Eluting stent with containers

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to developing expandable medical devices, particularly stents, and can be used for treating restenosis in a vessel lumen. A presented implantable medical device involves intraluminal frame (IF) comprising a number of openings. The IF has a tubular configuration and comprises a number of cylindrical sections connected by the number of connective elements. Each of the cylindrical sections of the IF is formed of a mesh of elongated braces connected by plastic pivots and peripheral braces. Different openings of the IF are filled with at least two various therapeutic agents. At least one therapeutic agent filling one of the openings is incorporated into poly(lactic-co-glycolic acid) (PLGA) matrix to control a release rate and a cumulative released dose of the therapeutic agent into the surrounding tissue.

EFFECT: invention provides the effective combination therapy by using two or more drugs and/or active substances filling the different openings of the devices keeping its wall thickness the same with no limitation of its movement, as well as by enabling the drug delivery with various release kinetics and/or clearance period.

6 cl, 2 tbl, 3 ex

 

The prior art INVENTIONS

1. The technical field to which the invention relates.

For this application priority is claimed in accordance with the provisional application U.S. No. 61/148,610, filed January 30, 2009

The present invention relates to supporting tissues to medical devices and, in particular, to the growing (expanding) non-removable devices that are implanted into the lumen of the body of a living animal or person to support the body and maintain the open state and which contain holes for delivery of multiple therapeutic agents to the site of intervention, as well as the surface coating of antithrombotic agents.

2. An overview of the state of the art

've developed a permanent or biodegradable devices for implantation in the passage in the body to maintain the open state of the aisle. These devices are usually introduced percutaneous and held transluminal before installation in the desired location. Then these devices or expand mechanically, for example by expanding mandrel or cylinder located inside the unit, or expand independently by release of stored energy after stepping inside the body. After expansion within the lumen of these devices called stents, are encapsulated within the tissues of the body and become permanent the implant.

A known design of stents contain spiral stents of the single core wire (U.S. patent No. 4969458); welded metal frames (U.S. patent No. 4733665 and 4776337); and generally, thin-walled metal cylinders with axial slits formed around the circumference (U.S. patent No. 4733665; 4739762; and 4776337). Known structural materials for use in stents include polymers, organic woven materials and biocompatible metals such as stainless steel, gold, silver, tantalum, titanium and alloys with shape memory, such as a Nickel-titanium alloy.

In U.S. patent No. 6241762, which fully incorporated into the present application by reference, it is proposed not prismatic design of the stent, which eliminates some of the disadvantages of the functional characteristics of the previous stent. In addition, preferred embodiments of described in this patent, provide the stent with large inelastic spacer and connecting elements, which may contain holes, does not reduce the mechanical properties of the spacer and connecting elements or devices in General. In addition, these wells can serve as a large protected capacity for delivery of various therapeutic agents to the site of implantation of the device, without requiring surface coating on the stent.

Among many is their problems, which can be addressed through the local delivery of therapeutic agents from the stent, one of the most important is restenosis. Restenosis is a major complication that can occur after vascular interventions like angioplasty and stent implantation. According to a simple definition, restenosis is wound-healing process, which reduces the diameter of the vessel lumen in the deposition of extracellular matrix and proliferation of vascular smooth muscle cells, and which may, ultimately, be a consequence of the re-narrowing or even re-occlusion of the lumen. Despite improved surgical techniques, devices and pharmacological means, the overall rate of restenosis for bare metal stents, according to reports, remains in the range of approximately twenty-five percent to about fifty percent within six to twelve months after surgery, angioplasty. For the treatment of this condition often requires additional revascularization procedures, which increases injury and increases the risk for the patient.

Conventional stents with surface coatings of various therapeutic agents have shown promising results for the reduction of restenosis. In U.S. patent No. 5716981, for example, a stent, which supplied the Yong surface coating composition, containing the polymer carrier and paclitaxel. The patent describes methods of coating on the surface of the stent, such as spraying and dipping, as well as the desired character of the coating, namely: the floor should be covered stent smoothly and evenly and to provide a uniform, predictable, long-lasting release of antiangiogenic factors". However, surface coatings, can provide only a small actual regulation of the kinetics of release of therapeutic agents. Coverage data are necessarily very thin, typically, a depth of from five to eight micrometers. The surface area of the stent is relatively very large, and therefore the entire volume of therapeutic agent is characterized by very short by diffusion to release into the surrounding tissue. The resulting profile of cumulative drug release is characterized by an initial sharp rise, followed by a rapid achievement of the asymptotes, instead of the required "uniform, continuous release, or linear release.

The increase in the thickness of the surface coating has a positive effect on the improvement of the kinetics of drug release, including, gives the possibility to better control the drug release and increase drug tab. But is liczenie the thickness of the coating leads to an increase in the overall wall thickness of the stent. This is undesirable for several reasons, including the possibility of increased injury of the vessel lumen during implantation, reducing the available flow cross-section of the lumen after implantation and increased vulnerability of the coating to mechanical damage or damage during expansion and implantation. The thickness of the coating is one of several factors that affect the kinetics of release of therapeutic agent, and, therefore, limits the thickness limit of the speed range, timing and similar release characteristics that can be provided.

Surface coatings may also limit the delivery of several drugs from the stent. For example, if the surface coating was required to deliver multiple drugs, speed of release, delivery periods and other characteristics of the release could not easily be adjusted mutually independent manner. However, restenosis involves several biological processes and most can be effectively treated by a combination of drugs selected for impacts on these different biological processes.

In the article "Physiological Transport Forces agreement alone govern Drug Distribution for Stent-Based Delivery", the authors Chao-Wei Hwang et al., shows the important relationship between the characteristics of the spatial-temporal distribution of drugs drug eluting stent is mi and mechanisms of cellular transport of drugs. In attempts to achieve higher mechanical performance and structural properties, structures stents were given a more complex geometric shapes with specific heterogeneity of the district and the longitudinal distribution of the struts of the stent. Examples of this trend are typical of commercially available stents that are expanded to approximately diamond-shaped or polyhedral shape when deployed in the body lumen. Stents of both forms were used to deliver therapeutic agents in the form of surface coatings. Studies have shown that areas of the tissue of the lumen adjacent to the spacers, get a higher concentration of the drug, the more remote areas of tissue, such as the sites located in the middle of the diamond-shaped spacer cells. Characteristically, the concentration gradient of the drug inside wall of the lumen remains over time is higher for hydrophobic therapeutic agents, such as paclitaxel or rapamycin, which proved to be the most effective antirestenotic drugs at the present time. Because the local concentration of drugs and their gradients intricately linked to biological action, the initial spatial distribution of the sources of therapeutic agents (struts of a stent) is a decisive factor effect and the property.

In addition to suboptimal spatial distribution of therapeutic agents, there are other potential drawbacks of stents with surface coating. Some polymeric carriers with chemically bound matrix used in the coating device, usually indefinitely retain a significant percentage of therapeutic agent in the coating. Since these therapeutic agents, such as paclitaxel, can be cytotoxic, there may be subacute and chronic problems, such as chronic inflammation, late thrombosis and late or incomplete healing of the vessel wall. In addition, the polymers themselves-the media often cause inflammation of the tissue of the vessel wall. On the other hand, the use of biologically absorbable polymer media on the surfaces of the stent can lead to "bad contact" or empty spaces between the stent and the tissue of the vessel wall after resorption of the polymer carrier. Empty space allow the relative movement between the stent and the surrounding tissue. Arising, as a result, problems include microsyringe and inflammation, slow the movement of the stent and the impossibility of endothelization the walls of the vessel.

Initial clinical trials in humans suggest the possibility of some of the shortcomings associated with delivering Les is ARSTA devices of the first generation. A subsequent study of patients participating in clinical trials, six - eighteen months after implantation of drug-eluting stent shows that poor contact of the struts of the stent to the arterial walls and edge restenosis can occur for a large number of patients. Edge restenosis appears directly over the proximal and distal edges of the stent and develops near the edges of the stent and the inner (luminal) space, which often requires repeated revascularization of the patient.

Another potential disadvantage is that the expansion of the stent can create tension in the applied polymeric coating, causing the coating delamination, cracks or breaks that may affect the kinetics of drug release, or cause other adverse effects. These effects were observed in the first generation stents with antiproliferative coating when the stents were expanded to a larger diameter, which prevented so far the mentioned stents in the arteries of larger diameter. In addition, the extension mentioned stents with coatings in atherosclerotic blood vessel will cause the impact of district efforts shift to a polymer coating that could lead to separation of the coating from the underlying surface is the surface of the stent. This separation may cause adverse effects, including embolization of fragments of the coating, causing blockage of blood vessels.

Another problem that can be solved through local delivery of therapeutic agents from the stent consists of thrombosis. The stent can be coated antithrombotic agent in addition to at least one therapeutic agent for the treatment of restenosis.

The INVENTION

In view of the shortcomings of the prior art, it is advisable to establish a stent capable of delivering a relatively large volume of medicines in travmirovannomu place in the lumen of the vessel, with the exception, however, numerous potential problems associated with surface coatings that contain drugs, but without increasing the effective wall thickness of the stent and without adverse effects on the mechanical properties of expansion of the stent.

In addition, it is advisable to establish supporting tissues of the device with different therapeutic agents located in different holes to get the desired spatial distribution of at least two therapeutic agents.

In addition, it is advisable to establish the supporting tissue of the device with different therapeutic agents located in different holes to obtain the desired different throw the ku release, at least two different therapeutic agents from the same device.

In addition, it is advisable to establish the supporting tissue of the device with all surfaces coated with an antithrombotic agent, and then applying the primer in the hole or holes in the above-mentioned device, to enhance adhesion of the at least one therapeutic agent that fills the hole.

BRIEF DESCRIPTION of DRAWINGS

The above and other features and advantages of the invention evident from the below detailed description of preferred embodiments of the invention, presented in the attached drawings.

Figure 1 is an isometric depiction of an expandable medical device with therapeutic agent at the ends in accordance with the present invention.

Figure 2 is an isometric depiction of an expandable medical device with therapeutic agent at the Central site and no medical means at the ends in accordance with the present invention.

Figure 3 is an isometric image of an expandable medical device with different therapeutic agents in different holes in accordance with the present invention.

Figure 4 is an isometric image of an expandable medical device with different therapeutic agents in alternate holes in the CE is accordance with the present invention.

Figure 5 is an enlarged side view of the plot expandable medical device with holes therapeutic means in the connecting elements in accordance with the present invention.

Figure 6 is an enlarged side view of the plot expandable medical device with the bifurcation opening in accordance with the present invention.

