RU2506944C1 - Method for improving transdermal permeability of therapeutic or cosmetic topical preparations, method for dermal administration of liquid xenon - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic and pharmaceutical industry and represents a method for improving the transdermal permeability of therapeutic or cosmetic topical preparations involving the dermal administration of 1.0 to 300.0 vol. % of liquid xenon as a part of an acceptable neutral carrier or a therapeutic or cosmetic preparation.

EFFECT: invention provides the higher therapeutic or cosmetic effectiveness ensured by improving the transdermal transport of bioactive compounds.

8 cl, 13 ex, 4 dwg

Description

The group of inventions relates to the field of cosmetology / dermatology, and in particular, to methods for increasing transdermal permeability of cosmetic or therapeutic agents for external use by introducing inert xenon gas into the skin.

The principle of increasing the effectiveness of drugs intended for external use (creams, ointments, plasters) is well known. Currently, for this purpose, transport systems for transdermal delivery of active substances included in the compositions of these agents are increasingly used (Mbah CJ, Uzor PF, Omeje EO. Perspectives on transdermal drug delivery / J Chem. Pharm. Res. - 2011, - V .3 (3), - P.680-700; Milind MT, Pancholi SS Review of penetration enhancement techniques in transdermal delivery system / American J of PharmTech Research. - 2012, - V.2 (1). - P.256- 273). In 2009, in the United States, out of 129 different transport systems for drugs undergoing clinical trials, 51% were transdermal and dermal delivery systems. Currently, the United States has approved 20 original transport systems for a number of drugs for the treatment of skin diseases, diabetes mellitus, pathology of the heart and blood vessels, nicotine addiction, hormone replacement therapy in women, as well as analgesics and anesthetics.

There are several main technological trends in the development of transdermal transportation systems of active substances:

1. Use of carriers (liposomes, transfersomes, ethosomes, niosomes, aspasomes, nanosomes, dendrimers, eutectic systems, etc.).

2. Physical methods to increase the permeability of the skin - iontophoresis, ultrasound, electroporation, thermoporation, magnetophoresis, microneedles, needleless injections, etc.

3. Chemical compounds - enhancers - sulfoxides, alcohols, polyols, alkanes, ethers, terpenes, etc.

The advantages of enhancers compared to other methods are that they are simply introduced into the composition of the product, while eliminating the need for additional production of carriers (liposomes, etc.), and additional equipment for iontophoresis, ultrasound exposure, etc. . The main mechanism of action of enhancers (from the English "enhance" is to enhance, enhance) is a modification of the physicochemical parameters of the stratum corneum, loosening it, violation of the integrity and ordering of the structure of the intercellular lipid layer of the epidermis, which improves the fluidity of this layer and the solubility of active substances in the stratum corneum layer.

The disadvantage of chemical enhancers is the risk of developing side-effects of inflammation associated with irritation, redness, peeling, etc. The penetration of these chemical compounds or their metabolites deep into the skin and into the bloodstream can have an undesirable systemic effect on the whole body. In addition, such enhancers increase the risk of overdose or changes in the biological activity of substances contained in cosmetic or therapeutic agents (Patel HJ, Trivedi DG, Bhandari AK, Shah DA Penetration enhancers for transdermal drug delivery system: A review / IJPI's Journal of Pharmaceutics and Cosmetology. - 2011. - V.1 (2). - P.67-80).

The search for ways to increase the effectiveness of cosmetic and therapeutic agents for external use by introducing enhancers into their transport systems remains relevant.

Known methods for treating various diseases using phytochitodes and chitosan-containing ointments, for example, in surgical practice to influence the wound process in order to accelerate healing of various wounds and prevent suppuration [RU 2151601 C1, 2000], in the treatment of chronic gastritis, gastric ulcer and duodenal ulcer intestines [RU 2150271 C1, 2000], acute purulent periostitis [RU 2153318 C1, 2000].

There is a method of increasing the effectiveness of the treatment of atopic dermatitis [RU 2170092 C1, 2001]. The method consists in the local use of foci of a glucocorticosteroid ointment, additionally containing heparin, while the dose of steroids is reduced by 13-40 times. The method leads to an increase in the effect of treatment and a decrease in the complications of steroid therapy.

Devices for transdermal drug delivery containing O-Desmethylvenlafaxine (ODV) or its salts [RU 2008106935 A, 2009], essentially representing a transdermal patch for administering a topical composition containing a therapeutically effective dose of ODV or a pharmaceutically acceptable salt thereof and at least one physiologically acceptable carrier or excipient.

Known pharmaceutical composition for increasing skin permeability for improved local drug delivery [RU 94019942 A1, 1995], comprising a safe and effective amount of a pharmaceutically active substance, 0.05% -5% non-ionic polyacrylamide with a molecular weight of 1,000,000-30000,000.

A topical pharmaceutical composition is also known in the art [RU 2005132004 A, 2006], wherein the agent for increasing permeability through the skin is a substance selected from the group of urea, pyrrolidone, N-methylpyrrolidine, decylmethyl sulfoxide, sodium lauryl sulfate and dimethyl sulfoxide.

A biologically active substance of cosmetics is known that stimulates metabolic processes in integumentary tissues [RU 2033789 C1, 1995], in which a block copolymer of ethylene oxide and propylene oxide (a copolymer of polyoxy ethylene polyoxypropylene) of the general structural formula is used

having a molecular weight of 3-25 Kg and a ratio of oxypropylene and oxyethylene parts (20-2) :( 80-2).

A tetracyclic compound is known to be used to increase skin permeability for a pharmaceutically active compound, and a method for increasing skin permeability for a pharmaceutically active compound [RU 2007105687 A, 2008], comprising treating the skin with a tetracyclic compound and administering a pharmaceutically active compound, is proposed.

