Device for transdermal delivery of pharmaceutical agents

Abstract

The invention relates to the field of medicine, and more particularly to devices for the local transdermal delivery of pharmaceutical agents into patients, and is a flexible applicator. The structure of the device comprises at least two electrodes, each of which includes a substrate layer and a hydrogel layer with a filler in the form of MgCO3. The electrodes also contain a conductive layer in the form of a conductive paste. Electronic components are arranged in the same plane as the conductive layer and are fastened to contact pads formed by screen printing using conductive inks. The electronic components are enclosed in a housing and include a chemical source of current in the form of cells consisting of current collectors, an anode mass, a cathode mass, a separator and an electrolyte, as well as an ON button and a status indicator. The invention permits the safe transdermal delivery of pharmaceutical agents, with the power supply and electronic components being hermetically sealed inside a single flexible housing, and also protects against oxidation of the conductive layer and inhibits the formation of sodium hydroxide and hydrochloric acid on the surface of the skin during electrophoresis.

Description

[0001] TRANSDERMAL DELIVERY DEVICE FOR PHARMACEUTICAL SUBSTANCES

[0002] Field of technology.

[0003] The invention relates to the field of medicine and medical technology, namely to devices for local transdermal delivery of pharmaceutical substances to patients, including drugs, vaccines, for the delivery of immunobiological drugs, including mRNA-based drugs for gene therapy, as well as cosmetics, and is a flexible applicator.

[0004] State of the art.

[0005] The following solutions are known from the prior art.

[0006] A device is known for local transdermal delivery of pharmaceutical substances to patients, comprising a substrate having a matrix of electrodes located thereon, and a gel located on the substrate in electrical contact with each electrode, wherein the gel contains a substance containing a medicinal agent, and is designed with the possibility of changing the release rate of the substance containing the medicinal agent, based on the voltage or current provided by at least one electrode pair. The gel contains one of the following substances: a polyacrylic acid copolymer, a polyvinyl alcohol, or a carboxylic acid copolymer (US 2010010418, 14.01.2010).

[0007] The disadvantage of the known device is that during the passage of current through the skin, the process of electrolysis inevitably occurs and by-products in the form of sodium hydroxide and hydrochloric acid are formed, which causes burns on the skin, an effect known to qualified doctors. Significant limitation of the current strength to prevent visible damage does not allow the introduction of drugs or a sufficient therapeutic dose of drugs that require more power of the device or the passage of current between the electrodes through the skin. It is also indicated that the device is aimed at releasing drugs from the gel by changing the rheological properties of the gel when passing an electric current, and the effect of electrophoresis is a side effect, which indicates the non-directivity of electrophoresis for delivery and the low efficiency of delivery of large molecules.Such small molecules may include Fentanyl (2 kDa in size), which itself can penetrate the skin, but its dose must be controlled, which can be achieved by controlling the release of Fentanyl from the gel by using the invention US 2010010418, molecules over 10 kDa require significant current to move and especially into the intercellular space. The product also requires a separate power source. A device for transdermal delivery of pharmaceutical substances to patients is also known, comprising a power supply unit and two electrode sequences connected to the electrodes. The power supply unit is designed to form an electric amplitude-modulated oscillatory signal on the electrodes independently of each other. The pad contains a flexible strip of textile or polymer material with a plurality of electrodes mounted on it. The electrodes contain corresponding pins.The pins are connected to the electrical signal supply unit. The second version of the pad is made in the form of a strip. The strip has an anatomical configuration corresponding to the body part (RU 2262358, 20.10.2005).

[0008] The disadvantage of the known device is that there is a separate power supply and the product is not intended for mobile use, there are a number of connecting angles, pins, connectors, which in themselves increase the resistance and reduce the efficiency of the product.

[0009] The closest analogue of the invention being patented is a device for transdermal delivery of pharmaceutical substances to patients, which is an adaptable thin, flexible and wearable applicator capable of taking the shape of a skin surface profile, including a first electrode configured to deliver an active substance to the skin by passing an electric current through the skin surface, a thin separator connected to the first electrode, wherein said separator is configured to activate the composition, a second electrode configured to close an electric circuit through the skin surface, a thin and flexible power source providing electric current and voltage, connected through a conductive medium to the first and second electrodes (US 7979117, 12.07.2011).

