RU2563387C2 - Implanted device, controlled by magnetic field, and method of medication release therefrom - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medical equipment, namely to means for the delivery of medications by implanted devices, controlled by the magnetic field. The device consists of a body, an external periphery and a covering, which takes at least a part of the external periphery and includes the following layers in the order from internal to external: the first insulating layer, a layer of a magnetic material with positive and negative magnetocaloric effect of not less than 3 K/T, a layer of a sensitive material, which contains an active substance and is capable of holding and controlled release of the active substance, the second insulating layer, permeable for the active substance. The method of the controlled release of medications consists in implanting the device into the patient's body and influencing the implant by the magnetic field to release the active substance.

EFFECT: application of the invention makes it possible to increase safety for surrounding healthy tissues when the medication is released.

18 cl

Description

FIELD OF TECHNOLOGY

The invention relates to medicine, pharmacology and biotechnology, in particular to drug delivery systems at a given point in time, implantable and activated in the patient’s body, and in particular to magnetic field controlled implantable devices.

BACKGROUND OF THE INVENTION

Implants are medical devices made to replace lost biological functions, support damaged tissues and expand the capabilities of existing organs. The surface of the implants in contact with biological tissues should consist of biomedical material with the aim of better survival in the tissues. In some cases, the implants contain electronic devices, such as artificial pacemakers and cochlear implants. Some implants have biological activity, for example subcutaneous drug dispensers in the form of implantable pills or drug-coated stents.

The modern development of implantation technologies has led to significant progress in medicine, and the number of surgical operations using implants is constantly growing. Implants with magnetic elements are also beginning to play an increasingly important role in medicine. Examples of such magnetic implants are magnetic field concentrators for targeted drug delivery using injected magnetic nanoparticles [Zachary G. Forbes et al., Validation of high gradient magnetic field based drug delivery to magnetizable implants under flow, IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, v. 55, Issue: 2, p. 643-649}, implants for magnetic fixation of jaw prostheses [Dental Magnetic Attachments http://www.aichi25steel.co.jp/ENGLISH/pro_nfo/pro_ntro/elect_1.html], multifunctional permanent magnet implants [Bulletin of the Magnetic Society , Vol.14 (3), p.7 (2014)] and others.

Other examples include biodegradable devices with the functionality of the reusable dispensers described in Grayson ACR, Choi IS, Tyier BM, et al. Multi-pulse drug delivery from a resorbable polymeric microchip device. Nat Mater. 2003; 2 (11): 767-772. The device consists of a biodegradable polymer microchip with microcontainers filled with various drugs. In another approach (Yang R, Gorelov AV, Aldabbagh 5 F, Carroll WM, Rochev Y. An implantable thermoresponsive drug delivery system based on Pettier device. International journal of pharmaceutics. 2013: 447 (1-2): 109-14) use Peltier elements with a thermosensitive membrane that regulates the release of medicine in the aquatic environment. With the help of such a device, a pulsating regime of drug release under the influence of pulses of electric current was realized. However, the implantation of chips, whose dimensions are about a centimeter, limits the possible areas of application of such systems.

A more technologically advanced solution is to coat implants with thermosensitive polymers with nanoparticles heated by external influences, such as, for example, near-infrared radiation, which causes plasma resonance in the nanoparticles of the coating [Sershen SR, Westcott SL, Halas N], West JL. Temperature-sensitive polymer-nanoshell composites for photothermally modulated drug delivery. Journal of Biomedical Materials Research. 2000; 51 (3): 293-298]. However, biological tissues are not completely transparent even for infrared and microwave radiation.

In the patents US 2002/0128704, US 2005/0278014 describes the activity control of the drug covering the metal implant (for example, a stent), or the drug inside it.

In this method, heating the stent allows you to release the medicine from the coating layers, activate medicinal substances, the biological activity of which is reduced or completely absent at body temperature, and also intensify the interaction with surrounding tissues at specified time periods. The drug may be released from the heat-sensitive material inside the stent or on its surface. Heat is supplied by exposing the stent to an appropriate magnetic susceptibility to an electromagnetic field, preferably at a frequency of less than 1 MHz. The authors argue that inductive heating is non-invasive and precisely controlled. However, heat generation due to inductive heating is not so easy to control, since it depends on many parameters, including the stent material and its position inside the body. Therefore, this technique is inherent in the risk of overheating of the tissues surrounding the implant, or their insufficient heating, which will reduce the effectiveness of the treatment. Due to the induction nature of heating, only metallic materials can be used. Accordingly, the use of biodegradable and plastic implants is excluded.

According to another approach described in US 6,544,163, controlled embolization in aneurysm is achieved using a magnetic field. The magnetic embolization system includes a catheter, the distal end of which is adapted for insertion into the aneurysm cavity of a blood vessel of a permanent magnet or electromagnet, creating an internal magnetic field necessary for controlled embolization. However, the introduction of such foreign and rather large bodies creates great difficulties during operations.

