Stent with double drug release

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to implanted medical devices. A device for drug delivery includes an implanted intra-lumen framework, which has a luminal surface and abluminal surface; a multitude of through hollows in the intra-lumen framework, where each of the multiple through holes contains a composition, selected from the following groups. Compositions of a mTOR inhibitor and base structure, which has the configuration, which will make it possible for the mTOR inhibitor in the composition of the mTOR inhibitor to elute, mainly in the abluminal direction for seven (7) to one hundred and twenty (120) days, with the composition of the mTOR inhibitor containing a polymer in a combination with the mTOR inhibitor and the base structure containing a multitude of polymer layers with the absence of mTOR inhibitors; compositions of a phosphodiesterase III inhibitor and an upper covering structure, which has the configuration, making it possible for the phosphodiesterase III inhibitor in the composition of the phosphodiesterase III inhibitor to elute, mainly in the luminal direction for five (5) to sixty-one (61) day, with the composition of the phosphodiesterase III inhibitor containing the polymer in a combination with the phosphodiesterase III inhibitor, and the upper covering structure containing a multitude of polymer layers in the absence of the phosphodiesterase III inhibitor.

EFFECT: invention makes it possible to provide independent on each other rates of sirolimus and cistazol release, simultaneously providing the targeted delivery of each of the medications.

6 cl, 30 dwg, 7 tbl

 

Background of the INVENTION

1. Field of the invention

The present invention relates to the local application of therapeutic agents and/or combinations of therapeutic agents for the prevention and treatment of vascular diseases, and more particularly to intraluminal medical devices for local delivery of therapeutic agents and/or combinations of therapeutic agents.

2. Review of materials used in the examination of the application

Many people suffer from circulatory disease caused by progressive occlusion of blood vessels, perfuziruya heart and other vital organs. More intensive occlusion of blood vessels such people often leads to hypertension, ischemic injury, stroke or myocardial infarction. Atherosclerotic vascular disease, limiting or blocking of the coronary blood flow, are a major cause of coronary heart disease. Medical procedure whose purpose is to increase blood flow in the artery is called percutaneous transluminal coronary angioplasty. Percutaneous transluminal coronary angioplasty is the preferred treatment of stenosis of the coronary arteries. The increasing use of this method due to Dov�the comparatively high rate of success and minimal invasiveness compared with coronary bypass surgery. The disadvantage of percutaneous transluminal coronary angioplasty is the risk of sudden closure of the vessel, which may occur immediately after the procedure and restenosis that develops in the later stages after the procedure. Additionally, restenosis is a common complication in patients who underwent arteriovenous bypass grafting using the saphenous vein of the thigh. The mechanism of acute occlusion involves several factors and may be due to reduction of the vessel lumen with resultant closure of the artery and/or deposition of platelets and fibrin along the damaged area just expanded blood vessel.

Restenosis after percutaneous transluminal coronary angioplasty is a more gradual process, caused by damage to the vessel. Each of the multiple processes, including thrombosis, inflammation, release of growth factor and cytokine, cell proliferation, cell migration and synthesis of extracellular matrix, contributes to the development of restenosis.

Although the exact mechanism of restenosis is not enough studied, the main stages of this process installed. In the normal arterial wall, the proliferation rate of smooth muscle cells is low, approximately less than 0.1% per day. Smooth muscle cells in the walls of blood vessels are basically the contractile phenotype, characterized by the fact, th� 80 to 90% of the volume of the cytoplasm is the contractile apparatus. The share of the endoplasmic reticulum, the Golgi complex and free ribosomes are small and localized, they are in a related field. Extracellular matrix surrounds the smooth muscle cells; it is rich in heparin glycosaminoglycans, which are supposed to be responsible for maintaining the contractile phenotype of smooth muscle cells (Campbell and Campbell, 1985).

In the process of angioplasty in expanding coronary balloon catheter under pressure to a damage of smooth muscle cells and endothelial cells within the vessel walls; in response to injury triggers thrombotic and inflammatory response. Cellular growth factors such as platelet derived growth factor, basic fibroblast growth factor, epidermal growth factor, thrombin, etc., released by platelets, migratory macrophages and/or leukocytes, or directly smooth muscle cells, cause the response the proliferation and migration of smooth muscle cells of the media. These cells undergo a change in phenotype: the contractile phenotype changed to a synthetic phenotype, which is characterized by the presence of a small quantity of bundles of contractile fibers, a well-developed granular endoplasmic reticulum, Golgi and free ribosomes. Proliferation/migration usually begins in t�within one to two days after injury and peaks several days after beginning (Campbell and Campbell, 1987; Clowes and Schwartz, 1985).

Daughter cells migrate to the intimal layer of smooth muscles arteries and continue to proliferate and to secrete significant amounts of extracellular matrix proteins. Proliferation, migration and synthesis of extracellular matrix continue until such time as you won't recover the damaged endothelial layer, after which proliferation within the intima is slowing that occurs, usually within seven to fourteen days after the injury. The newly formed tissue is called neointima. Further vessel constriction that occurs in the next three to six months, mainly a consequence of the negative or constrictive remodeling.

Simultaneously with local proliferation and migration of cells of the inflammatory infiltrate desirous to the damaged area of the vessel. Within three to seven days post-traumatic period, the cells of the inflammatory infiltrate migrate into the deeper layers of the vessel wall. In experimental animal models, where it was used as an introduction balloon catheter and stent implantation, the cells of the inflammatory infiltrate was present in the place of damage of the vessel at least thirty days (Tanaka et al., 1993; Edelman et al., 1998). Thus, the present inflammatory cells infiltration method can�of experiencing the development of acute and chronic phases of restenosis.

Numerous drugs have been tested for the presence of putative antiproliferative action when restenosis and have shown some effect in experimental animal models. Drugs that have demonstrated the ability to successfully reduce the extent of intimal hyperplasia in animal experiments include: heparin and heparin fragments (Clowes, A. W. and Karnovsky M., Nature 265: 25-26, 1977; Guyton, J. R. et al., Circ. Res., 46: 625-634, 1980; Clowes, A. W. and Clowes, M. M., Lab. Invest. 52: 611-616, 1985; Clowes, A. W. and Clowes, M. M., Circ. Res. 58: 839-845, 1986; Majesky et al., Circ. Res. 61: 296-300, 1987; Snow et al., Am. J. Pathol. 137: 313-330, 1990; Okada, T. et al., Neurosurgery 25: 92-98, 1989), colchicine (Currier, J. W. et al., Circ. 80: 11-66, 1989), Taxol (Sollot, S. J. et al., J. Clin. Invest. 95: 1869-1876, 1995), angiotensin converting enzyme (ACE) inhibitors (Powell, J. S. et al., Science, 245: 186-188, 1989), angiopeptin (Lundergan, C. F. et al. Am. J. Cardiol. 17(Suppl. (B):132B-136B, 1991), cyclosporin A (Jonasson, L. et al., Proc. Natl., Acad. Sci., 85: 2303, 1988), antibody goat to the platelet growth factor rabbit (Ferns, G. A. A., et al., Science 253: 1129-1132, 1991), terbinafine (Nemecek, G. M. et al., J. Pharmacol. Exp. Thera. 248: 1167-1174, 1989), trapidil (Liu, M. W. et al., Circ. 81: 1089-1093, 1990), tranilast (Fukuyama, J. et al., Eur. J. Pharmacol. 318: 327-332, 1996), interferon-gamma (Hansson, G. K. and Holm, J., Circ. 84: 1266-1272, 1991), rapamycin (Marx, S. O. et al., Circ. Res. 76: 412-417, 1995), steroids (Colburn, M. D. et al., J. Vasc Score. Surg. 15: 510-518, 1992), see also Berk, B. C. et al., J. Am. Coll. Cardiol. 17: 111B-117B, 1991), ionizing radiation (Weinberger, J. et al., Int. J. Rad. Oc. Biol. Phys. 36: 767-775, 1996), hybrid toxins (Farb, A. et al., Circ. Res. 80: 542-550, 1997), antisense oligonucleotides (Simons, M. et al., Nature 359: 67-70, 1992) and gene vectors (Chang, M. W. et al., J. Clin. Invest. 96: 2260-2268, 1995). Antiproliferative activity against smooth muscle cells in vitro have demonstrated many of the above funds, including heparin and heparin conjugates, Taxol, tranilast, colchicine, angiotensin converting enzyme inhibitors (ACE-I), hybrid toxins, antisense oligonucleotides, rapamycin and ionizing radiation. Thus, drugs with different mechanisms of inhibition of smooth muscle cells may have a therapeutic effect in reducing intimal hyperplasia.

However, unlike animal experiments, attempts to prevent restenosis in people who have had angioplasty, with systemic pharmacological agents still did not succeed. Any combination aspirin-dipyridamole or ticlopidine or anticoagulant therapy (heparin for emergency treatment, warfarin for long-term use, hirudin or hirulog), neither the blockade of thromboxane receptors or steroids do not have efficacy in preventing restenosis, although platelet inhibitors have been effective to prevent acute occlusion after angioplasty (Mak and Topol, 1997; Lang et al., 1991; Popma et al., 1991). Antagonist �P II b/IIIareceptors of platelet Reopro (Reopro®) is still being studied, but to date the final effect of the use of Reopro (Reopro®) in reducing restenosis after angioplasty and stenting is not observed. Other means, also proved ineffective in the prevention of restenosis, include calcium channel blockers, prostacyclin mimetics, angiotensin converting enzyme inhibitors, blockers of serotonin receptors and antiproliferative funds. These funds should be applied systematically, however, the achievement of a therapeutically effective dose may not be possible. The concentrations required for anti-proliferative (or antirestenotic) effect, may exceed the known toxic concentrations of these funds, so the level of drug in the blood, sufficient for inhibition of smooth muscle, can not be reached (Mak and Topol, 1997; Lang et al., 1991; Popma et al., 1991).