Figure 7 is a cross - section of an expandable medical device containing a combination of the first active substances, such as anti-inflammatories in the first set of holes, and the second active substance, such as antiproliferative funds in the second set of holes, in accordance with the present invention.

Figure 8 is a graph of the speed of release of one example of anti-inammatory and antiproliferative funds delivered an expandable medical device, shown in figure 7, in accordance with the present invention.

Figures 9A-9C is a local schematic diagram of an alternative exemplary variant implementation of the expandable medical device in accordance with the present invention.

Figure 10 - diagram of the conjugation reaction between PLGA (copolymer of lactic and glycolic acid with carboxyl end group and a low molecular weight PEI (polyethylenimine) in accordance with this izobreteny the M.

Figure 11 - diagram of the conjugation reaction between PLGA with carboxyl end group and molecular or branched PEI in accordance with the present invention.

Figure 12 - the kinetics of release from the tank depending on the surface coating in accordance with the present invention.

A DETAILED DESCRIPTION of the PREFERRED embodiments

The figure 1 shows an expandable medical device, containing a number of holes containing a therapeutic agent for delivery to tissue expandable medical device. Expandable medical device 10, depicted in figure 1, cut from a tubular material for forming cylindrical expandable device. Expandable medical device 10 contains a number of cylindrical sections 12, connected by a set of connecting elements 14. The connecting elements 14 allow the supporting tissues of the device axially to bend when passing through the winding paths in the vasculature to the deployment and allow the device to bend axially, when necessary, respectively, the curvature of the lumen, which should be supported. Each of the cylindrical tube 12 is formed by a grid of elongated struts 18, which are interconnected by plastic hinges 20 and County raspor the AMI 22. During expansion of the medical device 10, the plastic hinges 20 are deformed, and the spacers 18 are not deformed. For more information about one example of an expandable medical device is shown in U.S. patent No. 6241762, which is entirely included in the present description by reference.

As shown in figure 1, the elongated struts 18 and circumferential struts 22 contain holes 30, some of which contain a therapeutic agent for delivery into a lumen in which the implanted expandable medical device. In addition, other parts of the device 10, for example, the connecting elements 14 may include holes, as described below with reference to figure 5. In a preferred embodiment, the holes 30 are located in the non-deformed parts of the device 10, for example, the spacers 18 that the holes were inelastic, and a therapeutic agent is delivered without the risk of destruction, displacement or other damage during expansion of the device. Additional description of one example of the manner in which a therapeutic agent can be incorporated into holes 30 provided in the application for U.S. patent No. 09/948,987, filed September 7, 2001, which is entirely incorporated into the present application by reference.

Exemplary embodiments of the present invention may be further optimized using analysis methodology the finite element and other methods, to optimize the placement of therapeutic agents in the holes 30. Essentially, the shape and location of the holes 30 can be modified to maximize the volume of voids, while maintaining a relatively high strength and stiffness of the struts relative to the plastic hinges 20. In accordance with one preferred embodiment of the present invention, the openings have an area of at least 5×10-6square inches and, preferably, at least 7×10-6square inches. Typically, the holes are filled therapeutic agent at from about fifty percent to about ninety-five percent.

Definition

The terms "active substance", "therapeutic agent" or "therapeutic agent" as suggested in the context of this application, have the widest possible interpretation and is used to include any therapeutic agent or drug, as well as inert substances, such as barrier layers, layers, carrier layers therapeutic or protective layers.

The terms "drug" or "therapeutic agent" are used equivalently to refer to any therapeutically active substance that is delivered into the lumen of the body of a living being to create a desired, usually beneficial, effect the KTA. A therapeutic agent may contain at least one drug or therapeutic agent.

The present invention is particularly well suited, in particular, for the delivery of anticancer agents, antiangiogenic funds, angiogenic factors, anti-inflammatory drugs, immunosuppressants, such as rapamycin, antirestenotic funds, antiplatelet agents, vasodilators, anti-thrombotic funds, antiproliferative means, such as paclitaxel, and antidemidovich tools, such as heparin.

The term "blur" means a process in which components of the environment or matrix of biologically dissolvable and/or degradable, and/or destroyed by chemical or physical, or enzymatic processes. For example, with regard to biodegradable polymer matrices, blur may occur through the gap or hydrolysis of the polymer chains, increasing, thus, the solubility of the matrix and held in the form of mist remedies.

The term "speed blur" is a measure of the amount of time it takes to blur, and usually measured in square units per unit time.

The terms "matrix" or "biologically absorbable matrix" are used equivalently to refer to the environment or material, which, after implantation in h the rights, not cause harmful response, it is sufficient, as a result, to the exclusion matrix. By itself, the matrix usually provides no therapeutic response, although the matrix may contain or surround with a therapeutic agent, which is defined in this application. The matrix is also the environment that may simply provide a support, structural integrity or structural barriers. The matrix can be a polymer, polimernoi, hydrophobic, hydrophilic, lipophilic, amphiphilic, etc. in Addition, it should be understood that the term "biologically absorbable matrix" means the complete resorption of the matrix by the body over time.

The term "openings" includes both through-hole and the recess.

The term "pharmacologically acceptable" refers to a particular lack of toxicity against the recipient or patient and suitability to support the stability of therapeutic agent and deliver therapeutic agents to target cells or target tissue.

The term "polymer" refers to molecules formed in the form of chemical compounds, at least two repeating elementary units, called monomers. Accordingly, the term "polymer" may include, for example, dimers, trimmers and oligomers. The polymer can be Sint the political, natural or semi-synthetic. In a preferred form, the term "polymer" refers to molecules, which typically have a molecular weight (Mw) greater than about 3000 and preferably greater than about 10,000 and Mw, which is less than approximately 10 million, but, preferably, less than about one million and more preferably less than about 200,000. Examples of polymers include, but without limitation, polyesters, alpha-hydroxy acids such as polylactic acid (PLLA or DLPLA (D,L-polylactic acid)), polyglycolic acid, a copolymer of polylactic acid and glycolic acid (PLGA), a copolymer of polylactic acid and caprolactone; polymers of type (block-ethylene oxide-block copolymer of lactide and glycolide), (PEO (polyethylene oxide)-block-PLGA and PEO-block-PLGA-block-PEO); polyethylene glycol and polyethylene oxide, polymer type (block-ethylene oxide-block-propylene oxide-block-ethylene oxide); polyvinylpyrrolidone; complex polyarteritis; polysaccharides and derivatives of polysaccharides, for example polyaluminum acid, poly(glucose), polietilenovoy acid, chitin, chitosan, derivatives of chitosan, cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, cyclodextrins and substituted cyclodextrins, for example sulfobutyl esters of beta-cyclogest the ina; polypeptides and proteins, such as polylysine, polyglutamic acid, albumin; polyanhydride; polyoxyalkylene, such as polyoxometalate, polyoxometalate etc.

The term "mainly", in relation to the directed delivery means in the main direction of the delivered quantity greater than approximately fifty percent of the total amount of therapeutic agent delivered into a blood vessel.

Various exemplary embodiments of the present invention described in this application provide a bookmark different remedies in different holes in the expanding device or therapeutic agent in some holes, but not in others. The specific structure of the expandable medical device can be modified without going beyond the merits of the invention. Because each hole is filled separately, treatment means in each outlet can give a special chemical compositions and pharmacokinetic properties.

One example of the application of different therapeutic agents in different openings in the expandable medical device or medical means in some holes, but not in others, refers to the elimination of edge restenosis. As stated above, the current generation of stents with coatings may be faced with a complex problem boundary restenosis restenosis, arising directly behind the edges of the stent and developing around the stent and the inner luminal space.

Causes of edge restenosis when used to deliver drugs stents of the first generation are not fully understood at present. It is possible that the area of tissue damage due to angioplasty and/or stent implantation continues beyond the area of diffusion of therapeutic agents of the modern generation, such as paclitaxel, which are, usually, intensely disintegrate in the tissue. A similar phenomenon was observed in radiation therapy, in which a small dose of radiation at the edges of the stent was stimulating in the presence of damage. In this case, irradiation at length, extended so far as to irradiate undamaged tissue, solved the problem. In the case of delivering drugs stents, placement of larger doses or higher concentrations of therapeutic agents at the edges of the stent placement at the edges of the stents of different active agents that diffuse faster through the fabric, or the placement of different therapeutic agents or combinations of therapeutic agents at the edges of the device can help to eliminate the problem of edge restenosis.

The figure 1 depicts the expandable medical device 10 with the so-called "active end" or licensestream, secured in the holes 30a at the ends of the device to treat and reduce edge restenosis. The rest of the holes 30b in the Central area of the device can be empty (as shown) or may contain a lower concentration of therapeutic agent.

Other mechanisms of edge restenosis may affect the cytotoxicity of specific drugs or combinations of drugs. These mechanisms can include physical or mechanical reduction of tissue, similar to the reduction observed in the formation of epidermal scar tissue and the stent can prevent a backlash reduction within its own boundaries, but not beyond its edges. In addition, the mechanism of this last form of restenosis may be associated with long-term consequences or local drug delivery to the arterial wall, which manifest even after the medicine itself is no longer present in the wall. That is, restenosis may be a response to the appearance of toxic lesions associated with medication and/or a carrier of drugs. In this situation, it might be useful to exclude some active means of use on the edges of the device.

The figure 2 shows an alternative exemplary variant of implementation of the expandable medical device 200 that contains many holes 230, from which Erste 230V in the Central part of the device filled with a therapeutic agent, and openings 230a at the edges of the device remain empty. The device shown in figure 2, is called the device "inert."

In addition to using to loosen the edge restenosis, an expandable medical device 200 shown in figure 2, can be used in combination with the expandable medical device 10 shown in figure 1, or other delivering medication stent when the original procedure stenting should be supplemented with additional stent. For example, in some cases, the device 10 shown in figure 1, with the active ends or device with a uniform distribution of the drug can be implanted properly. If the doctor determines that the device does not cover a sufficient area of the lumen, at one end of an existing device, you can add additional device, slightly overlapping an existing device. When implanted, the accessory device 200 shown in figure 2, is used to inert the ends of the medical device 200 to prevent the doubling of the dose of therapeutic agent in the areas of overlap of the devices 10, 200.

The figure 3 shows an additional alternative exemplary variant of the invention, in which in different holes expandable medical device is 300 are different remedies. The first therapeutic agent is provided in the holes 330a at the ends of the device, and the second therapeutic agent is provided in the holes 330b on the Central plot device. A therapeutic agent may contain different drugs the same drugs in different concentrations, or different versions of the same drugs. A sample implementation is shown in figure 3, can be used to provide an expandable medical device 300 or active ends" or "inert."

