Therapeutic and diagnostic drug and biologically active substance carrier and application thereof for making drugs and method of regulated controlled drug or biologically active substance delivery with regulated desorption
SUBSTANCE: invention refers to a carrier for drugs, biologically active substances, biological objects used in medicine for diagnostics and treatment in pharmaceutical industry. The carrier represents a material sensitive to external magnetic or electric fields and consisting of magnetic or ferroelectric material filmed with biocompatible thermosensitive, biodegradable polymer and/or dispersed in thermosensitive medium properties of which change with varying temperature relative to that of human body within 15.9 to 42°C. The magnetic or ferroelectric materials are made of substance with great magnetocaloric or electrocaloric component effect 1 to 13 K, have temperature of magnetic or ferroelectric phase transition within temperature range 33 to 37°C, and are chosen from the group including rare-earth, transition and precious metals, their alloys and compounds.
EFFECT: invention also concerns methods of controlled drug delivery by means of such carrier with enabling release thereof (regulated desorption) in the preset point.
32 cl, 9 ex
The invention relates to medicine, pharmaceuticals and biotechnology, and specifically relates to methods of delivery of drugs or therapeutic agents, or other biologically-active substances in the human body and controlled release.
The known method of administration (delivery) of medicinal substances by applying the pathological focus pads, impregnated drug substance, for simultaneous stopping of blood flow in the area of the lesion and exposure to ultrasound for 30 min with periodic relaxation harness (SU 556805, 05.05.77 year).
However, this method does not provide sufficient penetration of medicinal substances through the skin and the penetration depth does not exceed the thickness of the epidermis of the skin.
A known method of delivery (injection) drug substances in the wound surface, which consists in spraying the medicinal solution in the form of a torch medicinal aerosol voiced by ultrasound (SU 1106485, 22.10.1982). This method ensures that the penetration of medicinal substances only in areas of tissue with impaired Horny layer of the epidermis. Shipping drugs into the tissue through the intact skin is difficult, because the stratum corneum serves as a protective barrier, virtually impervious to fluid entering the C external environment.
The above methods are intended only for the delivery of medicinal (therapeutic) funds in foreign, mainly wound, the surface of the tissue, i.e. have a limited purpose.
From RU 2250102 C2, 20.04.2005 known method of injection for directed migration and subsequent release of biologically - active compounds in the animal body after contact with mucous membranes, especially to the way oral and vnutricerepnogo introduction. The biologically active compound is enclosed in a microcapsule of a biologically compatible polymer or copolymer, which can pass through the gastrointestinal tract and stored on the mucosal surface without being destroyed or subjected him to a minor extent, which ensures the supply of biologically - active compounds in Peyer's plaques or other associated with mucosal lymphatic tissues and entry to them at the original effective amounts. The term biocompatible polymeric material refers to a polymer that does not have toxic, carcinogenic or inflammatory action in the body. Preferably, indifferent polymeric material of the microcapsules were subjected to biodegradation, i.e. destroyed during physiological processes to products that do not accumulate in the tissues and yogasana from the body. The microcapsules should have such dimensions and physico-chemical properties, which would ensure their effective selective input in Peyer's plaques. The invention solved the problem of directional transfer of biologically-active compounds in Peyer's patches and other associated with mucosal tissue, and include.
However, the known method relates only to the method of oral administration of antigen to animals, in which he reaches of Meyerovich plaques and is included in them, stimulating, thus, the immune system of the mucosa, without loss of immunogenic activity in the transport process along the gastro-intestinal tract.
This known method of oral administration of biologically active compounds to animals provides its transport and incorporation into Peyer's plaques to create a local or systemic concentration of the drug, but relates to the delivery of very specific pharmacological forms of therapeutic products containing biologically active ingredient and containing the polymer or copolymer indifferent material, preferably amenable to biodegradation, which is suitable for transfer to the mucous membranes of this method.
When medication and diagnosis of diseases is required, unless it is necessary to carry out the adjustable visvobodi is their one or more substances in a patient's body, in particular, the body of a mammal, for a long period of time.
Adjustable release over a long period of time, however, cannot be achieved using conventional methods of medication, such as ingestion or direct injection of the drug. Instead of getting an adjustable concentration of the drug over a long period of time, these ways of accepting lead to immediate release in the body, followed by a decrease in the concentration of drug in the blood over time. Instant drug release with a subsequent decrease in the level of drug in the blood over time is often not the preferred method. The treatment of the disease or condition of the patient is often more effective when the level of drug in the blood can be maintained at a desired constant level over a long period of time. In addition, the instantaneous input medicines in the body can lead to the creation of the concentration of drug in excess of the ability of the active centers to perceive it, and may exceed the ability of the metabolic and excretory mechanism of a living organism. If the drug level will remain high, this can have a negative effect on tissues or organs.
Complianc is Noah controlled drug release over a long period of time also has significant clinical advantages. For example, when the treatment of the medicinal product should last for a long period of time, the medication inside or direct injection creates inconvenience associated with the need for re-admission. In addition, when the treatment requires re-admission medications, there is a likelihood that the patient will forget or deliberately not going to take the medicine. If it will be possible continuous taking medication, so that will be adjustable release over an extended period of time, eliminating the need for re-admission.
To achieve the desired level of drug in the blood over a long period of time have been developed various implants, which upon reception by the patient to provide continuous controlled release.
The implants contain an active ingredient or drug in combination with a polymeric delivery system that controls the drug release. The drug is physically enclosed in the polymeric matrix and is released from the matrix by diffusion through the polymer or at break of the polymer matrix. Typically, the polymer delivery system is biocompatible resorbable polymer matrix. Polymer matrix, however, is not always absorbable. It is always used non-absorbable implants, requires surgical removal of the implant after the release of drugs.
For controlled release of the drug has developed a range of matrices, including polymer matrix, manufactured on the basis of, for example, hydrogels, gelatin, cellulose, organopolysiloxane rubbers, polyurethanes, waxes, polyvinyl alcohol, polyglycolic acid and polylactic acid. Often the polymer matrix is a copolymer of lactic acid and glycolic acid ("PLGA, polylactic glycolic acid). The drug released from the PLGA matrix under the action of hydrolytic cleavage of the matrix. When the polymer matrix is broken down, the medicine is released into the surrounding body fluids.
On the rate of drug release is influenced by many variables, including, for example, the choice of the polymer matrix, the concentration of drug in the matrix, the size and shape of the implant, a method of manufacturing an implant, the implant surface area and pore size.
From RU 2272617, 27.03.2006, in particular, is known such a method of controlled release of the drug in the patient's body, which consists in the introduction of the pharmaceutical implant, comprising microparticles of one or more drugs dispersed in the biodegradable polymer microparticles which sufficiently related to each other for the holding of a pre-defined shape of the implant without full sintering of the polymer, and in which the implant disintegrates into individual microparticles over a certain period of time after administration. When the implant is injected intramuscularly or subcutaneously.
Currently widespread in medicine have various physical methods of treatment, for example, methods such as magnetic therapy, based on effects on the body's electromagnetic field and the use of different magnetic materials.
So, for example, from US 5236410, 1993 known method of treatment of tumors, based on the use of magnetic particles in conjunction with a therapeutic agent and exposure to electromagnetic fields. The method consists in the selective catheterization of the hepatic artery or tumor of the kidney renal artery through a catheter under the control of fluoroscopy impose a suspension of hexaferrite barium or strontium oil solution dioxalate when you hover over the area of the tumor of the external magnetic field. With larger tumor blood flow after reducing metal spiral. 1-3 days for tumor effect of microwave electromagnetic field or ultrasound until a temperature in the tumor 43-43 .5°C and continue to impact at this temperature for 5 to 45 min at 6-7 and 15-20 days and 3-6 months. Perform a needle biopsy of the tumor and the presence of viable tumor the cells repeat the hyperthermia.
This method is due to the simultaneous effect on tumor cells chemotherapy and hyperthermia restricts the penetration of tumor cells and their decay products in the overall flow, which decreases the likelihood of metastasis and reduces intoxication. The use of rotary instruments of embolisate allows you to monitor the status of the tumor and, if necessary, to carry out repeated courses of hyperthermia.
In this regard, and taking into account other important factors, many applications are magnetized connections, including medicinal substance.
Delivery of drugs to organs-targets in the human body is one of the main problems, for example, chemotherapy. One way to solve this problem is, as follows from the above, the use of magnetically sensitive drug carriers substances which are injected into the blood vessels, are carried by the blood stream and are located in the designated place by the magnetic field. Known magnetically sensitive and biologically compatible nanospheres or nanoparticles having a diameter of not more than 1500 nm, intended for insertion into blood vessels and localization in a certain place, which consist of crystalline carbohydrate matrix and magnetic particles (application RS is no WO 83/01738). Carbohydrate crystalline matrix represents a starch, glycogen, dextran or derivatives thereof. A well-known carrier does not have a sufficiently high hydrolytic and enzymatic stability.
Also known magnetic composite microspheres based on net organosilicone polymer that consist of a kernel representing namagnichivaemost material size of less than 300×10-4microns, uniformly distributed in the grid polysilsesquioxane containing more than 2 vinyl groups in the molecule and possibly ionic and/or newiniinfo active group, and the surface layer, which represents the net organic silicon polymer (EPO application No. 0435785, 1991). However, the polymer matrix of this well-known media does not have a sufficiently high biological compatibility.