[0010] The disadvantage of the closest analogue is that during the passage of current through the skin, the process of electrolysis inevitably occurs and by-products in the form of sodium hydroxide and hydrochloric acid are formed, which causes burns on the skin, an effect known to qualified doctors. Significant limitation of the current strength to prevent visible damage does not allow the introduction of drugs or a sufficient therapeutic dose of drugs that require greater power of the device or the passage of current between the electrodes through the skin.The description of the invention states that an open chemical current source with an aqueous electrolyte is used, which must always be open, which is a significant drawback due to the inability of the patient to accurately control the amount of water on which the resistance of the aqueous electrolyte depends, and by-products of the cathode and anode mass in the form of nanodispersed particles can get on human skin, which can be harmful to health. Of the known current sources based on aqueous electrolytes, alkaline, acidic and salt ones are known.Alkaline and acidic ones, when used openly, will immediately cause the destruction of parts of the patch and cause serious burns to a person when they are pulled out, and if we talk about salty ones, then the known salty chemical current sources do not have sufficient current and power in a mobile or suitable for body use size in the form of a patch to carry out an effective electrophoresis procedure due to the instability of the discharge voltage and low specific energy density. The known device uses fairly large cells of the current source, which is also a significant drawback.

[0011] Disclosure of invention.

[0012] The technical problem solved by the development of the claimed device consists of eliminating oxidation of the conductive layer and inhibiting sodium hydroxide and hydrochloric acid on the skin surface during electrophoresis, which allows preserving the integrity of pharmaceuticals and mRNA in liposomal or exosomal capsules for local gene therapy.

[0013] The task at hand is solved by the design of the product.

[0014] The technical result of the patented invention is the creation of a device for safe transdermal delivery of pharmaceutical substances with the provision of sealing of the power source and electronics in a single flexible housing and protection from oxidation of the conductive layer and inhibition of sodium hydroxide and hydrochloric acid on the skin surface during electrophoresis.

[0015] The claimed technical result is achieved due to the design of a device for transdermal delivery of pharmaceutical substances to patients, containing at least two electrodes, each of which includes a substrate layer, a hydrogel layer with a filler in the form of MgCCh, a conductive layer, which is a conductive paste, as well as electronic components placed in the same plane with the conductive layer and secured to contact pads formed by screen printing with conductive ink, the electronic components are contained in a housing and include a chemical current source in the form of cells consisting of current collectors, anode mass, cathode mass, separator, electrolyte, a power button and a status indicator.

[0016] In a particular case of implementing the invention, the substrate is made of non-woven polymer material.

[0017] In a particular case of implementing the invention, the substrate is made of hydrogel.

[0018] In a particular case of implementing the invention, the conductive paste is made by screen printing and consists of silver powder, ethylene-vinyl acetate copolymer and solvent.

[0019] In a particular case of the invention, the body is made by a stencil method from a melt of a copolymer of ethylene and vinyl acetate or polyolefin. In a particular case of the invention, the anode mass, oxidized during the discharge of the chemical current source, consists of tin powder with an admixture of a polymer.

[0020] In a particular case of implementing the invention, the cathode mass, which is restored during the process of discharging a chemical current source, consists of silver oxide with an admixture of graphite and polymer.

[0021] In a particular case of implementing the invention, the separator is made of melamine powder.

[0022] In a particular case of implementing the invention, the electrolyte is an aqueous solution of potassium hydroxide.

[0023] The device is an applicator that can be made in the form of a mask, a patch, and can be used for various parts of the body. Electrodes, conductive paths, electronic components, and a chemical current source are located on the same plane and are inseparable from each other. A flexible product is provided by making both the structural elements themselves and the connections between them using a printing method of conductive paste and conductive ink. Reliable sealing of electrical components and a chemical current source is provided by making the body of the chemical current source in one body with electronic components using a stencil method.The described sealing is necessary for working with both medicines and immunobiological preparations (vaccines, toxins, allergens), in connection with which pH control is important, since such preparations are very sensitive to changes in pH, especially mRNA, which, if the integrity of the electronic component of the device is compromised, can be damaged and harm skin cells, penetrating it under the influence of current.