In the preferred embodiment, each end section of the device 300, which contains holes 330a, containing a first therapeutic agent, continues in length from at least one hole to approximately fifteen holes from the edge. This distance corresponds to the section from approximately 0.005 to approximately 0.1 inch from the edge of the unexpanded device. The distance from the edge of the device 300, which contains the first therapeutic agent, preferably, approximately equal to one section, where section is limited between the connecting elements.

Different therapeutic agents containing different drugs can be in different holes in the stent. This allows delivery of at least two therapeutic agents from one stent according to any desired scheme delivery. Alternatively,different remedies, containing the same drug in different concentrations, can be in different holes. This allows the medication evenly distributed in the fabric, when the inhomogeneous structure of the device.

At least two different therapeutic agents provided in the devices described in this application may include (1) different drugs; (2) the same drug in different concentrations; (3) the same medicine with different release kinetics, i.e., different speeds of the blur matrix; or (4) different forms of the same medication. Examples of different medicinal products containing the same drug with different release kinetics can use different media to obtain elution profiles with different forms. Some examples of different forms of the same drugs contain forms of medications with varying hydrophilicity or lipophilicity.

In one example, the device 300 shown in figure 3, the holes 330a at the ends of the device filled first therapeutic agent containing a drug with a high lipophilicity, whereas holes 330b on the Central plot device tucked second therapeutic agent with reduced lipophilicity. First vysokololtnoe drug to active ends will diffuse into the surrounding tissue rapidly the ray and thereby, loosen edge restenosis.

The device 300 may contain sharp transition line at which the drug is replaced with a first means to the second means. For example, all the holes to within 0.05 inch from the edge device may contain a first tool, while the other vents the second tool. Alternatively, the device may contain a gradual transition between the first tool and the second tool. For example, the concentration of drugs in the holes can consistently increase (or decrease) to the ends of the device. In another example, the quantity of the first medication in the holes increases, whereas the amount of the second medication in the holes decreases with movement to the ends of the device.

The figure 4 shows an additional alternative exemplary variant of implementation of the expandable medical device 400, in which different therapeutic agents are in different holes 430a, 430b in the device, alternating or random. Thus, several therapeutic agents can be delivered into the fabric of the entire area or the area of the support device. This rough version of the implementation will be useful for delivery of multiple therapeutic agents, when combining several tools into a single composition for filling in a device of the problems with the interaction between therapeutic agents or their stability.

In addition to the application of different therapeutic agents in different holes for different concentrations of drugs in different defined areas of the fabric, dressing different remedies in different holes can be used to provide a more uniform spatial distribution of therapeutic agent to be delivered in the cases when the expandable medical device has a non-uniform distribution of holes in the extended configuration.

The use of different drugs in different holes random or alternating allows the delivery of two different drugs that cannot be delivered, when combined within the same composition of the matrix polymer/drug. For example, the drugs can interact in an undesirable manner. In the alternative, two medicines may not be compatible with same polymer to form the matrix or with the same solvents for delivery of the polymer matrix/drugs in the hole.

In addition, a sample implementation is shown in figure 4, containing different drugs in different holes in the random scheme, provides the ability to deliver different drugs with very different desired release kinetics from the same medical device or stent and to optimize the kinetics of release is based on mechanism of action and properties of the individual active agents. For example, the solubility of the active tool greatly affects the release of the active means of a polymer or other matrix. Compound with high solubility usually will very quickly be delivered from the polymer matrix, whereas the lipophilic vehicle will be delivered from the same matrix over a longer time. Therefore, if the hydrophilic agent and lipophilic agent is required to deliver in the form of a combination of two drugs from the medical device, then, for these two active agents to be delivered from the same polymer matrix, it is difficult to obtain the desired release profile.

The system, shown in figure 4, allows for convenient delivery of hydrophilic and lipophilic drugs from the same stent. In addition, the system shown in figure 4, allows you to deliver two active funds with two different release kinetics and/or periods of injection. Each characteristic from the initial release for the first twenty-four hours, speed of release after the first twenty-four hours, the total period of introduction and any other release characteristics of the two drugs can be controlled independently. For example, the speed of release of the first therapeutic agent can be adjusted to be delivered, less than the least forty percent (preferably, at least fifty percent) deliver drugs for the first twenty-four hours, and the second drug can be adjusted to deliver less than twenty percent (preferably, less than ten percent) deliver drugs for the first twenty-four hours. The period of introduction of the first drug may be about three weeks or less (preferably two weeks or less), and the period of introduction of the second drug may be about four weeks or more.

Restenosis or recurrent occlusion after the intervention involves a combination or sequence of biological processes. These processes include activation of platelets or macrophages. Cytokines and growth factors contribute to the proliferation of smooth muscle cells, and increasing regulation of metalloproteinase genes and lead to cell growth, the restructuring of the extracellular matrix and migration of smooth muscle cells. Drug therapy, which suppresses many of these processes using combinations of drugs, may be the most successful antirestenotic therapy. The present invention provides a means to achieve this successful combination drug therapy.

The following examples explain what some of the combined dosage systems which benefit from the ability to release different drugs in different holes or holes. One example of a therapeutic system for the delivery of two drugs from the random or alternating holes is the delivery of anti-inflammatory drugs or immunosuppressant in combination with an antiproliferative agent or antimigration means. For targeted impact on several biological processes involved in restenosis, you can also use other combinations of data and active means. Anti-inflammatory agent reduces the initial inflammatory response of the vessel to angioplasty and stenting and delivered first at high speed, with subsequent delayed delivery within the time period about two weeks to negotiate with the maximum of the growth of macrophages that stimulate the inflammatory response. Antiproliferative tool is delivered with a relatively uniform speed over a longer time period to ease the migration and proliferation of smooth muscle cells.

In addition to the examples below, the following table illustrates some of the useful options duplicating combined pharmacotherapy, which can provide PU is eat bookmarks drugs in different holes in the medical device.

Station reserve fuel facility2-CdaEpothilone DMachinemessiah GleevecThe analogue of rapamycinPimecrolimusRKS-412DexamethasoneFarglitazarInsulinComplex VIPApoA-I Milano
Station reserve fuel facilityxxxxxxxx
2-Cdaxxxxx
EPO is Ilon D xxxsxxx
Machinemessiah Gleevecxxxx
The analogue of rapamycinxxxxx
Pimecrolimus xxxxx
RKS-412xxxx
Dexamethasonexx
Farglitazarxx
Insulinx
Complex VIPx
ApoA-I Milano

Bookmark drugs in different holes allows you to adjust the kinetics of release, according to specific active substance, regardless of hydrophobicity or l is podobnosti drugs. Some examples of layouts for the delivery of lipophilic drugs with essentially constant or linear rate of release is described in the document WO 04/110302, published December 23, 2004, which is entirely incorporated into the present application by reference. Some examples of layouts for the delivery of hydrophilic drugs are described in the document WO 04/043510, published may 27, 2004, which is entirely incorporated into the present application by reference. The above hydrophilic drugs include CdA, Gleevec, VIP, insulin and ApoA-I MILANO. The above lipophilic drugs include paclitaxel, epothilone D, rapamycin, pimecrolimus, PKC-412, and dexamethasone. Farglitazar (faglitazar) is a partially lipophilic and partially hydrophilic.

In addition to the delivery of several drugs for targeted effects on different biological processes involved in restenosis, the present invention makes it possible to deliver two different drugs from the same stent for the treatment of various diseases. For example, the stent can deliver antiproliferative drug, such as paclitaxel or limos, from one set of holes for the treatment of restenosis, with simultaneous delivery of stabilizing the myocardium medications, such as insulin, from the other outlets for the treatment of acute myocardial infarction.

In many of the well-known extensible devices and for devices shown in figure 5, the coating device 500 more on a cylindrical tubular sections 512 of the device than on the coupling elements 514. Coverage is defined as the ratio of the surface area of the device to the area of the lumen in which the deployed device. When the device is variable coverage used to deliver a therapeutic agent contained in the holes in the device, the concentration of therapeutic agent delivered to the tissue near the cylindrical tubular sections 512, higher than the concentration of therapeutic agent to be delivered into the tissue near the coupling elements 514. To account for such longitudinal changes in the structure of the device and other changes in the working zone of the device, which lead to non-uniformity of the delivered concentration of therapeutic agent, the concentration of therapeutic agent can be changed in the holes on the parts of the device to provide a more uniform distribution of therapeutic agent across the fabric. In the case of an approximate variant of the implementation shown in figure 5, the holes 530a in tubular sections 512 contain a therapeutic agent with a lower concentration of the drug than the hole 530b in the coupling elements 514. Uniform delivery of active funds can be provided in a variety of methods, including changing the concentration of the medication, the diameter or army holes, the number of active funds in the hole (i.e., the percentage duty cycle of the holes), the matrix material or the dosage form.

Another example of application tasks use different remedies in different holes is expandable medical device 600, shown in figure 6, is made with the possibility of a bifurcation in a vessel. Bifurcation devices contain a side opening 610, which is located so as to allow blood flow through the side branch vessel. One example of a bifurcation device described in U.S. patent No. 6293967, which is entirely incorporated into the present application by reference. Bifurcation device 600 contains a structural element in the form of lateral openings 610, interrupting the regular structure of the rods that form the rest of the device. Because the area around the bifurcation is particularly problematic area from the point of view of restenosis, in holes 830a in the area surrounding the lateral hole 610 of the device 600, the concentration of antiproliferative drugs can be increased to deliver higher concentrations of drugs, if necessary. Other openings 630b in a zone remote from the side holes contain a therapeutic agent with a lower concentration of antiproliferative drugs. Increased the th number of antiproliferative drugs, delivered in the area surrounding the bifurcation hole, may be provided with another therapeutic agent containing a different drug or other therapeutic agent containing a higher concentration of the same drug.

In addition to the delivery of various therapeutic agents to moralnoi or abdominales side expandable medical device for treatment of the vessel wall, therapeutic agent can be delivered to luminale side expandable medical device for preventing or reducing thrombosis. Medications that are delivered into the bloodstream with luminaries side of the device, can be located at the proximal end of the device or the distal end of the device.