Know of any other route of administration intravenous biologically erodible magnetically sensitive carrier containing magnetic particles coated with a polymer matrix (U.S. patent No. 4247406, 1981). As the magnetic particles of the carrier contains Fe3O4and as a polymeric shell albumin in the number of 5-350 parts by weight of Fe3O4on 100 parts by weight of albumin. The media provides a relatively fast release of drug or biologically-active substances in the aquatic environment or blood and what if the microspheres are not exposed to the proteolytic enzyme, the carrier maintains its integrity and activity up to 48 hours
The method has the disadvantage that the carrier does not have a sufficiently high hydrolytic and enzymatic stability, and magnetic susceptibility.
Managed delivery of medicinal (therapeutic) means using, for example, magnetic media is important because it creates the prerequisites for the delivery of a drug to the target organ" under the influence of an external magnetic field. The use of magnetic drugs, as a rule, reduces the toxicity of the medicinal substance, and also leads to increased duration of action that allows you to reduce the dose of medicinal substance. In addition, this work has theoretical value, and it suggests what medicinal substance (structural analogues) can be used to obtain a magnetic connection.
Known methods for producing magnetized medicinal substances, based on the assessment of the active substance and the magnetic component in linking membrane (Giano Guan, Lin Shi yin, Zhang Xizeng, Zhongguo uaxue zazhi. Chin Pharm. G. - 1996. - 31, N1. - C.27-29; Tmic, Nofchissey, Everlock, Doctor. case (Lcar. right.), 1997. - 1. Pp.37-78) and sorbirovaniya medicinal substances on the surface of the particles magnitno the media (RF patents 2030618, 2068703), upon receipt of a magnetic component and forming on the surface of the polymer shell, into which the medicinal substance (RF patent 2065302; Formulation and characterization of magnetic poiyglutaraldehyde nanoparticles as carriers for polu-1-lysinemethotrexate/C.T. Hung, Mcleod A., Gupta P.K. // Drug Dev. And Ind.Pharm. - 1994. - 16,3. S-521; Nilakantha, Lieutenat, Nasrudinov, Bull. Sib. The CTD. The Academy of medical Sciences of the USSR, 1989. - 1. - P.17-21). Known highly effective medicinal preparations obtained by granulation of a mixture of magnetic materials, anticancer drugs (fluorouracil, bleomycin, chromomycin) and adhesive water-soluble polymers (hydroxypropylcellulose and others). (Application 2-9813 Japan), as well as preparations containing magnetic materials and their use: ito Ritsuko, Matida Ishihara, Asaminami Takane, Nagai, Cuneus. - 6339599 // RJ. 19. Chemistry. Sodo. So/VINITI. -1991 - 60. - P.76).
A known method of delivery, for example, adriablastin on magnetic media (RF patent 2018312). Technology is realized by the application of adriablastin on the ferromagnet in aqueous solution using as ferromagnetic freshly prepared magnetite or powder recovered iron, pre-activated 0,05 N. the solution of mineral acid. When this separately receive magnetite and an aqueous solution of a therapeutic agent, and then carry out the application of drugs among the STV powders of ferromagnetic materials. This stage is as follows: a certain amount of aqueous suspensions of synthetic magnetite or activated iron powder containing 1 g of dry ferromagnet placed in a reaction vessel equipped with a mixer. To the reaction mixture was added an aqueous solution of adriablastin concentration (1-5) 10-4mol/l and stirred at 20°C for 0.5-4. The obtained product is separated from excess aqueous medium by decantation.
Known another method of drug delivery using magnetospirillum media. Magnetophosphenes media consists of microcapsules made of high-molecular organic compounds incorporating magnetically sensitive particles. The drug is applied on the carrier and used in the treatment of neoplastic diseases with the use of directional transport means to the lesion using an external source of the magnetic field (K.Widder et al., J. of Pharm. Sci, 1976, v. 68, No. 1, pp.79-89).
However, the known magnetic microcapsules did not find its real application in oncological practice for several reasons:
- obtaining the magnetic microcapsules involves serious technological difficulties;
- not resolved the issue of standardization of microcapsules obtained in a known manner;
not resolved the issue realizatsiyashchenkov release microcapsules. Furthermore, the method of obtaining the known microcapsules involves the use of corrosive environments and/or high temperatures that are incompatible with many drugs. Mandatory component known microcapsules - high-molecular organic compounds carry the risk of allergic reactions, exposure to which the population in recent years is growing.
From RU 2143266, 27.12.1999 known method of delivery (and treatment) drugs in the human body using magnetic media, which consists in the introduction through the catheter connected to the blood vessels that feed the tumor, drugs, sorbed on Zelenogradsk particles, localization means in the lesion by placing the magnet on the surface of the body, projecting into the tumor using a magnet that generates a gradient magnetic field strength is not lower than 3 T/m, and suspension anti-cancer drugs injected at a rate no higher than 1-2 ml/min as local chemotherapy and/or radiation antineoplastic agents. This localization tools in metastases at the expense of the natural tropism Zelenogradsk particles to places of localization of the tumor conglomerates, and after his magnetic localization in the area of tumor growth, it has biotransformed and the resulting complex compounds stimulate haematopoiesis and antitumor immunity.
However, this method is more relevant to the delivery of drugs in the treatment of neoplastic diseases.
Known controlled magnetic field, the method of drug delivery, in which use stainless steel SUS 316L coated magnetic hydrogel gelatin (Li-Ying Huang et al, Abstract PSTu-L-494 of ICM 2006, Kyoto, Japan, August 20-25, 2006). Gelatin is used extensively in systems of drug delivery due to better swelling properties and biocompatibility. The pore size of the hydrogel can be controlled by changing the composition of the polymer, the bonding conditions and the concentration of the magnetic precursor. The model drug was introduced in the gel film after application of the magnetic field. The rate of release of the drug was significantly decreased compared with the case of absence of the field. That, apparently, may be associated with more dense configuration hydrogel caused by the aggregation of magnetic nanoparticles and decreasing pore size of the gel. The gel showed relatively low cytotoxicity to L929 cell line, indicating good biocompatibility. Used method shows good opportunities for such biomedical devices, such as cardiovascular stent with drug delivery, and tissue engineering. A good example of the application of thermosensitive polymers for delivery of cells is PR is the application of the copolymer of N-isopropylacrylamide and acrylic acid for delivery of chondrocytes in the reconstruction of cartilage (J Biomed Mater Res A, 69,2,367-372, Au, etc). In such a system the temperature can be changed during the application of a magnetic field.
It is known that thermo-sensitive ferrofluid (type F127), consisting, for example, magnetic nanoparticles coated from Pluronic F127 can be used for controlled magnetic field desorption drugs (Ting - Yu Liu, et al, Abstract We A1-C2-3, ICM 2006, August 20-25, 2006, Kyoto, Japan). It is noted that such F127 the ferrofluid formed a gel at temperatures above 23,8°C, which is considerably lower than for pure Plutonic F127 (40,5°C). Medication may be homogeneous distributed inside F127 a ferrofluid below the critical temperature of dissolution and then at a temperature above the critical enclosure (ferrogel. Heating of the alternating magnetic field of the magnetic particles can be used to form such gels (J.H.Park et al, J.Magn. Magn. Mater, 2005, v. 293, p. 328; D.H.Kim et al, J. Magn. Magn. Mater, 2005, v. 293 p. 320). The experiments also showed that desorption of drugs in such gels may also be controlled by a permanent magnetic field. After application of a magnetic field to the gel out of vitamin b12increased by 20%.
However, the physical and chemical mechanisms that cause the increase of desorption for the application of a constant magnetic field, is unknown and therefore cannot be controlled.
Method of using an alternating magnetic field, causing Perama nikiana magnetic moments of the particles and their subsequent heating, known and used in hyperthermia.
The technical objective of the claimed group of inventions is to improve the manageability of delivery of a drug or biologically active substances, sorption capacity, the efficiency of drug delivery to the desired location, and efficiency of localization in a predetermined location, and further adjustable desorption of one or more drugs at a specified place, and expanding opportunities for the creation of different tools used in medicine for diagnosis and treatment.
The purpose of this invention is the use of change (increase or decrease) the temperature of the magnetic or ferroelectric material due to the magnetocaloric and/or electrocaloric effect to improve the efficiency of interaction or activate a chemical or biological processes in the human body or animal. Under the processes of interaction refers to the process of non-covalent binding of the magnetic particles with biological macromolecules (proteins and lipoproteins), interaction of magnetic nanoparticles with cells, DNA, and the interaction of magnetic nanoparticles, decapsulating in polymers (poly - GMA)capable of selective binding with other studied molecules.
So, this object is achieved by the creation of media for medicines, biologically active substances, biological objects used in medicine for diagnosis and treatment, in the pharmaceutical industry, which represents a sensitive device or a ferroelectric material and consisting of a magnetic component or ferroelectric, covered with a film of biocompatible thermosensitive substance (polymer) and/or distributed in the heat-sensitive medium, whose properties change when heated or cooled at a temperature above or below human body temperature, the magnetic component or ferroelectric material is made from a material with a large value of the magnetocaloric or electrocaloric effect, having a transition temperature lying near human body temperature, and is selected from the group comprising rare earth, transition and noble metals, their alloys and intermetallic compounds.
Magnetic component or ferroelectric material are, for example, particles of small dimensions, in particular, down to the nanoscale, i.e. nanoparticles with dimensions of, for example, from a few nanometers to 400 nm; this may be a carbon nanotubes filled with magnetic the m substance (material), or ferroelectric, and, in particular, nanowires, such as gadolinium or alloy of Fe0,49Rh0,51.