Among gaseous enhancers, oxygen is known [RU 2191566 C1, 2002; RU 2119790 C1, 1998; RU 2304959 C2, 2007]. This technology is used by the Russian company Faberlik, which uses Aquaftem in its products - a nano-sized compound (200 nm) based on perfluorocarbons (perfluorodecalin), which actively sorb molecular oxygen. The authors argue that the main effect of such “oxygen cosmetics” is to stimulate the metabolism of skin cells as a result of increasing the formation of energy substrates in the mitochondria and, as a result, stimulating the regeneration and rejuvenation processes by increasing the content of collagen and elastin proteins in the dermis and restoring elasticity skin, as well as effects in the treatment of burns. Indeed, the oxidase pathway (when molecular oxygen does not integrate into the molecule of the oxidized substrate) takes place in the cytochrome oxidases of the respiratory tract of mitochondria. Nevertheless, as a result of two more ways - mono- and dioxygenase, either one or the whole oxygen molecule is embedded in the substrate molecules, as a result of which active oxygen forms (ROS) are formed - initiators of the processes of free radical oxidation (CPO) and lipid peroxidation (POL) , proteins, DNA molecules with impaired function and irreversible destruction [Kuzmenko DI, Serebrov V.Yu., Udintsev SN Free radical lipid oxidation, reactive oxygen species and antioxidants: a role in the physiology and pathology of cells / Tomsk, 2007. - 214 p.]. Similar processes occur in the skin, in particular, against the background of excessive ultraviolet radiation (photoaging of the skin). Oxygen, according to their data, among the above effects, also enhances the penetration into the deeper layers and assimilation by skin cells of biologically active substances, for example, RALA (R-alpha-alpha-lipoic acid), popular recently in cosmetology, and enhances the activity of other cosmetic preparations, in particular sunscreens. Thus, Aquaftam is also considered as an enhancer.

The disadvantage of this invention is the formation of an excess of reactive oxygen species — the development of oxidative stress, and the Aquaftem effect as an enhancer should be considered not only as a result of increased utilization of active compounds by skin cells as a result of metabolic activation, but more so as a result of exposure to aggressive reactive oxygen species that initiate processes free radical oxidation and peroxidation of lipids, proteins, DNA molecules with impaired function and irreversible destruction. Similar processes occurring in skin cells lead to its loosening and violation of the integrity of lipid intercellular structures, as a result of which its permeability to active substances increases. The risk of developing oxidative stress due to excess oxygen requires additional introduction of actioxidants into the composition, which was done by Faberlic - after the creation of Aquaftem, Aquaftem Protect appeared, in which the propylphenol compound was added, the antioxidant properties of which are an order of magnitude higher than that of vitamin E. This The product is also used by the company as an enhancer for the components of the essential oils with which it is combined.

By their action, lipophilic inert gases, such as krypton, argon, xenon, are of interest. Especially among them, I would like to single out xenon, which is known as an inhaled anesthetic, since this inert gas has anesthetic and analgesic effects.

A known US patent [US 2005255169, 2005], in which the authors propose using anesthesia (inhalation) with xenon or a gas mixture containing xenon, as a means to enhance the effect (enhancer) of pharmacological preparations intended for antiviral, antibacterial, antifungal therapy, and also neuroprotectors, antitumor drugs, parasympathomimetics, antispasmodics, sympathomimetics, tricquilizers, vitamins, hormones.

The disadvantage of this invention is that xenon anesthesia requires special equipment, can only be carried out in medical institutions by specialist anesthetists and, therefore, is not available for mass use and, moreover, as a means to increase the effectiveness of cosmetics.

A known drug for adaptogenic therapy and a method for its manufacture [RU 2228739 C1, 2004]. The preparation is equipped with a sealed package and contains a filler - a fat emulsion or a solid sorbent in which a gaseous active component is dissolved or adsorbed, which is at least one gas from the group comprising: xenon, krypton, nitrous oxide. Preferably, the filler is a fat emulsion having a pH of at least 6.0, the fat emulsion contains fat, namely: cattle or small cattle milk or other emulsion based on animal oil, or as a filler contains vegetable oil or activated carbon or thermoxide. The invention provides a non-toxic drug with an increased ability to regulate the body's resistance to extreme conditions due to humoral regulation, metabolic regulation and psycho-emotional regulation of the patient.

The method of obtaining the drug for adaptogenic therapy is selected as the closest method of the same purpose to the claimed method in the group of inventions.

An object of the invention is the creation of a new method of increasing the effectiveness of drugs or cosmetics by introducing (delivering) inert gas of xenon into the skin due to xenon manifesting an enhancer effect.

Another technical challenge facing the developers was the development of a new method of introducing gaseous xenon into the skin.

The task in the implementation of the claimed group of inventions is achieved by the fact that the claimed method of increasing transdermal permeability of therapeutic or cosmetic preparations for external use includes the introduction into the skin of from 1.0 to 300.0 vol.% Gaseous xenon as part of an acceptable neutral carrier or therapeutic or cosmetic preparation .

In addition, at least one substance is selected as an acceptable neutral xenon gas carrier.

An effective amount of gaseous xenon is dissolved in an acceptable neutral carrier, or a therapeutic or cosmetic preparation.

In this case, an acceptable neutral xenon carrier, therapeutic or cosmetic preparation is used in gaseous or liquid, or semi-solid, or solid form.

To care for skin, nails, hair, mucous membranes, an effective amount of gaseous xenon is the amount of xenon sufficient to achieve an improved condition of the skin, nails, hair, mucous membranes.

For the treatment of diseases of the skin, nails, hair, mucous membranes, subcutaneous fat, connective tissue, musculoskeletal system, muscle tissue, an effective amount of xenon gas is an amount of xenon sufficient to increase the effectiveness of the therapy.

The objective is also achieved by the fact that the inventive method of introducing gaseous xenon into the skin is that, to increase the transdermal permeability of medical or cosmetic preparations for external use, introducing into the skin from 1.0 to 300.0 vol.% Gaseous xenon in an acceptable neutral carrier or a therapeutic or cosmetic preparation, is carried out topically according to any one of claims 1 to 6.

The introduction of gaseous xenon into the skin to increase the transdermal permeability of medical or cosmetic preparations is carried out with diversity in time and priority, or simultaneously.