WO 2005/042142 describes a biocompatible heat-sensitive polymer carrier with encapsulated magnetic or metallic colloidal particles and nanoparticles, which is heated by an external high-frequency alternating field. As a result of inductive heating in the polymer matrix, the physical structure changes, which leads to the release of the bioactive substance encapsulated in the matrix in a short period of time. Drug carriers arranged as described above can be applied locally using standard methods of drug administration, such as injection, implantation, soaking, dialysis or biopsy. Exposure to magnetic particles can be enhanced by concentrating them in the desired location using a strong permanent magnet or electromagnet. As soon as the polymer particles are at the site of exposure, they can be heated above body temperature using a high-frequency alternating magnetic field, which leads to a change in the physical structure of the polymer matrix. This change triggers the process of exposure to bioactive substances that is intense and localized in space and time. However, in order to heat the aforementioned metal and magnetic particles to the desired temperatures, a specially designed magnetic field source with predetermined frequency characteristics and spatial field configuration is needed. Polymer particles can diffuse uncontrollably from the site of exposure, so the use of such systems in some cases, such as treatment of vascular walls, is difficult. Moreover, a typical drug release time is about 5 minutes, which is undesirable in the case of prolonged drug exposure.

Thus, it is necessary to develop implantable devices with improved properties that can selectively act on affected tissues and safely release the medicine in the right place in a controlled manner for surrounding healthy tissues.

SUMMARY OF THE INVENTION

This invention relates to implantable devices that ensure the preservation and magnetic field controlled release of drugs in a given place at a desired point in time.

In particular, the invention relates to an improved version of implantable devices. It ensures the preservation of the drug substance during the installation of the implant, prevents its loss and at the same time allows for the salvo or pulsation mode of release of the bioactive substance, while at the same time preventing overheating or insufficient heating of the device.

In a technical aspect, the invention relates to implantable devices consisting of a device body having an outer periphery and a coating occupying part of the outer periphery and consisting of the following layers in order from the inner regions of the device to the outer:

- the first insulating layer;

- a layer of magnetic material with a positive or negative magnetocaloric effect, with a value of at least 3 K / T;

- a layer of sensitive material containing the active substance, which is able to control the retention / release of the active substance;

- a second insulating layer, with a large number of pores, permeable to the active substance.

In accordance with one implementation of the above description, the first layer is selected from a heat insulating layer or coating that reflects infrared radiation, as well as combinations thereof.

Preferably, the first insulating layer is adjacent to the outer periphery of the housing, however, where necessary, an additional layer can be used below or above the first insulating layer.

According to one implementation, the second insulating layer contains pores and is permeable to the active substance, i.e. under certain conditions, the medicine passes through itself. The second insulating layer is selected from a porous heat insulating material, a porous material reflecting infrared radiation, or a combination thereof.

In accordance with one implementation, the insulating layer consists of polystyrene, silica gel, polyurethane, bioceramics, or a combination thereof.

According to one implementation, the infrared reflective layer consists of a metal or metal alloy, preferably medical stainless steel, an alloy based on titanium or tantalum.

In accordance with one implementation, the magnetic material is selected from the group of rare earth metals such as gadolinium, terbium, dysprosium, holmium; transition metals such as iron, nickel, cobalt, manganese; noble metals such as rhodium, palladium; their oxides, compositions, combinations, solid solutions and alloys, such as Gd ₅ Si ₄ , Gd ₅ Si _2.06 Ge _1.94 , Gd ₇ Pd ₃ , MnFeP _0.35 As _0.65 , Fe _0.5 Rh _{0 5} , Ni-Mn-Ga and MnAs.

In some implementations, the magnetic material has a positive, in others, a negative magnetocaloric effect of at least 0.5 K / T, at least 1 K / T, at least 1.5 K / T, at least 2 K / T, at least at least 2.5 K / T, not less than 3 K / T, not less than 3.5 K / T, not less than 4 K / T, not less than 4.5 K / T, not less than 5 K / T, not less than 5 5 K / T, not less than 6 K / T, not less than 6.5 K / T, not less than 7 K / T, not less than 7.5 K / T, not less than 8 K / T.

In accordance with the implementation of the present invention, the layer of sensitive material consists of at least one material related to polymers, copolymers, hydrogels, biopolymers, or a combination thereof.

In accordance with the implementation of this invention, the layer of sensitive material contains:

- a mixture of two or more polymers; and / or

- two or more layers of various polymers; and / or

- two or more inserts with different polymers.

In accordance with the implementation of the present invention, at least one of the polymers (preferably two or more) is a heat-sensitive material with a phase transition temperature near body temperature.

In accordance with one implementation of the present invention, various heat-sensitive layers have different phase transition temperatures.

In accordance with the implementation of the present invention, the heat-sensitive polymer is selected from the following group of substances: polybutyl methacrylate (rVMA), poly-N-isopropyl acrylamide (PNIPAM), a copolymer of N-isopropyl acrylamide (NIPAM), N-isopropyl methacrylamide (NIPMAM) and acrylamide (AAm) and / or their combinations.