[0024] Brief description of the drawings.

[0025] The solution is further explained by references to figures, which show the following.

[0026] Fig. 1 - top view of a device for transdermal delivery of pharmaceutical substances to patients.

[0027] Fig. 2 - side view of the electrode.

[0028] Fig. 3 - side view of the cells of the chemical power source.

[0029] Fig. 4 - basic electrical diagram.

[0030] Fig. 5 - graph of the discharge curve of the used CIT.

[0031] Fig. 6 - illustration for example 1, assembled device.

[0032] Fig. 7 - illustration for example 1, the device in disassembled form.

[0033] Fig. 8 - illustration for example 2, assembled device. Fig. 9 - illustration for example 2, disassembled device.

[0034] Fig. 10 - illustration for example 3, assembled device.

[0035] Fig. 11 - illustration for example 3, the device in disassembled form.

[0036] Implementation of the invention.

[0037] The device for transdermal delivery of pharmaceutical substances to patients is made in the form of two electrodes connected to a chemical source of direct current.

[0038] Each electrode includes a substrate layer 1, a hydrogel layer 2 and a conductive layer 3. The electrodes can be of various shapes and sizes.

[0039] The substrate 1, which directly contacts the patient's skin when the applicator is applied to the body part to be affected, is a non-woven material, such as non-woven polypropylene, or a hydrogel substrate. The substrate 1 is water-permeable and has hydrophilic properties (can absorb or retain liquid). The medicinal solution to be delivered to the patient's skin is applied to the substrate.

[0040] The next layer applied to the substrate 1 by the screen printing method is a hydrogel layer 2 and consists of a mixture of MgCCh and carboxylated polyvinyl alcohol. This layer has ion-conducting and hydrophilic properties. In the prior art, CaCO3 was used as a hydrogel filler (e.g., patent RU 199722). However, the use of MgCOs as a hydrogel filler is preferable, since Mg(OH)2 is formed when interacting with NaOH, which is significantly less harmful to the body than Ca(OH)2. Ca(OH)2 has a corrosive effect of "3" in the NFPA 704 health hazard scale: "Very short-term exposure may cause death or major residual damage." Mg(OH)2 has a "1" in the NFPA 704 health hazard scale: "Exposure may cause only irritation with minimal residual damage."

[0041] This layer is necessary to protect human skin and protect against oxidation of the conductive layer 3 by inhibiting HCl and NaOH during the electrophoresis process in humans and mammals.

[0042] The conductive layer 3 of the electrode includes a layer applied by printing with conductive paste using a stencil method. The conductive paste contains silver powder, a copolymer of ethylene and vinyl acetate, and a solvent.

[0043] Silver powder is obtained by electrolysis of silver nitrate in the presence of sodium lauryl sulfate, which prevents the silver particles from sticking together during the powder production process. The conductive paste is obtained by adding 2 parts of ethylene-vinyl acetate copolymer and 8 parts of solvent (xylene or white spirit) to 10 parts of silver powder.

[0044] All electronic components are located on the same plane as the conductive layer 3, which eliminates the need to produce an additional printed electronic board and ensures flexibility of the electronic part of the product.

[0045] To secure the electronic components and connect them, contact pads are formed by printing them with conductive ink 12, which has the same composition as the conductive paste described above, using the stencil method. Then, electronic components are lowered onto the wet contact pads so that they connect to the contact pads, after which drying is carried out to glue the electronic components to the contact pads, thereby ensuring electrical contact.

[0046] The electronic components include a chemical current source in the form of battery cells 8 consisting of current collectors made of conductive paste having the same composition as the conductive paste included in layer 3 described above and applied using a screen printing method, anode mass 5, cathode mass 6, separator and electrolyte 7, power button 9 and device status indicator 11 (for example, a light-emitting diode), as well as resistors 10.

