incubated in aqueous medium with Methyl-ALA (MAL), ALA or BF-200 ALA for a maximum of 3 hours. When selected the drug concentration, all three incubation medium had a similar pH. After incubation, cells were carefully washed and added a fresh environment. The PpIX production was measured in different periods of time by measuring the fluorescence. Figure 5 shows the results obtained for HELA cells.

Effect of increasing concentrations of nano-emulsions BF-200 (at a constant concentration of ALA) on the synthesis of PpIX presented on figure 5. PpIX fluorescence in the cells was higher with increasing concentration of BF200 and reached the maximum at 3% BF200.

Example 5.

The effectiveness of the composition of nano-emulsions of 5-ALA for photo dynamic therapy of senile keratosis shown in phase II clinical trials for the selection of doses, which began in the fall of 2006, and was sponsored Biofrontera Bioscience GmbH. The study controlled for placebo, randomized and double-blind study was conducted in 13 clinical centers in Germany under supervision of Prof. Dr. Rolf-Markus Szeimies, University Clinics of Regensburg. Used three active doses (1, 3, and 10% ALA), and placebo. To confirm the efficiency connections, 105 patients were treated once by photodynamic therapy with one of three different concentration of the ALA or placebo.

Included patients with 3-10 centers senile keratosis on the face or on the skin of the skull. Each patient received one treatment (1%, 3% or 10% of 5-aminolevulinic acid (ALA) or a placebo) on all his/her lesions. Used red light after 3 hours after conditioning. After treatment, the subject returned to the clinic in 3 weeks, 8 weeks and 12 weeks to monitor the outcome of the disease and the cure. Each time, researchers have identified a range of senile keratosis (AK) to determine the remaining areas with signs of AK and clinical symptoms. The main value of efficiency was the General level of purification from all AK lesions at week 12 visit, defined as the number of foci, showing complete remission (lesions completely cleared out and was no longer observed in the presence of adherent removable stains AK). Also monitored the occurrence of pain during irradiation after application of BF-200 ALA.

Results: it Was found that pre-treatment with 10% ALA prior to PDT, proved to be the most effective for one-third of the tested concentrations in the purification of AK lesions (statistically significantly superior to placebo). When patients were assessed 12 weeks after the initial treatment with BF-200 ALA, at least 60-70% of the treated lesions were completely healed, depending on the clinical evaluation is introw and head area. The cleanup levels for placebo was approximately 5-15% of treated lesions, depending on the evaluation of the clinical centers. The cleanup levels corresponded well with published results from studies of ALA-PDT with conducted a similar study, but with large concentrations of active substances 5-ALA or Methyl ALA. Cosmetic results were excellent. Only 6% of patients complained of severe pain. Significant side effects were not found during the study, the cosmetic results were excellent. There were no hazards related to the four groups during PDT and over a period of 12 weeks after PDT.

As an additional security measure, this part for determining the dose contained pharmacokinetic evaluation. Measured levels of ALA and its metabolite of photoprotein IX system in plasma and urine. The concentrations of these compounds in plasma and urine were not increased compared with the normal physiological values at each of the individuals.

1. Nanoemulsion for delivery of active agent containing a) at least one aqueous component and b) a carrier, which contains (i) at least one lipophilic component, which is present in an amount of from 0.1 wt.% up to 15 wt.%, ii) at least one surfactant; and (iii) at least one alcohol, where at least one alcohol is of the propyl alcohol and/or 1-propyl alcohol, and where the average diameter of emulsified particles is less than 100 nm.

2. The nanoemulsion according to claim 1, in which the carrier is present in the aqueous component.

3. The nanoemulsion according to claim 1 or 2, in which the surfactant is present in an amount of from 1 wt.% up to 30 wt.% and the alcohol is present in an amount of from 0.1 wt.% up to 10 wt.%, based on the total weight of the nano-emulsion.

4. The nanoemulsion according to claim 1, in which the water component is present in an amount of from 50 wt.% up to 98 wt.%, based on the total weight of the nano-emulsion.

5. The nanoemulsion according to claim 1, in which at least one lipophilic component is represented by triglycerides and/or their mixture.