Additional clinical trials, which studied the effectiveness of the use of food supplements containing dietary fish oil or holesterinoponizhayuschim drugs in the prevention of restenosis have yielded conflicting or negative results. Thus, there is currently no clinically available pharmacological agents for the prevention of postage�plastic restenosis (Mak and Topol, 1997; Franklin and Faxon, 1993: Serruys, P. W. et al., 1993). Modern studies suggest that hypolipidemic/antioxidant drug probucol can be used to prevent restenosis, but this study requires confirmation (Tardif et al., 1997; Yokoi, et al., 1997). Currently probucol (Probucol) is not approved for use in the United States, and thirty-day period of pre-treatment eliminates the possibility of its application in case of emergency angioplasty. In addition, the use of ionizing radiation has shown promising results in reducing or preventing restenosis after angioplasty in patients with implanted stents (Teirstein et al., 1997). However, to date the most effective treatments for restenosis are repeat angioplasty, atherectomy or coronary artery bypass grafting, because no therapeutic agent is not approved for use to prevent postangioplasty of restenosis by FDA food and drug administration.

Unlike systemic therapy drugs, stents have proven effective in significantly reducing restenosis. Typically, stents are metal tubes of mesh page�of Keturah (usually but not necessarily, made of stainless steel), expandable with a balloon, which, after expansion within the lumen of the coronary arteries subjected to angioplasty, provide structural support through rigid support artery wall. This support helps to maintain patency of the vessel lumen. In two randomized clinical trials, stents contributed angiographic success after percutaneous transluminal coronary angioplasty, by increasing minimal lumen diameter and reducing the incidence of, but does not prevent restenosis at six months (Serruys et al., 1994; Fischman et al., 1994).

In addition, it was found that the coating of stents with heparin has created an additional positive effect, expressed as reduction of subacute thrombosis after stent implantation (Serruys et al., 1996). Thus, permanent mechanical expansion of the stenotic coronary artery using a stent, as it turned out, to some extent, contributes to the prevention of restenosis, and the surface coating of stents with heparin has demonstrated both the feasibility and clinical efficacy of local delivery of drugs directly to the site of tissue damage.

As indicated above, the use of stents coated with heparin, showed the feasibility � clinical efficacy of local drug delivery. However, the method of fixing concrete means or combination of means on the delivery device also plays an important role in the effectiveness of this type of treatment. For example, methods and materials used for fixing tools/combination tools on the device for local delivery, shall not prevent the action tools/combination tools. In addition, the processes and materials must be biocompatible, but also have to keep the tool/combination of tools on the device for local delivery in the delivery process and for a predetermined period of time. For example, removal tools/combination tools in the delivery process from the surface of the device for local delivery could potentially cause malfunctioning of the device.

Thus, there is a need for the drug/combination of their devices for local delivery to prevent and treat damage to the blood vessels, causing thickening of the intima, which have either a biological cause, such as atherosclerosis, or applied by mechanical means, such as percutaneous transluminal coronary angioplasty.

BRIEF description of the INVENTION

The stent described in the present invention distinguishes two medicinal substances and has no restrictions to p�the applicatio, typical of the known methods and devices described above.

In one of the embodiments of the present invention relates to a device for drug delivery. A device for drug delivery includes an implantable intraluminal frame having a luminal surface and abdominally surface, the plurality of holes in the intraluminal frame, the first portion of the plurality of holes comprises a composition of an mTOR inhibitor and a basic structure having a configuration that allows the mTOR inhibitor in the composition is an inhibitor of mTOR to elyuirovaniya mainly in alumininum direction, and the second part of the plurality of holes comprises a composition of an inhibitor of phosphodiesterase III and at least one base or top covering structure having a configuration that allows the inhibitor of phosphodiesterase III in the composition is an inhibitor of phosphodiesterase III to elyuirovaniya mainly at least in luminal or alumininum direction.

The present invention relates to a vascular stent, providing two medicines that have the tanks, as described above, where a portion of these tanks contains a composition which releases sirolimus (rapamycin), mainly in parietal or alumininum direction, and in the rest of �of eservoirs composition contains, secreting Cilostazol primarily in a luminal direction. More specifically, after the stent implantation, providing two drugs into the artery of the patient, sirolimus eluated locally in the tissue of the artery, has a therapeutic effect and inhibits the development of restenosis in the artery, whereas Cilostazol eluated directly into the bloodstream and provides an antithrombotic effect as in the lumen of the stent, providing two medicines and locally in the artery wall adjacent to the stent, releasing the drug. Thus, dual antithrombotic effect, i.e. the reduction of clot formation in the implanted stent, providing two medicines, or around the stent, and the inhibition of platelet aggregation and deposition in the implanted stent, providing two medicines, or around the stent. In addition, in cases where the stent providing two medicines is used to treat patients with acute myocardial infarction, Cilostazol may provide a cardioprotective effect against myocardial tissue, perfuziruemah blood of the stented artery, preventing the development of the phenomenon of "unrecovered blood flow after stenting, reducing reperfusion injury and/or size info�rcta. The stent providing two medicinal substances, also can improve the outcome of disease in patients, which are characterized by slow healing, for example in patients with diabetes.

In this example embodiment of the invention the stent providing two medicinal substances, equipped with tanks that are needed for the targeted delivery of two different therapeutic agents or drugs from the stent. A composition comprising a polymer and sirolimus, is intended for controlled prolonged local delivery of sirolimus from a part of the tanks on alumininum edge of the stent, the tissue of the artery of the patient. A composition comprising a polymer and Cilostazol, is intended for controlled prolonged delivery of Cilostazol luminal different from and separate reservoirs of the stent or directly into the bloodstream testiruemi artery, or later, after the stent implantation in biological tissue covering the luminal surface of the stent.

It should be noted that, although described here and isolated, and individual tanks that can be used by any other suitable mechanism for targeted delivery.

Stent design with dual drug coating described in the present invention, provides independent from each other, the velocity is�and release of sirolimus and Cilostazol, and also the directed delivery of each of these funds.

BRIEF description of the DRAWINGS

The above and other features and advantages of the invention will become apparent after the following more detailed description of preferred embodiments of the invention, illustrated with the aid of the accompanying drawings.

Fig.1 shows a longitudinal view of a stent (ends not shown) prior to expansion; visible outer surface of the stent and the characteristic cellular structure of the stent.

Fig.2 shows a perspective view of the stent of Fig.1 along its length, where the stent is provided with a tank in accordance with the present invention.

Fig.3 is a schematic view of the first embodiment of the invention in the form of a stent coated with a combination of sirolimus and Cilostazol in accordance with the present invention.

Fig.4 presents a graphical representation of in vitro release kinetics of combination of sirolimus and Cilostazol covering the stent, the first example of implementation in accordance with the present invention.

Fig.5 is a schematic view of the second embodiment of the invention comprising a stent coated with a combination of sirolimus and Cilostazol in accordance with the present invention.

Fig.6 presents graphical�th image in vitro release kinetics of combination of sirolimus and Cilostazol, covering the stent, the second example implementation in accordance with the present invention.

Fig.7 is a schematic view of a third embodiment of the invention comprising a stent coated with a combination of sirolimus and Cilostazol in accordance with the present invention.

Fig.8 presents a graphical image antithrombotic activity eluting stent combination of sirolimus and Cilostazol in vitro, in experimental models of circulatory system with the use of bovine blood in accordance with the present invention.

Fig.9 presents a graphical image of in vivo release kinetics of sirolimus and Cilostazol of the stent shown in Fig.11.

Fig.10 presents a graphical depiction of the in vitro release kinetics of sirolimus and Cilostazol of the stent shown in Fig.11.

Fig.11 is a schematic view of a fourth embodiment of the invention comprising a stent coated with a combination of sirolimus and Cilostazol according to the present invention.

Fig.12 presents a graphical image of in vivo release kinetics of sirolimus and Cilostazol of the stent shown in Fig.3.

Fig.13 presents a graphical depiction of the in vitro release kinetics of sirolimus and Cilostazol of the stent, �provided in Fig.3.

Fig.14 presents an isometric image of an expandable medical device with therapeutic agent placed at the ends of the device according to the present invention.

Fig.15 shows an isometric image of an expandable medical device with a therapeutic agent, located in the Central part of the device, and no medical means at the ends of the device according to the present invention.

Fig.16 presents an isometric image of an expandable medical device with different therapeutic agents in different openings according to the present invention.

Fig.17 shows an isometric image of an expandable medical device with various therapeutic agents in the striped holes according to the present invention.

Fig.18 shows an enlarged side view of part of an expandable medical device with openings filled with a therapeutic agent, the connecting elements (bridges) according to the present invention.

Fig.19 shows an enlarged side view of part of an expandable medical device with bifurcation hole according to the present invention.

Fig.20 shows a sectional view showing a medical device in which the combination of first means, e.g. anti-inflammatory �Reparata, placed in the first plurality of holes and a second tool, such as an antiproliferative drug, placed in the second plurality of holes according to the present invention.

