Method for producing a topical agent with a stable and long-lasting inert gas content

Abstract

The invention relates to the cosmetic and pharmaceutical industries and consists in a method for enhancing the penetration effect of therapeutic or cosmetic agents having a stable and long-lasting inert gas content. The method includes introducing gaseous krypton or a mixture thereof with xenon using an installation for the introduction of gas consisting of a mixer reactor, and a retractable or submersible homogenizer in an upper or lower position, said installation further comprising a vacuum pump and an automatic gas supply module, to produce a target agent containing from 3 to 31 vol.% gaseous krypton. The automatic module comprises a control unit, and gas supply assemblies, the structural parameters of which depend on the dimensions of the homogenizer system. To produce a target agent, the speed and quantity of the gas being introduced into liquid media are controlled.

Description

[0001] METHOD FOR OBTAINING A TOPICAL AGENT WITH A STABLE, LONG-TERM CONTENT OF INERT GAS

[0002] The invention relates to the cosmetic and pharmaceutical industries and is a method for enhancing the effect of penetration of medicinal or cosmetic products with a stable, long-term content of inert gas.

[0003] The use of inert gas xenon in cosmetic creams is known (https: / / tass.ru / v-strane / 71O8989).

[0004] It is also known that therapeutic xenon inhalations improve a person's general condition, including during stress. These procedures are not yet very widespread, since xenon is expensive (a liter of gas costs more than 6 thousand rubles, one inhalation requires about 4-5 liters).

[0005] There are many known methods for correcting the manifestations of local edema and neuropathy and improving blood supply, both medicinal and physiotherapeutic, for example, medicinal electrophoresis, magnetic therapy, ultratonotherapy, local darsonvalization, ultrasound therapy (Nuvakhova M.B., Marchenkova L.A., 2017). All the described methods are aimed at improving microcirculation and blood supply and reducing the phenomena of local edema in the area of ​​the affected skin.

[0006] An invention is known that relates to medicine, namely to cosmetology and physiotherapy (RU patent 2735464, A61M 5 / 142U published on November 2, 2020). The procedure is carried out using the CarboxyPen device by mesotherapeutic administration of carbon dioxide using mesotherapeutic needles, 30G on the Gage scale, 6 to 13 mm long: intradermally or subcutaneously, at 3-10 points, to a depth of 3-6 mm. In this case, 2 to 5 ml of carbon dioxide is used per 1 injection. The total amount of carbon dioxide for one procedure is 10-20 ml. The course of treatment is 5-6 times, every other day. In this case, carbon dioxide injections are carried out near the areas of the skin where there are manifestations of edema and neuropathies, at a distance of 0.1-1 cm from them and along the postauricular, submandibular and cervical collectors, at a distance of 0.1-1 cm from them. A number of technical solutions have been identified from the level of technology, which describe various methods of introducing inert gases in the treatment and prevention of various diseases.

[0007] A method for introducing xenon into the human body during xenon therapy is known (RU Patent 2706424, A61M 16 / 10, published on 11 / 19 / 2019). To introduce into the body the amount of xenon necessary for the prevention and treatment of the disease, a xenon clathrate compound is used, which is a compound in which xenon molecules are located in the voids of the framework formed by the crystal lattice of ice, the xenon clathrate is introduced into the gastrointestinal tract of the body through a carrier of the dosage form for oral administration.

[0008] Disadvantage - requires a special heat-stable shell, storage at low temperatures.

[0009] A method of xenon therapy is known, which is based on the inhalation of xenon, namely, inhalation of a gas mixture of xenon and oxygen. For example, technical solutions (see Russian patents No. 2446837, No. 2392011, No. 2339409, No. 2319515, No. 2305565).

[0010] But to carry out such therapy, trained specialists and special equipment are needed. Due to the peculiarities of xenon absorption, the total duration of the procedure is 30-40 minutes.

[0011] A method for increasing the transdermal permeability of medicinal or cosmetic preparations for external use, a method for introducing gaseous xenon into the skin is known (RU Patent 2506944, A61K 9 / 00, A61K 33 / 00, A61P 17 / 00, A61P 19 / 00, A61P 21 / 00, A61K 8 / 00, A61Q 5 / 00, A61Q 19 / 00, published on 20.02.2014). The invention relates to the cosmetic and pharmaceutical industries and is a method for increasing the transdermal permeability of medicinal or cosmetic preparations for external use.