6. The nanoemulsion according to claim 1, in which at least one surfactant is lecithin and/or surfactant type polyoxyethylene.

7. The nanoemulsion according to claim 6, in which lecithin is a soy lecithin and surfactant type is a polyoxyethylene Polysorbate 80.

8. The nanoemulsion according to claim 7, in which soy lecithin has phosphatidylcholine content equal to at least 80 wt.%.

9. The nanoemulsion according to claim 1, in which the average diameter of emulsified particles is in the range from 10 nm to 50 nm.

10. The nanoemulsion according to claim 1 in which the aqueous component contains from 5 mm to 30 mm phosphate buffer.

11. Method of preparation of nano-emulsion according to any one of claims 1 to 10, comprising the following stages:
a) providing a water component,
b) ware the media, containing at least one lipophilic component, at least one surfactant and at least one alcohol,
where at least one alcohol is isopropyl or 1-propyl alcohol, and
c) mixing the aqueous component from stage a) with a carrier from stage b) for the formation of nano-emulsion at a temperature between 50°C and 60°C.

12. The use of nano-emulsion according to any one of claims 1 to 10 for the manufacture of pharmaceutical compositions for local production of medicines.

13. The use of nano-emulsion according to any one of claims 1 to 10 for the production of cosmetic compositions for application to the skin.

14. Composition for photodynamic therapy containing a nanoemulsion according to any one of claims 1 to 10, and an active agent selected from the group consisting of 5-aminolevulinic acid, its derivative, precursor and/or metabolite.

15. The composition according to 14, in which 5-aminolevulinic acid, its derivative, precursor and/or metabolite attached to the outer monolayer of the particles of the nano-emulsion.

16. The composition according to 14, in which the composition is represented in the form of a gel and contains from 0.01 wt.% up to 50 wt.% active agent, from 1 wt.% up to 60 wt.% nano-emulsion, from 0.01 wt.% up to 4 wt.%, at least one of a filler, from 1 wt.% up to 3 wt.%, at least one stabilizer based on the total weight of the composition, and the balance of supports, m is Nisha least one solvent.

17. Diagnostic composition for the detection of proliferating cells containing the nanoemulsion according to any one of claims 1 to 10, and an active agent selected from the group consisting of 5-aminolevulinic acid, its derivative, precursor and/or metabolite.

18. The composition according to 17, in which 5-aminolevulinic acid, its derivative, precursor and/or metabolite attached to the outer monolayer of the particles of the nano-emulsion.

19. The composition according to 17, in which the composition is represented in the form of a gel and contains from 0.01 wt.% up to 50 wt.% active agent, from 1 wt.% up to 60 wt.% nano-emulsion, from 0.01 wt.% up to 4 wt.%, at least one of a filler, from 1 wt.% up to 3 wt.%, at least one stabilizer based on the total weight of the composition, and the balance of supports, at least one solvent.

20. The method of preparation of the composition according to 14, comprising the following stages:
a) providing a water component,
b) providing a carrier containing at least one lipophilic component, at least one surfactant and at least one alcohol,
where at least one alcohol is isopropyl alcohol and/or 1-propyl alcohol,
c) mixing the aqueous component from stage a) with a carrier from stage b) for the formation of nano-emulsion at a temperature between 50°C and 60°C,
d) adding the active agent PE the ed and/or after the formation of the mentioned nano-emulsion from stage C) and (e) optionally adding additional additives and/or fillers to stage d).

21. The method according to claim 20, in which the active agent in stage d) is added after the formation of the mentioned nano-emulsion of the stage).

22. The use of a composition according to 14 for the manufacture of a medicinal product for photodynamic therapy.

23. The application of article 22, which specified the composition is applied to the patient in an effective amount and shall be kept for a period of time from 1 h to 8 h, preferably 4 h, after which the fabric is subjected to irradiation of light.

24. The use of a composition according to 14 for the manufacture of a medicinal product for the treatment of senile keratosis.