Magnetic component or a ferroelectric material can be pre-printed on traditionally used in the technology for their substrate, for example, inorganic substrates, preferably of silicon dioxide or magnesium oxide; it can also be pre-coated with a protective layer, preventing further possible oxidation, for example, a layer of graphite or silicon dioxide or glass.
When receiving media can be used simultaneously by two or more magnetic or ferroelectric material with a different value of the magnetocaloric or electrocaloric effect. Also can be used two or more heat-sensitive polymer or environments with different temperatures of phase transitions.
Heat-sensitive environment in the claimed invention are, in particular, heat-sensitive polymer film temperature-sensitive hydrogels. As a thermosensitive polymer can be used polymers and copolymers with a lower critical point solubility. For example, as heat-sensitive monomers can be used N-ethylacetamide, N-n-propylacetamide, N-n-propylbetaine, N-isopropyl ilamed, N-isopropylacrylamide, N-cyclopropylamine, N-cyclopropylmethyl, N-ethoxyethylacetate, N-ethoxyethylacetate, N,N-di-substituted (meth)acrylamide, such as N,N-dimethyl (meth)acrylamide.
As co monomer for thermosensitive copolymers can be used N-substituted acrylamide and methacrylamide, O-substituted acrylates and methacrylates, as well as other monomers, allowing the copolymerization with the monomers forming the heat-sensitive polymers. In addition acrylamido and methacrylamido, as thermosensitive polymer with a lower critical point solubility can be used polymers based on N-vinylcaprolactam and on the basis of poloxamers, such as tribocorrosion consisting of polyacetylene and polyoxypropylene.
In addition to synthetic polymers with a lower critical point solubility can be used biopolymers, with the ability to gelation at elevated temperature, for example, methylcellulose. Heat-sensitive medium may be solutions and gels on the basis of gelatin and collagen.
Heat-sensitive material to form particles of a magnetic component or ferroelectric solutions, gels, colloidal solutions, suspensions and dispersions with well-known target of additives that contribute to their formation.
In an hour the particular the magnetic component may be a heat-sensitive ferrofluid, for example ferromagnetic liquid in the form of a suspension of ferromagnetic particles in a biologically-active substances, such as plant extracts of biologically active substances, in particular in the aloe extract; or ferrosilicon liquid.
Biologically-active substances in the claimed group of inventions are antigens, antibodies, nucleotides, gelatinous agents, enzymes, bacteria, yeast, fungi, virus, polysaccharides, lipids, proteins, hormones, carbohydrates, cellular material. They are bioacoustical material upon receipt of the biosensors obtained with the use of media, claimed as one of the inventions claimed in the group.
Biosensors (bioacoustical elements, biochips) are intended for use in the composition, in particular, sensors in bioanalytical assays in biotechnology, in particular, in immunoassays, widely used in clinical diagnosis to determine the disease or physiological condition.
The biosensor includes a substrate carrier, claimed as one of the inventions claimed the group to which is attached biologically active substances, such as antibodies against .Pylori or antigen-binding fragments, which together with biomolecule the temperature-sensitive environment (with repulsive biomolecules) form a layer of sensitive material, specific to search for the analyzed object, such as bacteria, yeast, viruses, antibodies IgG, IgM, IgA, IgD and IgE, carcinoembryonic antigen, the antigen of Streptococcus group a, viral antigens, antigens associated with autoimmune disease, allergens, tumor antigens, antigens of Streptococcus WBG, antigen, HIV I or HIV II antibodies to viruses; antigens specific to RSV, antibody, antigen, enzyme, hormone, polysaccharide, protein, lipid, carbohydrate, drug, nucleic acid, Neicceria meningitises groups a, b, C, Y and W sub-groups 135, Streptococcus pneumoniae, E. coli K1, Haemophilus influenza type a/b, an antigen derived from microorganisms, antigens PSA and CRP, a hapten, a drug, abusive, drug, environmental agents, or antigens specific to hepatitis.
Next, the interaction of the biological sample obtained from a patient suffering from infection with the biosensor with application of an external magnetic or electric field and detecting the signal, resulting in the formation of a complex of antibody-antigen.
The media according to the invention, obtained using magnetic component or a ferroelectric with a large amount of magnetocaloric or electrocaloric effect in combination with the heat-sensitive substance (heat-sensitive biopolymer, thermosensitive with the food), can also be used in the manufacture of various implants, in particular osteoblasts.
Human bone, when it is treated with a method for differential removal of bone mineral to obtain "demineralized bone" (DMB), has the ability to actively induce the growth of new bone at transplantirovali her man (J.N.Kearney and R.Lomez, Advances in Tissue Banking, 1997, 1, 43-71). Such materials are widely used in dentistry and maxillofacial surgery, as osteoinductive capacity of such allogeneic bone allows the transformation of primitive progenitor cells of the mesenchyme in chondroblasts or osteoblasts (C.J.Yim, Advances in Tissue Banking, 1999, 3, 87-111). The method of the present invention allows to transform DMB in a material with significantly improved osteoinductive activity that accelerates formation and improves the quality of newly formed bone.
Using media according to the claimed invention for obtaining implants, such as osteoblasts, helps to stimulate the growth of osteoblasts, accelerates delivery of these implants topically to a wound or defect of the bone.
Such pharmaceutical implant is intended for controlled drug release, after his introduction into the body using an external magnetic or electric field is n splits (detached first - desorbed from the substrate carrier) on a separate microparticles for some necessary and specified period of time after receiving the injection.
The invention thus provides for an implant intended for controlled drug release in the body of the patient. Pharmaceutical implant comprises microparticles of one or more drugs dispersed in absorbable (biodegradation) polymer (heat-sensitive environment), in which the microparticles are sufficiently interrelated to maintain a predetermined shape of the implant without the full adhesion of the polymer, and in which the implant is resorbed into individual microparticles over time after administration, and which is deposited on a substrate carrier, claimed as an invention.
The number of medications may be approximately from 0.5 to 95% (wt./wt.) microparticles. Preferably, the amount of the drug is approximately 5 to 75% (wt./wt.) microparticles.
Resorbable (biodegradable) polymer can be a polymer of lactic acid, glycolic acid, polyethylene glycol, poly-(ortho-ester), polycaprolactones, or their copolymers.
Pharmaceutical implant may additionally include one or more additives. Supplements can present is a resorbable (biodegradable) polymers, mannitol, dextrose, Inositol, sorbitol, glucose, lactose, sucrose, sodium chloride, calcium chloride, amino acids, magnesium chloride, citric acid, acetic acid, malic acid, phosphoric acid, glucuronic acid, gluconic acid, Polysorbate, sodium acetate, sodium citrate, sodium phosphate, zinc stearate, aluminum stearate, magnesium stearate, sodium carbonate, bicarbonate sodium, sodium hydroxide, polyvinylpyrrolidone, glycols, carboxylmethylcellulose, methylcellulose, starch or mixtures thereof.
Pharmaceutical implant may have a cylindrical shape with a diameter of approximately from 0.5 to 5 mm and a length of approximately from 0.5 to 10 cm, Preferably its diameter is approximately 1 to 3 mm and a length of approximately 1 to 5 cm
The above media, which is one of the claimed inventions may be used to produce substrates (coated with a thermosensitive polymer) in cellular technologies and provides detaching cultured on cells in vitro for subsequent transplantation without the use of proteolytic enzymes and dissociative agents.
As thermosensitive polymers used mainly copolymers of N-isopropylacrylamide (NIP) and N-tributylamine (NTBA).
The detaching of the cells is provided by the ri lowering the temperature below the critical value, defined critical temperature of dissolution in aqueous solutions of polymers, when used as a carrier polymer substrate of magnetic material (component) or a ferroelectric with a large amount of magnetocaloric or electrocaloric effect.
As cultured cells using, for example, fibroblast line NCTC clone L929. Cells were cultured in the medium Needle in the modification Dulbecco (WHOI)containing 10% fetal calf serum (ETS), 50 µg/ml penicillin, 50 µg/ml streptomycin and 1% L-glutamine at 37°C in a humid atmosphere containing 95% air and 5% CO2.
This object is achieved also by a method of controlled controlled delivery of drugs or therapeutic drug or biologically-active substances in an organism, comprising the administration of a medicinal product consisting of a drug or a therapeutic drug or biologically active substance adsorbed to the magnetic material or a ferroelectric substance, covered with a film of heat-sensitive polymer and/or distributed in other heat-sensitive environment, providing adjustable desorption medicinal or therapeutic drug or biologically active substances due to the phase transition from insoluble to dissolve imoe condition by reducing the temperature below the critical value, defined critical temperature the solubility of the polymer and below the temperature of the human body, the magnetic or ferroelectric material is made from a material with a large value of negative magnetocaloric or electrocaloric effect, and having a transition temperature lying near human body temperature, and is selected from the group comprising rare earth, transition and noble metals, their alloys and intermetallic compounds, such as FeRh alloys, the localization of the drug or therapeutic agent or biologically active substances necessary in a given place, and lowering the temperature of the environment in a given place, causing desorption of drug or therapeutic drug or biologically active substances, carried out with application of an external magnetic or electric field and magnetic cooling or magnetocaloric material, due to the negative magnetocaloric effect and provides cooling of the heat-sensitive polymer or other heat-sensitive environment.