[0012] The method involves introducing 1.0 to 300.0 vol.% of gaseous xenon into the skin as part of an acceptable neutral carrier or a medicinal or cosmetic preparation. The invention provides for an increase in the effectiveness of medicinal or cosmetic products by increasing the transepidermal transport of bioactive compounds. A disadvantage of the known solution is the impossibility of ensuring a stable content of the inert gas introduced as part of the external agent, as well as the high cost of xenon.

[0013] The objective of the claimed invention is to create a method that increases the penetration rate and effectiveness of medical and cosmetic products due to krypton or its mixture with xenon, and also ensures a stable content of the inert gas introduced using a gas introduction unit. Krypton is an inert monatomic gas without color, taste and smell. It is obtained as a by-product in the form of a krypton-xenon mixture in the process of air separation in industrial plants. In the process of air separation by the low-temperature rectification method, a liquid oxygen fraction containing liquid hydrocarbons, krypton and xenon is constantly selected (selection of the oxygen fraction with hydrocarbons is necessary to ensure explosion safety).To extract krypton and xenon from the fraction being collected, hydrocarbons are removed in catalytic furnaces and sent to an additional rectification column to remove oxygen; after enrichment of the Kr+Xe mixture to 98–99%, it is re-purified in catalytic furnaces from hydrocarbons, and then in a block of adsorbers filled with silica gel (or another adsorbent). After cleaning the gas mixture from residual hydrocarbons and moisture, it is pumped into cylinders for transportation to a Kr and Xe separation unit (this is due to the fact that not every enterprise operating air separation units has a Kr and Xe separation unit).

[0014] Xenon is an inert noble gas, absolutely non-toxic, does not react with biological molecules, does not exhibit mutagenic, teratogenic, cyto- and immunotoxic properties. It has been used in medicine since 1951 for inhalation anesthesia. When introduced into the body, the gas is completely eliminated 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 the gas has been shown in neurotoxicity of various origins, Parkinson's disease, schizophrenia, and 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. NY Acad. Sci. 2005, 1053: P.289-300). The gas is increasingly used in subnarcotic (small) doses for therapeutic anesthesia in neurotoxicity of various origins (Abraini J.H., David H.N., 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 when liposomes with this gas are introduced into the vessels of the brain, which contributes to a significant acceleration of the restoration of brain tissue reparation and a decrease in neurotoxicity after stroke (Britton GL, Kim H., Kee R.H. et al. In Vivo Therapeutic Gas Delivery for Neuroprotection with Echogenic Liposomes / Circulation. 2010, 122(16): 1578-1587).

[0015] It is known that the inert gas xenon has antioxidant properties.

[0016] The stated problem is solved in that the method for increasing the degree of penetration and effectiveness of medical or cosmetic products with a stable long-term content of inert gas includes the introduction of gaseous krypton or its mixture with xenon using a gas introduction unit consisting of a reactor-mixer, a remote or submersible homogenizer with a lower or upper location, wherein the unit additionally contains a vacuum pump and an automated module for feeding gases, with the production of a final product containing from 3 to 31 vol.% of gaseous krypton.

[0017] The automated module consists of a control unit, gas supply units, the design parameters of which depend on the size of the homogenizer system.

[0018] The gas injection unit uses a gas supply unit, which is made in the form of, for example, a tube, the design parameters of which depend on the dimensions of the homogenizer system. The method controls gas injection by controlling the speed and amount of gas injection into liquid media. The gas flow in the direction of the homogenizer is adjusted using regulating gas valves. At least one substance is selected as an acceptable carrier of gaseous krypton or its mixture with xenon. A therapeutic or cosmetic agent in liquid, soft or semi-solid form is used as a carrier of krypton or its mixture with xenon.

[0019] The method uses two peristaltic pumps, each connected to a separate gas cylinder. This creates two gas supply lines into the liquid. A vacuum pump is used to degas the liquid, and an electro-vacuum meter is used to control the pressure, allowing negative and positive pressure to be controlled. The device is controlled by a microprocessor.