[0047] The electrical circuit is shown in more detail in Fig. 4. The cathode of the battery cell 8 is connected by conductive ink 12 to the contact pad 16, which is connected to one of the electrodes of the open power button 9. The anode of the battery cell 8 is connected by conductive ink to the contact pad 15 and to the electrode that is adjacent to the human skin 17 (the skin is shown schematically as a resistor, which is what it essentially is). After pressing / closing the circuit with the power button 9, simultaneous events occur: full charging of the capacitor 14, which is connected to the electrode of the power button 9, supplying voltage to the base of the N-channel transistor 18, which leads to its opening and the beginning of current flow through the circuit. Since the capacitor becomes charged, it maintains the transistor in a fully open state until the CIT is completely discharged. The device has two circuits: battery (HIT) - human skin 17 and battery (HIT) - device status indicator 11 (LED).Resistor 10 limits the LED current and regulates its brightness. The second electrode on the human skin is directly connected to contact pad 13.

[0048] Thus, the conductive layer 3 of the device as a whole includes conductive layers of electrodes, current collectors and contact pads made of conductive paste, the composition of which is described above. The switch button 9 of the device can be made in the form of a closing electrode or in the form of a spring tact button.

[0049] The amount of charge in the HIT is proportional to the amount of a specific substance delivered to the skin. Thus, the time of complete discharge of the HIT linearly depends on the time of delivery of the calculated amount of substance. When the battery is completely discharged, the device switches off. In this case, the amount of charge and the amount of time of complete discharge of the HIT linearly depend on the delivery time due to the fact that the HIT has a stable voltage until complete discharge, unlike, for example, lithium-ion batteries, so there is no need for a controller. Fig. 5 shows the graph of the discharge curve of the HIT used. If the voltage decreased during the discharge, then, according to Ohm's law, less current would pass and, consequently, less substance, since a certain current strength is required to ensure active movement of substances into the skin, when which the substance slows down or stops its movement altogether. The use of the HIT with the proposed design eliminates this drawback.

[0050] The device is distinguished by the fact that the chemical current source (hereinafter referred to as CCS) is produced in a single technological process with the production of the product itself and is produced using a stencil method, making the CCS an inseparable part of the device.

[0051] A separate cell of the CCS consists of current collectors, anode mass, cathode mass, separator, electrolyte and housing. The anode mass, separator and cathode mass are arranged with a planar orientation, i.e. the separator composition is located between the cathode and anode mass in one plane. The traditional layer-by-layer arrangement of these elements, in which the separator is applied to the anode and the cathode is applied as the third layer, has a disadvantage consisting in the fact that in this solution the separator layer contains water, which entails the impossibility of drying the upper layer (cathode). When applying the cathode mass, separator and anode mass in one layer (planar arrangement), drying of each component is performed in turn. At the last stage, liquid electrolyte is applied and then the housing is formed.

[0052] The HIT used in the claimed device differs from other printed HITs in that the anode mass consists of tin powder with a polymer admixture, the cathode mass consists of silver oxide with a polymer admixture, and the separator is made of melamine powder, the electrolyte is a potassium hydroxide solution. This HIT composition allows to reduce the release of hydrogen during the oxidation of the anode and to produce powerful (up to 30 mA / cm2), soft, with a nominal voltage of 1.28 V, printed and completely closed HITs without the use of mercury, which is impossible for existing alkaline HITs with the use of zinc, zinc alloys with tin and other components.

[0053] This configuration of the CIT and printing technology allows to reduce the size, increase the efficiency of using components and raw materials. Current collectors are conductive paths (included in the conductive layer 3 of the device), applied to the substrate by the stencil method. The anode current collector is covered by the stencil method with a graphite conductive paste, which includes graphite, a copolymer of ethylene and vinyl acetate or polyolefins and solvent. Such paste is made as follows and in the following proportions: 10 parts of graphite are added to 2 parts of a copolymer of ethylene and vinyl acetate or polyolefins and 8 parts of solvent (xylene or white spirit).

[0054] The anode active mass 5, on which the oxidation reaction occurs, consists of tin powder in a polymer matrix. Tin powder is obtained by electrolysis of an aqueous solution of tin chloride in the presence of sodium lauryl sulfate, which prevents the adhesion of tin particles during the powder production process.