Fig.21 presents a graphic representation of the speed of release of anti-inflammatory and antiproliferative funds delivered using an expandable medical device shown in Fig.20, in one of the examples according to the present invention.

Fig.22A, 22B, 22C presents a partial schematic drawing of an embodiment of the invention, comprising an expandable medical device with alternating according to the present invention.

Fig.23A, 23B, 23C shows the approximate lactide (dimers), used in the synthesis stereospecific polylactic acid called PLA according to the present invention.

Fig.24 depicts a poly-L-lactide in accordance with the present invention.

Fig.25 depicts a poly-D-lactide in accordance with the present invention.

Fig.26A, 26B and 26C presents the scheme of coating or depositing with the use of alternating layers of polymers having identical chemical compositions, but having a different optical rotation, with therapeutic means according to the present invention.

Fig.27A, 27B presents the scheme of coating or depositing with the application of solutions, soda�as containing poly-D-lactic acid, and poly-L-lactic acid in a molar ratio of one-to-one according to the present invention.

Fig.28 shows the graphical side image of a portion of the stent, providing two medicinal substances, according to the present invention.

Fig.29 shows the graphical representation of the cumulative in vivo release of medicinal substance in percentage according to the present invention.

Fig.30 shows a graphic representation of the cumulative in vivo release of medicinal substance in a weight ratio according to the present invention.

DETAILED DESCRIPTION of PREFERRED IMPLEMENTATION

Tool/combination of tools and devices of delivery covered by the framework of the present invention can be used for effective prevention and treatment of vascular diseases, in particular diseases of the blood vessels caused by damage to the blood vessels. Various medical devices used in the treatment of vascular diseases, may eventually cause further complications. For example, the procedure is balloon angioplasty used to improve blood flow through the artery and is the preferred treatment of stenosis of coronary vessels. However, as described above, this procedure usually leads to a certain damage of the vessel wall, thereby potentially usug�this comment has been flagged the problem in the future. Although other procedures and diseases may also cause this kind of damage, the embodiments of the present invention will be described with reference to the treatment of restenosis and related complications resulting from percutaneous transluminal coronary angioplasty and other similar manipulation of arterial/venous vessels, including the procedure for connection of the arteries, veins and other vessels carrying liquid. In addition, there will be described various methods and apparatus for efficient delivery of medical devices with coating.

While the embodiments of the present invention will be described with reference to the treatment of restenosis and related complications resulting from percutaneous transluminal coronary angioplasty, it is important to note that local delivery tools/combination tools can be used to treat a wide range of pathological conditions using any number of medical devices or to improve and/or increase the service life of the device. For example, intraocular lens, implanted to restore vision after cataract surgery, often provoke the development of secondary cataracts. The latter, as a rule, is the result of an overgrowth of cells on the surface of the lens that�anchialine can be minimized if you use the device in combination with means or means. For other medical devices which often fail due to ingrown tissue or deposition of proteinaceous material in, on or around the device, such as shunts in hydrocephalus, catheters for dialysis, the device for attaching colostomy bags, ear drainage tubes, electrodes, pacemakers and implantable defibrillators, the approach "the combination of a delivery device-the tool can also be useful. The use of devices that serve to improve the structure and function of the tissue or organ, in combination with suitable means or drugs also has more advantages. For example, improved osteointegration of the prosthesis to enhance the stabilization of the implants can potentially be achieved by combining them with tools such as bone morphogenetic protein. Similarly, other surgical tools and devices, sutures, staples, anastomosis, vertebral disks, bone rods, clamps suture, hemostatic barriers, brackets, screws, a metal plate for the connection of bone fragments, clips suturing devices, vascular grafts, tissue adhesives and sealants, fabric frames, various types of dressings, �ameritel bones, intraluminal devices and support vessels can also provide a significant therapeutic effect for patients, if we apply the approach "the combination of a delivery device-a means". In particular, can be effective perivascular wraps by themselves or in combination with other medical devices. Perivascular wraps can provide additional delivery of the drug to the treatment site. In fact, any medical device can be in some way covered drug or combination of drugs that improves the results of treatment compared with the use of devices or pharmaceuticals separately.

In addition to various medical devices coatings deposited on these devices, can be used to deliver medicinal or pharmaceutical agents including antiproliferative/antimitotic means, including natural products such as Vinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine), paclitaxel, epileptogenesis (i.e. etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase, which systematically IU�analiziruet L-asparagine and remove cells unable to synthesize their own asparagine); antiplatelet agents such as inhibitors of G(GP) IIb/IIIaand receptor antagonists vitronectin; antiproliferative/antimitotic alkylating agents such as nitrogen IPrice (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamine (hexamethylmelamine and thiotepa), alkylsulfonate-busulfan, nitrosoanatabine (carmustine (BCNU) and analogs, streptozocin), trazan - dacarbazine (DTIC); antiproliferative/antimitotic antimetabolites such as analogs of folic acid (methotrexate), pyrimidine analogs (fluorouracil, floxuridine and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chloromethoxypropyl {cladribine}); coordination complexes of platinum (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutetimid; hormones (i.e. estrogen); anticoagulants (heparin, synthetic salt of heparin and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abtsiksimab; antimigrant; antisecretory means (brefeldin); anti-inflammatory agents such as adrenocortical steroids (cortizo�, cortisone, fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), nonsteroidal funds (salicylic acid derivatives, namely aspirin; derivatives of paraaminophenol, namely, acetaminophen; indole and indene acetic acids (indomethacin, sulindac and etodalac), heteroaryl-acetic acid (tolmetin, diclofenac, and Ketorolac), arylpropionic acids (ibuprofen and derivatives), Anthranilic acids (mefenamic acid, and meclofenamic acid), analogue acids (piroxicam, tenoxicam, phenylbutazone and occidentalise), nabumeton, gold compounds (auranofin, aurothioglucose, aurothiomalate sodium); immunosuppressants (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents: growth factor vascular endothelial (VEGF), fibroblast growth factor (FGF); angiotensin receptor blocker therapy; nitric oxide donors; antisense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and kinase inhibitors signalproxy receptors, growth factor; retinoids; inhibitors detected/cyclin-dependent kinase (CDK) inhibitors; hydroxy-methylglutaryl (HMG) coenzyme reductase inhibitors (statins); and protease inhibitors.

As described above, the implantation of coronary stent in conjunction with balloon angioplasty JW�makes a highly effective method for the treatment of acute vessel closure and may reduce the risk of restenosis. Intravascular ultrasound studies (Mintz et al., 1996) suggest that coronary stenting effectively prevents vasoconstriction and that in most cases, late luminal loss of the lumen after stent implantation is due to the growth of plaques, which in turn can be caused prevents neointima appearence) hyperplasia. The frequency of late luminal loss after coronary luminal stenting is almost two times higher than after conventional balloon angioplasty. Thus, as the stent hinder the development of at least part of the process of formation of restenosis, the use of combinations of drugs, substances, or compounds that inhibit the proliferation of smooth muscle cells, reduce inflammation, slow down the process of coagulation, or inhibit proliferation of smooth muscle cells through multiple mechanisms, reduce inflammation and slow down the coagulation process, in combination with a stent may provide a more effective prevention postangioplasty restenosis. The systematic application of tools, substances, and compounds in combination with local delivery of these or other tools/combinations of means can also provide a more effective method of treatment.

Local delivery of funds/combinations of funds from PT�NTA has the following advantages: prevention of narrowing of the lumen and remodeling of blood vessels due to frame function of the stent, the oppression of many links prevents neointima appearence) hyperplasia or restenosis, as well as reducing inflammation and the risk of thrombosis. The local introduction of drugs, substances, or compounds in testirovanie coronary artery may also bring additional therapeutic benefit. For example, higher concentrations of drugs, agents or compounds in tissue can be achieved rather through local delivery than by systemic administration. In addition, local delivery, in contrast to systemic administration, reduces the overall toxicity while maintaining a higher concentration of funds in the tissue. In addition, in the case of local delivery from the surface of the stent, in contrast to systemic administration, to ensure good compliance of the patient can be quite a procedure. An additional advantage of treatment using a combination of drugs, agents or compounds may be a reduction in the dose of each drug, agent or compound, reducing their toxicity, while still achieving reduction in restenosis, inflammation and thrombosis. Local therapy based on the use of the stent, thus is a means of increasing therapeutic index (efficacy/�oxicell) antirestenotic, anti-inflammatory, antithrombotic agents, agents or compounds.

There are many different stents that may be used after percutaneous transluminal coronary angioplasty. Although in accordance with the present invention can be applied any number of stents, for simplicity, in the embodiments of the present invention will be described in a limited number of stents. Specialists in this field will be clear that, with respect to the present invention may use any number of stents. In addition, as described above, the possible use of other medical devices.

The stent is typically a tubular structure left inside the lumen of the channel to eliminate occlusion. Typically, the stent is inserted into the lumen in unexpanded form, and then expand offline or using another device in situ. A typical method of expansion is the expansion of using the angioplasty balloon mounted on the catheter; the balloon is inflated within the stenosed vessel or channel of a body to dissect and destroy the obstacles associated with elements of the vessel wall, and to expand the lumen.