Xenon is an inert noble gas, it is absolutely non-toxic, does not react with biological molecules, does not exhibit mutagenic, teratogenic, cytotoxic and immunotoxic properties. Used in medicine since 1951 for inhalation anesthesia. When introduced into the body, gas is completely excreted within 4 hours (Sanders RD, Franks NP, Maze M. Xenon: no stranger to anaesthesia / Brit J Anaesthesia, 2003. - V.91 (5). - P.709-717 ) The therapeutic effect of gas with neurotoxicity of various origins, Parkinson's disease, schizophrenia, cerebral ischemia [Burov N.E., Potapov V.N., Makeev G.N. Xenon in anesthesiology - M., Pulse., 2000. - 356 p .; Abraini J.H., David H.N., Lemaire M. Potentially Neuroprotective and Therapeutic Properties of Nitrous Oxide and Xenon - Ann. N.Y. Acad. Sci. 2005, 1053: P.289-300]. Gas is increasingly being used in sub-narcotic (small) doses for therapeutic anesthesia for neurotoxicity of various genesis (Abraini JH, David HN, Lemaire M. Potentially Neuroprotective and Therapeutic Properties of Nitrous Oxide and Xenon - Ann. NY Acad. Sci. 2005, 1053: P.289-300). Xenon is also effective in the introduction of liposomes with this gas into the vessels of the brain, which significantly accelerates the restoration of brain tissue repair and reduces neurotoxicity after stroke (Britton GL, Kim N., Kee R.N. et al. In Vivo Therapeutic Gas Delivery for Neuroprotection with Echogenic Liposomes / Circulation. 2010, 122 (16): 1578-1587).

As the main mechanism of action of xenon, its effect on mediator systems providing the conduction of a nerve impulse, primarily, the blockade of N-methyl-D-aspartate (NMDA) receptors, is considered. This signaling system was originally described for the central nervous system, but was subsequently also found in bone and blood-forming tissues, pancreas, in deep tissues (muscles, tendons, joints), nerve endings in the heart muscle, and myocardiocytes (Skerry T.M., Genever PG Glutamate signalling in non-neuronal tissues / Trends Pharmacol Sci, 2001. V.22. - P.174-181; Alfredson N., Lorentzon RJ Chronic tendon pain: no signs of chemical inflammation but high concentrations of the neurotransmitter glutamate. Implications for treatment / Curr Drug Targets, 2002. - V. 3. - P.43-54). Identified NMDA receptors in the basal prickly and granular layers of human skin - (Kinkelin I, Brocker EB, Koltzenburg M. et al. Localization ionotropic glutamate receptors in peripheral axons of human skin / Neurosci Lett, 2000.- V. 283. - P.149-152; Nahm WK, Philpot BD, Adams MM et al. Significance of N-methyl-D-aspartate (NMDA) receptor-mediated signaling in human keratinocytes / J Cell Physiol, 2004 .-- V. 200 (2 ) .- P.309-317; Fischer M., Glanz D., William T. et al. N-methyl-D-aspartate-receptors influence the intracellular calcium concentration of keratinocytes / Experimental Dermatology, 2004. - V.13 ( 8) .- P.512-519). Currently, NMDA receptors are considered targets for treating human skin diseases (Nahm WK, Philpot BD, Adams MM et al. Significance of N-methyl-D-aspartate (NMDA) receptor-mediated signaling in human keratinocytes / J Cell Physiol, 2004.- V. 200 (2) .- P.309-317). The effect on them is associated with the effectiveness of the topical use of calcium channel antagonists that accelerate the repair of the epithelial barrier (Fuziwara S., Inoue K., Denda M. NMDA-type glutamate receptor is associated with cutaneous barrier homeostasis / J. Invest. Dermatol, 2003, - V. 120. - P. 1023-1029). A decrease in the severity of hyperalgesia, inflammatory hyperemia, and muscle pain in humans has been shown with local superficial intradermal administration of the NMDA antagonist ketamine and phentamine opioid (Koppert W., Zeck S., Blunt JA, Schmelz M. The Effects of Intradermal Fentanyl and Ketamine on Capsaicinin-Induced Hyperalgesia and Flare Reaction / Anesth Analg, 1999 .-- V. 89 (6) - p. 1521-1527; Cairns BE, Svensson P., Wang K. et al. Activation of Peripheral NMDA Receptors Contributes to Human Pain and Rat Afferent Discharges Evoked by Injection of Glutamate into the Masseter Muscle J Neurophysiol, 2003. - # 90. - P.2098-2105).

Hyperactivation of NMDA receptors is a critical factor in tissue damage mechanisms under oxidative stress (Said SI, Pakbaz N., Berisha HI, Raza S. NMDA receptor activation: critical role in oxidant tissue injury / Free Radical Biology and Medicine, 2000. - V. 28 (8) .- P. 1300-1302). In this regard, the above mechanism of action of xenon is directly related to another of its mechanism - the ability to regulate the antioxidant status of the body. This phenomenon was identified by Russian scientists in experiments on animals in which, with the introduction of gas, a decrease in the activity of lipid peroxidation processes was noted (Burov N.E., Potapov V.I., Makeev G.N. Xenon in anesthesiology / M., Pulse, 2000. - 356 s; The use of xenon in medicine. Edited by N.I.Suslov, M.N.Shispman, V.N. Potapov / Tomsk, 2008. - 300 s). Since xenon is an inert gas, it is not able to directly inactivate the toxic products of lipid peroxidation, and its effect is determined by the properties of a structural (non-specific) antioxidant. Such compounds change the configuration of the structural elements of the membrane lipid bilayer, increasing its resistance to the toxic effect of peroxide radicals (Kuzmenko D.I., Serebrov V.Yu., Udintsev S.N. Free radical lipid oxidation, reactive oxygen species and antioxidants: a role in physiology and cell pathology / Tomsk, 2007 .-- 214 s). Xenon also has a high affinity for the main lipid component of biomembranes - phosphatidylcholine, the solubility of which in gas is 6 times higher than in other lipids. Included in it, xenon changes the surface area and thickness of the membranes, as well as the configuration of the fatty acid chains, shielding portions of lipids predisposed to the formation of active radicals (Stimson LM, Vattulainen L, Rog T. Et al. Exploring the effect of xenon on biomembranes. Cellular & Molecular biology letters, v. 10, 2005, p. 563-569; Yuan H .; Jameson CJ; Murad S. Exploring gas permeability of lipid membranes using coarse-grained molecular dynamics. Molecular Simulation, Volume 35, Issue 10 & 11 September 2009, pages 953-961). By changing the physicochemical characteristics of membranes, including their viscosity, xenon also affects their permeability, thereby exhibiting enhancer properties, the effect of which is two-stage. At the first stage, xenon reduces the viscosity of lipids, changes the conformation of membranes, on the one hand, increasing their throughput for molecules of active substances, on the other hand, showing a protective effect as an antioxidant. The second stage is the effect of gas on the NMDA receptors of the skin, as a result of which its homeostasis changes (Fuziwara S., Inoue K., Denda M. NMDA-type glutamate receptor is associated with cutaneous barrier homeostasis / J. Invest. Dermatol, 2003, - V. .. 120. - P. 1023-1029). Finally, xenon exhibits the specific analgesic effect described above, which creates the conditions for enhancing (potentiating) the effect of active substances with a similar effect.