A polymer layer consisting of several polymers makes it possible to repeatedly activate thermosensitive polymers during heating, when passing through different transition temperatures for different layers, and also provides thermal insulation of the device, so that a temperature lower or higher than other tissues can be maintained for a sufficient to isolate the drug for a period of time without significant heat transfer with surrounding tissues.

In accordance with one implementation of the present invention, at least one of the sensitive polymers (preferably two or more) is sensitive to mechanical deformation with a low tensile strength, in particular a copolymer of lactic and glycolic acids.

In accordance with one implementation of the present invention, the layer of sensitive material may also contain a contrast agent that allows you to control the amount of drug released by magnetic resonance imaging.

According to an embodiment of the present invention, a porous / permeable polymer layer allows interstitial fluid or blood plasma to pass through them and thus release active substances.

In accordance with the implementation of this invention, the implantable device is a stent, catheter, joint prosthesis, joint and bone endoprosthesis, bone suture, denture, pacemaker, insulin dispensers, silicone implants, neuroimplants, microcircuits implanted in the brain (chip implants), cochlear prosthesis and dental implants.

Another aspect of the present invention is a controlled drug release method consisting of the following steps: implanting a magnetic field controlled device into a patient's body; exposure of the implantable device to a magnetic field in order to controlled release of the active substance.

In accordance with one implementation of the present invention, an alternating magnetic field from an external source with a frequency of from 1 kHz to 100 kHz.

In accordance with one implementation of the present invention, a constant magnetic field from an external source is applied at certain time intervals.

The magnetic field controlled device described in this application provides several technical effects and new advantages over previously known devices.

In particular, the device described in the invention ensures the preservation of the active substance during implantation and holds it for the necessary time until the moment of discharge. Previously known devices typically lost 85 to 90% of the drug during installation, and only 10-15% remained on the surface of the implant.

Also, studies show that the described device allows salvo and pulsating discharge of the active substance. This ability is very important because it reproduces the natural functioning of living systems, minimizes side effects and, therefore, provides an optimal therapeutic effect.

In practice, a device controlled by a magnetic field represents a body and a multilayer coating with insulating layers that border a layer of magnetic material characterized by a positive or negative magnetocaloric effect of not less than 3 K / T. It is assumed that the temperature of the device will remain close to the patient’s body temperature due to the self-regulation mechanism. This is achieved by selecting a magnetic material with a phase transition temperature near body temperature. As a result, overheating or insufficient heating of implantable devices characteristic of previously proposed solutions is avoided. It is especially worth noting that this result is achieved without the use of invasive temperature sensors.

Thus, the described device has several advantages. Therefore, it can be successfully used in many cases. In particular, the implantable device can be used as a stent, catheter, joint and bone endoprosthesis, bone suture, denture, pacemaker, insulin dispenser, silicone implant, neuroimplant, microchip implanted in the brain (chip implants), cochlear prosthesis and dental implant.

In addition, the described device can be used to control complex biomedical systems and processes using an external magnetic field, in particular, the magnetically controlled mode can be used for devices for the controlled release of hormones and other implantable devices, such as microrobots, sensors, etc.

The advantage of the magnetic control method in comparison with other methods of exposure - ultrasonic, microwave or infrared radiation - is that the magnetic field penetrates freely through biological tissues and does not have side effects on the body.

The implantable device described in the application can be replenished on site (after installation) by intravenous administration of magnetic nanoparticles containing the active substance. Magnetic drug carriers, spreading through the circulatory system, are collected on the implant due to magnetic attraction, thus replenishing it with the medicine.

DETAILED DESCRIPTION OF THE INVENTION

Each interval of values of physical quantities described in this application is understood as a set of values belonging to this interval. Therefore, each interval includes all values belonging to this interval, as well as all intervals included in it. Unless otherwise specified, the boundary points of the intervals are assumed to be included in the interval. For example, if the interval [0; 1], then this means all numbers, for example 0.76 and 0.1, which are in the interval. Also, the notation [0; 1] suggests that all subintervals, such as [0.2; 0.3] and [0.23; 0.7] are also part of the description.

In this application, “magnetic field controlled implantable device” means a device or apparatus that can be placed in a patient’s body and activated by applying a magnetic field. The body of the device has a shape and functionality designed to be placed in the patient’s body and subsequent therapeutic effects.

In accordance with various implementations of the above description, the device body is made in the form of a stent, catheter, joint or bone endoprosthesis, bone suture, denture, pacemaker, insulin dispensers, silicone implants, neuroimplants, microchips implanted into the brain and in other forms. In addition, the housing can be made in the form of a spiral and function as an oscillating circuit.