Ways bookmarks of various treatments in different openings in the expandable medical device may include known methods such as dipping and coating, as well as the famous microstrain piezoelectric methods. Microinjector device can work with computer control to supply the exact quantities of at least two liquid therapeutic agents in the exact position on the expandable medical device known method. For example, an inkjet device for the two active agents may submit two active funds in holes simultaneously or sequentially.When therapeutic agents are placed in through holes in the expandable medical device luminally side through holes can be cut during the bookmarks elastic holder to pursue a remedy in liquid form, for example with a solvent. Therapeutic agents can also lay a hand injection devices.

EXAMPLE 1

The figure 7 shows duplicately stent 700, containing anti-inflammatory and antiproliferative agent, are delivered from different holes in the stent, to provide independent kinetics of release of the two drugs, which are specially programmed accordingly biological processes of restenosis. In accordance with this example, dualcurrency stent contains anti-inflammatory pimecrolimus in the first set of holes 710 in combination with an antiproliferative agent paclitaxel in the second set of holes 720. Each active agent is provided in the matrix material within the holes of the stent under the special scheme bookmarks, designed to ensure the kinetics of release are shown in figure 8. Each drug is delivered mainly in maralou region for the treatment of restenosis.

As shown in figure 7, pimecrolimus provided in the stent for directed delivery to moralnoi side of the stent, using barrier 712 on luminale side of the hole. Barrier 712: open the IAOD biologically absorbable polymer. Pimecrolimus fill in the holes in such a method that creates the kinetics of release, has two phases. The first phase release of pimecrolimus is provided moralnoi region 716 of the matrix, which is characterized bystrousvoyaemaya composition containing pimecrolimus and biologically absorbable polymer (PLGA) with a high percentage concentration of drugs, such as approximately ninety percent of the drugs on approximately ten percent of the polymer. The second phase of the release provided by the Central region 714 matrix with pimecrolimus and biologically absorbable polymer (PLGA) in the ratio of, approximately, fifty percent of the drugs on fifty percent of the polymer. As you can see on the graph shown in figure 8, in the first phase release of pimecrolimus delivered approximately fifty percent filled the medication for approximately the first twenty-four hours. In the second phase release delivered the remaining fifty percent within about two weeks. This release is programmed, in particular, to match the development of the inflammatory process after angioplasty and stenting. In addition, or alternatively, the change in the concentration of the drug between the two areas to ensure wojtasek release you can apply different polymers or different ratios of the comonomers of the same polymer in different areas for the two drugs to provide two different speeds of release.

Paclitaxel fill in the holes 720 in such a way as to create the kinetics of release, which is characterized essentially linear after the first release of approximately twenty-four hours, as shown in figure 8. Holes 720 under paclitaxel refilled with the creation of three regions, including the base region 722 of, mainly, polymer with minimal amount of medication, luminale side of the hole, the Central region 724 with paclitaxel and polymer (PLGA), with a gradient of changes in their concentrations, and the covering region 726, mainly with the polymer, which regulates the release of paclitaxel. Paclitaxel is released with an initial release in the first day, approximately five to fifteen percent of the total filling medications and subsequent, essentially, a linear release over approximately twenty to ninety days. Additional examples of layouts of paclitaxel in the hole with a gradient change in the concentration described in the aforementioned document WO 04/110302.

In figure 7, medicinal, barrier and cover the area shown in the form of the CTD is selected regions within the holes for ease of explanation. It should be understood that these areas do not have clear boundaries and formed by the mixing of different areas. Thus, although the barrier layers are represented mainly by the polymer without medication, depending on the applied manufacturing technologies, some small amounts of drug are further areas may be incorporated in the barrier region.

The amount of delivered drug varies depending on the size of the stent. For stent with three dimensions mm on six mm, number of pimecrolimus is from about fifty to about three hundred micrograms, preferably from about one hundred to about two hundred and fifty micrograms. The amount of paclitaxel delivered from such a stent ranges from about five to about fifty micrograms, preferably from about ten to about thirty micrograms. In one example, delivered approximately two hundred micrograms of pimecrolimus and approximately two hundred micrograms of paclitaxel. Drugs can be in alternating holes of the stent. However, due to the large differences between the subject delivery doses of two drugs, it may be desirable to place paclitaxel in each third of the four holes in the stent. Alternatively, the openings for delivery Lek is rstv, to be delivered in small doses (paclitaxel), you can do less than that of the holes for large doses.

Bookmark polymer/drug form methods piezoelectric injection with computer-controlled, described in document WO 04/026182, published April 1, 2004, entirely incorporated into the present application by reference. The laying of the first active means can be formed first followed by formation of the tabs of the second active means using a piezoelectric ink-jet pump. Alternatively, the system described in document WO 04/02182 possible to provide a dual piezoelectric dispensers for simultaneous bookmark two active funds.

EXAMPLE 2

In accordance with this example, dualcurrency stent contains a substance Glivec (Gleevec) in the first set of holes 710 in combination with an antiproliferative agent paclitaxel in the second set of holes 720. Each active agent is provided in the matrix material within the holes of the stent under the special scheme bookmarks, designed to ensure the kinetics of release are shown in figure 8.

Substance Gleevec delivered by the scheme of a two-phase release, including intensive initial release for the first day and subsequent slow release over from the ne to two weeks. In the first phase release of substances Gleevec delivered approximately fifty percent filled the medication for the first approximately twenty four hours. In the second phase release delivered the remaining fifty percent within approximately one to two weeks. Paclitaxel fill in the holes 720 in such a way as to create the kinetics of release, providing essentially linear release after the first of about twenty-four hours, as shown in figure 8 and explained above in example 1.

The amount of delivered drug varies depending on the size of the stent. For stent with three dimensions mm on six mm, amount of substance Gleevec is from about two hundred to about five hundred micrograms, preferably from about three to about four hundred micrograms. The amount of paclitaxel delivered from such a stent ranges from about five to about fifty micrograms, preferably from about ten to about thirty micrograms. As in example 1, the drugs can be in alternating holes of the stent or random, non-interleaved way. Bookmark polymer/drug form thus, as described in example 1.

EXAMPLE 3

In compliance and with this example, duplicately stent contains PKC-412 (regulator of cell growth) in the first set of holes, in combination with an antiproliferative agent paclitaxel in the second set of holes. Each active agent is provided in the matrix material within the holes of the stent under the special scheme bookmarks, designed to ensure the kinetics of release explained next.

Substance PKC-412 is delivered essentially constant speed release after the first of about twenty-four hours, during the period of release from about four to about sixteen weeks, preferably, from about six to twelve weeks. Paclitaxel fill in the holes in such a way as to create the kinetics of release, which is characterized essentially linear release after the first of about twenty-four hours, during the period of release of approximately four to sixteen weeks, preferably, from about six to twelve weeks.

The amount of delivered drug varies depending on the size of the stent. For stent with three dimensions mm on six mm, amount of substance PKC-412 ranges from approximately one to approximately four hundred micrograms, but preferably, from about a hundred and five is esati to approximately two hundred and fifty micrograms. The amount of paclitaxel delivered from such a stent ranges from about five to about fifty micrograms, but preferably from approximately ten to approximately thirty micrograms. As in example 1, the drugs can be in alternating holes of the stent or random, non-interleaved way. Bookmark polymer/drug form by the methods described in example 1.

A therapeutic agent

The present invention relates to the delivery antirestenotic funds, including paclitaxel, rapamycin, cladribine (CdA) and their derivatives, as well as other cytotoxic or cytostatic means and means stabilizing the microchannels. Although, in the present application is described mainly antirestenotic means, the present invention can also be used for delivery of other active agents one at a time or in combination with antirestenotic means. Some of therapeutic agents for use with the present invention, which can be transmitted mainly in luminally side, mainly in maralou side or both sides and can be delivered one at a time or in combination, include, but without limitation, antiproliferative agents, antithrombin, immunosuppressants, including sirolimus, antilipidny tools, anti-inflammatory, which means antineoplastic agents, antiplatelet funds angiogenic tools, antiangiogenic remedies, vitamins, antimitoticescoy tools, inhibitors of metalloproteinases, donors of NO (nitric oxide), estradiol, antisclerotic tools and vasoactive tools, endothelial growth factors, estrogen, beta blockers, AZ-blockers, hormones, statins, insulin-like growth factors, antioxidants, membrane stabilizing means, calcium antagonists, retinoids, bivalirudin, phenoxodiol, etoposide, ticlopidine, dipyridamole and trapidil, alone or in combination with any therapeutic agent mentioned in this application. Therapeutic agents also include peptides, lipoproteins, polypeptides, polynucleotides encoding the polypeptides, lipids, protein drugs, drug-conjugates of proteins, enzymes, oligonucleotides and their derivatives, ribozymes, other genetic material, cells, antisense oligonucleotides, monoclonal antibodies, platelets, prions, viruses, bacteria, and eukaryotic cells such as endothelial cells, stem cells, ACE inhibitors (angiotensin converting enzyme), monocytes/macrophages or vascular smooth muscle cells, which are only a small part of the examples. A therapeutic agent may also be a prodrug, which prevrashaetsja the process of metabolism in the required medication, when it is introduced into the recipient. In addition, a therapeutic agent can be pre-compiled in the form of microcapsules, microspheres, microvesicles, liposomes, NRENs, emulsions, dispersions or something similar before they incorporate in therapeutic layer. A therapeutic agent may also be radioactive isotopes or active substances, activated energy to some other form, such as light or ultrasonic energy, or other circulating in the body molecules that can enter the system methods. A therapeutic agent can perform several functions, including the modulation of angiogenesis, restenosis, cell proliferation, thrombosis, platelet aggregation, blood coagulation and sosudorasshiratmi.

Anti-inflammatory agents include, but without limitation, nesteroidnyi anti-inflammatory drugs (NSAID), such as derivatives areluxury acids such as diclofenac; derivatives arylpropionic acids such as naproxen; and salicylic acid derivatives, such as diflunisal. Anti-inflammatory agents also include glucocorticoid (steroids), such as dexamethasone, aspirin, prednisone, and triamcinolone, pirfenidone, meclofenamic acid, tranilast and nesteroidnyi anti-inflammatory drugs. Protivovesa the tion tools can be used in combination with antiproliferative means for attenuating the response of the tissue at the antiproliferative agent.