Fig.1 shows an example of a stent 100 which may be used in accordance with embodiments of the present invented�me. Expandable cylindrical stent 100 includes a structure with many holes, intended for placement in a blood vessel, duct or lumen to hold the vessel, duct or lumen open, more particularly for protecting a segment of artery from restenosis after angioplasty. The stent 100 may be expanded circumferentially and maintained in the expanded configuration, i.e., it remains fixed on the circumference or radius. The stent 100 is flexible in the axial direction, and when bent to the side, the stent 100 will not include any outwardly projecting elements.

The stent 100 generally comprises first and second ends with an intermediate section between them. The stent 100 has a longitudinal axis and contains numerous longitudinally arranged strips 102, where each band 102 determines the boundaries of the continuous wave along a segment parallel to the longitudinal axis. Many connecting links 104, spaced around the circumference, supports a strong tubular structure of the bands 102. In essence, each longitudinal strip 102 is connected to the set of periodic sites through short connecting links 104, spaced around the circumference, with a connecting strip 102. Wave associated with each band 102, has approximately the same basic spatial frequency in the intermediate segment, and the strip 102 spaced�s thus, that wave associated with them, usually located on one line to coincide in phase with each other. As shown in the figure, each located longitudinally of the strip 102 passes through approximately two cycles before connecting link connecting it with the adjacent band 102.

The stent 100 may be made of any of a variety of ways. For example, the stent 100 may be fabricated from a hollow or formed stainless steel tube that may be machined using a laser, electrical discharge milling, by chemical etching or other means. The stent 100 is inserted into the body and placed at a desired location in unexpanded form. In one embodiment of the invention the extension is made in a blood vessel using a balloon catheter, where the final diameter of the stent 100 is a function of the diameter of the balloon catheter used.

Note that the stent 100 in accordance with the present invention may be made of a material with memory effect shape, including, for example, an appropriate alloy of Nickel and titanium or stainless steel. Structure made of stainless steel, can be samarasiri that is provided by a given configuration of steel, for example a particular type of weaving. In this example embodiment of the invention, after the stent 100 has been formed�IAOD, it can be compressed in such a way as to take up quite little space to ensure that it can be inserted into a blood vessel or other tissue by using appropriate means, which include a suitable catheter, or flexible rod. Leaving the catheter, the stent 100 thanks to its expanded configuration by taking the necessary shape, wherein the expansion takes place automatically or is triggered by changes in pressure, temperature or by electrical stimulation.

Fig.2 shows an embodiment of the present invention with the use of the stent 100 shown in Fig.1. As shown in the figure, the stent 100 can be modified to supply him with one or more reservoirs 106. Each of the tanks 106 can optionally be opened or closed. These tanks 106 may be specially designed to hold them in tools/combination tools that are to be delivered. Whatever the design of the stent 100, it is preferable to use the specific dose used tools/combination tools and sufficient concentration to provide an effective dosage in the affected area. The size of the tanks, located in the bands 102, preferably should be sufficient to accommodate the dose tools/combination tools in the correct location � in the required amount.

In another example embodiment of the invention the inner and outer surface of the stent 100 can be entirely covered with the tool/combination of tools in therapeutic dosages. Detailed description of remedies for the treatment of restenosis, as well as examples of methods of coating are described below. However, it is important to note that the methods of coating may be different depending on the medium/combinations of means. Also the methods of a coating depend on the material of the stent or other intraluminal medical device.

Rapamycin is a macrocyclic triene antibiotic, the producer of which is a Streptomyces hygroscopicus, according to U.S. patent No. 3929992. Found that rapamycin, among other things, inhibits the proliferation of smooth muscle cells of blood vessels in vivo. Thus, rapamycin or rapamycin can be used in the treatment of hyperplasia of intimal smooth muscle cells, restenosis and vascular occlusion in a mammal, particularly after biological or mechanical damage blood vessels or in conditions that predispose to vascular damage in a mammal. Rapamycin perform the function of inhibiting the proliferation of smooth muscle cells and does not impede endothelization of the vessel walls.

Rapamycin reduces vascular hyperplasia, counteracting Pro�operacii of smooth muscle cells in response to mitogenic signals, produced during the damage caused by angioplasty. It is believed that the inhibition of proliferation of smooth muscle cells, mediated by growth factor and cytokine, in the late G1 phase of the cell cycle is a dominant mechanism of action of rapamycin. However, we know that with systemic administration of rapamycin prevents T-cell proliferation and differentiation. This is based on its immunosuppressive action and its ability to prevent rejection of the implant.

In the framework of the present invention, the term "rapamycin includes rapamycin and all analogs, derivatives and conjugates that bind to FKBP12, and other immunophilins, and possesses the same pharmacologic properties as rapamycin including inhibition of TOR.

Although the antiproliferative effect of rapamycin can be achieved through systemic treatment, the best results can be achieved by local delivery of the compound. Rapamycin is predominantly active in tissues that are in the vicinity of the connection, and as the distance from the delivery device effect is reduced. In order to maximize this effect, it is necessary to ensure direct contact of rapamycin with the walls inside the vessel. Therefore, in a preferred embodiment of the invention rapamycin is placed �and the surface of the stent or in parts of it. In a preferred embodiment the rapamycin incorporated into the stent 100 shown in Fig.1, where the stent 100 is in contact with the wall of the lumen.

Rapamycin may be deposited on the stent or attached to the stent in a variety of ways. In one embodiment of the invention rapamycin is incorporated directly into the polymeric matrix and sprayed on the outer surface of the stent. Over time rapamycin released from the polymer matrix and penetrates into the surrounding tissue. Preferably, rapamycin remained on the surface of the stent, at least during the period from three days to six months, more preferably the period from seven to thirty days.

Rapamycine coating can be applied to the stent by dipping, spraying or centrifuging and/or combining the mentioned techniques. Acceptable use of different polymers. For example, using poly-(a copolymer of ethylene and vinyl acetate) and polybutylmethacrylate. Can also be used and other polymers, including, among others, a copolymer of polyvinylidene fluoride and hexaferrite and a copolymer of polimetilmetakrilata and vexillarius. Barrier or the outer cover can also be used to modulate the allocation of rapamycin from the polymer matrix.

It is important to note that the stent, as described� above, can be made of various materials, including various metals, polymers and ceramic materials. Therefore, for fixing different types of medicines, agents, and combinations of compounds can be used different technologies. In particular, in addition to the polymeric matrices described above can be applied biopolymers. In most cases, the biopolymers can be classified as natural polymers, while the above-described polymers are synthetic polymers. Examples of biopolymers that can be used include agarose, alginate, gelatin, collagen and elastin. Besides drugs, agents or compounds may be used in combination with other medical devices imposed by percutaneous, such as implants and perfusion cylinders.

Molecular mechanisms responsible for the effect of rapamycin, a known antiproliferative funds, which are aimed at reducing the severity of symptoms and duration prevents neointima appearence) hyperplasia, are still being explored. However, it is known that rapamycin enters the cells and binds to high-affinity cytosolic protein called FKBP12. The complex of rapamycin and protein FKPB12, in turn, binds and inhibits phosphoinositide (Pl)-3 kinase, otherwise known as "target of rapamycin in mammalian" TOR. TOR is a protein kinase that plays a key role in mediating signaling pathways associated with mitogenic growth factors and cytokines in smooth muscle cells and T-lymphocytes. This pathway involves the phosphorylation of p27, phosphorylation of p70 s6 kinase and phosphorylation of 4BP-1, an important regulator of protein translation.

It is a recognized fact that rapamycin reduces restenosis by inhibiting prevents neointima appearence) hyperplasia. However, there is evidence that rapamycin may also inhibit another important component of restenosis, namely, negative remodeling. Remodeling is a process whose mechanism is poorly understood, however it is known that the result of remodeling in humans is thinning of the outer elastic membrane and narrowing of the vessel lumen during the period of three to six months.

Negative or constrictive vascular remodeling can be expressed quantitatively as a percentage of angiographic narrowing of the lumen of the vessel in the lesion, where there is no stent impeding the process. If a late loss of lumen eliminated in the site of the lesion, it can be assumed that negative remodeling is suppressed. Another method of determining the degree of remodeling includes metering in place powergenerating elastic membrane using intravascular ultrasound (IVUS). Intravascularly ultrasound is a method which allows to obtain an image of the external elastic membrane and lumen of the vessel. Changes in external elastic membrane proximally and distally relative to the stent, starting with the post-operative period and thereafter up to four and twelve months follow-up, are a reflection of remodeling changes.

Evidence that rapamycin influence the remodeling process derived from research implant man stents coated with rapamycin, which showed a very low degree of restenosis at the site of injury and in-stent stenosis. The parameters of the fault is usually measured by making an indentation of approximately five millimeters from each of the ends of the stent, i.e., in the proximal and distal direction. Because in those areas where there is no stent, but which are under the action of balloon expansion, control of the remodeling process is impossible, we can assume that rapamycin prevents vascular remodeling.

The data in table 1, presented below, demonstrate that the site of injury percentage of narrowing of the lumen in the patient groups, which were injected with rapamycin, even below twelve months. Thus, these results support presumably�Linux, that rapamycin slows remodeling.

Table 1
Angiographic measure of the percentage of narrowing of the lumen at the site of injury (%, mean±allowed deviation and ”n=”) in patients who have been implanted with a stent coated with rapamycin
Cover BandAfter implantation4-6-month observation periodThe 12-month observation period
Brazil10,6±5,7 (30)13,6±8,6 (30)22,3±7,2 (15)
Netherlands14,7±8,822,4±6,4-

Additional evidence confirming a slowdown in negative remodeling with rapamycin derived from data intravascular ultrasound, which were obtained during clinical research program, carried out in cases where for the first time, plans to introduce the study agent in humans (first-in-man), and are presented in table 2 below.