In accordance with the implementation of the housing of the device can be made of non-metallic material, in particular biodegradable. Any suitable biodegradable material may be used, including but not limited to the following list of components: polylactic acid, 3-hydroxypropionic acid, or a combination thereof. Suitable biodegradable polymers are also known, see, for example, Averousand L, Pollet E. (eds.), Environmental Silicate Nano-Biocomposites Green Energy and Technology, Springer-Verlag London 2012, Ch. 2. In another implementation, the body of the implantable device is made of a mixture of biodegradable polymers.

In another implementation of this device, the housing is made of a metal material, in particular a biocompatible metal or alloy.

In this application, the term "magnetocaloric effect" will be understood to mean the release (with a positive magnetocaloric effect) or the absorption (with a negative magnetocaloric effect) of heat in a magnetic material under the influence of a magnetic field. If the process can be considered adiabatic or quasi-adiabatic, it manifests itself in an increase or decrease in the temperature of the sample when placed in a magnetic field. The magnetocaloric effect is based on the ability of a magnetic material to change its temperature and entropy under the influence of a constant magnetic field, similar to what happens in ordinary refrigerators when gas or steam expands or contracts.

A change in the temperature of the magnetic material occurs as a result of the redistribution of internal energy in the system between the subsystem of magnetic moments and the crystal lattice.

In particular, the magnetocaloric effect determines the magnetothermal properties, and the more it is, the more efficiently heat is generated or absorbed by the magnetic material under the influence of a magnetic field.

According to an embodiment of the invention, the magnetic layer consists of a magnetic material that has a phase transition temperature near the temperature of a human or animal body.

In accordance with the implementation of this invention, the magnetic material is selected from the following groups of substances, but is not limited to: rare earth materials, such as gadolinium, terbium, dysprosium, holmium; transition metals such as iron, nickel, cobalt, manganese; noble metals such as rhodium, palladium; their oxides, compositions, combinations, solid solutions and alloys, such as Gd ₅ Si ₄ , Gd ₅ Si _2.06 Ge _1.94 , Gd ₇ Pd ₃ , MnFeP _0.35 As _0.65 , Fe _0.5 Rh _{0 5} , Ni-Mn-Ga and MnAs.

Other examples of materials with a high magnetocaloric effect near body temperature (between 36 and 37 ° C) can be found in AM Tishin, YI Spichkin. Magnetocaloric effect and its application. Institute of Physics Publishing, Bristol and Philadelphia, 2003, pp. 410-411. In particular, these are alloys containing noble metals (rhodium, palladium, platinum), rare-earth elements (metals), such as gadolinium Gd (with a Curie temperature of about 295 K and a magnitude of magnetocaloric effect ΔT = 5.8 K at H = 2 T) , alloys or intermetallic compounds, such as an alloy of rhodium Fe _0.49 Rh _0.51 (with a temperature of a magnetic phase transition between antiferromagnetic and magnetic states of about 310-316 K and a magnetocaloric effect of 13 K in a field of 2 T); gadolinium and silicon alloys Gd5Si4 (with a magnetocaloric effect, which reaches a maximum at T = 336 K with a value of ΔT = 8.8 K in a field of 5 T); gadolinium-silicon-germanium alloy Gd ₅ Si _2.06 Ge _1.94 (ΔT = 8 K in the field of 5 T and T = 306 K); gadolinium-paladium alloy Gd ₇ Pd ₃ (ΔT = 8.5 K at T = 323 K and H = 5 T); Manganese-iron-phosphorus-arsenic alloy MnFeP _0.35 As _0.65 (maximum effect at T = 332 K); MnAs-arsenic alloy MnAs (ΔТ = 13 K at Т = 318 K and Н = 5 Т) and others.

From magnetic measurements it is known that the temperature of the magnetic phase transition strongly depends on the concentration of metals in the alloy and rare-earth elements (REE). The desired magnetocaloric effect can be achieved at the required temperature, for example, at body temperature, by varying the content of certain elements in the alloy. Usually, a magnetic phase transition can be observed at a field magnitude of several kOe (kiloersted) to 60 kOe or more.

In accordance with the implementation of this description, the magnetic material may be a combination of two or more magnetic materials with different magnitudes of the magnetocaloric effect. Moreover, various magnetic materials can be arranged in layers, each layer can be composed of materials with different magnetocaloric effects. In one implementation, the layers of magnetic material have a thickness in the region of 10 to 100 microns. In another implementation, the thickness varies between 15 μm and 30 μm.

The layers of magnetic material can be manufactured using various technologies, in particular, plasma deposition in an inert medium (for example, argon) from metal particles with an initial size of, for example, 50-100 microns or, for example, by a method close to that described in patent SU 1746162 , 7/7/1992, or by deposition of layers of nanoparticles on a substrate.