[0020] The operating procedure of the device in different modes is given below. Figure 1 shows a diagram of the device for implementing the method.

[0021] Mode 1. Introduction of krypton with maximum content in the product:

[0022] The reactor-mixer (9) equipped with a submersible homogenizer (11), frame stirrer (14) and top cover (10) is filled with the agent. The top cover (10) is hermetically sealed. The frame stirrer and vacuum pump (8) are switched on. Degassing of the liquid medium begins. The degassing time varies and depends on the nature of the liquid medium and the degree of its contamination with ballast gases. The vacuuming process is monitored using a pressure gauge (6). When the pressure gauge reading reaches a negative pressure of - 0.2 MPa, a signal is sent to the microprocessor (7), as a result of which the vacuum pump (8) is switched off. Then the homogenizer is switched on with the simultaneous opening of the valve (3.1) at the outlet of the reducer (2.1) of the cylinder with krypton (1.1), the valve at the inlet to the reactor-mixer (5.1) and the peristaltic pump (4.1) on the krypton line. The pump speed and duration of its operation are pre-set on the microprocessor control panel (7) so that 2 to 10 liters of gas are supplied per 100 liters of liquid medium in 1 minute.During the first minutes of the process, krypton is dissolved in the volume of liquid, partially exiting it, filling the vacuum space under the cover (10) of the reactor-mixer (9). When the space under the cover (10) is completely filled with krypton, the pressure is equalized, and the signal from the electric pressure-vacuum meter (6) is fed to the microprocessor (7), while the peristaltic pump (4.1) is simultaneously stopped and the valves (3.1) and (5.1) of the krypton line are closed. In this way, the maximum concentration of krypton in the carrier is obtained. In this mode, using a mixture of oils: olive oil / sunflower oil / cedar nut oil in the ratio 5 / 3 / 2 (from Example 2), we obtained a concentration of krypton in this mixture of oils of 31 vol.%.

[0023] Mode 2. Introduction of krypton with a given content in the agent:

[0024] Fill the reactor-mixer (9) with the agent, equipped with a submersible homogenizer 11, a frame stirrer 14 and an upper cover 10. Close the upper cover (10) hermetically. Turn on the frame stirrer and the vacuum pump (8). Degassing of the liquid medium begins. The degassing time varies and depends on the nature of the liquid medium and the degree of its contamination with ballast gases. The vacuuming process is monitored using a pressure gauge (6). When the pressure gauge reading reaches a negative pressure of -0.2 MPa, a signal is sent to the microprocessor (7), as a result of which the vacuum pump (8) is switched off. Then the pressure is equalized by letting in air. Then the homogenizer is switched on with the simultaneous opening of the valve (3.1) at the outlet of the reducer (2.1) of the cylinder with krypton (1.1), the valve at the inlet to the reactor-mixer (5.1) and the peristaltic pump (4.1.) on the krypton line. The pump speed and the duration of its operation on the microprocessor control panel (7) allow you to control the amount of gas supplied to the reactor.In this way, the required amount of krypton is introduced into the carrier from the minimum to the maximum possible.

[0025] Mode 3. Introduction of krypton and xenon in the medium:

[0026] The reactor-mixer (9) equipped with an immersion homogenizer (I), a frame stirrer (14) and an upper cover (10) is filled with the agent. The upper cover (10) is hermetically sealed. The frame stirrer and the vacuum pump (8) are switched on. Degassing of the liquid medium begins. The degassing time varies and depends on the nature of the liquid medium and the degree of its contamination with ballast gases. The vacuuming process is monitored using a pressure gauge (6). When the pressure gauge reading reaches a negative pressure of - 0.2 MPa, a signal is sent to the microprocessor (7), as a result of which the vacuum pump (8) is switched off. Then the homogenizer is switched on with the simultaneous opening of the valve (3.1) at the outlet of the reducer (2.1) of the cylinder with krypton (1.1), the valve at the inlet to the reactor-mixer (5.1) and the peristaltic pump (4.1) on the krypton line. The pump speed and duration of its operation are pre-set on the microprocessor control panel (7) so that 2 to 10 liters of gas are supplied per 100 liters of liquid medium in 1 minute.During the first minutes of the process, krypton dissolves in the volume of liquid, partially exiting it, filling the vacuum space under the cover (10) of the reactor-mixer (9). When the space under the cover (10) is completely filled with krypton, the pressure equalizes, and the signal from the electric pressure-vacuum meter (6) is fed to the microprocessor (7), while the peristaltic pump (4.1) is simultaneously stopped and the valves (3.1) and (5.1) of the krypton line are closed.