The introduction of xenon or a gaseous mixture containing xenon into an acceptable carrier has been found to increase the effectiveness of drugs or cosmetics applied to the skin or mucous membrane due to increased transepidermal transport of the bioactive compounds in the composition of these agents.

The term "acceptable neutral carrier" means gaseous, liquid, solid, semi-solid carriers. Carriers may also contain various active and targeted additives, and carriers may also include standard components.

The term "standard components", included in an acceptable carrier used in this text of the description, means the necessary ingredients that make up any composition, i.e. a mixture of natural and synthetic products, namely: vegetable and animal oils, stabilizers, structure-forming agents, thickeners, gel-forming agents, emulsifiers and co-emulsifiers, silicones and their derivatives, preservatives, perfumes, rheological additives, active substances and their mixtures, and any other known and used in the manufacture of cosmetic products.

The amount of xenon in the final composition in the proposed embodiments of the composition is 1-300 vol.%. In this case, the amount of xenon introduced is determined mainly on the basis of the content of the fat (oil) phase in an acceptable neutral carrier, or a medicinal and / or cosmetic preparation.

The upper limit of xenon concentration (300 vol.%) Is justified by possibly the maximum solubility of the gas in pure oil. The lower limit of xenon concentration in an acceptable neutral carrier, or a medicinal and / or cosmetic preparation (1 vol.%) Is justified by the fact that from this value of the xenon content the manifestation of the properties of this gas becomes noticeable.

The proposed acceptable neutral carrier, or drug and / or cosmetic product may be in liquid form, for example, in the form of a solution, aerosol, foam, drops, suspension, emulsion, gel, liquid ointment or other forms suitable for application to skin or mucous membranes shell. They can also be in solid or semi-solid form, for example, in the form of powder, granules, pessary, suppository, cream, gel, solid ointment or other forms suitable for application to skin or mucous membranes.

The term "effective amount of gaseous xenon" in cosmetics for the care of skin, nails, hair, mucous membranes implies an amount sufficient to achieve an improved condition of the skin, nails, hair, mucous membranes. And for the treatment of diseases of the skin, nails, hair, mucous membranes, subcutaneous fat, connective tissue, musculoskeletal system, muscle tissue, an effective amount of gaseous xenon is the amount of xenon sufficient to increase the effectiveness of the therapy.

The invention is illustrated by examples and illustrations displayed in figures 1-4.

Figure 1 - shows the border of normal skin and a full-layer wound.

Figure 2 - shows the creep of the epithelium after 7 days of the experiment.

Figure 3 - shows the restoration of the skin on the 15th day of the experiment.

Figure 4 - shows the normal structure of the sebaceous glands on the 15th day of the experiment.

Example 1

To demonstrate the claimed effects of xenon on increasing the permeability of the skin for external components, tests were carried out using standard equipment (Franz diffusion chambers) on the skin of outbred rabbits. As a sample of external funds used the base emulsion of the following composition:

deionized water - 85.0%,

emulsifier DC 5329 (PEG-12 dimethicone) - 3.0%,

cyclomethicone - 4.0%,

capric / caprylic triglyceride - 6.0%,

emulsifier / thickener SEPIGEL EG - 2.0%

Ascorbic acid in an amount of 2.0% was added to this base emulsion during preparation as an active ingredient. Test leather was prepared in a standard manner. The diffusion area of the skin was 2.55 cm, the volume of the lower, receiving chamber was 15 ml. In the lower chamber was phosphate buffer (pH 7.4). The temperature in the chamber was 37 ° C. At the beginning of the test, 1 ml of an ascorbic acid emulsion was applied to the skin from above. The test was carried out for 24 hours. The effectiveness of skin permeability was determined by measuring the amount of ascorbic acid by a spectrophotometric method. For this, 1 ml samples were taken from the lower chamber. By standard calculations and summing the results within 24 hours, the amount of ascorbic acid passed through the skin into the lower chamber was obtained. The results were expressed as% of the amount of ascorbic acid contained in the emulsion, applied in the upper part from above to the skin.

The test method described above was used to study the effects of xenon in various methods of administration to the skin.

The first method: the introduction of xenon in the composition of the emulsion containing ascorbic acid. In this method, when preparing the emulsion, xenon was introduced into the oil phase in various amounts previously in the following way: a certain amount of the oil phase was drawn into a 150 ml syringe, then the required amount of xenon was collected through a tube from the balloon, then it was mixed vigorously, dissolving xenon and compensating for the decrease in volume by moving the piston. The oil phase in the emulsion is 10%. Accordingly, in volume percent, the xenon content in the test samples of the emulsion was 2 vol.%, 5 vol.%, 10 vol.%, 20 vol.% And 30 vol.% Per 100 g of emulsion. Xenon-free emulsion was applied to control skin samples.

Received the following results, shown in table 1.