In this application, “insulating layer” refers to a layer of material with low thermal conductivity, providing a decrease in heat transfer between the interior of the coating and the environment. Materials that can serve as heat insulating layers are well known and include, in particular, bioceramics, polystyrene, silica gel and polyurethane. The heat-insulating layer prevents the loss of heat that is released in the magnetic material. The thickness of the heat insulating layer is from 1 to 100 microns, in particular between 3 microns and 20 microns, more precisely between 5 microns and 15 microns. Layers of heat insulating material can be prepared using known techniques, such as film casting or centrifugation.

The heat insulating layer may be part of the first insulating layer, the second layer, or both.

If the housing of the device is made of a non-metallic material, in particular a polymer, then the presence of a heat insulating layer in the first insulating layer is not necessary. In this case, the housing of the device is heat insulating. The heat insulating layer in the second insulating layer is made of mesoporous material and contains many pores. Pores allow the release of the active substance in the form of molecules and nanoparticles. The pores are large enough to allow drug particles to pass along with the intercellular fluid and blood plasma, and at the same time are small enough to prevent direct contact of the blood stream and the associated heat transfer. Pores are impervious to cells and blood cells. In some places, pore sizes range from 1 to 100 nm, in particular in the range from 2 to 50 nm, more specifically from 5 to 30 nm.

In this application, “reflective layer” refers to a layer of material that can reflect infrared radiation from the adjacent layer back. Materials that can be used as a reflective layer are known, and include, in particular, biocompatible metals and metal alloys, in particular medical stainless steel, alloys based on titanium and tantalum. The reflective layer prevents heat transfer from the magnetic material from the side not adjacent to the thermopolymer. The thickness of the reflective layer is in the range between 0.1 μm and 1 μm, in particular in the range of 0.3 μm and 0.7 μm, more specifically, between 0.4 μm and 0.6 μm. A layer reflecting infrared radiation can be created using various techniques, in particular cold gas spraying or chemical metallization.

The reflection layer may be part of a first insulating layer, a second insulating layer, or both.

If the casing of the device is made of metallic material, then there is no need for a reflective layer in the first insulating layer. In this case, the housing of the device can serve as a layer reflecting infrared radiation.

The reflective layer located in the second insulating layer must have many pores for free penetration of the active substance. The pores of the reflective layer should be approximately the same size as that of the heat insulating layer. In some implementations, the pore size is in the range from 1 to 100 nm, in particular in the range from 2 to 50 nm, more specifically from 5 to 30 nm.

In this application, “sensitive layer” refers to a layer of material capable of changing its structure and properties in response to an increase or decrease in temperature or under the action of applied mechanical stress sufficient to release the desired amount of active substance.

In accordance with one implementation of the description, the sensitive layer consists of at least one material belonging to the class of polymers, copolymers, hydrogels, biopolymers, or a combination thereof.

In accordance with one implementation of the description, the sensitive layer is a layer of heat-sensitive material.

The heat-sensitive material has the ability to control the retention / release of the drug substance, which implies the possibility of various effects on the release rate of the drug. For example, the active substance may be encapsulated in a heat-sensitive material. In another embodiment, the active substance may be dissolved in a heat-sensitive material, in which case the release rate of the active substance will depend on the solubility and diffusion rate.

In accordance with one implementation of the description, the layer of heat-sensitive material consists of a mixture of two or more different polymers, which at least partially cover the layer of magnetic material. The layer of heat-sensitive material consists of two or more layers of different polymers or two or more surface sections of different polymers. At least one layer consists of a heat-sensitive polymer.

The multilayer structure of polymers allows for multiple phase transitions at different temperatures (which allows for a phased release of the drug), and also provides thermal insulation of the device, so that the increased or decreased temperature can be maintained longer without heat exchange with surrounding tissues.

In accordance with one implementation of the description, the polymeric material may consist of a thermosensitive polymer or copolymer exhibiting a phase transition from insoluble to soluble state near the lower critical temperature of dissolution (NCTR). The polymer at a temperature below the NCTR (in a hydrophilic state) is brought into contact with the active substance, in particular in the form of an aqueous solution. The polymer in solution swells and absorbs the active substance. Then the polymer is heated above the NCTR (becomes hydrophobic), which leads to the collapse of the polymer and the capture of the active substance inside the polymer. The active substance is released at the location of the implant when the temperature of the thermosensitive polymer falls below a critical temperature that determines the phase transition in the hydrogel due to thermal contact with a lower temperature magnetic material.

Polymers and copolymers with a lower critical temperature can be prepared from the following heat-sensitive monomers: N-ethyl acrylamide, Nn-propyl acrylamide, Nn-propyl methacrylamide, N-isopropyl acrylamide, N-isopropyl methacrylamide, N-cyclopropyl acrylamide, N-cyclopropyl methacryls N-ethoxyethyl acrylamide, N-ethoxyethyl methacrylamide, N, N-disubstituted methacrylamides, such as N, N-dimethyl methacrylamide and copolymers based thereon.

Nitrogen-substituted acrylamides and methacrylamides, oxygen-substituted acrylamides and methacrylamides and other monomers capable of copolymerization with monomers that form heat-sensitive polymers can be used as monomers for heat-sensitive polymers.