The magnetic or ferroelectric material is particles of small sizes down to the nano range, in addition they can be made in the form of plates, and, in addition, magni is hydrated or ferroelectric material may be a nanotube, filled with a magnetic substance or a ferroelectric, magnetic material or a ferroelectric may consist of nanowires made of Nickel or an alloy of Fe0,49Rh0,51200 nm in diameter and 20 μm in length, in addition, they can be made of magnetic nanoparticles, films or other objects form another ordered or unordered-dimensional structures with a large surface area and, therefore, good heat transfer, obtained by applying on a substrate; and a magnetic material or a ferroelectric can be pre-coated with a thin protective layer that prevents further oxidation. When this protective layer is made of graphite or silicon dioxide or glass. A ferroelectric with a high negative electrocaloric effect (with application of an external electric field) may be in the form of modified films based on PbZrof 0.95Ti0,05O3.
The invention also concerns another method regulated controlled delivery of drugs or therapeutic drug or biologically-active substances in an organism, comprising the administration of a medicinal product consisting of a drug or a therapeutic drug or biologically active substance adsorbed on the magnetic mother who Le or a ferroelectric substance, covered with a film of heat-sensitive polymer and/or another heat-sensitive environment, providing adjustable desorption medicinal or therapeutic drug from the polymer matrix due to the phase transition from an insoluble to a soluble state by raising the temperature above a critical value determined by the temperature of dissolution of the polymer, and above human body temperature, the magnetic material or the ferroelectric made from a substance with a large positive value magnetocaloric or electrocaloric effect, and having a transition temperature lying near human body temperature, and is selected from the group comprising rare earth, transition and noble metals, their alloys and intermetallic compounds, localization of the drug in the required specified location, and increasing the temperature of the polymer, causing desorption of drug or therapeutic drug or biologically active substances, carried out by heating a magnetic material or a ferroelectric under the application of a constant external magnetic or electric field to a magnetic material or a ferroelectric with a positive magnetocaloric or electrocaloric effect.
As tarmac stiteler polymer, providing an adjustable desorption medicinal or therapeutic drug or biologically-active substances in the specified location (localization) in the method according to the invention using, for example, (CO) polymers, poly-N-isopropylacrylamide, other (CO) polymers of(meth)acrylamide, such as propylbetaine, polymers containing ethylenoxide links, derivatives of cellulose, such as metilgidroxiatilzelllozu, cellulose acetate and others.
The film formation temperature-sensitive polymer on the magnetic material or ferroelectric (medium, medium) is carried out, for example, from alcohol solutions of (CO) polymers. Get a heat-sensitive substrate, on which surface adsorbed drug (or) therapeutic drug or biologically-active substance.
Removal (desorption) of a medicinal product is carried out by reducing the temperature below the critical value determined by the temperature of the phase transition in aqueous solution of the polymer. Thermosensitive polymers experience a phase transition from insoluble (solid substrate) into soluble in water at temperatures called the lower critical temperature of solvation (NCTS).
For example, at T=37°C, the polymer is poly-N-izopropilakrilamid is a solid (insoluble) condition h is about can be used as a solid substrate, where can absorb the drug. The temperature drops below the NCTS, for example, to a temperature of about 33°C for the above polymer causes hydrating the polymer and release of the drug from the surface of the substrate. Thermosensitive polymers have NCTS in the physiological range. Depending on the nature of the polymer, the ratio of monomers in the copolymer can vary the value of the NCTS. For example, CNTS for polymer N-isopropylacrylamide is set to 32.4°C, for its copolymers with N-tributylamine (NTBA) CNTS varies from 25,2°C (15% NTBA) to 9.6°C (50% NTBA). When removing the application of an external magnetic field desorption terminated and repeated exposure, she resumed; and so on until the complete desorption of the drug.
The content of magnetic particles or particles of a ferroelectric in the media may vary from 1 to 99 wt.%; this sorption capacity, respectively, from 3.0%to 96%. The adsorption capacity estimate for the mass of sorbed dye methylene blue. Magnetic or electric susceptibility of the magnetic particles or radiation depends on the chemical composition of the magnetic particles or radiation.
So, as claimed in the invention, the method of controlled drug delivery includes the introduction of the drug is the result of the drug, for example, in the form of magnetically sensitive or electroacoustically suspension containing magnetic particles or particles of a ferroelectric small sizes down to the nanoscale particles, localization entered the medicinal product at the specified location, the desorption of the drug using an external magnetic or electric field, the matrix of thermosensitive polymer, due to the magnetocaloric or electrocaloric effect of the magnetic particles of the carrier or of a ferroelectric, which leads to its cooling or heating, the temperature of the medium above or below human body temperature and NCTS.
In the claimed invention effective use of the magnetic material in the form of magnetic particles or radiation, providing more efficient transport (shipping), localization of medicinal (therapeutic) means and adjustable release it in the specified location when using an external magnetic or electric field based on the so-called magnetocaloric or electrocaloric effect, or due to the heat generated, for example, the magnetization switching of magnetic particles in an alternating magnetic field.
Magnetocaloric effect (IEC) or elektrotelluricheskih effect is the emission or absorption of heat in the magnetic or signedobject the ICA under the influence of the magnetic or electric field. If these changes occur under adiabatic conditions, it leads to increase or decrease the temperature of the sample. FEM was opened Everbrom in 1881 the basis of FEM is the ability of any magnetic material to change its temperature and entropy under the influence of a constant magnetic field, as is the compression or expansion of gas or vapor, for example, in conventional refrigerators.
Changing the temperature of the magnetic material occurs as a result of redistribution of the internal energy of the magnetic material between the magnetic moments of its atoms and lattice.
Magnetocaloric or elektrotelluricheskih effect can be used, in particular, in the technology of magnetic or electric cooling, for example, in air conditioning systems of large buildings, equipment storage of food, and, in particular, when creating a refrigeration both industrial and household. In these, for example, magnetic refrigerators operating on the principle of magnetocaloric cooling as a working body, using different magnetic materials.
Magnetocaloric effect, in particular, determines thermomagnetic properties of magnetic materials, and the higher it is, the better results in the release or absorption of heat in magnetic materials with ostatnie him of the magnetic field, which leads to the expansion of business opportunities of magnetic materials and increases the efficiency of drug delivery to the desired location, and, in particular, the holding magnet therapy of various diseases, for example, magnetic therapy of malignant tumors.
Examples of materials used in the proposed method, with high magnetocaloric effect and having a temperature of, for example, magnetic phase transition, lying near human body temperature (36°C to about 37°C) is described (A.M.Tishin, Y.I.Spichkin. Magnetocaloric effect and its application, Institute of Physics Publishing, Bristol and Philadelphia, 2003, p.410-411). In particular, alloys based on noble metals (rhodium, palladium, platinum), rare earth elements (metals), such as, for example, gadolinium (Gd Curie temperature of about 295K and the value of the MCE ΔT=5,8K when N=2 t), alloys or intermetallic compounds such as, for example, an alloy of iron-rhodium Fe0,49Rh0,51(temperature magnetic phase transition of the antiferromagnetism - ferromagnetism is about 310-316 K, and the value of the MCE reaches minus 13K in the field of 2 t); gadolinium-silicon Gd5Si4(maximum temperature FEM ΔT=8,8K at T=336K and N=TL); gadolinium-silicon-germanium Gd5Si2,06Ge1,94(ΔT=8K field TL and at T=306K); gadolinium-palladium Gd7Pd3(ΔT=8,5K PR is T=323K and N=TL); manganese-iron-phosphorus-arsenic MnFeP0,35Asof 0.65(the point of maximum FEM T=332K); manganese-arsenic MnAs (ΔT=13K at T=318K and N=TL); and others.
An example of a ferroelectric material can be a film based on the material type PbZrof 0.95Ti0,05O3or Pb0,99Nb0,02(Zr0,75Sn0,20Ti0,05)0,98O3. Both materials are used with chemical additives, allowing to shift the temperature range, where there are large values electrocaloric effect in the area of the human body temperature. In the desorption process applied electric field up to 25V. The temperature of the ferroelectric may vary by up to 10-12K (i.e. to 0.48 KV-1) (A.S.Mischenko, et al., Science, 2006, v. 311, p. 1270-1271).
Another example of a ferroelectric material may be of 0.9(PbMn1/3Nb2/3O3)0,1(PbTiO3). Upon application of an electrical voltage V=25B effect was 5K at 60°C (A.S.Mischenko et al., arxive: condmat/0604268. v.1, 11 April 2006).
These magnetic materials or ferroelectric is used in the form of particles with a size of, for example, from 400 nm to 1.0 nm. From magnetic measurements it is known that in alloys and compounds of rare-earth metals (REM) temperature magnetic phase transitions strongly depend on the concentration of the fusion-bonded metals and elements. Variation of the content of a particular e is ment in the alloy it is possible to achieve the required magnetocaloric effect and provide the necessary temperature, for example, magnetic phase transition, lying near human body temperature. As a rule, for example, the magnetic phase transition is carried out in a wide range of magnetic fields with the magnetic field from several EC up to 6 T and more.
Particles of a magnetic material or a ferroelectric get various well-known technologies, for example, a plasma method in an inert atmosphere (e.g. argon atmosphere) of particles of one or the other (metal element) to the original size, for example, 50-100 microns, or, for example, in the same way as described in SU 1746162, 07.07.1992 or sputtering a layer of nanoparticles on a substrate.