Table 1 The effect of xenon on ascorbic acid transport through the skin The amount of ascorbic acid passing through the skin, in% of the content in the emulsion Control, emulsion without xenon 35.1% Experience No. 1.2 vol.% Xenon 38.2% Experience No. 2, 5 vol.% Xenon 37.7% Experience No. 3, 10 vol.% Xenon 42.5% Experience No. 4, 20% vol. Xenon 56.6% Experience No. 5, 30% vol. Xenon 58.2%

The results showed that the maximum effect on the permeability of the skin has the introduction of xenon at a concentration of 20 vol.% And 30 vol.%. A small effect is observed when the xenon content in the emulsion in the amount of 2 vol.% And 5 vol.%.

The second method: pre-treatment of the skin with a xenon carrier. As xenon carriers, deionized water or polyisobutene was used. Xenon was introduced into water in the following dosages: 1 vol.%, 5 vol.%, 10 vol.%. In polyisobutene - 5 vol.%, 10 vol.%, 50 vol.%, 100 vol.%, 200 vol.%, 300 vol.%. The introduction of xenon into water and polyisobutene was carried out using a syringe, as described above.

Control skin samples were pre-treated separately with water and polyisobutene without xenon by 3 times wetting the surface of the skin samples. Prototypes were treated in the same way, but with xenon content, as described above. Immediately after treatment, an emulsion with ascorbic acid was applied.

The test results shown in tables 2, 3.

table 2 The effect of xenon on ascorbic acid transport through rabbit skin Xenon Carrier - Water The amount of ascorbic acid passing through the skin, in% of the content in the emulsion Control No. 1 (water without xenon) 33.2% Experience No. 1-1, 1 vol.% Xenon 32.8% Experience No. 1-2, 5 vol.% Xenon 38.2% Experience No. 1-3, 10 vol.% Xenon 45.1%

The results showed that pre-treatment of the skin surface with water with xenon increases its permeability to ascorbic acid. The greatest effect is observed with a xenon content of 10 vol.%.

Table 3 The effect of xenon on ascorbic acid transport through rabbit skin Xenon Carrier - Polyisobutene The amount of ascorbic acid passing through the skin, in% of the content in the emulsion Control No. 2 (polyisobutene without xenon) 27.8% Experience No. 2-1, 5 vol.% Xenon 31.2% Experience No. 2-2, 10% vol. Xenon 37.3% Experience No. 2-3, 50% vol. Xenon 43.4% Experience No. 2-4, 100% vol. Xenon 49.9% Experience No. 2-5,200% vol. Xenon 54.7% Experience No. 2-6, 300 vol.% Xenon 57.4%

As a result of the test, results were obtained showing that pre-treatment of the skin surface with a carrier (polyisobutene) with xenon increases the skin permeability to ascorbic acid. The effect increases with increasing xenon content in the carrier.

Similar effects were obtained when a carrier with xenon was applied to the skin before an emulsion with ascorbic acid, or when both compositions were applied simultaneously.

Example 2

To study the effect of xenon-saturated water on hydration of the skin of the face, a test was conducted on volunteers (15 women) aged 24 to 39 years who did not have any pronounced changes in the skin of the face. All subjects were divided into 3 groups, 5 people each.

For research, deionized water was prepared with different xenon contents: 1%; 5%; 10%. As a control, deionized water was used.

Test design: for 8 days, the subjects in groups covered the left side of the face with a gauze cloth, abundantly moistened with water with xenon, for 10 minutes, in the appropriate concentration, daily, in the afternoon and in the evening. The right side of the face (control) in all subjects was also treated with water without xenon.

Skin hydration was determined using a Moisture Monitor, (SK, China) portable skin moisture meter in% every 2 days in the morning. The results in the groups were evaluated in%, summarized, and expressed in average terms.

The test results are shown in table 4.

Based on the data obtained, it is seen that the greatest moisturizing effect was observed when using water with a xenon content of 10 vol.% After 4 days of observation. A less pronounced effect was observed when using water with a xenon content of 5 vol.%. When the content of xenon in water in an amount of 1 vol.% The effect was not observed. The results show that surface treatment of the skin with water with xenon increases the skin's permeability to water, thus moisturizing it.

Example 3

In the experiments presented below, we investigated the effect of xenon on the healing process of wound skin damage in the experiment. This work was carried out on 30 outbred white male rats weighing 150-180 g. All animals under mild ether anesthesia, in the central region of the upper third of the back, a full-layer excision of the skin area was performed. Previously, on this surface, the hair was removed. The wound had a rounded shape with a diameter of 6 mm.

The healing of the wound area in all rats was carried out by primary tension with the formation of a characteristic scab of dark brown color. Material for the study was taken on the 7th and 15th day after the operation. Histological preparations were stained with conventional survey methods (hematoxylin-eosin, neutral red, azure II-eosin). All experimental animals were divided into 3 groups. The first group (10 rats) - control, i.e. these animals after excision of the skin were not exposed to any effects. The second group (10 rats) is experimental. After excision of the skin of these animals, a xenon-free cream was applied to the wound surface daily morning and evening. The third group (10 rats) - experimental. This group of animals after excision of the skin was exposed to a cream with xenon daily also in the morning and in the evening, the results are shown in figures 1-4.

The cream was prepared in accordance with one of the simple recipes, which includes: olive oil, aqueous St. John's wort extract, xenon, thickener / emulsifier DC RM 2051, preservative (mixture of parabens). Using DC RM 2051 allows you to enter into the composition of this cream a large amount of oil (40%). Before mixing and homogenizing the components, xenon was added to olive oil at the rate of 200 ml of xenon per 100 ml of oil. The final concentration of xenon in the cream was 80 vol.%.

As a result of morphological studies in animals of the first group, a slight decrease in the size of the wound was observed macroscopically during the first 7 days. Morphologically, the beginning of the crawl of the epithelium on the wound surface is noted. On day 15, the wound healing with scab rejection is macroscopically observed in animals of this group. On histological preparations, restoration of the epithelium is visible, however, elements of the dermis and appendages of the skin are poorly developed.