In particular, copolymers of M-isopropyl acrylamide (NIPAAm) and N-tert-butyl acrylamide (tBuAM) can be used as heat-sensitive polymers.

In addition to acrylamides and methacrylamides, the following compositions with lower critical solubility temperatures can be used as thermosensitive polymers: N-vinyl caprolactam and polyoxamers based on them, such as triblock copolymers formed from polyoxyethylene and polyoxypropylene.

In addition to the listed polymers with a lower critical dissolution temperature, biopolymers that form a gel with increasing temperature, such as methyl cellulose, can be used. The heat-sensitive substance may be a gelatin or collagen-based solution or gel.

More generally, a layer of a thermosensitive material may consist of any thermosensitive polymer medium, in particular a thermosensitive hydrogel or biopolymer.

In accordance with one implementation of the description, the layer of sensitive material is a layer of material that is sensitive to deformation.

In accordance with this implementation of the description, the layer of strain-sensitive material consists of a mixture of two or more different polymers, at least partially covering the layer of magnetic material. The layer of deformation-sensitive material may consist of two or more layers of different polymers, as well as two or more fragments of different polymers. At least one polymer of the polymers forming the strain-sensitive layer is a strain-sensitive material.

One of the possible mechanisms for the release of the active substance from a layer of material sensitive to deformation is the deformation of a magnetic material under the influence of a magnetic field. Being subjected to a magnetic field, the magnetic material experiences mechanical deformation due to the effect of magnetic shape memory or magnetostriction, which leads to mechanical stresses in the material and to the formation of cracks in it. In this case, the active substance flows out of the polymer or is released in some other way through the cracks formed. The material sensitive to deformation consists of a polymer with a low tensile strength, in particular a copolymer of lactic and glycolic acids. Some magnetic materials, in particular Ni-Mn-Ga alloy, experience relative deformations of up to 10% due to the effect of magnetic shape memory.

In accordance with one implementation of the description, the layer of sensitive material also contains a contrast agent. It allows you to control the degree of drug release from the polymer using magnetic resonance imaging methods.

In this application, “active substance” refers to a substance that belongs to the following list, but is not limited to: chemical agent, drug, biologically active substance, genetic structures.

For medical applications, it is preferable to choose the active substance from the following list of substances, but not limited to: anti-inflammatory agents, antibiotics, painkillers, antiallergic, antihistamines, antitumor, antiviral, anti-diabetic and antiulcer drugs, antihyperlipidemic, antithrombotic agents, beta-blockers, vasodilators , bone resorption inhibitors, antiproliferative agents and others.

The term "drug" refers to a substance that causes a certain biological reaction. A medicinal product refers to any medicine administered by a mammal, including humans, domestic animals, wild animals, as well as cattle and other farm animals. The term “drug” includes, but is not limited to, the following classes of substances: drugs, prophylactic agents, and diagnostic drugs. The following substances are examples of drugs that can be placed in a polymer matrix: colchicine, painkillers, gold salts, corticosteroids, hormonal drugs, antimalarial drugs; derivatives of indole; drugs for the treatment of arthritis; antibiotics, including: tetracycline, penicillin, streptomycin, chlortetracycline; anthelmintic and anti-carnivore plague agents applied to domestic animals and cattle, such as, for example, phenothiazine; sulfur-containing preparations, for example sulfisoxazole; antiproliferative agents (paclitaxel, sirolimus); anti-cancer drugs; drugs that control the effects of addiction, such as alcoholism, smoking; drug addiction agents, such as methadone; means of weight control; agents that control the functioning of the thyroid gland; analgesics; fertilization medications and birth control hormones; amphetamines; antihypertensive drugs; anti-inflammatory agents; antitussive and sedatives; drugs providing neuromuscular relaxation; antiepileptic drugs; antidepressants; antiarrhythmic drugs; vasodilators; antihypertensive diuretics; antidiabetic drugs; anticoagulants, antituberculosis drugs, antipsychotics; hormones and peptides. It is assumed that the above list is not complete and simply shows a wide variety of drugs that can be included in the polymer layer. Preferably, the drug relates to peptides.

The amount of substance distributed in the layer of heat-sensitive material depends on many factors, including, for example, the characteristics of the drug substance; the functions that it performs; the required period of time required to release the medicine; the amount of drug administered and the size of the implant. In general, the dose of the drug, i.e. the amount of substance in the heat-sensitive material is selected from the range of mass fractions of 0.5% to 95%, in particular from 5% to 75% and even more precisely from 10% to 60%.

In accordance with another implementation of the present invention, the active substance may be associated with a sensitive material.

The term “bound” in this context is understood, in particular, in the form of an adsorbed and absorbed substance, in the form of a dissolved, dispersed, suspended and encapsulated drug, bound by covalent or van der Waals bonds, by means of binders, peptide bonds, in the form a drug enclosed in a semipermeable membrane or attached mechanically or by other physical mechanisms, such as magnetic or electric forces, such as dipole-dipole bonds.