[0027] Then the xenon line is switched on: simultaneously the peristaltic pump (4.2) is started and the valves (3.2) and (5.2) are opened to supply xenon from the cylinder (1.2) through the reducer (2.2) into the reactor-mixer (9). The pump speed and the duration of its operation are preliminarily set on the microprocessor control panel (7) so that from 2 to 200 liters of gas are supplied per 100 liters of liquid medium in 1 minute. During this process, xenon dissolves in the liquid medium. The amount of gas required for introduction into the liquid is controlled by setting the speed and operating time of the peristaltic pump (4.2) of the xenon line on the microprocessor control panel (7). When the pressure under the cover (10) of the reactor-mixer (9) increases to 0.1 MPa, a signal is sent from the electric pressure-vacuum meter (6) to the microprocessor (7) for simultaneous stopping of the peristaltic pump (4.2) and the valves (3.2) and (5.2) of the xenon line. In this way, possible technological losses of xenon are eliminated.Homogenizers (11), (12) ensure complete dissolution of gases in liquid, and the frame stirrer distributes gas throughout the entire volume of liquid.

[0028] The operation of the device was tested on industrial equipment for the production of cosmetic products and means with a 20-liter reactor-mixer equipped with an immersion homogenizer, frame mixer, and vacuum pump.

[0029] Examples of specific implementation of the invention are given below:

[0030] Example 1.

[0031] The described method was used to introduce two gases, xenon and krypton, into a cosmetic cream using equipment with a reactor-mixer with a total volume of 20 l and a working volume of 16 l. Thus, the space under the lid above the cosmetic product was 4 l. 2.0 l of xenon and 5.0 l of krypton were introduced into the cosmetic cream (composition: water, silica gel, heliophil, cetyl alcohol, plant squalane, glycerin, panthenol, niacinamide, preservative), while 4.0 l of krypton filled the space under the reactor lid, i.e. the krypton / xenon ratio in the product was 1 / 2. The finished product was poured into airless dispensers with a volume of 50 ml. After one week, the measurement of the xenon content in the cream showed 10.8 vol.% and krypton 4.9 vol.%, which corresponds to 1.8 l of xenon and 0.8 l of krypton. It should be taken into account that 4.0 l of krypton was used to fill the space under the reactor lid after vacuuming for the purpose of degassing the cosmetic cream. The minimum gas losses are shown here.After 9 months, gas concentration measurements showed the following results: xenon - 10.1 vol.% and krypton - 4.7 vol.%. In this case, long-term stability of the xenon and krypton content in the cream is demonstrated, which is important for confirming the shelf life of the finished product.

[0032] In another case, krypton and xenon were introduced into the same product in other ratios: 3 vol.% krypton and 9 vol.% xenon (krypton / xenon ratio 1 / 3). Then the produced cream was packaged in 50 ml aluminum tubes, sealed and stored under normal conditions. We present measurements of the content of inert gases in the cream at 5 time points: immediately (0), after 2 weeks, after 4 weeks, after 24 weeks and after 48 weeks. Table 1 shows the values ​​of the content of krypton and xenon for different time periods.

[0033] Table 1

[0034] In the same cream, measurements were carried out in an open test tube, with a volume of 50 ml, the evaporation / contact area with air was 2.5 square cm. The total content of inert gases was 12% (9% xenon, 3% krypton).

[0035] We present measurements of the inert gas content in the cream at 5 time points: immediately, after 1 day, after 3 days, after 6 days, after 30 days and after 60 days. Table 2 shows the krypton and xenon content values ​​for different time periods.