Table 2
Agreed these IVUS obtained in the study of patients who were implanted with the stents coated with rapamycin
Parameter IVUSAfter implantation (n=)A 4-month observation period (n=)The 12-month follow-up (n=)
The average area of the proximal segment of the vessel (mm2)Formed 16.53±3,53 (27)16,31±4,36 (28)RUR 13.96±2,26 (13)
The average area of the distal segment of the vessel (mm2)13,12±3,68 (26)13,53±4,17 (26)12,49±3,25 (14)

The data from this study showed that the loss of the area of the vessel proximal or distal to a minimum, which in turn talks about the suppression of the negative process of remodeling in vessels, in which stents were implanted with rapamycin coating.

With the exception of the stent has no other effective solutions to the problem of remodeling of blood vessels. Thus, rapamycin may represent a biological approach to the control of the phenomenon of remodeling soudo�.

We can assume that rapamycin is able to reduce negative remodeling in several ways. By specific blockade of proliferation of fibroblasts in the vascular wall in response to injury rapamycin can reduce the formation of scar tissue in the vessel. Rapamycin can also affect the translation of key proteins involved in the formation and metabolism of collagen.

In a preferred embodiment of the invention for delivery of rapamycin, which controls the negative remodeling segment of the artery after balloon angioplasty by reducing or preventing restenosis, a device is used for local delivery. Although you may use a delivery vehicle, in a preferred embodiment the delivery device includes a stent having a coating or shell, which aluinum releases or rapamycin. The delivery system for such a device may comprise a local infusion catheter that delivers rapamycin at a speed controlled by the specialist performing the introduction. In other embodiments, can be used injection needle.

Rapamycin may also be given systemically in the form of dosage forms for oral use or injectable deposited dosage forms for long-term treatment�th application or as a patch for delivery of rapamycin for the time period ranging from seven to forty-five days to reach the tissues of the vessel levels sufficient to suppress negative remodeling. Such therapy should be used to reduce or prevent restenosis, providing administration of rapamycin, a few days before elective angioplasty with the use of a stent or not.

Data resulting from studies in experimental models of pigs and rabbits, show that the release of rapamycin into the vascular wall of refractory erosion of the polymer coating of the stent in the range of doses (35-430 µg/15-18 mm coronary stent) provides a reduction reaction prevents neointima appearence) hyperplasia of 50-55%, as shown in table 3 below. This reduction reaction, reaching a maximum at 28-30 day, usually not stored in the next 90-180 days in models on the pigs, as reflected in table 4 below.

Table 3
Animal studies, which were implanted stents with rapamycin coating
Values are average±standard error of the mean
ResearchDurationStent1 RapamycinNRegion prevents neointima appearence) growth (mm2)% change
PolymerMetal
Pig
9800914 daysMetal82,04±0,17
1X+rapamycin153 micrograms81,66±0,17*-42%-19%
1X+TC300+rapamycin 155 mcg81,51±0,19*-47%-26%
9900528 daysMetal102,29±0,21
9Of 3.91±0,60**
1X+TC30+rapamycin130 mcg82,81±0,34+23%
1X+TC100+rapamycin120 mcg92,62±0,21 +14%
9900628 daysMetal124,57±0,46
COMECON/PBMA 3X12Of 5.02±0,62+10%
1X+rapamycin125 mcg112,84±0,31* **-43%-38%
3X+rapamycin430 mcg123,06±0,17* **-39%-33%
3X+rapamycin157 mcg122,77±0,41* **-45%-39%
9901128 daysMetal113,09±0,27
114,52±0,37
1X+rapamycin189 mcg14 3,05±0,35-1%
3X+rapamycin/Dex182/363 mcg142,72±0,71-12%
9902160 daysMetal122,14±0,25
1X+rapamycin181 mcg122,95±0,38+38%
��
9903428 daysMetal85,24±0,58
1X+rapamycin186 mcg82,47±0,33**-53%
3X+rapamycin/Dex185/369 mcg62,42±0,64**-54%
2000128 daysMetal�� 61,81±0,09
1X+rapamycin172 mcg51,66±0,44-8%
20007
30 daysMetal92,94±0,43
1XTC+rapamycin155 mcg101,40±0,11* -52%*
Rabbits
9901928 daysMetal81,20±0,07
COMECON/PBMA 1X101,26±0,16+5%
1X+rapamycin64 mcg90,92±0,14-27%-23%
1X+rapamycin 196 mcg100,66±0,12* **-48%-45%
9902028 daysMetal121,18±0,10
COMECON/PBMA 1X+rapamycin197 mcg80,81±0,16-32%
1Nomenclature stent: COMECON/PBMA 1X, 2X and 3X mean about 500 μg, 1000 μg and 1500 μg total mass (polymer+medium), respectively. TC, the outer cover 30 μg, 100 μg or 300 μg containing medicines BUTYLMETHACRYLATE; biphasic; 2 x 1X layers of rapamycin in EVA/PBMA, separated 100 g not containing medicines layer of butyl methacrylate.20.25 mg/kg/d×14 d with predshestvuyuschei� loading dose 0.5 mg/kg/d×3 d prior to stent implantation.
*p<0.05 of COMECON/PBMA control layer. **p<0,05 made of metal;
#Assessment of inflammation: (0=no intimal lesions; 1= < 25% intima affected; 2=≥25% intima diseased; 3= > 50% intima affected).

Table 4
The study on pigs injected with stents with rapamycin coating (180 days)
Values are given in average±standard error of the mean
ResearchDurationStent1RapamycinNRegion prevents neointima appearence) growth (mm2)% changeAssessment of inflammation #
PolymerMetal
200073 daysMetal100,38±0,061,05±0,06
(ETP-2-002233-P)1XTC+rap�mycin 155 mcg100,29±0,03-24%1,08±0,04
30 daysMetal92,94±0,430,11±0,08
1XTC+rapamycin155 mcg101,40±0,11*-52%*0,25±0,10
90 daysMetal103,45±0,340,20±0,08
1XTC+rapamycin155 mcg103,03±0,29-12%0,80±0,23
1X+rapamycin171 mcg102,86±0,35-17%0,60±0,23
180 daysMetal103,65±0,39 0,65±0,21
1XTC+rapamycin155 mcg103,34±0,31-8%1,50±0,34
1X+rapamycin171 mcg103,87±0,28+6%1,68±0,37

The release of rapamycin from refractory erosion of the polymer coating of the stent in the vessel wall of a man allows you to achieve excellent results, given the intensity and duration of the reduction reaction prevents neointima appearence) hyperplasia within the stent as compared with the vascular walls of animals as above.

People, to whom stents were implanted with rapamycin coating containing rapamycin in the same dosage as the studies in animal models, and using the same polymer matrix as described above, was more intense reduction prevents neointima appearence) hyperplasia than in experimental animals, based on the intensity and duration of neointima regression. Clinical�Skye human response to rapamycin shows the almost complete elimination prevents neointima appearence) hyperplasia inside the stent, as confirmed by angiographic and intravascular ultrasound. The results were tracked at least for one year, as shown in table 5 below.

Range (min, max)
Table 5
Patients (N=45 patients), which is implanted stents with rapamycin coating
Performance indicatorsSirolimus FIM (N=45 patients, 45 lesions)95% border authenticity
The success of the procedure (CSA)100,0% (45/45)[92,1%, 100,0%]
4-months. the narrowing of the lumen inside the stent (%)
Mean±TO (N)4,8%±6,1% (30)[2,6%, 7,0%]
Range (min, max)(-8,2%, 14,9%)
6-months. the narrowing of the lumen inside the stent (%)
Mean±TO (N)8,9%±7,6% (13)[4,8%, 13,0%]
(-2.9 percent, 20.4 percent)
12-mo. the narrowing of the lumen inside the stent (%)
Mean±TO (N)8,9%±6,1% (15)[5,8%, 12,0%]
Range (min, max)(-3,0%, to 22.0%)
4-months. late lumen loss in-stent (mm)
Mean±TO (N)0,00±0,29 (30)[-0,10, 0,10]
Range (min, max)(-0,51, 0,45)
6-months. late lumen loss in-stent (mm)
Mean±TO (N)0,25±0,27 (13)[0,10, 0.39 in]
Range (min, max)(-0,51, 0,91)
12-mo. late lumen loss in-stent (mm)
Mean±TO (N)0,11±0,36 (15)[-0,08, 0,29]
Range (min, max)(-0,51, 0,82)
4-months. the amount of occlusion (%) (IVUS)
Mean±TO (N)10,48%±2,78% (28)[9,45%, 11,51%]
Range (min, max)(4,60%, 16,35%)
6-months. the amount of occlusion (%) (IVUS)
Mean±TO (N)7,22%±4,60% (13)[4,72%, 9,72%]
Range (min, max)(3,82%, 19,88%)
12-mo. the amount of occlusion (%) (IVUS)
Mean±TO (N)2,11%±5,28% (15)[Is 0.00% and 4,78%]
Range (min, max)(0,00%, 19,89%)
6-months. revascularization at the site of intervention (TLR)0,0% (0/30)[0,0%, and 9.5%]
12-mo. revascularization at the site of intervention (TLR0,0% (0/15)[0,0%, 18,1%]
CSA = Quantitative coronary angiography
TO = allowed deviation
IVUS = Intravascular ultrasound

Rapamycin give unexpected positive effect in people if they are delivered to the tissue from the surface of the stent, causing a significant decrease in reaction prevents neointima appearence) hyperplasia inside the stent, wherein the result is stored in at least one year. The severity and duration of this effect in humans cannot be predicted on the basis of data from studies in animal models. Rapamycin used in this context includes rapamycin and its analogs, derivatives and congeners that bind FKBP12 and possess the same pharmacologic properties as rapamycin.