The bioactive composition in accordance with the implementations of this description are antigens, antibodies, nucleotides, gelling agents, enzymes, bacteria, yeast, fungi, viruses, polysaccharides, lipids, proteins, hormones, carbohydrates and cellular material.

The polymer load of the drug can be from 0.5 to 95% of the mass fraction of the polymer material. Preferably, the drug content is from 5 to 75% of the mass fraction of microparticles.

In accordance with another implementation of this description, a controlled drug release method is proposed having the following steps: implanting the described device into the patient’s body and exposing the implanted device to a magnetic field for controlled release.

In some implementations, the magnetic field is variable, generated by an external source with a frequency between 1 kHz and 100 kHz.

In some implementations of the invention, a magnetic field is applied at certain intervals of time (pulsed mode). This mode can be realized by means of a permanent magnet present, by placing a magnetic resonance tomograph in the solenoid, or by other methods involving the presence of a constant field for one period of time and its absence in another. Both time periods last about an minute and are determined by the practitioner; acquiring such an experience does not require much time.

The device is implanted in the right place on the patient’s body by a professional physician. Before implantation, the device is loaded with the required amount of active substance necessary for therapeutic purposes.

The magnetic field is applied in a certain place at a certain time for a certain period of time for cooling / warming up the magnetic material and bringing it to a temperature that ensures the discharge of the drug in a certain place at a certain time.

In some cases, when the most suitable mode is a single discharge of the active substance, a single application of a magnetic field is sufficient. This is a constant magnetic field of the order of 1 T. In particular, from 0.5 to 5 T, in more particular cases from 1 T to 3 T.

In other cases, an alternating magnetic field is used to continuously release the active substance.

This description can be illustrated by the following examples, but they are not exhaustive.

Example 1. The manufacture of an implantable device controlled by a magnetic field

The magnetic field-controlled implantable device described above was tested to test its ability to encapsulate and release the active substance upon application of a magnetic field. The prototype of the implantable device was made by depositing a 0.1 mm thick gadolinium film on a polystyrene plate. Gadolinium has a positive magnetocaloric effect of about 3 K / T at 294 K. Then, a film of pNIPAM polymer in a collapsed state having a thickness of 10 μm was created by casting on gadolinium foil. The resulting composite structure was placed in a colchicine solution with a concentration of 1 mg / cm ³ with a temperature of 25 ° C — lower than the NCRP pNIPAM (32 ° C). In this case, the polymer film was in a swollen hydrophilic state with a thickness of 100 μm, which allowed it to be loaded with colchicine. The composite structure was then washed with hot water (with a temperature above NCTR), which led to the collapse of the polymer and drug capture in the bulk of the substance, while no colchicine remained on the surface. The amount of colchicine per 1 square centimeter of the surface was 0.1 μg. Finally, the polymer was covered with a layer of ZrO ₂ mesoporous bioceramics, as a result of which a sandwich structure was formed with a composite of layers of a thermosensitive polymer and magnetocaloric material sandwiched between two heat-insulating layers.

Example 2. The release of the active substance, as measured by the results of the cytotoxic test

In the cytotoxic test, the prototype of Example 1 and the NCTC clone L929 cell line were used. A culture containing solution maintained at 37 ° C was placed in a 10 ml tube. The prototype of Example 1 was immersed in a solution. Then, slowly (so that the process would occur isothermally and the heat released in the gadolinium due to the magnetocaloric effect could be dissipated), a permanent magnet was brought in, thereby gradually increasing the field in the tube to 2 T at a constant solution temperature of 37 ° C. Then the magnet was sharply removed, which led to a drop in temperature to 32 ° C due to the magnetocaloric effect and the release of colchicine. After that, the solution was kept at 37 ° C for 24 hours. Then, the number of living and dead cells was calculated by observation under a microscope in a Goryaev chamber using Syto9 dyes and propidium iodide. Syto9 dye penetrates through the membranes of living and dead cells, staining DNA and RNA in green. Propidium iodide penetrates only dead cell membranes, staining the nucleus red. This allows you to make visible dead and living cells for counting in a microscope.

In this example, only 10% of the cells survived after 24 hours. In the case of direct addition of colchicine with a concentration of 0.1 μg / cm ³ to the solution, 99% of the bacteria survived.

Such a significant difference in cytotoxicity can be explained by adsorption of cells on the surface of the prototype of the implant, near which the concentration of colchicine is increased due to its release from the polymer layer. This fact is an advantage, since in most cases complications develop in the area adjacent to the surface of the implant, and it is in this area that there should be an increased concentration of the drug. At the same time, intravenous administration is similar to the direct introduction of colchicine into a solution in an experiment, which leads to a low concentration of the drug near the surface of the implant and to the development of side effects in healthy tissues.