[0055] This paste is made in the following manner and proportions: 0.2 g of ethylene-vinyl acetate or polyolefin copolymer and 0.8 g of solvent (xylene or white spirit) are added to 1 g of tin powder. The anode mass is applied using a stencil or slot method directly to the current collector (layer 3). Then it is dried at a temperature of 60-70C.

[0056] The cathode active mass 6, on which the reduction reaction occurs, consists of silver oxide powder, silver powder, graphite powder and a polymer matrix.

[0057] This paste is prepared in the following manner and proportions: 0.8 g of silver powder, 0.2 g of graphite powder, 1 g of ethylene-vinyl acetate or polyolefin copolymer and 1 g of solvent (xylene or white spirit) are added to 1 g of silver oxide powder. It is applied using a stencil or slot method directly to the current collector at a distance of at least 0.2 mm from the anode active mass 5. Then it is dried at a temperature of 60-70C.

[0058] The separator and carrier of electrolyte 7 is melamine powder, which is easy to apply and prevents the diffusion of cathode mass particles. After application, the electrolyte is absorbed by the active masses, and the paste becomes denser.

[0059] The electrolyte is an aqueous solution of potassium hydroxide at a concentration of 8 M per 1 l. The thickener or carrier is melamine powder. Preparation of the electrolyte paste: 1.5 g of an aqueous solution of potassium hydroxide is added to 1 g of melamine powder.

[0060] The electrolyte is applied by a slotted stencil method directly to the active masses of the CCS (cathode active mass 6 and anode active mass 5), as well as to the space between them. This approach simplifies the production of the CCS, since the installation of the separator and electrolyte occurs in one stage. The CCS cells can be connected in series and / or in parallel to obtain the required power and voltage of the device.

[0061] The case 4 of the product, covering the alkaline chemical power supply and electronic components, is made by the stencil method of applying a melt of ethylene and vinyl acetate copolymer or polyolefin. This method ensures reliable sealing of the electronics and the alkaline chemical power supply in a single case, which eliminates the leakage of the alkaline chemical power supply through the current leads, as in analogs, simplifies production.

[0062] The device works as follows.

[0063] The device is initially packed in a sealed package, from which the device is taken out before use, applied to the skin area in the target area of ​​​​impact by applying the device with the substrate 1 to the open surface of the skin, exerting slight pressure on it, pressing it into the skin improves its adhesion to the skin. After making sure that the substrate fits tightly to the skin, press the power button 9 once, the button activates the device, closing the electrical circuit, the operation indicator lights up and supplies the required, preset current and voltage to the electrodes for a specific type of drug and applicator size. After this, the drug is administered. After the required dose of the drug has been administered, the indicator goes out and the device can be removed from the skin by hooking the edge of the patch with your fingers and peeling it off the skin. Then put it back in the package and throw it away or in a specialized container for medical products or in a container for plastic waste.

[0064] Examples of implementation of the invention.

[0065] The device can be a mask, a plaster, a patch placed on the forehead or eyes or between the eyebrows, for the spine. The device can also be implemented as a contact lens for the eyes, a nail pad, a butterfly-shaped armpit patch for the treatment of hyperhidrosis, a pad on the teeth and the inner surface of the oral cavity, a patch for the treatment of diabetic foot, in the form of an insole.

[0066] The device is held on the skin due to the physical properties of the gel itself (stickiness).

[0067] Example 1.

[0068] The device is made in the form of a patch for the skin in the forehead area (Fig. 6, 7). The substrate has a standard shape of a cosmetic patch with dimensions of 150 mm by 70 mm, the electrodes are made in the shape of a butterfly, the anode 19 has a thickness of 2 mm in the narrowest part and expands to form a rounded zone with a diameter of up to 30 mm, the cathode 20 is made in the form of a triangular shape with rounded corners, 110 mm by 50 mm in size, the thickness of the anode and cathode is no more than 0.2 mm, made by printing with conductive ink. A special feature is that it is segmented as shown in the figure (Fig. 6), each segment has a different internal resistance, namely an increase in resistance towards the anode 19, which allows you to equalize the amount of current passing between any of the points of the anode 19 and the cathode 20, which in turn allows you to evenly introduce the drug into the skin over the entire surface of the electrodes.The medicinal product used is polypeptide botulinum toxin in the amount of 0.2 ng with the addition of dimethyl sulfoxide in the amount of 1%. The operating voltage of the product is 12 volts, the current is 1.5 mA, the operating time is 15 minutes.