25. Set for photodynamic therapy containing composition 14 and at least one component selected from
a) photoresistance cover,
b) means for attaching the specified coverage to the area of application, and
c) means for applying a specified composition to a site of application.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention can be used in chemical industry. Method of obtaining basic zinc carbonates includes chemical conversion of coarse-dispersed zinc oxide in water solution of carbon dioxide and ammonia, further formation of target product, its filtration, drying, condensation and return of gaseous products to the stage of chemical conversion. Chemical conversion of zinc oxide into basic zinc carbonate is performed in ammonia-carbonate water solution in heterogenic conditions with molar ratio carbon dioxide:ammonia, equal 1:(5-9), temperature 15-50 °C and atmospheric pressure.

EFFECT: invention makes it possible to obtain amorphous sediments of pentazinc hexahydroxodicarbonate Zn5(CO3)2(OH)6 of stoichiometriccomposition with particle size, which does not exceed 50 nm, to simplify the process, reduce energy consumption and ecological load on the environment.

1 dwg, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention can be used in electronics, material science, instrument-making, metrology, information technology, chemistry, ecology, biology and medicine. Initial product of electric arc synthesis is separated into light and heavy fractions by distillation in "boiling layer" mode or by floatation. For "boiling layer" mode air is used as carrier-gas and is supplied at rate, which provides mode of laminar flow of light fraction. Sodium nitrate solution with specific weight 1.26-1.37 g/cm3 is used as floatation liquid. Heavy fraction is processed with concentrated hydrochloric acid and ultrasound, washed, dried and successively oxidised with air oxygen at 450 °C and 600 °C with intermediate processing with concentrated hydrochloric acid and ultrasound, washing and drying until constant weight is obtained.

EFFECT: reduction of process duration, improved quality of separated nanotubes due to reduction in them of metal and amorphous carbon.

4 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention can be used for obtaining carbon nanotubes and nanofibres. Solid disperse catalyst is periodically loaded into reactor, gases are injected and subjected to contact with catalyst particles at the temperature of carbon nanomaterial synthesis. Loading of each following portion of catalyst is performed on the layer of growing nanomaterial. Alternate pressure of gaseous medium is created in reactor by injection of gases when pressure in reactor increases and their discharge, when pressure decreases. Stages of injection of gases into reactor and discharge of gases from reactor are performed by repeated periodical creation of vacuum in lock-chamber.

EFFECT: simplification of hardware process realisation, increased productivity due to uniform catalyst distribution.

2 cl, 2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: method involves mixing phosphates, calcium and silicon compounds, milling and mechanochemical synthesis, wherein the starting components used are disubstituted anhydrous calcium phosphate, annealed calcium oxide and amorphous hydrated silicon oxide with water content of less than 0.5 mol, with specific surface area of 200-450 m2/g in amount of not more than 1.2 mol silicon per elementary cell of hydroxylapatite; mechanochemical solid-phase synthesis is carried out in high-energy planetary mills with drum rotation speed of 1200-1800 rpm for 12-30 minutes. Calcium oxide is annealed preferably at temperature of 900°C for 5 hours.

EFFECT: invention enables to obtain a powdered nanocrystalline single-phase product for 30 minutes of solid-phase mechanical activation.

2 cl, 1 tbl, 6 ex, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention can be used in chemical industry and metallurgy. The method of producing molybdenum carbide nanoparticles involves dissolving molybdenum pentachloride in ethanol in ratio of 1:(1-3). Urea is added to the obtained solution. Annealing is then carried out in two steps. At the first step, heating is carried out in a vacuum at a rate of not more than 5°C/min to temperature of 430-450°C. At the second step, heating is carried out in a nitrogen atmosphere to temperature of 550-600°C, followed by holding at said temperature for 2.5-3 hours.

EFFECT: invention lowers the process temperature and enables to obtain molybdenum carbide particles with size of 5-10 nm.

2 dwg, 2 ex

FIELD: nanotechnology.