Example 3. An implantable device based on an alloy of Fe _0.49 Rh _0.51 , controlled by a magnetic field.

The same test protocol, as in examples 1 and 2, was observed in relation to this sample, with the difference that instead of gadolinium foil, a foil of Fe _0.49 Rh _{0.51 was used} . Alloy Fe _0.49 Rh _0.51 exhibits a negative magnetocaloric effect of -6 K / T at 294 K. Accordingly, the cooling required to discharge colchicine was carried out by quickly bringing the permanent magnet to the tube with the drug, thus ensuring a quick change in the magnetic field from zero to 2 T and sample cooling. After establishing thermodynamic equilibrium at a temperature of 37 ° C, the magnet was slowly removed from the tube. The temperature of 37 ° C was maintained using a thermostat for 24 hours. After this time interval, by the method described above in example 2, the number of living and dead cells was estimated. In this case, 3% of living cells remained after 24 hours.

Claims (18)

1. An implantable device controlled by a magnetic field, consisting of a housing, an outer periphery and a coating, occupying at least a portion of the outer periphery, consisting of the following layers in order from inner to outer: first insulating layer; a layer of magnetic material with a positive or negative magnetocaloric effect of not less than 3 K / T; a layer of sensitive material containing the active substance and capable of retaining and controlled release of the active substance; a second insulating layer permeable to the active substance. 2. The implantable device according to claim 1, characterized in that the first insulating layer consists of a heat insulating layer and a layer reflecting infrared radiation, or a combination thereof. 3. An implantable device according to any one of claims 1, 2, characterized in that the second insulating layer permeable to the active substance contains many pores and is a porous / permeable heat insulating layer, as well as a porous / permeable layer reflecting infrared radiation, or their combination. 4. The implantable device according to any one of claims 1, 2, characterized in that the insulating layer consists of polystyrene, silica gel, polyurethane, bioceramics, or a combination thereof. 5. An implantable device according to any one of claims 1, 2, characterized in that the infrared reflecting layer consists of a metal or metal layer, preferably medical stainless steel, an alloy based on titanium or tantalum. 6. An implantable device according to any one of claims 1, 2, characterized in that the magnetic material is selected from the group of materials, including rare-earth metals, such as gadolinium, terbium, dysprosium, holmium; transition metals such as iron, nickel, cobalt, magnesium; noble metals such as rhodium, palladium; their oxides, combinations, solid solutions, alloys, such as Gd ₅ Si ₄ , Gd ₅ Si _2.06 Ge _1.94 , Gd ₇ Pd ₃ , MnFeP _0.35 As _0.65 , Fe _0.5 Rh _0.5 Ni-Mn-Ga and MnAs. 7. The implantable device according to claim 1, characterized in that the sensitive material layer consists of at least one material related to polymers, copolymers, hydrogels, biopolymers, or combinations thereof. 8. The implantable device according to claim 1, characterized in that the layer of sensitive material contains:
- a mixture of two or more different polymers; or
- two or more layers of different polymers; or
- two or more inserts of various polymers in the coating layer. 9. The implantable device according to claim 7, characterized in that at least one of the polymers, preferably two or more, are substances with a phase transition point lying near the temperature of the human body. 10. The implantable device of claim 8, characterized in that the various heat-sensitive polymers have different phase transition temperatures. 11. An implantable device according to any one of claims 9, 10, characterized in that the heat-sensitive polymer is selected from the class of materials polybutyl methacrylate (rVMA), poly-N-isopropyl acrylamide (PNIPAM), copolymer of N-isopropyl acrylamide (NIPAM), N-isopropyl methacrylamide (NIPMAM ) and acrylamide (AAm), or a combination thereof. 12. An implantable device according to any one of claims 1, 2, characterized in that preferably two or more sensitive polymer layers are sensitive to deformation and have a low tensile strength, in particular, a copolymer of lactic and glycolic acids can be used. 13. The implantable device according to claim 1, characterized in that the layer of sensitive material includes contrast agents that allow you to control the amount released from the polymer drug by magnetic resonance imaging. 14. An implantable device according to any one of claims 1, 2, characterized in that the pores allow interstitial fluid or blood plasma to penetrate the insulating layer and cause diffusion of the active substance. 15. The implantable device according to claim 1, characterized in that it is a stent, catheter, joint prosthesis, bone suture, denture, pacemaker, insulin dispenser, silicone implant, neuroimplant, a microcircuit implanted in the brain (chip implant), cochlear denture and dental implant. 16. A method for the controlled release of a drug, consisting of the following steps: implanting a device according to any one of claims 1 to 15 into a patient’s body; the impact on the implanted device with a magnetic field in a controlled manner with the release of the active substance. 17. The method according to clause 16, characterized in that the exposure is carried out by an alternating magnetic field created by an external source with a frequency of from 1 kHz to 100 kHz. 18. The method according to clause 16, characterized in that the exposure is carried out by a magnetic field from a periodically carried or retractable permanent magnet.