In the method according to the invention particles of a ferroelectric or above magnetic particles can be coated with particles of carbon (graphite) with known methods (for example, from SU 1722256, 1991) or they can be used in the form of carbon nanotubes, filled or coated with ferroelectric or magnetic particles of substances with a large amount electrocoloring or magnetocaloric effect. And next on their surface put thermosensitive polymer. The particle size varies from ultrafine to nanoscale.
Further to this, for example, magnetic media put thermosensitive polymer and absorb medicinal therapeutic Ave is parathas, prepared by, for example, in suspension and transported it to the desired location by imposing an external magnetic field using magnetic particles with high magnetocaloric effect (MCE). Used magnetic particles should have a high dispersion of the powder, ensuring the free movement of vessels in the media with the drug at its introduction in vitro; to have a saturation magnetization enough to control movement of the carrier with the drug - source of external magnetic fields with relatively low tension; to provide an adjustable delivery of the drug at the desired predetermined location. All this is provided by the used magnetic particles with a large amount of negative or positive magnetocaloric effect.
As drugs delivered into the body by the method according to the invention, use of various medicinal substances, drugs, enzymes, such as adriablastin, adriamycin, Riboflavin (vitamin b20), procaine, chinosol such anticancer drugs as perorate, bleomycin, chromomycin and other medicinal and therapeutic drugs. The concentration of the finished medicinal product used either in aqueous solutions or in the form of solutions, susp is NSI, in a physiologically acceptable carrier may also be different depending on its type and the action.
In particular, heat-sensitive polymer (as previously mentioned) in this case is a polymer desorption properties which increase during heating due to phase transition from an insoluble state to a soluble state. When this drug (or therapeutic) agent may consist of two active drugs, which can if necessary and under certain conditions (for example, when the contact and the influence of external magnetic or electric field) to communicate with each other, thus increasing therapeutic effect of them; and only one (first) current drug adsorbed on the media (described above), and desorption it is carried out if necessary at that point in time and/or in a given place, when injected into the body (or is already present in the body) the second active drug (or biologically the active substance).
For example, it is known that the novocaine not show anesthetic action for a sufficiently long period of time.
For example, we discovered that the products of interaction novocaine and dextran have properties that enable their use in therapeutic practice as anestesiologi the medication long-term local action. The content of novocaine in the final product is 0.1-95,0 wt.%. Mainly 1-30 wt.%. Synthesis of novocaine and dextran was performed by activating the hydroxyl group of dextran of bromine cyan with the formation of cyclic aminocarbonyl forming with pyramidographia novocaine Homo-polar connection.
Using media according to the invention, it is possible to increase the duration of anesthetic action analgesic, while adsorbed on the media one of these medicinal substances released by the method according to the invention the desorption at the right time and in the right place at the introduction of a second drug substance.
Thus, it is possible to achieve enhance therapeutic effect during delivery into the body of different drugs, drugs of the claimed method.
For example, one of the drug adsorbed on the media (as active material), for example, in the form of liposomes in the form of formproperty, and, in particular, anti-inflammatory, antiseptic or healing, antibiotics are the second medicinal substance introduced into the body. When the release (desorption) of one of them (the first) and the introduction (at the right time and place) the other is the strengthening of therapeutic action of them due to the possible interaction between them.
You can also enter (for example, in the gastro-Kish is hydrated tract) as the active beginning of the microbial mass of live bifidobacteria, adsorbed on the carrier according to the invention, with subsequent desorption their stated method of delivery and the introduction of a second drug substance, for example, biologically-active ingredients immunomodulating, regenerating and protective action of the drug may contain lysozyme, interferons, immunoglobulins, hyaluronic acid, biologically active peptides, growth factors, bifidobacteria, as well as antimicrobial, antiviral or antifungal agents.
It should be noted that bifidobacteria in compositions or independently used to create and maintain normoflora intestine, for the regulation of the intestinal microflora, treatment of intestinal dysbiosis, dysentery, colic in newborns, post-infectious reactive arthritis, atopic dermatitis, for receiving immunomodulator, to reduce the concentration of urea in the body to regulate cholesterol levels in the blood plasma, biological deodorizer and so on (DE 2755037 AL., EP 0482530 A3, SU 1286212 A1, SU 1258414 A1, DE 3716938, SU 1553132 A1, SU 1816215 A3, EN 2023445, DE 3406772 A1, EP 0181170 B1 0208818 B1, EP 0228861 B1).
You can also use two drugs, each of which is sorbed by the above method. With the release of both drugs or chemicals occurs simultaneously in the right place. After h is th their interaction and the subsequent effects on the body or the body leads to the expected therapeutic effect in the desired time. Each of these tools or substances separately is bioinert and individually has no effect on the human body.
The use of two-component approach is also possible for the following purposes. On one of the substrates adsorbed drug, which enhances the effect of vehicle or vehicles, deposited on another substrate, or ameliorate the effects of his actions, or, for example, is different in comparison with the first tool.
In the case of particularly strong drugs in capsules can also use the first component for the destruction of the capsule material with simultaneous or posted in time to the release of the second component (drug).
It is also possible the use of thermosensitive polymers with different temperatures of phase transitions of each component. This can lead, for example, that the first component will be released or application fields TL, and the second when the application field of 2 t.
The following examples illustrate the invention but without limiting it.
A specific example of implementation No. 1
The method can be carried out, for example, by the following method: magnetic coated with thermosensitive polymer hardened magnetic material Fe0,49Rh0,51together with Carstensen drug (for example, anti-inflammatory) in the form of particles with a size of about 300 nm is injected into the body through the catheter and deliver the particles to the desired organ or tissue. In areas where concentrated particles, applied magnetic field of 2 t. Magnetic material is cooled to 13°C, which leads to the cooling of heat-sensitive polymer, such as (CO) polymer of N - isopropylacrylamide, to a temperature below NCTS, in this case up to 24°C and the desorption of the drug from the surface of thermosensitive polymer.
A specific example of implementation No. 2.
The method is carried out, for example, as follows: magnetic material Gd5Sito 2.06Ge1,94with the phase transition point, located about C (K.A. Gschneidner, Jr. and Pecharsky V.K., 2002, in Intermetallic Compounds - Principles and Practic ed J.H.Westbrook and R.L.Fleischer, New York, Wiley, v.3), coated with thermosensitive polymer together with the medicinal product (anticancer) in the form of particles with sizes of about 100 nm is injected into the body through a catheter, in particular, applied magnetic field TL. The magnetic material is magnetized and o adiabatically (through inclusion of a constant magnetic field), causing an increase in temperature on the magnitude of the magnetocaloric effect (ΔT=4,5K at T=306K), i.e. heating takes place; in the future for scatalogia with blood and tissues of the magnetic material cools; next, the magnetic field is switched off, and is adiabatic demagnetization cooling of heat-sensitive polymer, such as (CO) polymer of N - isopropylacrylamide, to a temperature below NCTS, in this case to 32.2°C, and the cleavage of the medicinal product (release, desorption) from the film surface of thermosensitive polymer.
When carrying out the claimed methods use magnetic field created by permanent magnets (magnetic field), a working magnetic material in the form of particles, as well as assistive devices, if necessary, providing the introduction of the magnetic material in the tumor and its movement and concentration at the specified location.
The magnetic field may also be generated, for example, a superconducting solenoid. The concentration of particles in a specific location of the tumor increases in advance due to the applied magnetic field.
A specific example of implementation No. 3
Under the action of magnetic fields together in tumors particles of magnetic material is uniformly heated. When they due to heat generation due to FEM or due to the magnetization reversal of the alternating magnetic fields heat the surrounding tissue to a temperature of 40-42°C (313-315K), the cancer cells die, after which the particles due to heat exchange with surrounding tissues are cooled to the initial the temperature, close to the temperature of the human body; after that, the particles of the material demagnetized due to off the field (cooled) and cooled thermo-sensitive polymer. After lowering the temperature is desorption of the drug from the polymer surface; it is then possible to re magnetization. Thus, they are again under the action of the magnetic field are heated to the required temperature and heat affected tissue, i.e. in the basis of the method is to work on a specific thermodynamic cycle.
When delivery of a drug to tumors simultaneously runs the magnetic therapy (hyperthermia), carried out using the method according to the invention, which help (with drugs) to kill cancer cells, while healthy cells remain unharmed.
Example 4. Analogously to example 1 perform the introduction into the body of a medicinal product Adriablastin, the magnetic carrier is an alloy of iron-radium Fe0,49Rh0,51on the surface of which is coated with a film of a copolymer of NIP with 35 mol.% NTBA, in this advance on the surface of the alloy deposited protective layer of graphite (to prevent oxidation); the magnetic material in the form of plates.
After delivery of a drug in the body is ISM and localize it according to the stated method, the desorption is carried out at cooling the substrate with a film of thermoplastic polymer to a temperature below the temperature of the NCTS - in this case, to a temperature of 15.9°C. the desorption Time 30±5 minutes.
Example 5. Carried out analogously to example 4, but as the particles of the magnetic carrier used carbon nanotubes (20-30 nm and length up to 4 mm)coated with magnetic particles of iron-rhodium Fe0,49Rh0,51size is about 100 nm.
Example 6. Carried out as in example 4, but as the magnetic material used of Nickel nanowires with a length of 20 μm and a diameter of 200 nm.
Example 7. Carried out analogously to example 4, but at the same time using two different (or the same, but modified) thermosensitive polymer with different temperatures of phase transitions, characterized by 5°C. And the release of drug from the first polymer with a higher phase transition point occurs when the application fields 1T (ΔT=5-6°), and the desorption of the second when the application fields 2T (δ t-13°C).