Active means can also comprise means with antilimfocitarnyi activity; substances with antimicrobial activity; immune modulating means; a cyclo-oxygenase inhibitors; antioxidants; hypocholesterolemic drugs; statins and angiotensins in converting enzyme (ACE); fibrinolytic means; inhibitors of internal coagulation cascade; antihyperlipidemics means; and antiplatelet means; antimetabolites, for example 2-glottogenesis (2-CdA or cladribine); immunosuppressive agents, including sirolimus, everolimus, tacrolimus, etoposide and mitoxantrone; substances with antileykotsitarnaya activity, such as 2-CdA, inhibitors of IL-1, monoclonal antibodies anti-CD116/CD18 monoclonal antibodies to VCAM or ICAM (adhesion molecules), zinc-protoporphyrin; substances with antimicrobial activity, such as drugs that increase NO (nitric oxide); cell sensitizers to the insulin-containing glitazones; high-density lipoprotein (HDL) and derivatives; and synthetic copy of HDL, such as lipitor (lipator), lovastatin (lovestatin), pravastatin (pranastatin), atorvastatin, simvastatin, and derivatives of statins; vasodilator, such as adenosine and dipyridamole; nitric oxide donors; prostaglandins and their derivatives; compounds with activity against tumor necrosis factor (the STI-TNF activity); medicines against hypertension, containing beta-blockers, ACE inhibitors and calcium channel blockers; vasoactive substances containing vasoactive intestinal peptide (VIP); insulin; cell sensitizers to the insulin-containing glitazones, PPAR agonists (specific nuclear receptors) and metmorfin; protein kinase; antisense oligonucleotides, containing resten-NG (resten-NG); antiplatelet tools, including tirofiban, eptifibatide and abciximab; cardioprotective means, including VIP, pituitary adenylyl cyclase-activating peptide (PACAP), a means of apoA-l milano, amlodipine, nicorandil, Cilostazol (cilostaxone) and thienopyridine; cyclo-oxygenase inhibitors, including inhibitors of COX-1 and COX-2; and inhibitors pedidos (petidose) that enhance glycolytic metabolism, including omnipotent. Other medications that can be used to treat inflammation, contain gipolipidemicheskie tools, estrogen and progestin, antagonists of endothelin receptors and antagonists of interleukin-6, and adiponectin. A therapeutic agent can also contain phosphodiesterase inhibitors (PDEi), for example Cilostazol (cilastazol) and agonists of the adenosine receptor, preferably agonists A2A-receptor, for example regadenoson.

Active funds can also be delivered using the method based on gene therapy, in combination the expandable medical device. Gene therapy refers to the delivery of exogenous genes in a cell or tissue, forcing the target cells to Express the product of exogenous genes. Genes are usually delivered either mechanical or vector methods.

Some of the active agents described in this application can be combined with additives, which retain their activity. For example, additives containing surfactants, antacid agents, antioxidants and detergents, can be used to minimize the denaturation and aggregation of protein drugs. It is possible to use anionic, cationic or nonionic surfactants. Examples of non-ionic fillers include, but without limitation, sugar, contains sorbitol, sucrose, trehalose; dextrans containing dextran, carboxymethyl-(CM)-dextran, diethylaminoethyl-(DEAE)-dextran; derivatives of sugars, including D-glucosamine acid and diethylmercury D-glucose; simple synthetic polyesters, including polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP); carboxylic acids, including D-lactic acid, glycolic acid and propionic acid; surface-active substances with affinity for hydrophobic surfaces of the partition including n-dodecyl-beta-D-maltoside, n-octyl-beta-D-glucoside, esters of polyethylene oxide (PEO) and fatty acids (e.g., stearate (among the STV myrj 59) or oleate), esters PEO, sorbitan and fatty acids (e.g., Tween 80, PEO-20 servicemanual), esters sorbitan and fatty acids (e.g., SPAN 60, servicemonitor), esters PEO, glyceryl and fatty acids; esters of glyceryl and fatty acids (for example, glycerylmonostearate), ethers PEO hydrocarbons (for example, a simple PEO-10-operatir); tool Triton X-100; and lubrol. Examples of ionic detergents include, but without limitation, salts of fatty acids, including calcium stearate, magnesium stearate and zinc stearate; phospholipids including lecithin and phosphatidylcholine; (PC) CM-PEG; cholic acid; sodium dodecyl sulphate (SDS); docusate (AOT); and human beings need it to acid.

In accordance with another exemplary embodiment, the intraluminal stent or frame described in this application, it is possible to provide a coating of antithrombotic agents in addition to at least one therapeutic agent incorporated in the wells or holes. In one exemplary embodiment, the stent may be manufactured with the holes in the stent, and, before the introduction or tabs into the holes of the other therapeutic agents to the stent or the site, you can attach an antithrombotic agent with a binder carrier (polymer or polymer matrix) or without it. In this exemplary embodiment, luminally and AB is winalloy surface of the stent, and on the surface of the walls of the holes can be applied antithrombotic agent or coating. In an alternative exemplary embodiment, the stent can first apply an antithrombotic agent or coating, and then it is possible to form the holes. In this exemplary embodiment, only luminally and abdominally surface will contain an antithrombotic agent or floor and on the walls of the holes such coverage will not. In each of these embodiments, the entire surface of the stent or parts thereof, you can attach any number of antithrombotic funds. In addition, to attach antithrombotic agents to the stent can be used any number of known methods, such methods, which are used with floor HEPACOAT™ coronary stent, Bx Velocity® company Cordis Corporation. Alternatively, the stents may be made with surfaces with a rough texture, or may have mikroteksturoy to enhance the adhesion of cells and endothelialization, regardless of antithrombotic coatings, or in addition to it. In addition, holes can lay any number of therapeutic agents, and in different regions of the stent can use different active tool.

As stated above, it is important to note that, in accordance with this the current invention, you can use any number of drugs and/or active means, including: antiproliferative/antimitoticescoy active products, including natural products such as Vinca alkaloids (Vinca) (i.e. vinblastine, vincristine and vinorelbine), paclitaxel, epileptogenesis (i.e. etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubitsin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically hydrolyzes L-asparagine and deprives him of a cell which do not have the capacity to synthesize their own asparagine); antiplatelet agents, such inhibitors G(GP) IIb/IIIaand vitronectin receptor antagonists; antiproliferative/antimitoticescoy alkylating tools, such as nitrospray (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamine (hexamethylmelamine, thiotepa), alkyl-sulfonates - busulfan, nitrosoanatabine (carmustin (BCNU) and analogs, streptozocin), trazeni - dacarbazine (DTIC); antiproliferative/antimitoticescoe antimetabolites, such as analogs of folic acid (methotrexate), pyrimidine analogues (fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (mercaptopurine, tioguanin, pentostatin the 2-glottogenesis {cladribine}); coordination complexes of platinum metals (cisplatin, carboplatin), procarbazine, oxytocin, mitotane, aminoglutethimide; hormones (i.e. estrogen); anticoagulants (heparin, synthetic salt of heparin and other inhibitors of thrombin); fibrinolytic tools (e.g., tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; ANTIMIGRAINE means; antisecretory agents (brefeldin (breveldin)); anti-inflammatory: for example adrenal cortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, betamethasone and dexamethasone), non-steroidal drugs (salicylic acid derivatives, i.e., aspirin; derivatives of para-aminophenol, i.e., acetaminophen; indole - inden-acetic acid (indomethacin, sulindac and etodolac), heteroarylboronic acid (tolmetin, diclofenac, and Ketorolac), arylpropionic acid (ibuprofen and derivatives), Anthranilic acid (methenamine acid and meclofenamic acid), analogue acids (piroxicam, tenoxicam, phenylbutazone and occidentalise (oxyphenthatrazone)), nabumeton, gold compounds (auranofin, aurothioglucose, thiomalate gold-sodium); immunosuppressants: (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); giovannie tools: vascular endothelial growth factor (VEGF), fibroblastic growth factor (FGF); platelet-derived growth factor (PDGF), erythropoietin, lock angiotensinogen receptors; donors of nitrogen oxides; antisense oligonucleotides, and combinations thereof; inhibitors of cell cycle inhibitors, mTOR (target of rapamycin in mammals) and inhibitors of the kinase in the signal transduction of growth factor receptor.

Further to figures 9A, 9B and 9C schematically presents the plot of the stent.

As shown in figure 9A, the stent 900 contains a lot of essentially round holes 902. In this exemplary embodiment, the set of essentially round holes 902 continues through the wall of the stent 900. In other words, a lot of essentially round holes 902 continues from abdominales surface 904 of the stent to abdominales surface 906 of the stent, while the wall thickness defined as the distance between luminaries and abdominales surfaces. However, in other embodiments, implementation of the holes do not necessarily have to go through the wall of the stent 900. For example, holes or containers may go partially or luminally or from abdominales surfaces, or from both. The stent 900, shown in figure 9A, contains the raw surface 904 and 906 and empty holes 902.

As can be seen in figure 9B, on at least one surface a coating of t is repetitsionnogo means 908. Therapeutic agent preferably contains an antithrombotic agent, such as heparin; however, you can apply any antithrombotic agent. Antithrombotic tool can be attached using any method outlined above. In this exemplary embodiment, as abdominally and luminally surface contain attached antithrombotic agent. In addition, because currently, many essentially round holes 902 nothing contained, wall holes 902 may also contain some attached to them antithrombotic agent. The number of antithrombotic agents that are attached to the walls 910 holes depends on how attached the mentioned tool. For example, if the above tool is attached coating by the dipping method, the walls of the holes will contain more attached to them active funds than in the case when the active agent is attached using the method of coating by spraying. As described in the present application, in this exemplary embodiment, all exposed surfaces contain attached thereto massive antithrombotic coating; however, in alternative exemplary embodiments, implementation, only identify Lennie surface may contain attached antithrombotic coating. For example, in one exemplary embodiment, the antimicrobial agent can be processed only surface in contact with blood. In yet another alternative exemplary embodiment, the coating of antithrombotic agents may be applied onto one or both surfaces, but without drawing on the walls of the holes. This result can be obtained in a variety of ways, including filling the holes before coating or creating holes after joining antithrombotic agents.

Figure 9C depicts finally cooked a stent in accordance with this exemplary embodiment. As shown in this figure, a lot of essentially round hole 902 is filled at least one therapeutic agent for the treatment of vascular diseases such as restenosis and inflammation or any other disease that is described in this application. Each hole 902 may be filled in the same therapeutic tool or different active means, as explained in detail above. As shown in this figure, referred to different active means 912, 914 and 916 is used against a specific schema; however, as explained in detail above, any combination is possible, as well as the use of a single active funds in different concentrate is the walkie-talkies. Drugs such as rapamycin, you can lay in holes 902 in any suitable way. Methods bookmarks active means include backfilling micropipette and/or inkjet filling. In one exemplary embodiment, filling medication can be performed so that the drug and/or matrix of the drug/polymer in the hole will be located below the surface of the stent, in order to avoid contact with the surrounding tissue. Alternatively, the holes can be filled so that the drug and/or matrix of the drug/polymer may come in contact with the surrounding tissue. In addition, the total dose of each drug, if you use some drugs, you can count with the maximum flexibility. In addition, the rate of release of each drug can be adjusted individually. For example, the holes near the ends can contain more drugs for the treatment of edge restenosis.