SUBSTANCE: invention relates to the field of nanotechnology, and can be used to produce nanotubes and fullerenes. The carbonaceous material is evaporated in the volumetric thermal plasma, and condensed on the outer surface of the anode 2 and the inner surface of the cathode 3. A glow-discharge plasma is used, which is set by electrical voltage supply sufficient to break the inter-electrode gap between the coaxial hollow cathode 3 having a shape of a cup with a permeable bottom 4, and the anode 2 located with the ability to move axially. The carbonaceous material is fed through the permeable bottom 4 of the cathode 3 and is selected from the group consisting of methane, propane, butane for gaseous carbonaceous material or from the group consisting of crude oil, oil fuel, benzene, gas oil for liquid carbonaceous material. The bottom 4 is made in the form of a grid or a membrane.

EFFECT: invention enables to reduce the power consumption of the process, to broaden the types of the used hydrocarbon crude, to simplify the design of the device and to provide the ecological compatibility of the process and its high performance.

4 cl, 1 dwg, 2 ex

FIELD: process engineering.

SUBSTANCE: invention relates to power metallurgy, particularly, to production of metallic nano-sized powders.Initial powder of metal oxide compounds with particle size not exceeding 50 mcm is fed by carrier gas into reactor of gas discharge plasma. Initial material is heated to temperature exceeding that of oxides sublimation to evaporate metal and to reduce metal oxides in hydrogen flow or its mix with nitrogen or by argon. Metallic powder is isolated on cooling metal vapors by pulsating inert gas flow at gas flow rate of 1·10-6-1·10-3 m3/s.

EFFECT: ruled out or minimised agglomeration of condensed nano-sized pareticles.

7 cl, 3 ex

FIELD: process engineering.

SUBSTANCE: invention relates to physical chemistry and can be used for production of photon crystals with preset physical properties. Substrate with pre-applied silica microspheres is placed into reactor. Reactor chamber is evacuated to 10-4 torr. Substrate is heated to 192-230°C to feed precursor vapors at 45-56°C into reaction zone. Vapors are held for at least 1.5 s. Air is fed into reaction chamber to pressure of 10-2 torr. Reaction mix is held for, at least 2 seconds and reactor is evacuated to initial vacuum.

EFFECT: simplified process, expanded process performances due to production of preset size nanoparticles.

3 cl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, particularly toxicology and radiology, to drug preparations based on antioxidant proteins and methods of using them. The pharmaceutical composition for treating toxic conditions wherein the therapeutic effect is ensured by the action of antioxidant, antimicrobial, antitoxic human lacroferrin protein on the human body contains non-replicating nanoparticles of human adenovirus serotype 5 genome with inserted human lactoferrin expressing human lactoferrin in the therapeutically effective amount in the body, and an expression buffer with the particle content not less than 2.33×1011 of physical particles per ml of the expressing buffer. The method of therapy involves administering the composition in the therapeutically effective dose of 7×1011 of physical particles to 7×1013 of physical particles per ml of the expressing buffer per an individual; the composition is administered intravenously.

EFFECT: invention provides the stable therapeutic effect after the single administration of the composition.

17 cl, 14 ex, 4 dwg

FIELD: metallurgy.

SUBSTANCE: ingot manufacturing method involves tempering of an ingot, multiple forging with series change of orientation axis through 90° at the temperature interval of 773-923 K with total true deformation degree of not less than 3 and further annealing at the temperature above isothermic forging temperature by 50 K during 1-5 hours.

EFFECT: obtaining an austenitic steel ingot with nanocrystalline structure and improved strength properties.

2 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, pharmaceutics and nanotechnologies, and more specifically to a method for preparing nanosized amphotericin B for coating aluminosilicate nanotubes, used as a poorly soluble polyene macrocyclic antibiotic widely used for treating fungal diseases. What is presented is the method for preparing nanosized amphotericin B by mixing a solution of amphotericin B in dimethyl sulphoxide at room temperature with the aluminosilicate tubes to make 1-20 wt % of amphotericine B precipitate on the aluminosilicate tubes by water treatment of the prepared mixture while stirring thoroughly at water feed rate 10 ml/min. The technical effect consists in the fact that the presented method is simple and easy to implement, and enables producing a novel dosage form of amphotericin B represented by amphotericin B coating the solid inorganic structures that are the aluminosilicate tubes; the above shall provide the further development of new ointments, gels and magmas for treating fungal diseases.