In the second group of rats, the regeneration pattern (macro- and microscopically) was slightly different and corresponded to that described above. The scab almost disappeared on the 9-10th day.

In the third group, on day 7, more pronounced wound healing was observed. The size of the wound decreased by about 2/3, the scab almost disappeared. An accelerated restoration of the hairline in the wound area was observed. On the 15th day, the structure of the epidermis was approaching normal, active regeneration of the dermis and appendages of the skin was observed due to the proliferation of cellular dermal elements, neoplasms of blood vessels.

As a result of the experimental work, we have shown the effectiveness of introducing xenon into the cream applied to the wound surface to activate the skin regeneration processes. In addition, accelerated restoration of the hairline was observed.

Example 4

For research and confirmation of the claimed effect, two compositions were used. The first composition is a xenon carrier. Diisopropyl adipate (DIA) was used as a carrier, in which xenon was dissolved in the range from 1 to 300 vol% (1%; 3%; 5%; 10%; 50%; 100%; 200%; 300%;). The second composition is a cream gel, which includes the following standard ingredients: deionized water, carbopol 974, hyaluronic acid, poloxamer 188, diisopropyl adipate, vitamin A, turmerone (turmeric extract), ethanolamine, preservative taken in known proportions. The used cosmetic composition of the cream for the skin of the face has a moisturizing, antioxidant, smoothing effect.

A clinical study was conducted in which volunteers took part - 45 women aged 35-56 years with signs of age-related skin changes. The experiment involved women who did not take hormonal drugs, did not suffer from dermatitis and allergic diseases.

Both compositions were previously investigated in accordance with the requirements of SanPiN 1.2.681-97 "Hygienic requirements for the production and safety of perfumes and cosmetics", approved by the Decree of the Chief State Sanitary Doctor of the Russian Federation No. 26 of 20/11/97.

The results of microbiological, chemical-analytical, toxicological studies have shown that the studied compositions are safe for human health, does not have an irritating effect, do not cause allergies.

Women were divided into 9 groups of 5 people each. Participants of each group twice a day (morning and evening) for 30 days applied both compositions to the skin of the face according to the scheme: after a light cleansing of the skin, the first composition was applied first, then, after even distribution and absorption (after 5 minutes), this the same area was applied to the second composition. Evaluation of effectiveness was evaluated by the questionnaire method. Preliminary skin tests of control and experimental creams of all participants gave a negative result: 100% of the subjects had no signs of irritation and / or allergy. Overall satisfaction with the results in all women was positive.

A subjective assessment of the effectiveness of the use of the compositions was carried out according to the following indicators:

- organoleptic characteristics of the product: texture, comfort during use, lack of stickiness and oily sheen.

- indicators of the skin condition: level of keratinization, moisture, elasticity, skin microrelief, lifting effect.

- psycho-emotional state of patients: well-being, activity, level of neuroticism (lack of anxiety, irritability), performance.

The indicators were evaluated every 3 days of the test on a 5-point scale, summing up the estimates of each group. A total score of at least 20 points was considered a positive result.

The test results are shown in table 5.

Positive results obtained in the course of this study showed that the result of increasing the effectiveness of face cream is achieved by applying the first composition with xenon content already at 3-5 vol.%. The fastest effect in this test is achieved by using the xenon concentration in the first composition starting at 50 vol.%.

Similar effects were obtained when applied to the skin of the carrier with xenon before applying the cream gel or while applying both compositions.

Example 5

A clinical study was conducted in which volunteers took part - 26 women aged 42-56 years with complaints of pain in the lumbar spine. On the basis of a clinical examination, the diagnosis was established: Lumbar osteochondrosis, lumbalgia syndrome in the stage of moderate exacerbation.

The experiment did not involve women who underwent surgical interventions over the past 6 months, taking any medications or biologically active food supplements, hormonal drugs that suffer from dermatitis and allergic diseases.

For treatment, the drug DIKLAC-gel was used (the active substance is diclofenac, excipients are isopropyl alcohol, macrogol-7-glycerol cocoate, hypromellose, aromatic oil, water) for local exposure to the lumbar region.

The xenon content in the preparation was 1.0 vol%, 5.0 vol%, 10.0 vol%, 30.0 vol%.

Women were divided into 5 groups of 3-5 people each. Participants in each group twice a day (morning and evening) rubbed a drug without xenon (control) into the skin of the lumbar region for 1-2 minutes, or this drug containing xenon in accordance with the above concentrations (experimental groups).

Evaluation of effectiveness was evaluated based on the analysis of the terms of the disappearance of the pain syndrome.

The following results were obtained:

Group 1 (control): the disappearance of pain after 9-10 days. (5 patients). Group 2 (xenon content in the cream of 1.0 vol.%): The disappearance of pain after 7-11 days (3 patients).

Group 3 (xenon content in the cream of 5.0 vol.%): The disappearance of pain after 4-5 days (5 patients).

Group 4 (xenon content in cream 10.0 vol.%): The disappearance of pain after 4-5 days (5 patients).

Group 5 (xenon content in cream 30.0 vol.%): The disappearance of pain after 2-3 days (4 patients).

The results showed that the visible effect is manifested when the xenon content of 5.0% vol. In the drug DIKLAC-gel. The greatest effect - with a xenon content of 30.0 vol.%.

Example 6

A clinical study was conducted in which volunteers took part - 24 women aged 42-56 years with complaints of pain in the lumbar spine. On the basis of a clinical examination, the diagnosis was established: lumbar osteochondrosis, lumbalgia syndrome in the stage of moderate exacerbation.

For treatment, the drug DIKLAC-gel was used (the active substance is diclofenac, excipients are isopropyl alcohol, macrogol-7-glycerol cocoate, hypromellose, aromatic oil, water) for local exposure to the lumbar region.

As the second agent, an emulsion composition of the following composition was used: water, olive oil (20%), thickener / emulsifier RM 2051 (sodium polyacrylate and dimethicone and cyclopentasiloxane and tridetet-6 and PEG / PPG-18/18 dimethicone). Xenon was introduced into this composition in concentrations: 1%; 5%; 10%; fifty%; one hundred%; 200%; 300% in terms of oil content. The final xenon content in the test samples of the composition was: 0.2%; one%; 2%; 10%; twenty%; 40% 60% A control sample of this composition did not contain xenon.