Example 8. Carried out analogously to example 4, but as the magnetic carrier used simultaneously alloys Fe0,49Rh0,51and Feof 0.47Rhof 0.53. Moreover, these alloys absorb different components of the drug. Because the value of the MCE in these alloys differ by about 3K, then the application field TL happens cooling of Feof 0.47Rhof 0.53at 3,5K without phase transition in thermosensitive polymer and eSerbia the first drug is not going to happen. In exactly the same polymer deposited on the alloy Fe0,49Rh0,51the phase transition will occur even in the field TL, the alloy is cooled to 6,5K, and, therefore, will desorption of one of the components of a drug or chemical. When the application of 2 t the Feof 0.47Rhof 0.53cooled down to 7K, which leads to desorption of the second component.
Example 9. Carried out analogously to example 2, but instead of the magnetic material used ferroelectric material thin film on the basis of material type PbZrof 0.95Ti0,05O3or Pb0,99Nb0,02(Zr0,75Sn0,20Ti0,05)0,98O3. Both materials are used with chemical additives, allowing to shift the temperature range, where there are large values electrocaloric effect in the field of human body temperature. In the desorption process applied electric field up to 25V. The temperature of the ferroelectric may vary by up to 10-12K (i.e. to 0.48 KV-1) (A.S.Mischenko, et al., Science, 2006, v. 311, p. 1270-1271).
Thus, the method according to the invention improves the efficiency of delivery of a drug into the body, to increase the degree of localization in the specified place and to be further regulated desorption of a medicinal product for small is eriod of time for use in the method of magnetic material or a ferroelectric with a large amount of positive or negative magnetocaloric or electrocaloric effect, providing cooling thermosensitive polymer below NCTS and desorption of the drug or biologically active substances.
1. A carrier for drugs, biologically active substances, biological objects used in medicine for diagnosis and treatment, in the pharmaceutical industry, representing a material sensitive to the effects of external magnetic or electric fields and consisting of magnetic or ferroelectric material, covered with a film of biocompatible thermosensitive substances, natural or synthetic, biodegradable polymer and/or distributed in the heat-sensitive medium, whose properties change with temperature change relative to the temperature of the human body in the range from 15.9 to 42°C, with magnetic or ferroelectric material is made from a material with a large value of the magnetocaloric or electrocaloric effect component from 1 to 13 K, with a temperature magnetic or ferroelectric phase transition, lying in the temperature range from 33 to 37°C and selected from the group comprising rare earth, transition and noble metals, their alloys and compounds.
2. The carrier according to claim 1, characterized in that the magnetic material or ferroelectric mother is l represents particles of small sizes down to the nanoscale, i.e. nanoparticles.
3. The carrier according to claim 1, characterized in that the magnetic material or the ferroelectric material is a carbon tube, coated or filled with a magnetic material or a ferroelectric.
4. The carrier according to claim 1, characterized in that the magnetic material is a nanowire, in particular, Fe-Rh, gadolinium or Nickel.
5. The carrier according to claim 1, characterized in that the simultaneous use of two or more magnetic or ferroelectric materials with different magnitude of the magnetocaloric or electrocoloring effects in human body temperature.
6. The carrier according to claim 1, characterized in that the simultaneous use of two or more biocompatible thermosensitive substances, natural or synthetic, biodegradable polymer and/or distributed in the heat-sensitive environment polymers or environments with different values of critical points of solubility or the temperature of the phase transitions.
7. The carrier according to claim 1, characterized in that the magnetic material or the ferroelectric material previously deposited on a substrate (inorganic), in particular, silicon oxide and is made in the form of nanoparticles, films, or other ordered or unordered-dimensional structures with high surface area and large JV is the ability to heat transfer, obtained directly on the substrate surface.
8. The carrier according to claim 1, characterized in that the magnetic material or the ferroelectric material is pre-coated with a protective layer that prevents further oxidation.
9. The carrier according to claim 1, characterized in that the protective layer of magnetic material is made of graphite or glass.
10. The carrier according to claim 1, characterized in that the protective layer of ferroelectric material is made of graphite, silicon oxide or glass.
11. Media of claim 10, characterized in that together with the heat-sensitive medium is a gel, a solution, a colloidal solution, suspension or dispersion.
12. The carrier according to claim 1, characterized in that the magnetic material is a heat-sensitive ferrofluid.
13. The carrier according to claim 1, characterized in that as a biocompatible thermosensitive substances, natural or synthetic, biodegradable polymer and/or distributed in the heat-sensitive environment, use the substance, desorption properties which increase when heated above the critical point solubility or phase transition temperature due to the transformation from an insoluble state to a soluble state, the magnetic or ferroelectric material has a large positive value is about magnetocaloric or electrocaloric effect.
14. The carrier according to claim 1, characterized in that as a biocompatible thermosensitive substances, natural or synthetic, biodegradable polymer and/or distributed in the heat-sensitive environment, use the substance, desorption properties which increase with decreasing below the critical point solubility or phase transition temperature due to the transformation from an insoluble state to a soluble state, the magnetic or ferroelectric material has a large negative magnetocaloric or electrocaloric effect.
15. The carrier according to claim 1, characterized in that it is designed for use in biosensors in bioanalytical methods.
16. The carrier according to claim 1, characterized in that it is designed for the manufacture of implants for the reconstruction of tissues and organs based on cell cultures, in particular chondrocytes.
17. The carrier according to claim 1, characterized in that it is intended to obtain a substrate in cellular technologies, and providing detaching cultured on cells for subsequent transplantation without the use of proteolytic enzymes and dissociative agents.
18. Way adjustable magnetically controlled delivery of medicinal or therapeutic drug or biological is active substance into the body, includes the administration of a medicinal product consisting of at least one drug or therapeutic drug or biologically active substance adsorbed on the carrier - magnetic or ferroelectric material, covered with a film of biocompatible thermosensitive substances, natural or synthetic, biodegradable polymer and/or distributed in the heat-sensitive environment, providing adjustable desorption medicinal or therapeutic drug or biologically active substances due to the transformation of insoluble to soluble state when the temperature drops below the critical point solubility and below human body temperature, with magnetic or ferroelectric material is made from a material with a large value of negative magnetocaloric or electrocaloric effect and having a temperature of phase transition, lying near human body temperature and selected from the group comprising rare earth, transition and noble metals, their alloys and compounds, localization of the drug or therapeutic agent, or a biologically active substance, necessary in a given place, and lowering the temperature of the environment in a given place, causing desorption drugs the military or therapeutic drug or biologically active substances, carried out with application of an external magnetic or electric field and by cooling, magnetic or ferroelectric material, due to the negative magnetocaloric or electrocaloric effect, and providing a cooling film of biocompatible thermosensitive substances, natural or synthetic, biodegradable polymer and/or heat-sensitive environment.
19. The way regulated controlled delivery of drugs or therapeutic drug for p, characterized in that the use of ferroelectric material with a high negative electrocaloric effect arising from the application of an external electric field, representing, for example, the modified film on the basis of PbZrof 0.95,Ti0,05O3.
20. The way regulated controlled delivery of drugs or therapeutic drug in the body p, characterized in that the magnetic material or ferroelectric material is particles of small sizes down to the nanoscale.
21. The method according to p, characterized in that the magnetic material or the ferroelectric material is a carbon nanotube filled or coated with a magnetic or ferroelectric substance is.
22. The method according to p, characterized in that the magnetic or ferroelectric material is a nanowires, for example, from an alloy of Fe-Rh, gadolinium or Nickel.
23. The method according to p, characterized in that the magnetic material or the ferroelectric material previously applied to the inorganic substrate, in particular, silicon dioxide, magnesium oxide, and made in the form of nanoparticles, films, or other ordered or unordered-dimensional structures with high surface area and high capacity for heat exchange is obtained on the substrate surface.
24. The method according to p, characterized in that the magnetic material is a heat-sensitive ferrofluid.
25. The method according to p, wherein the drug or therapeutic drug consists of two active substances, medicines or drugs that can interact among themselves, with only one first active substance, drug, or drug adsorbed on the carrier and desorption it is at that point in time and/or in a given place, when injected into the body or present in the body of the second active substance, a drug, a drug or biologically active substance.
26. The method according to p, wherein the drug or therapeutic drug of the situation of the t of the two or more active substances, medications or drugs that can interact with each other, with both active substances, drug or drug adsorbed on the media and desorption of them is carried out simultaneously or sequentially, at a certain point in time.
27. The method according to p, characterized in that the carrier is a gel, a solution, a colloidal solution, suspension or dispersion.
28. The method according to p, characterized in that the cooling of the heat-sensitive polymer are sorption of substances that must be removed from the body.
29. The method according to p, characterized in that the delivery of drugs or therapeutic drug or other biologically active substances is carried out in the gastro-intestinal tract.
30. The method according to p, characterized in that the magnetic material is pre-coated with a protective layer, in particular, graphite, or glass, which prevents further oxidation.
31. The method according to p, wherein the ferroelectric material is pre-coated with a protective layer, in particular, graphite, or glass, which prevents further oxidation.