EFFECT: using the nanosized carrier promotes the uniform distribution of amphotericin B, while an aluminosilicate nature of the carrier is a good sorbent that provides prolonged action of amphotericin B with the carrier staying undisturbed that also allows for higher bioavailability of insoluble amphotericin B as compared to microforms thereof.

1 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of materials based on zirconium dioxide stabilised with yttrium oxide, and can be used in making composite ceramic articles used in electrical engineering, mechanical engineering, chemical industry, metallurgical industry and other industries. The method of making workpieces of ceramic articles involves producing zirconium dioxide stabilised with yttrium oxide by coprecipitation after mixing with constant stirring of zirconyl nitrate and yttrium acetate solutions and subsequent hydrothermal synthesis of oxides in a supercritical fluid reactor. Heat treatment is carried out by drying at temperature of 80°C for two hours and calcining in air at temperature of 500°C for 1.5 hours. The obtained nanopowder is granulated and workpieces are moulded, which are pre-sintered in air at temperature of 800-1000°C for 1 hour at heating rate of 5°C/min. After cooling in switched off furnace conditions, the workpieces undergo mechanical treatment and final sintering in air at temperature of 1200-1300°C for 5 hours.

EFFECT: method enables to make workpieces of ceramic articles with improved physical and mechanical properties: microhardness of at least 10000 MPa from weakly agglomerated high-purity nanopowder of zirconium dioxide stabilised with yttrium oxide.

1 ex, 4 dwg

FIELD: nanotechnology.

SUBSTANCE: invention relates to the field of nanomaterials. A method is proposed for production of fluorescent labels based on biocompatible and biodegradable nanoparticles of silicon for application in vivo by the reaction of disproportionation of silicon monoxide at a temperature of 950°C in air atmosphere followed by interaction of the resulting nanoparticles of silicon with dimethylsulfoxide. The proposed method enables to produce two outfits of nanoparticles with the size of 2.0-2.5 nm with photoluminescence peaks at 676 nm and 774 nm.

EFFECT: production of hydrophilic biocompatible and biodegradable fluorescent labels of nanocrystalline silicon, having sustained bright luminescence and narrow function of size distribution, resistant to high temperatures (up to 220°C) without the use of toxic substances in the process of their synthesis; resulting nanoparticles are applicable as labels in vivo in imaging of deep-seated tissues and organs.

1 cl, 3 dwg

FIELD: metallurgy.

SUBSTANCE: invention refers to nanostructured materials with ultra-fine grain structure, and namely two-phase alpha-beta titanium alloys which can be used for manufacture of semi-finished products and products in different branches of engineering, machine-building industry and medicine. Proposed alloy has microstructure consisting of ultra-fine grains of alpha-phase and beta-phase with the size of less than 0.5 mcm. In alloy microstructure the amount of grains with grain shape coefficient of not more than 2 is not less than 90%; at that, more than 40% of grains have wide-angle borders, and average density of dislocation is not more than 1014 m-2. the method for obtaining ultra-fine grain two-phase alpha-beta titanium alloy involves heat treatment with heating of a billet at the temperature of not more than 0.6 T"пп", further multicycle intense plastic deformation with achievement of accumulated true deformation degree e≥4. Then, plastic deformation is performed so that the billet shape is changed at the rate of less than 10-1 s-1 in several cycles to provide deformation degree ε≥50%.

EFFECT: improving strength and fatigue properties and preserving high ductility.

5 cl, 2 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a biodegradable highly filled thermoplastic composition used in making films and consumer packaging. The composition contains polyethylene, biodegradable filler in form of potato starch, process additives: oligoepoxy ether with molecular weight of 1800-3500 and content of epoxy groups of 2.0-4.0% in nano-form and nonionic and cationic surfactants.

EFFECT: obtained composition has good process parameters, articles made from the composition are biodegradable under the effect of light, moisture and soil microflora.