These results may depend on many factors. For example, most effectiveness of rapamycin in the human body due to the greater susceptibility of the mechanism (or mechanisms) of action to the pathophysiology of vascular injuries, compared with pathophysi�a wise animal models of angioplasty. In addition, the combination of the dose used and the stent and the polymer coating that controls the allocation of medicines plays an important role in the effectiveness of the funds.

As described above, rapamycin reduces vascular hyperplasia, counteracting the proliferation of smooth muscle cells in response to mitogenic signals generated during the damage caused by angioplasty. It is also known that with systemic administration of rapamycin prevent T-cell proliferation and differentiation. Also found that rapamycin exert local anti-inflammatory effect in the vessel wall in the allocation from the surface of the implanted stent in small doses over an extended period of time (approximately two to six weeks). Local anti-inflammatory effect is strong and unpredictable. In combination with an antiproliferative effect on smooth muscles this dual mechanism of action of rapamycin may be due to its exceptional efficiency.

Thus, rapamycin delivered from the platform device for local delivery, prevents neointima appearence) reduces hyperplasia, combining anti-inflammatory and antiproliferative effect on smooth muscles. Under rapamycin used in this context, refers rapamycin all its analogs derivatives and congeners that bind FKBP12 and possess the same pharmacologic properties as rapamycin. Platform for local delivery includes coating the stent sheath stents, implants and infusion catheters for local slow introduction of the drug, or porous balloons or any other suitable means for local delivery of drugs, agents or compounds in situ.

Anti-inflammatory effect of rapamycin follows from the data of the experiment are given in table 6; in the experiment, the effect of rapamycin delivered from the surface of the stent, compared with the action of dexamethasone delivered from the surface of the stent. Dexamethasone, a potent steroid anti-inflammatory agent, was used as a reference sample. Although dexamethasone is able to reduce the result of the inflammation in the points, rapamycin was significantly more effective than dexamethasone in reducing the result of the inflammation in the points. In addition, rapamycin unlike dexamethasone prevents neointima appearence) significantly reduces hyperplasia.

Table 6
The group Rapamycin RapN= Prevents neointima appearence) area (mm2)percent area stenosisAssessment of inflammation
Uncoated85,24±1.65 V54±190,97±1,00
Dexamethasone (Dex)84,31±3,0245±310,39±0,24
Rapamycin (Rap)72,47±0,94*26±10*0,13±0,19*
Rap+Dex62,42±1,58*26±18*0,17±0,30*
* = significance level P<0,05

It is established that upon delivery from the surface of the stent rapamycin reduce the level of cytokine in vascular tissue. The data in Fig.1 show that rapamycin effectively reduces the levels of monocyte chemotactic protein (MCP-1) in the vessel wall. MCP-1 is an example of proinflammatory/chemotactic cytokine that is produced when the damage to the vessel. The lower level� MCP-1 confirms the positive effect of rapamycin in reducing the expression of proinflammatory mediators and facilitate the expression of anti-inflammatory properties of rapamycin, delivered locally from the surface of the stent. It is a recognized fact that vascular inflammation in response to injury is a major factor in the development prevents neointima appearence) hyperplasia.

Since rapamycin demonstrate the ability to inhibit the local inflammatory processes in blood vessels, it is believed that this may explain the unexpected advantage of rapamycin in the inhibition of neointima formation.

As described above, rapamycin works on multiple levels to achieve such desired effects as the prevention of T-cell proliferation, inhibition of negative remodeling, reduction of inflammation and prevention of proliferation of smooth muscle cells. While the exact mechanism of these effects is poorly understood, it is possible to consider in more detail the mechanisms that have been identified.

Studies using rapamycin suggest that the prevention of proliferation of smooth muscle cells by blocking the cell cycle is an effective strategy to decrease the reaction prevents neointima appearence) hyperplasia. Efficient and stable reduction of late lumen loss and the volume of the plaque prevents neointima appearence) was investigated in patients receiving rapamycin delivered locally from the surface of the stent. The present invention goes beyond the description �of echanism action rapamycin, to cover additional methods of treatment with inhibition of the cell cycle and reduction prevents neointima appearence) hyperplasia, non-toxic.

The cell cycle is a tightly controlled cascade of biochemical events that regulate the replication process of the cell. After stimulation of cells with appropriate growth factors, they switch from G0(the rest) to the G1 phase of the cell cycle. Selective inhibition of the cell cycle in G1 phase before DNA replication (S-phase) may benefit from therapeutic means for the preservation and viability of the cells, keeping the antiproliferative efficacy compared to therapy that acts later in the cell cycle, namely in S-, G2 - or M-phase.

Thus, to prevent the reaction of intimal hyperplasia in blood vessels and other vessels that carry fluid in the body with the help of cell cycle inhibitors that act selectively at the G1 phase of the cell cycle. These inhibitors of the G1 phase of the cell cycle may represent molecules of small size, peptides, proteins, oligonucleotides or DNA sequences. More specifically, these tools or agents include inhibitors of cyclin-dependent kinases (cdk), which stimulates the passage of the G1 phase of the cell cycle, namely cdk2 and cdk4.

Examples of funds and�clients or connections providing selective action in the G1 phase of the cell cycle, can serve as a means of small synthetic molecules, such as flavopiridol and its structural analogs that have been found to inhibit cell cycle in late G1 phase by antagonism of cyclin dependent kinases. Can be used therapeutic agents that increase the level of endogenous protein kinase inhibitor,kipotherwise, P27, sometimes referred to as P27kip1that selectively inhibits cyclin dependent kinases. This includes funds from small synthetic molecules, peptides and proteins, which block the degradation of P27 or enhance cellular production of P27, including genetic vectors that can carry the gene for producing P27. Can also be used STS and related synthetic agents that block the cell cycle through the inhibition of protein kinases. Can also be used inhibitors of protein kinases, including class tyrphostins, which selectively inhibit protein kinases to antagonize signal transduction in smooth muscle cells in response to a wide range of growth factors such as platelet derived growth factor (PDGF) and fibroblast growth factor (FGF).

Any tool, agent or compound, discussed above, may be administered both systemically, for example orally, EXT�trevenna, intramuscularly, subcutaneously, intranasally or intradermally, or locally, for example to stand out from the coating of a stent from the stent sheath or delivered using a catheter. In addition, drugs or agents described above, can be produced in the form of dosage forms with rapid release or slow release with the objective of maintaining the funds or agents in contact with the tissue target during a period of time ranging from three days to eight weeks.

As described above, the complex of rapamycin and protein FKPB12 binds and inhibits phosphoinositide-3-kinase, otherwise known as "target of rapamycin in mammalian" or TOR. The antagonist of the catalytic activity of TOR, functioning as the active site inhibitor or as an allosteric modulator, i.e. allosteric modulating indirect inhibitor that reproduces the action of rapamycin, but not needs in interaction with FKBP12. The potential advantages of a direct inhibitor of TOR include the best penetration into the tissue and better physical/chemical stability. In addition, other potential advantages include greater selectivity and specificity of action, due to the specificity of the antagonist against one of the many TOR isoforms, which may exist in different tissues, and potentially different� range of downstream effects, leading to greater efficiency and/or safety of the medicine.

The inhibitor can be a small organic molecule (approximate molecular weight<1000), which is a product produced from synthetic or naturally. As agent, the inhibitory function of this class of proteins, may be used wortmannin. It can also be a peptide or oligonucleotide sequence. The inhibitor may be administered either systemically (orally, intravenously, intramuscularly, subcutaneously, intranasally or intradermally), or locally (to stand out from the coating of a stent from the stent sheath or delivered using a catheter). For example, the inhibitor can be released into the vessel wall of a man of intractable erosion of the polymer coating of the stent. In addition, the inhibitor can be produced in the form of dosage forms with rapid release or slow release with the objective of maintaining the rapamycin or other drug, agent or compound in contact with the tissue target during a period of time ranging from three days to eight weeks.

As described above, the implantation of coronary stent in conjunction with balloon angioplasty is highly effective in the treatment of acute vessel closure and may reduce the risk of restenosis. Intrave�molecular ultrasound studies (Mintz et al., 1996) suggest that coronary stenting effectively prevents vasoconstriction and that in most cases, late luminal loss of the lumen after stent implantation is due to the growth of plaques, which in turn can be caused prevents neointima appearence) hyperplasia. The frequency of late luminal loss after coronary luminal stenting is almost two times higher than after conventional balloon angioplasty. Thus, as the stent hinder the development of at least part of the process of formation of restenosis, the use of funds, agents or compounds that inhibit the proliferation of smooth muscle cells, reduce inflammation and slow down coagulation or inhibit proliferation of smooth muscle cells by complex mechanisms, combined with a stent may provide a more effective treatment postangioplasty restenosis.

Moreover in patients with insulin-dependent diabetes, who were implanted vascular devices emitting rapamycin, such as stents, there is a higher incidence of restenosis compared to patients with normal or non-insulin-dependent diabetes. Thus the combination of medicines may provide added value.