In accordance with this exemplary embodiment, the hole or holes can be made not only for the most effective drug therapy, but also to create a physical separation between different drugs. This physical separation may help to prevent interaction between the active substances.

In the context of this application, the term rapamycin which includes rapamycin and all analogs, derivatives and conjugates that bind to FKBP12 and other immunophilins and have the same pharmacologic properties as rapamycin, including inhibition of the TOR. In addition, all medicines and active substances described in this application, include their analogs, derivatives and conjugates.

As outlined in this application, a stent containing made it through holes, wells, reservoirs or openings, it is possible to apply a coating of antithrombotic agents and/or drugs or combinations of drugs, such as medication are described in the present application, and the holes can be filled, at least one therapeutic agent or in combination with at least one polymer. Essentially, the stent can be manufactured with holes in it, and, before the introduction or deposition only therapeutic agents or in combination with at least one polymer in the hole to the stent or the site, you can attach an antithrombotic agent with a binder carrier, or without it. In the exemplary embodiment described in this application, an antithrombotic agent can be applied to luminally and abdominally surface of the stent, as well as on the surface of the walls of the hole. In this exemplary embodiment, an antithrombotic agent contains heparin is in or its derivatives, for example, low molecular weight heparin (LMWH), although you can use any number of suitable antithrombotic funds. Heparin and/or LMWH have a very high negative charges.

On the entire surface of the stent described in this application, including the inner surface of the through-hole or holes, which are containers for a therapeutic agent and/or a combination of polymer and therapeutic agent, are first applied covalently bound heparin coating. Itself heparin coating associated with the metal surface of the stent with its own primer, containing alternating layers of poly(etilenimina), strongly cationic polymer, denoted by the known reduction in PEI, and dextran sulfate, anionic polymer. The application of the primer of this type known in the art and described in several patents, including U.S. patent No. 5213898, 5049403, 6461665 and 6767405. In particular, heparin covalently binds to the primer-containing layers PEI-dextran sulfate, which, in turn, binds to the metal surface. After all surfaces cause heparin mixture, each of the holes or containers filled with one of the technological processes described in this application.

In accordance with another exemplary embodiment, this is th invention relates to compositions and configurations of primers for amplification of adhesion delivering the drug matrix, for example, the combination of a therapeutic agent and a polymer, coated with heparin to the surface of the medical device, such as a stent. The present invention is useful in particular when heparin coating covalently bound to a metal or polymer surface of the medical device. In accordance with the present invention, the primer preferably contains a high molecular weight component or a low molecular weight component, and delivers the drug matrix that contains medication and/or other therapeutic agent and a filler, preferably a polymeric filler. In addition, the primer may also preferably contain a material having an electric charge opposite the electric charge in the underlying layer, such as heparin, and the charge density similar to the density of the underlying charge.

The principle of primer applied over a heparin layer or coating, to enhance the adhesion coated with heparin surface with any other matrix, or any other coating appears to be original, taking into account the fact that, usually, heparin surface is used to impart antimicrobial properties and, therefore, do not close for practical application. In the present invention, only the inner surface of the walls of the holes or openings in the stent, which sod is RIT capacity with drug and polymer, will cover the primer in accordance with the present invention, to thereby enhance the adhesion between the two layers and to reduce the potential loss of the matrix, the drug-polymer, without a material adverse effect on heparin surface on the outside of the containers. It is important to note that the blocking heparin primer in accordance with the present invention are biocompatible with their new intended use.

Primer in accordance with the present invention can be used with a stent of any type. In the exemplary embodiment described in this application, the primer is applied with a stent or stent shown in figures 1, 2, 3 and 4.

In accordance with one exemplary embodiment, the primer contains a conjugated polymer is poly(ethylenimine), for example, a copolymer of lactic and glycolic acids (PLGA) and poly(ethylenimine) (PEI) and/or PLGA-Protamine. Poly(ethylenimine) is a highly cationic polymer, which is associated with some negatively charged proteins or polysaccharides. In addition to PEI, other material, useful in the above-mentioned conjugate is Protamine. Protamine is a proven low-molecular-weight protein drug that is used as an antidote against the heparin. Protamine is rarely aqueous solution. Thus g is antowka can strongly interact with heparin coating, and containing the drug matrix, and thereby to enhance the adhesion between the two substances. Because heparin is poly(anionic) substance, it is expected that poly(cationic substance, such as Protamine, will strongly bind to heparin, but is sufficiently hydrophobic in other parts of its structure to allow a strong bond component PLGA matrix, the drug-polymer reservoir.

Binding assays between PLGA and PEI and between PEI and heparin may be an ionic binding or covalent binding. The figure 10 shows an example of covalent binding between PLGA and PEI. In particular, figure 10 shows the conjugation reaction between PLGA with carboxyl end group and a low molecular weight PEI. Alternatively, the primer may contain high molecular weight PEI or branched PEI. The figure 11 shows the conjugation reaction between PLGA with carboxyl end group and a high molecular weight PEI or branched PEI. As shown, the reaction can be adjusted on a one-to-one or conjugate of PLGA-PEI-PLGA with the ratio of 2:1 between PLGA and PEI.

The table below shows the effectiveness of PEI as a primer to enhance adhesion complex drug/polymer coated with heparin to surfaces. Experienced stents were immersed in the test medium containing a phosphate salt buffer the th solution and bovine serum albumin, which simulates conditions of physiological fluid. Complex drug/polymer contains rapamycin and PLGA.

(Abbreviations used in table:
PEI = Polyethyleneimine
DMSO = Dimethylsulfoxide
Avg = average
Stdev = standard deviation
RSD = relative standard deviation
n/a = not applicable

In an alternative exemplary embodiment, the primer may contain a low molecular weight cations, forming complexes with heparin, including benzalconi chloride and/or oligomeric containing arginine peptides, or high-molecular complexing cations, including polylysine, poly(arginine), Protamine, poly(dimethylaminoethyl)methacrylate or poly(dimethylaminoethyl)acrylate.

In accordance with the present invention, a process for enhancing the adhesion of the drug complex to heparin may include applying a first coat of adhesion promoter and then applying the solution to filling the polymer/drug or application Grun ovci-adhesion promoter and then the coating solution for filling PLGA with carboxyl end groups or a mixture of PLGA with carboxyl end groups and regular structure and PLGA/medicine.

Primer in accordance with the present invention will be applied on the inside, covered with heparin wall of the hole or holes in the stent prior to filling holes matrix for local delivery of drugs. In other words, ready, drug eluting-stent, the primer will occupy the space between the surface of the heparin coating and the basis for delivering the drug matrix and will enhance the adhesion between heparin coating and delivers the drug matrix. The increase in adhesion is achieved due to several factors, including a decrease in the osmotic concentration of the solution/the infiltration of water into the heparin coating during use, after the charge neutralization of the cationic primer, reducing the water solubility of the complex of heparin/cationic primer compared to the same heparin surface, ionic binding, covalent binding, and a stronger physical adhesion between the primer and the matrix polymer/drug due to surface tension, etc.

In another exemplary embodiment of the present invention, the primer in accordance with the present invention will preferably contain plot its molecular structure, which is charged positively to associate with negatively charged heparin coating, and the plot, for what that is hydrophobic, hydrophilic or balanced to associate with the polymer component of delivering the drug matrix. This section of the primer will vary depending on the nature of delivering the drug matrix. In particular, the primer is designed to enhance the adhesion of delivering the drug matrix covered heparin holes of the stent, so that no or essentially no holes or containers does not lose its contents when the stent comes in contact with fluids water-based, such as saline, blood and/or interstitial fluid.

Although the description of the primers in accordance with the present invention provides for a special purpose of enhancing adhesion between coated with heparin inner vessel wall of the stent and a mixture of drug/polymer filling capacity, this primer may be useful to connect or bind any of the substrate area covered with heparin surface. For example, on a plastic medical devices in contact with blood, often causing heparin coating to minimize thrombosis on the device, but perhaps it would be desirable to apply the above-mentioned coating on that surface later. A mixture of primers in accordance with the present invention in a solvent can be applied to selected areas of the device, actuarial you can vaporize to create a primer coated area on heparin surface, then primed area, you can associate a new subsystem.

The material of the primer is preferably applied in the form of a solution of a polymeric primer in a solvent, such as dimethyl sulfide (DMSO), N-organic, or in the form of its aqueous mixtures and can be made in the vessel using any of the methods of filling described in the application considered in the present moment. Then the primer mixture can be dried to provide a coating layer of the primer covered heparin surface. In a preferred embodiment, applying a layer of primer will require only one stage of deposition of the filling process of the stent. The choice of a suitable solvent for the deposition of cationic primer is largely determined by its ability to dissolve the primer and its compatibility with filling device and process described in this application.

The present invention can be characterized simply as an implantable medical device. The medical device comprises an intraluminal frame that contains many have made holes, the first coating containing a material having a first electric charge attached to at least the area of the intraluminal surface of the frame and the surface of many holes, the second coating containing a material having a second electric charge, attached to at least the area of the first coating, the second electric charge opposite to the first electric charge, and at least one therapeutic agent incorporated into at least one of the many holes, and, second floor made in the form of an intermediate layer between the first surface and at least one therapeutic agent.

The first coating may contain any appropriate antithrombotic agent, described in this application. For example, you can use a polysaccharide, such as heparin. The second coating may include a polymer cation or polymeric conjugate containing cationic segments described in this application. Examples of polymeric cations contain oligomeric containing arginine peptides, polylysine, poly(arginine), Protamine, poly(dimethylaminoethyl)poly(ethylenimine). Examples of the cationic polymer conjugates containing the first component, for example a copolymer of lactic and glycolic acids, and the second component containing any of the above cations. A therapeutic agent may contain antirestenotic agent, anti-inflammatory agent, an antithrombotic agent, an antiproliferative agent, a means for minimizing damage to the affected heart tissue, or any combination of the plumage is olenych funds.

More generally, the principle of the present invention can be extended to include primers that amplify the strength of adhesion between hydrophilic and hydrophobic surfaces. For example, other interest hydrophilic surfaces, the so-called "slippery" coating, such as coating, used in connection with catheters. Data hydrophilic surfaces are also covalently linked, but can be only conformal coatings. Examples of chemical structures, which are found in slippery surfaces, are patterns based on polyvinylpyrrolidone, hydroxyethylmethacrylate, poly(ethylene oxide) or poly(ethylene glycol), etc.