32. The way regulated controlled delivery of drugs or therapeutic drug or biologically active substance in the body, including the administration of a medicinal product, sostayashego is from a drug or a therapeutic drug, or biologically active substance adsorbed to the magnetic material or a ferroelectric substance, covered with a film of biocompatible thermosensitive substances, natural or synthetic, biodegradable polymer and/or heat-sensitive environment, providing adjustable desorption medicinal or therapeutic drug or biologically active substances of heat-sensitive matrix of transformation from the insoluble to the soluble state by reducing the temperature below the critical point solubility and below human body temperature, with magnetic or ferroelectric material is made from a substance with a positive value magnetocaloric or electrocaloric effect and having a temperature of magnetic or ferroelectric phase transition, lying near human body temperature and the selected from the group comprising rare earth, transition and noble metals, their alloys and compounds, localization of the drug in the required specified location, and lowering the temperature of the environment, causing desorption of drug or therapeutic drug or biologically active substances carry out the preliminary heating of a magnetic material or a ferroelectric is here the application of an external magnetic or electric field to a magnetic material or a ferroelectric with a large positive magnetocaloric or electrocaloric effect due to the heat, eye-catching in the magnetic material or the ferroelectric due to the magnetocaloric or electrocaloric effect, with subsequent natural cooling of the magnetic material or the ferroelectric to the temperature of surrounding tissues and the final cooling of the magnetic material below human body temperature due to removal of the applied magnetic or electric field.
SUBSTANCE: semiconductor photoelectric generator has a substrate, diode structure from semiconductor layers, antireflection coating, metallic contacts, several layers are deposited on the substrate, forming diode planar n+-p-p+ (p+-n-n+); n-p structure, connected in series in the direction of propagation of radiation. Layers of the same type contain metallic nanoclusters with size varying from 5 to 38 nm with concentration of nanoclusters in the said layers not exceeding (1 to 10)·10-2 volume parts. Distance between nanoclusters and layers of the other type, which are semiconductor nanocrystals, is not more than 1200 nm. One or two linear dimensions of each diode structure does not exceed the diffusion distance of minority carriers in the base region, and the thickness of the diode structure in the direction of propagation of radiation is inversely proportional to maximum coefficient of absorption of radiation in the semiconductor material. The method of making a planar semiconductor photoelectric generator involves making a diode structure from semiconductor layers on a semiconductor substrate, depositing antireflecting coating and metallisation. By successively depositing semiconductor layers, several layers with thickness varying from 8 nm to 20 mcm are formed, which form diode planar n+-p-p+ (p+-n-n+); n-p structure. In layers of the same type, metallic nanoclusters with size of 5 to 38 nm are introduced with concentration of nanoclusters in the said layers not exceeding (1 to 10)·10-2 volume parts, and the layers of the other type are made in form of semiconductor nanocrystals, where distance between nanoclusters and said nanocrystals does not exceed 1200 nm. One or two linear dimensions of each diode structure does not exceed the diffusion distance of minority carriers in the base region, and the thickness of diode structures in the direction of propagation of radiation is inversely proportional to the maximum coefficient of absorption of radiation in the semiconductor material. The cut-off effect of reverse-biased junctions is eliminated, forming a series connection of structures in the direction of propagation of radiation. The cut-off effect of reverse-biased junctions can be eliminated by applying pulsed voltage across the formed multilayer planar matrix and reverse-biased junctions are broken down, forming a series connection of structures in the direction of propagation of radiation.
EFFECT: invention increases efficiency of converting electromagnetic energy.
5 cl, 1 dwg,1 ex
SUBSTANCE: invention relates to analysis of the physical and chemical state of materials when studying the mechanism of action of external factors and can be used for controlling quality of materials when designing new materials, including based on nanotechnology. The method is based on analysis of the supramolecular structure of material before and after external action. During analysis of the supramolecular structure of material, its morphologic and textural parametres are measured, where the said parametres are average length of cracks and/or domain boundaries, surface area of the object occupied by cracks, mean angle of deviation of cracks from the direction to the centre of convergence of cracks, fractal dimension of the supramolecular structure. Change of uniformity of distribution of measured parametres indicates unstable state of the structure of the material, while retention of uniformity of distribution of parametres indicates stable state of the structure of the material. A test sample is used to determine the trend of processes taking place during restructuring. Morphologic and textural parametres of the supramolecular structure of the test sample are measured and compared with those of the analysed material before and after action, and ordering or disordering of the structure is determined.
EFFECT: provision for high accuracy of determining reaction of material to external action, increased reliability of obtained information and possibility of its quantitative evaluation.
3 cl, 4 dwg
FIELD: metallurgy industry.
SUBSTANCE: invention refers to field of nanotechnology, to method of creation of metal nanoparticles on surface of base. Method involves preliminary application of metal thin-film coating on base surface and exposure of resultant coating to high-energy ion beam till coating melting and formation of variform nanoparticles of coating material on base surface. In order to create nanoparticles with diametre up to 100 nm, metal thin-film coating with thickness up to 20 nm from material with melting temperature up to 1500°C is applied on base made of inorganic glass or ceramised glass or oxidised silicium and is exposed to 1-3 pulses of nanosecond duration of powerful ion beam (PIB) composed of 70% C+ and 30% H+ with energy 300 KeV and current density 5-50 A/cm2.
EFFECT: formation of nanoparticles of various forms and sizes without change of base electrical properties with reduce of exposure time to 60-180 nanosec.
SUBSTANCE: method of producing heat-resistant material for protective coating involves dissolving a polymeric binder in a solevent, where the binder is in form of poly(o-hydroxyamide), which is a product of polycondensation of dichloride of isophthalic acid with 3,3'-dihydroxy-4,4'-diaminodiphenylmethane in a solvent in molar ratio of reagents ranging from 1:1:7 to 1.05:1:15, and mixing with carbon nanofibres or carbon nanoclusters, obtained through hydrolysis of methane on a Ni/MgO catalyst with length of fibres from 50 to 100 mcm and diametre from 20 to 60 nm until obtaining a homogeneous composition.
EFFECT: obtained finished material is heat-resistant, is highly adhesive and has protective properties when deposited on surfaces of varying chemical nature.
3 cl, 5 ex
SUBSTANCE: composite material is proposed, which is based on zinc sulphide nanocrystals and carbon nanotubes, in which zinc sulphide crystals serve as the matrix and carbon nanotubes are the reinforcing filler. Carbon nanotubes are inside the nanocrystals, directly passing through their volume. Such a composite can be used as optical material, since its optical density is not greater than 0.01.
EFFECT: reinforcing filler from carbon nanotubes provides for high strength of material.
1 ex, 4 dwg
FIELD: metallurgy industry.
SUBSTANCE: as per the first version, the method involves activation of fine carbon base with laminate-type structure by being intercalated in water solutions of strong acids and further interaction of intercalated base with hexachloroplatinum acid by introducing it, reduction of interacting products till platinum is obtained and oxidation of carbon base. As per the second version, the method involves interaction of fine carbon base with hexachloroplatinum acid in the presence of chloride, reduction of interacting products till platinum is obtained and oxidation of carbon base.
EFFECT: simplifying manufacture and increasing economy of the process.
2 cl, 1 dwg, 3 ex
SUBSTANCE: invention relates to a method of making a nanosised system for delivering met-enkephalin on a hydrosol of SiO2 nanoparticles, involving mixing distilled water, hydrochloric acid and tetraethoxysilane, addition of a prepared NaOH solution, evaporation and filtration, obtaining a SiO2 hydrosol, ultrasonic treatment of the obtained SiO2 hydrosol, addition of met-enkephalin and surfactant solution in amount ranging from 0.5 to 2% of total volume of the obtained system.
EFFECT: system of delivering met-enkephalin is capable of penetrating the hematoencephalic barrier and deliver medicinal agents to brain cells.
2 ex, 2 tbl
SUBSTANCE: invention relates to electrochemical synthesis of tungsten compounds and can be used for producing nanodispersed pure powder of tungsten carbide, with developed surface and electrocatalytic properties. Electrolysis of a melt, containing, mol %: lithium tungstate 35.0 to 45.0, lithium carbonate 15.0 to 20.0, sodium tungstate - the rest, is carried out in open cells in galvanostatic mode with cathode current density ranging from 2.5 to 7.5 A/cm2.
EFFECT: possibility of obtaining powder with specific surface area ranging from 20,0 to 41,6 m2/g and fast synthesis of the desired product.
SUBSTANCE: invention relates to electrochemical synthesis of refractory tungsten compounds and can be used for producing nanodispersed hard-alloy compositions based on tungsten carbide and cobalt, with high melting points, hardness, strength, elasticity, chemical inertness. A melt, containing, mol %: lithium tungstate 30.0 to 40.0, cobalt tungstate 2.5 to 5.0, lithium carbonate 15.0 to 20.0, sodium tungstate - the rest, undergoes electrolysis in open cells in galvanostatic mode with cathode current density ranging from 2.5 to 7.5 A/cm2.
EFFECT: obtaining power with particles size ranging from 50 to 500 nm, doubling rate of synthesis of desired product, simplification of the process.
SUBSTANCE: invention relates to field of metallurgical manufacturing, particularly to method of receiving of continuous nonmetallic blanks. Blanks are received in crystalliser, one pair of walls of which is implemented with ability of reciprocating rotary motion, and the second pair - with ability of angular motion and allows in top part extended section with angle of slope to vertical. Method includes feeding of inert gas lengthwise the second pair of crystalliser's walls, spraying of metal in two rows of stream, clamping of metal, calibration of blank surface and its continuous ejection. In crystalliser it is sprayed preliminary prepared supercooled lower the crystallization temperature liquid metal, which is in amorphous state, two rows of streams, between which, lengthwise the second pair of crystalliser's walls, it is fed overheated liquid metal, similar to sprayed metal. Also in crystalliser it is implemented alignment of temperatures of overheated and supercooled metals and its simultaneous crystallisation .