[0069] Example 2.

[0070] Designed as a contact lens for the eyes. The substrate has a standard lens shape, 14 mm in diameter, up to 0.5 mm thick, corresponding to a classic contact lens for vision correction. The electrodes are made in the form of a ring 0.018 mm thick, the cathode is 1 mm wide, the anode is 0.25 mm wide. Between the internal hydrogel and the electrodes there is a hydrogel with MgCCh to inhibit sodium hydroxide and hydrochloric acid during operation. Sodium pyrenoxine can be used as a drug, which prevents coagulation (denaturation) of the lens protein, blocks aldose reductase, normalizes glucose metabolism in the lens and prevents sorbitol deposition. At the moment, this drug is used in the form of oral tablets with bioavailability of no more than 25%. The proposed device provides for the introduction of the drug directly into the eyeball, thereby increasing bioavailability, since it bypasses the primary metabolization cycle in the liver.For delivery, doses from 1 to 10 mg of the substance per lens are used, depending on the stage of the disease (cataract). Voltage up to 5V, current up to 0.1 mA for each lens. Duration of administration is not less than 5 hours. Thus, long-term continuous administration of the substance, activation of metabolism due to electrophoresis and, as a result, improvement of the therapeutic effect are achieved.

[0071] Example 3.

[0072] The device is made in the form of a patch for skin in the shoulder area. The substrate has a standard patch shape measuring 50 mm by 30 mm, the electrodes are made in the form of a rectangle, the anode and cathode have a thickness of no more than 0.2 mm, made by printing with conductive ink. The peculiarity is that the anode 19 and cathode 20 are segmented, each segment has a different internal resistance, namely, an increase in resistance towards the center of the patch, which allows you to equalize the amount of current passing between any of the points of the anode and cathode, which in turn allows you to evenly introduce the drug into the skin over the entire surface of the electrodes. An mRNA vaccine encoding the peptide of the human tumor-associated antigen gp 10025-33 (KVPRNQDWL) is used as a drug as a potential treatment for melanoma. The operating voltage of the product is 12 volts, the current is 1 mA, the operating time is 30 minutes.Local delivery of the mRNA vaccine allows for targeted action against melanoma without the systemic side effects of chemotherapy.

Claims

CLAUSE OF INVENTION 1. A device for transdermal delivery of pharmaceutical substances to patients, comprising at least two electrodes, each of which includes a substrate layer, a hydrogel layer with a filler in the form of MgCC, a conductive layer, which is a conductive paste, as well as electronic components placed in the same plane with the conductive layer and secured to contact pads formed by screen printing with conductive ink, wherein the electronic components are contained in a single housing and include a power button, a device status indicator, as well as a chemical current source in the form of cells consisting of current collectors, anode mass, cathode mass, separator, electrolyte.

2. The device according to item 1, characterized in that the substrate is made of non-woven polymer material.

3. The device according to item 1, characterized in that the substrate is made of hydrogel.

4. The device according to item 1, characterized in that the conductive paste is made by screen printing and consists of silver powder, ethylene-vinyl acetate copolymer, and solvent.

5. The device according to item 1, characterized in that the body is made using a stencil method from a melt of a copolymer of ethylene and vinyl acetate or polyolefin.

6. The device according to item 1, characterized in that the anode mass consists of tin powder with an admixture of polymer.

7. The device according to item 1, characterized in that the cathode mass consists of silver oxide with an admixture of polymer.

8. The device according to item 1, characterized in that the separator is made of melamine powder.

9. The device according to item 1, characterized in that the electrolyte is a solution of potassium hydroxide.

10. The device according to item 1, characterized in that the device status indicator is a light-emitting diode.

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