[0036] Table 2

[0037] Next, xenon alone was introduced into the same product at the same concentration of 9 vol.%. The cream was also packaged in 50 ml aluminum tubes. Measurements immediately (0), after 2 weeks, after 4 weeks, after 24 weeks, and after 48 weeks showed a stable xenon content of 9 vol.% for all test periods. Then the test was carried out under storage conditions in an open test tube also immediately, after 1 day, after 3 days, after 6 days, after 30 days, and after 60 days. Table 3 shows the xenon content values ​​for different time periods.

[0038] Table 3

[0039] Example 2.

[0040] In this example, a mixture of oils was used as a cosmetic product: olive / sunflower / cedar nut oil in a ratio of 5 / 3 / 2, into which krypton and xenon were also introduced. The mixture of oils is able to nourish and moisturize the skin, relieve itching and inflammation. Here, a remote homogenizer (13) was used, into which inert gases were introduced through a tube (15) built into the inlet pipe of the homogenizer, through which the liquid medium enters the homogenizer. Xenon was introduced into the oil mixture in a volume of 6.0 l and krypton - 5.0 l (of which 4.0 l filled the space under the lid above the oil mixture, i.e. the krypton / xenon ratio in the product was 1 / 6. After the procedure of introducing gases, the oil mixture was poured into a sealed container and sent for encapsulation in soft gelatin capsules. Then, the xenon and krypton content in these soft gelatin capsules was measured in the capsules during the week after encapsulation and after 9 months.The measurement results showed that after a week there was 35.7 vol.% xenon and 5.4 vol.% krypton, which corresponds to 5.7 l xenon and 0.9 l krypton per 16 l of oil mixture. Thus, this method shows minimal losses of xenon when it is dissolved in a liquid product. Good results were also obtained for krypton, given the fact that a significant amount of it (4.0 l) was used to fill the space between the lid and the oil mixture. Measurements of the xenon and krypton content after 9 months showed the following results: xenon - 33.7 vol.%, krypton - 4.5%, which shows long-term stability of their content.

[0041] In another case, the same mixture of vegetable oils was used to introduce krypton and xenon.

[0042] The final product contained 30 vol.% xenon and 10 vol.% krypton. The finished product was also packaged in soft gelatin capsules. The inert gas content was measured at 4 time points: immediately (0), after 2 months, after 6 months, and after 12 months.

[0043] Table 4 shows the values ​​of krypton and xenon content for different time periods.

[0044] Table 4

[0045] The results show that inert gases are stably contained in oils packed in gelatin soft spherical capsules. The same product was tested for xenon and krypton retention in open tubes. Measurements of krypton and xenon content were performed immediately, after 1 day, after 3 days, after 6 days, after 30 days and after 60 days.

[0046] Table 5 shows the values ​​of krypton and xenon content for different time periods.

[0047] Table 5

[0048] A gradual release of gases from the product is observed. This process stabilizes after about 6 days. Then only 30% xenon was introduced into the same oil mixture. The product with the introduced xenon was tested for gas retention in open test tubes.

[0049] Measurements of xenon content were carried out immediately, after 1 day, after 3 days, after 6 days, after 30 days and after 60 days.

[0050] Table 6 shows the values ​​of krypton and xenon content for different time periods.

[0051] Table 6 The test showed that the xenon yield from the product also stabilized after 6 days, but at a lower level than in the presence of krypton.

[0052] Example 3. Enhancement of lidocaine penetration through membranes and epidermis of the skin with krypton.

[0053] An experiment was conducted on Franz cells (3-well station), diffusion of lidocaine hydrochloride, 10% solution (commercial injection preparation) through artificial skin (Strat-M membranes). The lidocaine solution was saturated with 5.3 vol. % krypton, using the setup according to Example 1. The studied lidocaine solutions were placed in the upper compartment of the Franz cell in a volume of 2 ml. In all 3 experiments, krypton enhanced the diffusion of lidocaine through the membranes. On average, without krypton, the total lidocaine flux after 2 hours was 0.05 mg / cm sq. With krypton - 0.08 mg / cm sq. After 8 hours without krypton, the total lidocaine flux averaged 0.25 mg / cm sq., and with krypton - 0.39 mg / cm sq., which corresponds to a 1.56-fold increase in the penetration degree.