Women were divided into 8 groups of 3 people each. Participants in each group twice a day (morning and evening) rubbed the drug into the lumbar skin for 1-2 minutes, followed by application of the second agent / composition. The interval between the application of the drug and the prepared composition / cream was 5 minutes.

Evaluation of the effectiveness of the compositions was evaluated based on an analysis of the timing of the disappearance of the pain syndrome.

The following results were obtained:

Group 1 (control): the disappearance of pain after 9-11 days.

Group 2 (xenon content in the agent 0.2 vol.%): The disappearance of pain after 8-11

days.

Group 3 (xenon content in the agent 1 vol.%): The disappearance of pain after 6-8 days Group 4 (xenon content in the agent 1 vol.%): The disappearance of pain after 5-8

days.

Group 5 (xenon content in the tool 10 vol.%): The disappearance of pain after 3-4

of the day.

Group 6 (xenon content in the agent 20 vol.%): The disappearance of pain after 4-6

days.

Group 7 (xenon content in the tool 40 vol.%): The disappearance of pain after 2-3

of the day.

Group 8 (xenon content in the product 60 vol.%): The disappearance of pain through 2-Building.

As a result of the test, we can say - that a small effect was observed already when the content of xenon in the second agent was 1 vol.%. The maximum effect was observed with a xenon content of 10-60 vol.%.

Similar effects were obtained by applying a xenon carrier to the skin before applying the DIKLAC-gel preparation or while applying both compositions simultaneously.

Example 7

A clinical study was conducted in which volunteers took part - 18 men aged 30-48 years with infected household soft tissue wounds of various etiologies (cuts, burns).

In the treatment complex, the drug LEVOSIN-ointment for external use was used (the active substances are chloramphenicol, sulfadimethoxin, methyluracil, trimecain).

Xenon was introduced into the preparation. The gas content in the preparation was 1.0 vol.%, 5.0 vol.%, 10.0 vol.%, 50.0 vol.%, 100.0 vol.%.

Participants were divided into 6 groups of 3 people each. Participants of each group once in the morning applied a sterile gauze cloth soaked in a drug without xenon (control) or a drug containing xenon in accordance with the above concentrations (experimental groups) to the wound surface.

Evaluation of the effectiveness of the drug was evaluated based on the analysis of the timing of epithelization of the wound surface.

The following results were obtained:

Group 1 (control): epithelization after 6-7 days.

Group 2 (xenon content in the cream of 1.0 vol.%): Epithelization after 6-7 days.

Group 3 (xenon content in the cream of 5.0 vol.%): Epithelization after 6-7 days.

Group 4 (xenon content in cream 10.0 vol.%): Epithelization after 4-6 days.

Group 5 (xenon content in the cream of 50.0 vol.%): Epithelization after 4 days.

Group 6 (xenon content in the cream 100.0 vol.%): Epithelization after 3 days. Results: the maximum effect was observed when the xenon content in the preparation was 100.0 vol.%. A noticeable effect occurred when the xenon content of 10.0 vol.%.

Example 8

A clinical study was conducted in which volunteers took part - 17 men aged 28-54 years with open household wounds of soft tissues of the hands of various etiologies (cuts, burns) of a small area (4-7 cm2).

In the complex treatment, the drug LEVOSIN-ointment for external use was used (the active substances are chloramphenicol, sulfadimethoxin, methyluracil, trimecain).

As the second agent, an emulsion composition of the following composition was used: water, olive oil (20%), thickener / emulsifier RM 2051 (sodium polyacrylate and dimethicone and cyclopentasiloxane and tridetet-6 and PEG / PPG-18/18 dimethicone). Xenon was introduced into this composition in concentrations: 1%; 5%; 10%; fifty%; one hundred%; 200%; 300% in terms of oil content. The final xenon content in the test samples of the composition was: 0.2%; one%; 2%; 10%; twenty%; 40% 60% A control sample of this composition did not contain xenon.

The participants were divided into 7 experimental groups of 2 people each, in the control group there were 3 people. Participants of each group once in the morning applied a sterile gauze cloth impregnated with a medicinal product onto the wound surface, on top of which they applied the same cloth soaked with a second agent without xenon (control), or agents containing xenon in accordance with the above concentrations (experimental groups )

Evaluation of the effectiveness of the compositions was evaluated based on the analysis of the terms of epithelization of the wound surface.

The following results were obtained:

Group 1 (control): epithelization after 6-8 days.

Group 2 (xenon content in the agent 0.2 vol.%): Epithelization after 6-7 days.

Group 3 (xenon content in the agent 1 vol.%): Epithelization after 5 days.

Group 4 (xenon content in the tool 2 vol.%): Epithelization after 5-6 days.

Group 5 (xenon content in the tool 10 vol.%): Epithelization after 4-5 days.

Group 6 (xenon content in the agent 20 vol.%): Epithelization after 3-5 days.

Group 7 (xenon content in the tool 40 vol.%): Epithelization after 3 days.

Group 8 (xenon content in the vehicle 60 vol.%): Epithelization after 3 days.

As a result, we can conclude that the effect occurs already at a concentration of xenon in the second agent of 1 vol.%, And the maximum effect - with a xenon content of 20-60 vol.%.

Similar effects were obtained when applied to the skin of the carrier with xenon before applying the ointment - LEVOSIN or while applying both compositions.

Example 9

The study used olive oil in which the lipophilic dye was dissolved - Sudan black at a concentration of 1%. Xenon was dissolved in a test sample at a concentration of 100 vol.%. Both samples, control (without xenon) and experimental, were applied to the front surface of the skin in the forearm, the application area was 1 cm2, at a distance of 5 cm from each other. The observation was carried out continuously for 20 minutes, visually determining the area of spreadability and absorption on the skin. A total of five observations were carried out using different parts of the front surface of the forearms of both hands. The observation results were expressed as a percentage. As a result of observations, it was noted that the prototype had the ability to spread on the skin by an average of 38% more than the control. In addition, after removing samples from the skin by gently blotting with filter paper, more intense staining was observed at the sites of the test samples. Thus, xenon oil samples showed higher permeability in the epidermis of the skin.