Local delivery means, and�clients or connections from a stent has the following advantages: prevention of narrowing of the lumen of blood vessels and remodeling of blood vessels due to frame function of the stent and the prevention of many components prevents neointima appearence) hyperplasia. The local introduction of drugs, substances, or compounds in testirovanie coronary artery may also bring additional therapeutic benefit. For example, higher concentrations of drugs, substances or compounds in the tissue can be achieved rather through local delivery than by systemic administration. An additional benefit of drug therapy is the possibility of reducing the dose of therapeutic compounds, and consequently, reducing their toxicity, the effect of reduction of restenosis remains.

In another embodiment, rapamycin can be used in combination with Cilostazol. Cilostazol {6[4-(1-cyclohexyl-1H-tetrazol-5-yl)-butoxy]-3,4-dihydro-2-(1H)-chinoline} is a phosphodiesterase inhibitor type II (inhibited cyclic guanozinmonofosfata (cGMP) and has antiplatelet and vasodilating properties. Initially, Cilostazol was developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3. It was expected that the inhibition of phosphodiesterase 3 in platelets and smooth muscle cells of the vessels will provide antiplatelet and vasodilating effect, however, current preclinical studies have shown that Cilostazol also has the ability Engibarov�ü the capture of adenosine by different cells this property distinguishes Cilostazol from other inhibitors of phosphodiesterase 3, such as, for example, milrinone. Thus Cilostazol demonstrates the unique antiplatelet and vasodilator properties, based on a number of new mechanisms of action. Examples of other tools of this class include milrinone, vesnarinone, enoximone, pimobendan and merienda.

Studies have also shown the effectiveness of Cilostazol in the reduction of restenosis after stent implantation. See, for example, Matsutani M., Ueda H. et al.: Effect of cilostazol in preventing restenosis after percutaneous transluminal coronary angioplasty, Am. J. Cardiol 1997, 79:1097-1099, Kunishima, T., Musha, H., Eto, F., et al.: A randomized trial of aspirin versus cilostazol therapy after successful coronary stent implantation, Clin Thor 1997, 19:1058-1066, and Tsuchikane E. Fukuhara A., Kobayashi T., et al.: Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty, Circulation 1999, 100:21-26.

In accordance with the present invention Cilostazol can be made in the form of dosage forms with prolonged release of the medical device or coating medical devices with the aim of reducing the deposition of platelets and the formation of thrombosis on the surface of the medical device. As described above, the medical devices include any short-term or long-term implants, constantly in contact with blood, such as cardiovascular, peripheral and intracranial stents. Additionally�, Cilostazol can be incorporated into an appropriate polymer coating or matrix in combination with rapamycin or other potentially agents that prevent restenosis.

The incorporation and subsequent prolonged release of Cilostazol from the medical device or coating of a medical device in the preferred embodiment, reduces the deposition of platelets and the formation of thrombosis on the surface of the medical device. As described above, there are preclinical and clinical data showing that Cilostazol also prevents restenosis is partly due to its vasodilating action. Thus, the use of Cilostazol effectively on at least two kinds of devices in contact with blood, such as stents eluting the drug. Therefore, the combination of Cilostazol with other potentially preventing restenosis agents containing rapamycin, such as sirolimus and its analogs, derivatives, congeners and conjugates or paclitaxel, its analogues, derivatives, congeners and conjugates, can be used for local treatment of cardiovascular diseases and reduce the deposition of platelets and the formation of thrombosis on the surface of the medical device. Although the foregoing description is given with regard to stents, magnetmail, what drug combinations described in this specific example of implementation, can also be used in combination with a variety of medical devices, some of which are described here.

Fig.3 shows a first configuration example of the combination of Cilostazol and rapamycin covering the stent. In this embodiment of the invention used the stent Bx Velocity®the company Cordis Corporation. In this particular configuration, the stent 7500 has a three-layer coating. The first layer or the inner layer 7502 contains one hundred and eighty (180 mcg) micrograms of sirolimus, which is equivalent to forty-five (45) percentages by weight to the total weight of the inner layer 7502, and the copolymer matrix of a copolymer (poly)ethylene and vinyl acetate and polybutylmethacrylate, COMECON/PBMA equivalent to fifty-five (55) percentages by weight to the total weight of the inner layer 7502. The second layer or outer layer 7504 contains one hundred (100 mcg) micrograms of Cilostazol, which is equivalent to forty-five (45) percentages by weight to the total weight of the outer layer 7504 and the copolymer matrix of EVA/PBMA equivalent to fifty-five (55) percentages by weight to the total weight of the outer layer 7504. The third diffusion layer or the outer coating 7506 contains two hundred (200 mcg) micrograms of PBMA. Output content amounted to eight�Ty-five (85) percent of the nominal content of the drug for sirolimus and ninety-eight (98) percent of the nominal content of the drug for Cilostazol. Kinetics of in vitro release of Cilostazol and sirolimus shown in Fig.4 and described in detail below.

Fig.5 shows a second configuration example of the combination of Cilostazol and rapamycin deposited on the stent. As described above, are used the stent Bx Velocity® company Cordis Corporation. In this embodiment of the stent 7700 has a three-layer coating. The first layer or the inner layer 7702 contains one hundred and eighty (180 mcg) micrograms of sirolimus, which is equivalent to forty-five (45) percentages by weight to the total weight of the inner layer 7702 and the copolymer matrix of EVA/PBMA equivalent to fifty-five (55) percentages by weight to the total weight of the inner layer 7702. The second layer or outer layer 7704 contains one hundred (100 mcg) micrograms of Cilostazol, which is equivalent to forty-five (45) percentages by weight to the total weight of the outer layer 7704 and the copolymer matrix of EVA/PBMA equivalent to fifty-five (55) percentages by weight to the total weight of the outer layer 7704. The third layer or outer diffusion coating 7706 contains one hundred (100 mcg) micrograms of PBMA. And again the volume of output content amounted to eighty-five (85) percent of the nominal content of the drug for sirolimus and ninety-eight (98) percent of the nominal content of the drug for Cilostazol. Kinetics of visualaid�of in vitro Cilostazol and sirolimus shown in Fig.6 and described in detail below.

As can be seen from comparison of Fig.4 and 6, the rate of release of drugs sirolimus and Cilostazol from the configuration with a thicker outer coating diffusion of PMMA, i.e. two hundred micrograms instead of a hundred micrograms, was lower. Thus, the selective application of diffusion coatings can further control the speed of separation of both drugs, discussed in more detail in this document. By the selective application of diffusion coatings accounted for the thickness of the coating, and other features, including chemical compatibility.

Fig.7 shows a third variant of the configuration example of the combination of Cilostazol and rapamycin deposited on the stent. This configuration is identical in its structure to the configuration shown in Fig.3, however, the number of Cilostazol reduced to fifty (50 µg) micrograms. As in the previous version of the implementation used here, the stent 7900 and three additional layers of coverage: 7902, 7904 and 7906. The percentage by weight, however, remains the same.

Antithrombotic efficacy of the three configurations described above, is shown in Fig.8. Fig.8 shows antithrombotic properties of the coatings containing a combination of sirolimus/Cilostazol described above in vitro in experimental models cravens�Oh system using bovine blood. In experimental models of circulatory system with the use of bovine blood in vitro fresh bull's blood heparinized to lead an activated coagulation time (ICS) to two hundred (200) seconds. The blood platelets labeled with indium 111. In the study, the stent is placed in a silicone tube, which is part of a closed system in which blood circulates. Heparinized blood circulates in a closed system with a circulating pump. Over time on the surface of the stent accumulate blood clots and clot, which reduces the speed of blood flow circulating in stented closed system. The flow stops when the flow rate is reduced to fifty (50) percent of initial value or ninety (90) minutes, if any of the tested stents has reduced the flow in the fifty (50) percent. Total radioactivity (In 111) on the surface of the stent is calculated using a beta-counter and normalized using the controller specified in the Protocol one hundred (100) percent. A smaller value indicates that the surface is less thrombogenic. All three groups of double sirolimus/Cilostazol drug coatings reduced the deposition of platelets and thrombus formation on the surface of the stent more than ninety (90) percent for the CPA�those seen with the control stent, produce drug substance that does not contain additional compounds Cilostazol. Column 8002 represents control stent, releasing the medicinal substance, which was taken over one hundred (100) percent. As a control eluting stent substance was used coronary stent releasing sirolimus Cypher® company Cordis Corporation. Column 8004 is HEPACOAT® stent coated with heparin; supplied by the company Cordis Corporation, under the trademark coronary stent Bx Velocity®. Column 8006 is a stent with the above configuration based on the architecture shown in Fig.3. Column 8008 is a stent with the above configuration based on the architecture shown in Fig.5. Column 8010 represents the stent with the above configuration based on the architecture shown in Fig.7. As can be seen from Fig.8, Cilostazol greatly reduces the formation of thrombus.