EFFECT: productivity improvement of receiving of nonmetallic blanks.
4 cl, 2 dwg
SUBSTANCE: group of inventions concerns medicine and cosmetology and can be applied in focused local therapeutic and/or cosmetological effect on human tissues. It involves uniform activation of photodynamic therapy device without contact to damaged tissue by light exposure directly before medicine application. Then the medicine is applied onto damaged tissue, medicine excess removed. Photodynamic therapy device is activated by device including container with storage tank for photodynamic therapy device. One of the tank walls features optic system communicating with light source. Container has a lid. When the lid is removed, activation device included in electric unit closes electric circuit. Electric unit is connected to light source and also activates power unit and deactivation device. Deactivation device can be made in the form of time relay or microprocessor.
EFFECT: prevented complications related to body irradiation by activation of photodynamic therapy device and by body contact to inactivated photodynamic therapy device capable or preserving activated state long enough to affect damaged tissues.
7 cl, 3 dwg, 2 ex
SUBSTANCE: invention concerns medical equipment, namely, to the applicator for implant introduction, in particular, a scapiform implant, containing active substance, under the skin of a person or an animal. The applicator for introduction of a scapiform implant contains a case, a cannula, a cannula holder, a scapiform implant, established in a cannula and-or the holder of a cannula, a protective cover for the cannula and the mechanism which, at least, after putting off of a cover from the cannula, fixes a scapiform implant in the cannula and-or the holder of a cannula. The mechanism is executed with possibility of detachment of a scapiform implant, containing active substance during introduction of a cannula or after the cannula is entered, and before pushing out an implant from the cannula.
EFFECT: possibility to fix an implant in a cannula and-or the holder of a cannula and, on the other hand, to avoid implant damage, especially, during its introduction.
16 cl, 11 dwg
SUBSTANCE: invention concerns medical equipment, namely, to the applicator (for implant introduction), in particular, scapiform implant (2), containing active substance, under the skin of a person or an animal. The applicator contains a case, a cannula proceeding from the case, and the handle for capture and manipulation with the applicator and cannula during implant introduction. The handle continues on distance from and along, at least, part of length of the cannula, at least, during cannula introduction. The invention facilitates cannula introduction and positions the implant precisely.
EFFECT: simplification of cannula introduction and provision of exact implant positioning.
10 cl, 11 dwg
SUBSTANCE: invention refers to medicine and veterinary science, and can be used particularly for disconnection of the affected pulmonary region from ventilation with using programmed cell loss phenomenon (apoptosis). The device for chemicals delivery to bronchial tubes and other hollow organs of biological objects comprises two reservoirs inserted one inside the other. The reservoirs have apertures in their walls that are combined in relative relocation of the reservoirs to ensure escape of the interior reservoir content beyond the external reservoir within therapeutic action on the organ.
EFFECT: ease of fabrication.
SUBSTANCE: photosensitiser is preactivated with irradiation. The biologically active points are specified herewith considering specific involved organ, its regional lymph nodes of vessels and lymph nodes, anatomic position of off-organic mains. Then the fluid photosensitiser is introduced pharmapuncture through the biologically active points or by lymphotropic and pharmapuncture method through the biologically active points. After the therapeutic concentration of the photosensitiser in the tumour is achieved, introduction point is exposed to therapeutic optical radiation.
EFFECT: method allows improving clinical effectiveness, with reducing dosage of introduced photosensitiser, reducing irradiation readiness time, preventing intoxication, ensuring collateral therapeutic effect.
SUBSTANCE: invention pertains to medicine, surgery and may be used for hemostasis in pyloroduodenal ulcers when there is no clear visualisation of the source of bleeding. Endoscopic examination of the pyloroduodenal zone is done followed by consecutive injection of solution of vasoconstrictor. Injection points are selected from 6 points of pylorus at 1, 3, 5, 7, 9, and 11 hours of the reference clock-face. A point located in the central part of the upper wall of pylorus is accepted for 12 hours. With the source of bleeding located on the front wall of the bulb DNA injections are made into pylorus points corresponding to 7,9,11 hours of the reference clock-face. With the source of bleeding located on the upper wall of the bulb DNA injections are made into pylorus points corresponding to 1 and 11 hours of the reference clock-face. With the source of bleeding located on the back wall of the bulb DNA injections are made into pylorus points corresponding to 1,3,5 hours of the reference clock-face. With the source of bleeding located on the lower wall of the bulb DNA injections are made into pylorus points corresponding to 5 and 7 hours of the reference clock-face.
EFFECT: use of the method decreases number of complications through clear visualisation of the source of bleeding.
3 dwg, 4 ex
FIELD: medical equipment.
SUBSTANCE: ultrasonic skin care apparatus contains the casing equipped with applicator head transmitting ultrasound to user's skin, and driver circuit transmitting electric closing pulse to applicator head operation thus generating ultrasound. The applicator head of the generator contains vibrator and flange with mounting surface and surface faced to skin. Herewith the vibrator is provided on the mounting surface of the flange thus integrating uniform vibratory gross forming the applicator which creates the first electric equivalent resistance in case of rated loading within skin contact and the second electric equivalent resistance without loading. Besides, the device is provided with load record circuit which controls, whether specified uniform vibratory gross generates the first electric equivalent resistance or the second electric equivalent resistance, and generates load record signal only it is detected that this is first electric equivalent resistance, and control circuit which limits or stops electric pulse generation if load record signal is not received within preset time. The uniform vibratory gross is provided to restrict vibrations in its centre thus reducing parasitic resonance.
EFFECT: ensured safety and higher efficiency skin effect in combined application of active skin preparation and ultrasound.
15 cl, 35 dwg, 1 tbl
SUBSTANCE: for prevention of postoperative osteomyelitis use composition consisting of antimicrobial substances, dissolved in high-molecular polyvinylpyrolidone with molecular mass of 1 million. The composition is administered using a syringe into the medullar channel and in the intermuscular spaces surrounding a bone, on a measure of sealing of soft tissues after operation. Invention allows to give antimicrobial activity to tissues surrounding wound for long time at the expense of slow biodegradation of polyvinylpyrolidone and long-term diffusion of antimicrobial substances from a composition in a tissue.
EFFECT: long finding of antimicrobial substances in tissues, prevention of development of postoperative osteomyelitis.
FIELD: medical equipment.
SUBSTANCE: multipolar magnetic diamagnetic nanoparticles injector in biological tissue consists of multipolar magnet all poles of which are provided within one plane being loaded side of injector. Poles are not spaced.
EFFECT: invention allows for higher density of nanoparticles injection in biological tissue.
3 cl, 5 dwg, 1 tbl
SUBSTANCE: invention is referred to medicine area, namely to apiotherapy and can be used for treatment of various diseases in neurology, ophthalmology and other branches of medicine. Essence: a skin area that should be sting, is preliminary moistened with infusion of dead bees on 40-60% alcohol aqueous solution in the ratio of 100 units of dead bees on 100 ml of alcohol aqueous solution. The way allows accelerating and enlarging reliability of procedure.
EFFECT: provision of faster and more reliable treatment with bee sting.
SUBSTANCE: invention concerns medicine, namely surgery. A device is introduced into large intestine lumen through its wall to perform irrigation of large intestine. Thus large intestine is decompressed by puncturing its wall above and closer to the tumour with using a trocar with a polyvinyl tube. After an affected region of large intestine is resected, a sterile tube bushing made of medical polymer material with circular corbellings in its external surface is inserted into the lumen of proximal end. With using said corbellings, wall of proximal end of large intestine is tightly fixed with purse-string suturing on external surface of the tube bushing. Onto external surface of proximal end of large intestine fixed on the tube bushing, a sterile whole-cut evacuation polyethylene sleeve is fixed on circle of the tube bushing with interrupted ligature. Excess sleeve closes fixation point of wall of proximal end of large intestine with the tube bushing. The second end of the evacuation sleeve is placed in a container with an antiseptic. Through vermiform appendix, after its half-length resection, a metal catheter is inserted. Its diametre relates with the lumen of vermiform appendix. The catheter is fixed circumferentially with silk ligature to the rest of vermiform appendix. The second end of the catheter is tubed to a device that supplies perfusion solution into large intestine lumen. Large intestine is cleaned from intestinal contents within 30-40 minutes. Perfusion solution is 0.9% saline solution in amount 5-7 litres. At the end of large intestine irrigation procedure, the last litre of perfusion solution is additionally added with enterosorbent in amount 40-50 gram, metronidazole in amount 100 ml and Perftoran in amount 100 ml. After irrigation the catheter is removed from resected vermiform appendix that is followed with standard appendectomy. From proximal end of large intestine, the tube bushing with the evacuation sleeve within resection of wall of large intestine over the removed bushing. A single-layer anastomosis is formed without protective colostomies. In that specific case, as an enterosorbent in perfusion solution for cleaning large intestine from intestinal contents, Enterosgel is used.
EFFECT: method allows improving reliability of intraoperative irrigation of large intestine with simultaneous simplification of manipulation of large intestine in preparation thereof for resection and intraoperative irrigation, reducing operative injuries and risk of infection of abdominal cavity, providing consistency of intestinal anastomosis.
2 cl, 2 dwg, 3 ex