Example 10

Two products were used: GARNIER self-tanning milk (product No. 1) and body lotion also with DOVE self-tanning effect (product No. 2). Xenon was introduced into agent No. 1 at a concentration of 30 vol.%. Xenon was introduced into agent No. 2 at a concentration of 25 vol.%. Both agents with xenon (prototypes) and without xenon (control samples) were used in the test. Control and experimental samples were applied to the skin of the front surface of the forearm. The application area was 3 cm. The appearance of pigmentation was observed within 24 hours. The test was repeated 5 times with each agent.

The results are presented in table 6.

Table 6 The effect of xenon on the effectiveness of tanning In 2 hours In 6 hours After 12 hours After 18 hours Gamier, control Lack of pigmentation The appearance of pigmentation Clearly visible pigmentation Maximum pigmentation Gamier, experience The appearance of pigmentation Clearly visible pigmentation Maximum pigmentation Maximum pigmentation Dove, control Lack of pigmentation Minor appearance of pigmentation Pigmentation enhancement Maximum pigmentation Dove experience Lack of pigmentation Minor appearance of pigmentation Distinct pigmentation Maximum pigmentation

As a result of observations, it was shown that the introduction of xenon in the composition of commercial products Gamier and Dove at a concentration of 25-30 vol.% Accelerated the appearance of skin pigmentation.

Example 11

We conducted a study of the effect of xenon on the effectiveness of acne treatment. Sulfur ointment (10%) without xenon and with xenon at a concentration of 100 ml of xenon per 100 ml of ointment was used for treatment. Control and experimental samples of the ointment were applied to the affected areas of the skin 3 times a day, morning, afternoon, evening. According to the results of the work, a very good result was obtained in all 9 patients when using sulfuric ointment with xenon. The therapeutic effect was observed 1 day after application. Moreover, patients observed an acceleration of the absorption of the ointment. After 4-5 days, persistent signs of recovery were observed. When applying sulfuric ointment without xenon, signs of recovery appeared only after 7-8 days.

Conclusion: Xenon significantly increases the effectiveness of sulfuric ointment in the treatment of acne.

Example 12

We conducted a dermatological study of the action of xenon in patients with foot mycosis complicated by allergic contact dermatitis, and in patients with seborrheic dermatitis. Patients with pronounced symptoms of skin diseases were selected for the test. For the test, olive oil with xenon was prepared (200 ml of xenon per 100 ml of oil).

Two patients (women, 52 years old and 48 years old) were diagnosed with foot mycosis complicated by allergic contact dermatitis. For treatment was used cream "Terbizil", 1%. The treatment regimen: local effect on the right limb of Terbizil cream in alternation mode - morning-evening; on the left extremity - Terbizil cream mixed with xenon oil (1/2) in the same mode. Results were evaluated after 7 and 14 days. Evaluation of the results: on the left limb, after days the erythematous coloration of the foci and peeling decreased significantly more than on the right. There is a clear regression of rash elements. After 14 days, the left limb had normal skin color, rash elements regressed, cracks in the heel skin were not detected; peeling on the skin of the right extremity persisted, cracks in the heel were observed. The fungus was not detected microscopically on both limbs. Thus, an obvious reduction in the treatment time was observed when a traditional medicine (Terbizil cream, 1%) was applied to the skin in combination with xenon oil.

Example 13

We conducted a study in which 2 patients (women, 18 and 22 years old) participated, with an established diagnosis - seborrheic dermatitis in the scalp, forehead and nose. In the treatment of patients for 14 days, Elokon lotion was used according to the scheme: the right side of the head - Elokon lotion 2 times a day; the left part of the head is Elokon lotion mixed with xenon oil (1/2), also 2 times a day. As a result of treatment, it was noted that after 7 days on the left side of the scalp erythema and peeling were not observed, on the right side - the number of plaques and redness decreased, but is still preserved. After 14 days, the left side was completely healthy, on the right side, small foci of desquamation, erythematosus were noticeable. Based on the results, we conclude that accelerated clinical recovery when exposed to a traditional drug (Elokon lotion) in combination with xenon oil. *

Claims (8)

1. A method of increasing transdermal permeability of therapeutic or cosmetic preparations for external use, comprising introducing into the skin from 1.0 to 300.0% by volume of xenon gas as part of an acceptable neutral carrier or therapeutic or cosmetic preparation. 2. The method according to claim 1, in which at least one substance is selected as an acceptable neutral carrier of gaseous xenon. 3. The method according to claim 1, in which an effective amount of gaseous xenon is dissolved in an acceptable neutral carrier, or a therapeutic or cosmetic preparation. 4. The method according to claim 1, in which an acceptable neutral xenon carrier, therapeutic or cosmetic preparation is used in gaseous, or liquid, or semi-solid, or solid form. 5. The method according to claim 1, in which for the care of skin, nails, hair, mucous membranes an effective amount of gaseous xenon is the amount of xenon sufficient to achieve an improved condition of the skin, nails, hair, mucous membranes. 6. The method according to claim 1, in which for the treatment of diseases of the skin, nails, hair, mucous membranes, subcutaneous fat, connective tissue, musculoskeletal system, muscle tissue, an effective amount of xenon gas is an amount of xenon sufficient to increase the effectiveness of therapy. 7. The method of introducing into the skin of gaseous xenon, which consists in the fact that to increase the transdermal permeability of therapeutic or cosmetic preparations for external use, the introduction into the skin of from 1.0 to 300.0 vol.% Gaseous xenon in an acceptable neutral carrier or therapeutic or cosmetic the drug is carried out topically according to any one of claims 1 to 6. 8. The method according to claim 7, in which the introduction into the skin of an effective amount of gaseous xenon to increase the transdermal permeability of therapeutic or cosmetic preparations is carried out with diversity in time and order or simultaneously.

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