In accordance with another exemplary embodiment, the present invention relates to controlling the kinetics of release of therapeutic agent from the reservoir into the stent.

The NEVO stent™ (Menlo Park, CA) uses technology RES Technology for delivery of sirolimus. Delivery of sirolimus from reservoirs (RES Technology) containing PLGA, which is safely absorbed within 90-120 days of stenting, provides the ability to achieve clinical efficacy of the CYPHER stent®and characteristics of healing, similar to bare-metal stents. Security 3.5mm experienced stent NEVO™ confirm published kovanye data preclinical studies. The current study was conducted to test the safety and kinetics of release for the experimental design of the stent NEVO™ with a diameter of 2.5 mm

Experienced stent NEVO™ with a diameter of 2.5 mm, bare metal stents (BMS; stents with empty containers) and CYPHER stents®implanted in the LAD (left anterior descending), LCx (left circumflex) and/or right coronary artery of pigs 1, 3, 8, 14, 30, 60 and 90 days (C) to evaluate the kinetics of release of sirolimus, and at 30, 90 or 180 seconds to evaluate the histopathology and histomorphometry.

The kinetics of release of sirolimus stent NEVO™ technology RES Technology was characterized by a slightly lower rate than with CYPHER stents®within 1-14 days after implantation (figure 12). However, the content of sirolimus obtained in the arteries with the use of the NEVO stent™, was slightly higher than with CYPHER stents®. The number of absorbed sirolimus/release of sirolimus from the NEVO stent™ was approximately 3.2 times more than the number of absorbed sirolimus/release of sirolimus from CYPHER stents®. The data show that sirolimus be delivered using the technology of RES Technology, may be more effective than when delivered by CYPHER stents®. However, the content of sirolimus obtained in the arteries with the use of stent NEV™, is a safe and effective range, as previously set. Although the content of sirolimus obtained in the arteries with the use of the NEVO stent™, was slightly higher than with CYPHER stents®the healing of the vessel and the stent NEVO™ was similar to the obtained with stents BMS and CYPHER®. All stents were endotheliosis to the 30th day. Indicator of inflammation around the struts in the stent NEVO™ was minimal and significantly lower than in the BMS stents on the 30th day (NEVO™: 0,87±0,60 compared with BMS stents: 1,05±0,19, p<0,05; CYPHER stents®with 1.07±0,60). Inflammation was minimal at 90 and 180 days; and did not differ between groups. The thickness neointimal education did not differ between groups stents (on the 30th day, NEVO™: of 0.21±0.07 mm, the stent CYPHER®: 0,22±0.10 mm, BMS: 0,18±0.05 mm). As expected, fibrin about spacers 30 days in the NEVO stent™ and CYPHER® was significantly more than in the BMS stents, and gradually decreased to 90 mm and 180 mm days. These findings are consistent with the results observed previously experienced stent NEVO™ with a diameter of 3.5 mm

Experienced stent NEVO™ using technology RES Technology for delivery of sirolimus, is more effective than the CYPHER stents®; however, the healing of comparable vessels with stents CYPHER® and BMS. In addition, experienced stents NEVO™ with diameters of 2.5 and 3.5 mm have similar characteristics of the mi security.

Above shown and described embodiments of which are considered the most appropriate and preferred, but it should be understood that the specialists in this field will become apparent deviations from the specific illustrated and described structures and methods that can be used without going beyond being and scope of the invention. The present invention is not limited to the particular constructions described and shown in the figures, but is subject to interpretation as is consistent with all modifications that may fall within the scope of the claims appended claims.

1. Implantable medical device, comprising:
intraluminal frame that contains many have made holes, with intraluminal frame contains essentially tubular in configuration and contains a number of cylindrical sections connected by a set of connecting elements, each of the cylindrical sections formed from a grid of elongated struts, connected by a plastic hinge and County spacers; and
at least two different therapeutic agents incorporated in different holes
and at least one therapeutic agent incorporated into at least one of the many holes incorporated in the matrix is polymera of lactic and glycolic acids (PLGA) to control the rate of release and the cumulative released dose of therapeutic agent into the surrounding tissue.

2. Implantable medical device according to p. 1, where at least one therapeutic agent contains rapamycin.

3. Implantable medical device according to p. 1, where different therapeutic agents are different medicines.

4. Implantable medical device under item 1 or 2, where different therapeutic agents are the same drug in different concentrations.

5. Implantable medical device under item 1 or 2, where different remedies are one and the same medicine with different kinetics of release.

6. Implantable medical device under item 1 or 2, where different therapeutic agents are different forms of the same medication.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to biotechnology, more specifically to agents for preparing a therapeutic composition of seashell, which can be used in gerontological practice for preventing the initial forms of atherosclerosis in elderly patients. A method for preparing the composition consists in producing an acid hydrolysate of conch shell meat, and an alkaline hydrolysate of mussels. The prepared alkaline and acidic hydrolysates are combined in volume ratio 10:1; pH is reduced to 6.4-6.6 with constant stirring, and the mixed hydrolysates are evaporated in the vacuum environment 0.65 kg s/cm2 at temperature 95-97°C to 20-25% on a dry matter basis.

EFFECT: prepared composition amino acid and other ingredients balanced.

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is using 5α-androstane -3β,5,6β-triol for preparing neuroprotective drugs.

EFFECT: compound possesses the significant protective action against neuronal injuries caused by cerebral ischemia, spinal ischemia or hypoxia, and has no noticeable toxic reactions within its effective dose.

4 cl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, pharmacology and biology. What is presented is a complex of tris-(2-hydroxyethyl)amine and bis-(2-methylphenoxyacetate)zinc [cinkatran or citrimin] of formula: (HOCH2CH2)3N·Zn(OOCCH2OC6H4CH3-2)2 as an agent reducing cholesterol esterase activity.

EFFECT: reducing cholesterol esterase activity.

2 tbl

FIELD: medicine.

SUBSTANCE: method involves recovering DNA, detecting polymorphism of AGTR1 gene coding angiotensin II receptor type 1. That is followed by detecting polymorphism of ACE gene coding angiotensin converting enzyme; in case of having combinations of AC(AGTR1)/ID(ACE) or AA(AGTR1)/DD(ACE) genotypes detected, angiotensin II receptor blockers, in particular losartan 50mg twice a day are prescribed as a part of the complex therapy.

EFFECT: invention enables developing the treatment procedure involving the angiotensin II receptor blockers taking into account its genetic traits for increasing the therapeutic effectiveness of both nonobstructive, and obstructive forms of hypertrophic cardiomyopathy.

3 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substance - 2-ethyl-6-methyl-3-hydroxypyridine dichloroacetate of formula I its stable crystalline form and method of obtaining thereof. Substance (I) possesses antiatherosclerotic, hypolipidemic, antihypoxic, nootropic, anxiolytic and adaptogenic action with low toxicity (LD50=30000 mg/kg, rats, intragastrically) and absence of hygroscopicity. Substance is obtained with interaction of equimolar quantities of 2-ethyl-6-methyl-3-hydroxypyridine and dichloroacetic acid in presence of solvent.

EFFECT: increase of stability.

9 cl, 8 dwg, 10 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy, and concerns preventing and treating atherosclerosis. That is ensured by prescribing tablets or capsules with their active ingredients representing black elder blossom, marigold blossom and violet herb in certain proportions. Two tablets or two capsules are administered two times a day every 12 hours within the unlimited therapeutic course.

EFFECT: method provides the effective prevention and treatment of atherosclerosis, including reducing a thickness of carotid artery intima-medial thickness by suppressing the expression of anti-inflammatory cytokines and reducing blood serum atherogenicity.

FIELD: medicine.

SUBSTANCE: immunocorrective agent for the therapy of atherosclerotic diseases containing hawthorn blossom, common St. John's wort herb, as well as calcium stearate and silicone oxide taken in certain proportions.

EFFECT: agent is effective for the therapy of atherosclerotic diseases.

8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.

EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.

11 cl, 1 dwg, 2 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: therapeutically effective amount of ethyl methyl hydroxypyridine succinate and calcium atorvastatin, as well as additives in the form of lactose and magnesium stearate are encapsulated in gelatine. Ethyl methyl hydroxypyridine succinate and magnesium stearate is placed into an inner smaller gelatine capsule inside a main outer gelatine capsule containing atorvastatin, lactose and magnesium strearate. The ingredient ratio in the inner capsule makes, wt %: Ethyl methyl hydroxypyridine succinate 96.2-98.6; magnesium stearate 1.4-3.8, and the ingredient ratio in the outer capsule makes, wt %: calcium atorvastatin 10.0-45.0; lactose 52.0-89.0; magnesium stearate 1.0-3.8.

EFFECT: method enables providing the higher pharmaceutical effectiveness of the preparation and prolonging the shelf-life by preventing atorvastatin degradation.

3 cl, 3 tbl

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and medical equipment, namely to obstetrics and gynaecology, and can be used for the local treatment of inflammatory diseases of the uterine cavity. The method is implemented by inserting a waveguide of a presented device in a protection enclosure into the uterine cavity. A taper base of a narrow portion of the enclosure leans on an external orifice of the cervical uterus to prevent accidental perforation of the uterus. An infusion system regulator is used to set the spray supply of a therapeutic solution into an irrigation canal of the ultrasonic device. Thereafter ultrasonic vibrations are generated, and the uterine cavity is treated with the sounded therapeutic solution. The exposure length is 3-5 minutes at the ultrasonic vibration frequency of 25 kHz, infusion rate approximately 100-150 ml/min. The total infusion volume is not less than 300 ml. The ultrasonic treatment enables providing the continuous outflow of the uterine discharge. The device comprises an US generator, an acoustic assembly, the waveguide with the protection enclosure, the infusion system for the therapeutic solution supply. The acoustic assembly and waveguide comprises the irrigation canal. A working tip of the waveguide represents a short cylinder having a diameter greater than the rest portion. The irrigation canal of the waveguide has a diameter of 2 mm. The protection metal thin-wall enclosure has a crimped distal end and drain holes and represents two cylindrical elements of various diameters connected by a taper junction with milled grooves arranged so that to enable the fluid access to the working tip cylinder, the length of which makes no more than 3 mm.

EFFECT: inventions provide the effective cleansing of the uterine cavity from infected and necrotised tissues with improved comfort and safety of the procedure with using no endoscopic equipment, cervical dilation manipulations and uterine pre-probing.