[0054] The penetration of the same lidocaine solution through the epidermis of human skin was also studied (the epidermis preparation was prepared by peeling off the skin using heat treatment at 60° C for 1 minute). After 2 hours, the total lidocaine flow without krypton averaged 0.025 mg / cm sq, and with krypton - 0.12 mg / cm sq. After 8 hours, the total lidocaine flow without krypton averaged 0.07 mg / cm sq, and with krypton - 0.6 mg / cm sq. Thus, in the presence of krypton, the degree of lidocaine penetration through the skin epidermis increases by 8.5 times after 8 hours of the experiment.

[0055] Example 4. Enhancement of skin absorption of niacinamide with krypton and xenon.

[0056] In the experiment, Franz cells (3-well station) with a full-layer preparation of rat skin were used. A 10% solution of niacinamide in phosphate buffer was prepared. For experimental series #1, this solution was saturated with krypton (3.0 vol.%), series #2 - with xenon (9.0 vol.%), for series #3, krypton and xenon solutions were mixed. 2 ml of these solutions were placed in the donor chamber: series #1 - krypton 3.0 vol.%, series #2 - xenon 9.0 vol.%, series #3 - a mixture of krypton and xenon solutions. In all series, after 3 hours, the skin area that was in contact with the solution (area of ​​1 cm sq.) was cut out, dried, crushed and placed in phosphate buffer for resorption of niacinamide from the skin into the buffer. In all 3 cells of the experiment with krypton, the amount of niacinamide absorbed by the skin was higher - on average 43 mg / g skin, than in the control series without krypton and xenon - on average 27 mg / g skin.In the experiments with xenon, the amount of niacinamide absorbed was on average 71 mg / g skin, and in the experiments in series No. 3 (a mixture of krypton and xenon), the amount of niacinamide absorbed was 83 mg / g skin.

[0057] Thus, krypton and xenon increase the absorption of niacinamide by rat skin, with maximum absorption observed in experiments with a mixture of krypton and xenon. It is obvious that the increase in absorption occurs due to increased penetration into the skin.

[0058] Example 5: Enhance the penetration effectiveness of anti-acne cream

[0059] To study the effect of krypton on the effectiveness of external agents for the treatment of acne, a cream was prepared (formulation: water - 86.6%; olivem 2020 - 1.0%; Cetiol CC - 8.0%; tea tree oil - 3.0%; thymol - 0.2%; lecigel - 1.2%). The test involved 5 volunteers with severe acne. On both sides of the face. Every day, in the morning and in the evening, for 10 days, the volunteers applied the cream of the specified composition to the left side of the face, and cream with krypton (21.0 vol.%) to the right side, using the installation according to example 1. As a result of using the cream with krypton, the effect was manifested in the rapid resolution of acne elements, the release of comedones, increased absorption, and a decrease in skin inflammation after 3-4 days of observation. The cream without krypton had a therapeutic effect only in 2 volunteers and only after 8-9 days of observation.

[0060] The advantage of the claimed method is:

[0061] 1. Possibility of introducing two gases in one technological cycle;

[0062] 2. Preliminary removal of unnecessary ballast gases;

[0063] 3. Possible use of biologically active krypton gas as a process gas equalizing the pressure inside the reactor-mixer;

[0064] 4. Control over the introduction of inert gases.

Claims

FORMULA 1. A method for increasing the penetration rate and effectiveness of medicinal or cosmetic products with a stable long-term content of an inert gas, comprising introducing gaseous krypton or its mixture with xenon using a gas introduction unit consisting of a reactor-mixer, a remote or submersible homogenizer with a lower or upper location, wherein the unit additionally contains a vacuum pump and an automated module for feeding gases, with the production of a final product containing from 3 to 31 vol.% of gaseous krypton.

2. The method according to claim 1, consisting in that the automated module is a control unit, gas supply units, the design parameters of which depend on the dimensions of the homogenizer system.

3. The method according to paragraph 1, which consists in that in order to obtain the final product, the speed and amount of gas introduced into the liquid media are controlled.

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