2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention can be used in electronics, material science, instrument-making, metrology, information technology, chemistry, ecology, biology and medicine. Initial product of electric arc synthesis is separated into light and heavy fractions by distillation in "boiling layer" mode or by floatation. For "boiling layer" mode air is used as carrier-gas and is supplied at rate, which provides mode of laminar flow of light fraction. Sodium nitrate solution with specific weight 1.26-1.37 g/cm3 is used as floatation liquid. Heavy fraction is processed with concentrated hydrochloric acid and ultrasound, washed, dried and successively oxidised with air oxygen at 450 °C and 600 °C with intermediate processing with concentrated hydrochloric acid and ultrasound, washing and drying until constant weight is obtained.

EFFECT: reduction of process duration, improved quality of separated nanotubes due to reduction in them of metal and amorphous carbon.

4 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention can be used for obtaining carbon nanotubes and nanofibres. Solid disperse catalyst is periodically loaded into reactor, gases are injected and subjected to contact with catalyst particles at the temperature of carbon nanomaterial synthesis. Loading of each following portion of catalyst is performed on the layer of growing nanomaterial. Alternate pressure of gaseous medium is created in reactor by injection of gases when pressure in reactor increases and their discharge, when pressure decreases. Stages of injection of gases into reactor and discharge of gases from reactor are performed by repeated periodical creation of vacuum in lock-chamber.

EFFECT: simplification of hardware process realisation, increased productivity due to uniform catalyst distribution.

2 cl, 2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining nanocomposites based on polyolefins, used in obtaining different products, such as films, sheets, tubes, threads and fibres. Carbon nanotubes are preliminarily ground in water with addition of water-soluble polymer with concentration 0.01-0.1 wt %. After that, suspension is dispersed by ultrasound at maximal medium temperature not higher than 70° C. After that, suspension is applied on the surface of polyolefic granules and dried. Obtained granules of nanocomposite contain to 0.5 wt % of carbon tubes.

EFFECT: nanocomposite materials possess high volumetric and superficial electroconductivity, heat-conductivity and high rigidity, with simultaneous increase of tensile modulus of elasticity to 50%, and limit of tensile strength to 30%.

3 cl, 4 dwg, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to field of chemical technology of obtaining paints and varnishes. Composition for giving surface properties of self-cleaning based on lotus effect includes hydrophobising component amides or esters of perfluoropolyoxalkylene-sulfo- or perfluoropolyoxalkylene-carboxylic C17-46 acids, dissolved in organic solvent Freon, isopropanol or their mixture, structure-forming component, selected from the group: organosoluble silica sol with particle size 3-18 nm, tetrabutoxytitanium, tetraisopropoxytitanium, tetraethoxysilane or products of its partial hydrolysis, with weight ratio of hydrophobising and structure-forming components within 100:(4-7) and concentration of hydrophobising component in solvent 0.2-8 wt %.

EFFECT: invention provides self-cleaning properties of processed surface.

5 ex

FIELD: process engineering.

SUBSTANCE: invention relates to production of thin-film materials base on system of double oxides used fast developing areas of electronic lighting engineering, etc, as sensitive, decorative, filtering and distributing coatings, etc. Proposed method comprises preparing film forming solution and applying it on article surface. Fresh film forming solution is kept for 8-13 days at 6-8°C, drying is performed at 60°C for 30-40 min and nonlinear heating to 800-900°C in air and curing at 800-900°C for one hour and cooled in conditions of natural cooling down of muffle furnace at the following ratio of components in film forming solutions in wt %: tetraethoxysilane - 22.6-21.4; hydrochloric acid - 4.4-10-4-1.2-10-4, distilled water - 2.3-0; metal salt - NiCl2-6H2O 1.1- 8.4; ethanol - (98 wt %) making the rest.

EFFECT: simplified production of uniform coating with perfected properties.

2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic industry and represents a skin care composition containing at least one polyurethane prepared by a reaction of one or more water-insoluble, water-nondispersible polyurethane pre-polymers with isocyanate functional groups A) with one or more compounds B containing aminofunctional groups specified in primary and/or secondary amines, and/or diamines and additives.

EFFECT: invention provides creating the skin care composition which forms a nonadhesive and oil-free protective layer after distribution in skin.

11 cl, 5 ex

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