2 cl, 3 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medical equipment, namely to means of carrying out low-invasive surgical operations. A surgical ultrasonic instrument contains coordinating and conducting elements for the transmission of an ultrasonic signal and a working end connected to the conducting element. The conducting element and/or working end have at least one section with different physical and/or mechanical properties, obtained by performing its thermal and/or mechanical treatment or made from a material, different from the material of adjacent section(s). A device for the ablation of a pathological mass additionally contains a generator of ultrasonic fluctuations and an acoustic unit. The method of the pathological mass ablation from a biological tissue consists in the application of the device for the pathological mass ablation.

EFFECT: improvement of transmission of ultrasonic fluctuations, provision of sufficient dynamic stability of the ultrasonic instrument and control of the curvature of a trajectory of elastic deformation of the conducting element and working end of the ultrasonic instrument.

27 cl, 13 dwg

Reverse evaporator // 2532502

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to medical equipment. It can be used for surgeries and postoperative care of wounds (including injuries, burns, freezing injuries and trophic ulcers), as well as soft tissues and mucous membranes for bleeding control, prevention and treatment of suppurative complications, infectious and dermatologic diseases. The object of the presented device is providing the local, targeted haemostatic and/or antiseptic preparation of biological tissues with an ozone-oxygen mixture in a combination with the effective aspiration and deactivation of ozone from the used gas mixture, staying within the maximum permissible ambient ozone concentration. The assigned object is solved by the fact that the device additionally comprises a motor and storage portions combined together into a one-piece working circuit. A tip in the form of an ozone handle and peripheral aspiration and release pumps connected by a plastic retainer; pump inlets and outlets are presented in the form of junction pipes provided with conical nozzles with adapters, are parts of the motor portion. The storage portion comprises a chain of cross-pieces coupled in the same direction by supplying pipes and provided on each side from each cross-piece with a pair of hermetic ozone-oxygen packages on the opposite crossarms.

EFFECT: presented reverse evaporator enables avoiding sophisticated, bulky, immobile treatment apparatuses and using the aggressive gas media, like ozone-oxygen mixtures.

3 cl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medical equipment. Device contains cylindrical case element, plunger and cover, made with possibility f travel between closing position and dispensing position. Cover includes hole, which has specified dimensions to provide leaking of medication through cover, when cover is in dispensing position. Cylindrical case element has multitude of internal thread coils. Connection of cover and case is realised due to the fact that cover includes external wall and column, extending towards cylindrical case element, column includes external thread coils, or cylindrical case element includes multitude of external thread coils, and cover includes multitude of internal thread coils, which have such dimensions that they are capable of mating in thread coils of external thread of cylindrical case element, and/or cylindrical case element includes multitude of internal thread coils, and cover includes multitude of cogs, which have multitude of external thread coils, which have such dimensions that it is capable of mating in thread said coils of internal thread of cylindrical case element (12), or cylindrical case element includes flange part, passing from distal end, projection, formed near distal end, first groove and second groove, with cover including first holding bead, which has such dimensions that it is capable of interaction with flange part, and second holding bead, which has such dimensions that is capable of snapping shut in first groove, when cylindrical case element is in closing position, and has such dimensions that it is capable of snapping shut in second groove, when first holding bead interacts with flange part, in order to place cover in dispensing position. Device additionally contains holding means to hold cover on cylindrical case element, when cover is in dispensing position.

EFFECT: providing delivery of specified dose at any moment due to travel of case element between closing and dispensing position without separating cover from device.

13 cl, 14 dwg

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to gynaecology, and can be used in treating such diseases as dysfunctional uterine bleeding, menorrhagia, dysmenorrhoea, endometriosis, uterine fibroid, menopausal disorders, osteoporosis and urogenital atrophy. That is ensured by presenting an urogenital system comprising a frame forming an internal cavity enclosing an insert with a therapeutically effective dose of a biologically active compound. The insert is form-stable and damage-resistant when in use. The frame has an open structure providing access to a main portion of an external portion of the insert. The frame comprises one or more retaining element for frame holding in the uterine. What is also presented is a method for making the above intrauterine system.

EFFECT: group of inventions provides an effective controlled release drug delivery for a long period of time, as well as easy and safe administration and proper removal of the preparation.

14 cl, 9 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely traumatology, orthopaedics, and can be used for supporting treatment in large joint replacement. That is ensured by determining a volume of involved joint contracture six months before the operation. That is followed by X-ray and magnetic resonant examination of the involved and collateral joints to specify their state. Besides, a quality of the bone tissue is assessed by osteodensitometry. If observing changes in the bone tissue quality, the complex of the drug therapy is added with the preparations Bivalos and Calcemin. A pain syndrome intensity is assessed by the visual analogue scale three months before the operation. That is followed by the complex therapy aiming at optimising the state of extremity joints with added local injection therapy (LIT). That is ensured by preliminary exposing the biologically active periarticular zones in the proximal and distal direction from the involved joint to the focused infrared laser light. A mixture containing solutions of the therapeutic preparations: chondroprotectors, Contrykal, Lidocaine, vitamin B12 is injected into the same zones. Besides, Arthrofoon is administered for the whole preoperative period. If the pain syndrome intensity is less than 4 points, Arthrofoon is administered in a dose of 4 tablets a day. If the intensity value is more than 4 points, the preparation is administered in a dose of 8 tablets a day in a complex with a short course of a non-steroidal anti-inflammatory preparations and a chondroprotector. The replacement operation is immediately followed by fixing a collateral joint with an orthesis for the period of 3 months. The complex of the postoperative supporting therapy started three weeks after the operation is added with a single intravenous introduction of the preparation Aklasta, the preparation Arthrofoon in a dose of 4 tablets a day for three months, alpha calcidole and Calcemin continuously. A pectoral girdle of the extremities is reinforced by means of an individually specified set of therapeutic exercises and electric walking myostimulation. The LIT of the collateral joint is performed three months after the operation. If observing a degenerative process in the adjacent joints, the LIT is performed alternatively in these regions. Vasodilators, chondroprotectors, and the preparation Milgamma are administered with underlying LIT. If observing psychoemotional changes in the patient, the preparation Tenoten is additionally administered. A postoperative medication regimen, including the LIT is repeated 3-4 times every 6 months.

EFFECT: method provides optimising the effect of the surgical management and preventing developing complications both in the operated joint, and in the adjacent and symmetrical joints after the replacement, preventing developing instability of the endoprosthesis components, preventing developing or aggravating degenerative process in the symmetrical and adjacent joints that reduces a risk of the recurrent operations.

1 ex

FIELD: medicine.

SUBSTANCE: after a colocolonic anastomosis is created 10-12 cm in a proximal direction from the anastomosis, a double tube is inserted into an intestinal lumen. After a transanal insertion of the tube, an infusion pump is used for dosed introduction of a rifaximin suspension at 0.01 mcg of an active substance per 1 kg of a patient's body weight a minute through one channel and a passive outflow through the second channel. The rifaximin suspension is introduced continuously for the first days, then 3 times a day for 3 hours until observing active intestinal peristalsis.

EFFECT: method provides effective prevention of colocolonic anastomotic leakage, reduces a probability of postoperative complications ensured by avoiding microbial contamination, infection and development of anastomositis, as well as promotes reducing the length of treatment and postoperative stay in hospital.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to gynaecology, reflexotherapy and pelotherapy. A method includes carrying out a course of antibacterial and/or antiviral therapy, which is started on 5-7 day of a menstrual cycle. From 5-7 day of the following menstrual cycle a course of pharmacopuncture is performed by introduction of homeopathic preparations into acupuncture points (AP). On 1, 3, 5, 7, 9, 11 and 13 days of the course Traumel C is introduced into points E36 (2), V31 (2), V32 (2), V33 (2), V34 (2). On 2, 4, 6, 8, 10, 12, 14 days of the course Ovarium compositum is introduced in AP Rp6 (2). Simultaneously with the course of pharmacopuncture or starting from 5-7 day of the following menstrual cycle a course of pelotherapy is carried out. Introduction of gel, based on the Dead Sea mud, is performed rectally for 30 minutes, 1 time per day.

EFFECT: method ensures recovery of the two-phase menstrual cycle due to normalisation of endometrium and vagina biocenosis, improvement of local immune and vegetative status, increases duration of remission.

4 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to the field of medicine, in particular to vascular surgery, and is intended for transfer of medications onto an internal surface of a vessel wall. A device for transfer of medications onto the internal surface of the vessel wall contains a matrix, made in the form of a polymer film, covered with medication and placed on a flexible framework. The matrix and the framework have specified standard sizes. They are made with a possibility of placement in them of a cellular knitted metal temporary stent and with a possibility to be inside the temporary stent of an inflatable balloon with a fixed diameter and length and a cylindrical or conic shape when blowing under high pressure or a latex balloon with a possibility of filling the entire internal space of the temporary stent when blowing under low pressure.

EFFECT: invention makes it possible to simultaneously perform long-term efficient transfer of medication into the vessel wall with preservation of blood flow and efficient diameter of the affected vessel.

4 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: there are performed beam therapy, intracavitary therapy and chemotherapy. For 5-7 days before the beginning of the radiation, Colagel-Beta with 1 β-interleukin 20 ml is introduced into a vaginal tube daily. Each session of the intracavitary therapy is preceded by introducing Colegel with 5-fluoruracil 20-25 ml into an uterine cavity and exposed for 30-40 minutes. Besides, from the beginning of the beam therapy 40-50 minutes after the radiation session, sodium alginate gel 20 ml containing methyluracil, dimethyl sulphoxide and hydrocortisone are introduced into a rectum and a bladder in a therapeutically effective amount. 5-10 procedures are performed.

EFFECT: providing faster regression of the tumour, reducing the rate and severity of radiation injuries of the rectus and bladder adjacent with the uterus with no risk of severe systemic toxic manifestations, including in senior patients with comorbid inoperable diseases and extended tumours.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula and their pharmaceutically acceptable salts possessing antibacterial properties, as well as to a based pharmaceutical composition. In formula (I) R1 represents an alkoxy group; each of U and V represents CH, and W represents N, or U represents N, V represents CH and W represents CH or N, or each of U and V represents N, and W represents CH; R2 represents hydrogen or fluorine, if W represents CH, or R2 represents hydrogen, if W represents N; A represents O or CH2; Y represents CH or N; Q represents O or S; and n represents 0 or 1.

EFFECT: preparing the pharmaceutically acceptable salts possessing the antibacterial properties.

23 cl, 3 tbl, 15 ex

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