Other clinical indicator of the investigated device, covered with Cilostazol is the duration of release of the drug from the coating. This is of particular importance in the first two weeks after implantation of the device. In pharmacokinetic studies of the drug release models on pigs as Cilostazol and sirolimus slowly high�was obuzhdalis from the coating, the result is a prolonged release profile of drugs. The purpose of pharmacokinetic studies in models on pigs is to assess the local pharmacokinetics eluting stent means during the predetermined period of stent implantation. Typically, implanted three stents in three different pig coronary artery at a given time period, and then remove the stents to assess the overall excretion of the drug. The stents removed at specified time points, namely 1, 3 and 8 days. The stents removed and determine the total number of medicinal substances remaining on the stent, by analysis using HPLC (high performance liquid chromatography). The difference between the initial amount of the drug on the stent and the amount of the drug substance at the time of extraction of the stent represents the amount of drug substance released during this period. Sustained release of drug in the surrounding tissue of the artery is a factor hindering the growth of the neointima and the formation of restenosis in coronary arteries. Graph of the normal distribution is a percentage of the total amount of released drug substance (%, y-axis) and the period of implantation (day,�ü x). As shown in Fig.9, approximately eighty percent (80%) of the two drugs remained in the drug coating after eight (8) days after implantation. In addition, both the drug substance is released at the same speed, despite the rather large difference of the respective values of logP and various water-soluble compounds. Curve 8102 displays Cilostazol, and curve 8104 displays sirolimus. The corresponding release profiles in vitro is shown in Fig.10. Similar to the release profile in vivo as sirolimus, denoted by the squares and Cilostazol, denoted by diamonds, is released slowly enough so that the release of both drugs was approximately thirty-five (35) percent. Fig.9 and 10 are presented respectively in vivo and in vitro drug release rate of the substance from the stent coating, applied in accordance with the configuration shown in Fig.11, where sirolimus and Cilostazol contained in one layer instead of two separate layers. In this example configuration, the stent 8300 has a two-layer coating. The first layer 8302 comprises a composition of sirolimus, Cilostazol and a copolymer matrix of EVA/PBMA. The second diffusion layer or the outer coating 8304 includes only PBMA. More specifically, in this embodiment, the first layer tit combination of sirolimus and Cilostazol, percentage weight ratio is forty-five (45) percent of the total weight of the first layer 8302, and a copolymer matrix of EVA/PBMA percentage weight respect is fifty-five (55) percent of the total weight of the first layer 8302. Diffusion outer coating contains one hundred (100 mcg) micrograms of PBMA.

Fig.12 and 13 shows, respectively, in vivo and in vitro drug release rate of the substance from the stent coating applied in accordance with the configuration shown in Fig.3. Multilayer coating providing two drugs, showed a relatively greater rate of release of medicinal substance in pharmacokinetic research on the model in pigs compared with a base coating that contains two medicinal substances, as can be seen from comparison of Fig.12 and 9. Fig.12 curve 8402 displays Cilostazol, and curve 8404 displays sirolimus. However, the percentage release of both drugs was comparable at each time point. The corresponding profiles of drug release rate in vitro is shown in Fig.12, where diamonds marked Cilostazol, and squares - sirolimus. Compared with a base coating that contains two drugs, both medicinal substance is released much faster, which is reflected�but profile quick-release pharmacokinetic study in vivo. Thus, the Association drugs in the same coating layer as a result allows more control over the speed of separation of the drug substance.

The combination of rapamycin (sirolimus) and Cilostazol, as described above, it is more effective than using one drug substance to reduce proliferation and migration of smooth muscle cells. In addition, as shown herein, the release of Cilostazol from a combined coverage can be monitored constantly in order to achieve long-term prevent the deposition of platelet thrombus formation on the surface of the stent or the surface of another medical device in contact with blood. In the combined coating Cilostazol may be incorporated in one layer together with sirolimus or in a separate layer outside of the layer containing sirolimus. Due to its relatively low solubility in water Cilostazol potentially may remain in the coating over a sufficiently long period of time, being in the body after insertion of the stent or other medical device. Relatively slow disbursement in vitro compared with sirolimus in the inner layers suggests that possibility. Cilostazol is a stable compound,soluble in most organic solvents and compatible with the various techniques of coating, described here. It is important to note that as sirolimus and Cilostazol can be incorporated into reabsorbing polymeric matrix or absorbable matrix.

Fig.14 presents an alternative expandable medical device having a plurality of holes containing a medicinal substance for delivery to a tissue using an expandable medical device. Expandable medical device 9900, shown in Fig.14, cut from material of cylindrical shape, suitable for the manufacture of cylindrical expandable medical device. Expandable medical device 9900 contains many cylindrical sections 9902, interconnected connecting elements 9904. The connecting elements 9904 allow the device supporting the fabric to bend in the axial direction, passing through the difficult pathways of the vascular system to the location and allow the device to bend axially when it is necessary to adjust the curvature of the lumen requiring support. Each cylindrical section 9902 formed by a network of elongated structural members 9908, which are interconnected by flexible hinges 9910 and peripheral transverse connecting elements 9912. When expanding medical device 9900 flexible hinges 9910 deformed, whereas elongated� design elements 9908 not change. A more detailed description of the example of the expandable medical device are shown in U.S. patent No. 6241762, fully incorporated in the description by reference.

As shown in Fig.14, the elongated structural members 9908 and peripheral transverse connecting elements 9912 include holes 9914, some of which contain a therapeutic agent for delivery to the vessel lumen, where the implanted expandable medical device. In addition, other parts of the 9900 device, such as fasteners 9904, may include holes, as described below in relation to Fig.18. In a preferred embodiment the holes 9914 provided in non-deforming parts of the 9900 device, such as elements 9908, to avoid deformation of the holes and to deliver therapeutic substances without the risk of breaking up, removal or other damage that may occur during expansion of the device. Detailed description of the example of the method of placement of therapeutic substance within the holes 9914 given in the patent application U.S. serial No. 09/948987 dated September 7, 2001, is fully included in the description of the present invention by reference.

Illustrated embodiments of the present invention can be confirmed using the analysis by finite element method and other methods for optimization p�smesheniya therapeutic agents inside the holes 9914. Essentially, the shape and arrangement of holes 9914 can be adjusted to maximize the spaces should be kept sufficiently high strength and stiffness of structural elements relative to the flexible hinges 9910. In accordance with a preferred variant implementation of the present invention, the holes occupy an area of at least 3.2 PCs-5 cm2(5×10-6square inch), preferably at least 4.5 copies-5 cm2(7×10-6square inches). Usually the holes are filled therapeutic substance from fifty to ninety-five percent.

Various embodiments of the present invention described herein provide for the placement of different therapeutic agents in different openings in the expandable device or placing a therapeutic agent in some holes. In other embodiments, hole in one can apply combinations of therapeutic agents or therapeutic agents. The unique structure of the expandable device may change, without derogating from the General nature of the invention. As each hole is filled independently, at each port, therapeutic substance may be communicated to individual chemical structure and pharmacokinetic properties.

One example of the use of various therapeutic prophetic�STV in different openings in the expandable medical device or therapeutic substances only some of the openings combats edge restenosis. As described above, the problem of stents with a modern coating is edge restenosis or restenosis, which is formed directly over the edges of the stent and paced around the inside of the stent and the lumen.

Causes of edge restenosis with the use of stents for drug delivery of the first generation is currently poorly understood. Perhaps the area of tissue damage due to angioplasty and/or stent implantation continues outside the diffusive action of modern therapeutic agents, such as paclitaxel and rapamycin, which are distributed directly to the fabric. A similar phenomenon is observed in radiation therapy, where low doses of radiation at the edges of the stent showed a stimulating effect in the presence of damage. In this case, the radiation at greater length until the irradiation of healthy tissue solved the problem. In the case of stents for drug delivery placement of higher doses or higher concentrations of therapeutic substances along the length of the ends of the stent, placement of various substances that penetrate faster through the fabric at the ends of the stent or placement of various therapeutic substances or combinations of substances at the ends of the device helps eliminate the problem of edge restenosis.

Fig.14 shows an expandable medical�e device 9900 with "hot ends" or medicinal substance placed in the holes 9914a at the ends of the device to treat or reduce the severity of edge restenosis. The remaining holes 9914b in the Central part of the device can be blank (as shown) or may contain a lower concentration of therapeutic substance.

Other regional mechanisms of restenosis may be due to the cytotoxicity of certain drugs or combinations of drugs. Such mechanisms may include physical or mechanical compression of the tissue is similar to what happens in the formation of scar tissue; a stent can prevent reactive reduction within their borders, but not outside. In addition, the mechanism of formation of this late form of restenosis may be associated with the effects of prolonged and local delivery of the drug into the tissue of the arterial wall even after the tool itself is no longer present in the tissues of the arterial wall. So, restenosis may be a response to a form of toxic shock caused by drug and/or carrier of the medicine. In this situation it would be useful to abandon the use of certain substances at the ends of the device.

Fig.15 shows an alternative example of execution of the expandable medical device 10200, Nieuwe�about a lot of holes 10230, where the holes 10230b in the Central part of the device filled with therapeutic substance, and the holes 10230a at the ends of the device are empty. The device shown in Fig.15, applies to devices with the "cold ends".

In addition to use in order to reduce edge restenosis, an expandable medical device 10200 shown in Fig.15, may be used in combination with an expandable medical device 9900, shown in Fig.14, or another stent for delivery of the drug substance, if there is a need to complement the primary treatment, stenting of an additional stent. For example, in some cases, the device 9900 with "hot ends" shown in Fig.14, or a device with uniform distribution of the drug was implanted incorrectly. If the doctor determines that the device does not occupy a sufficient portion of the lumen of the vessel will need to attach the complementary device to one end already implanted device, cutting off a little already implanted device. After implantation complementary device device 10200 shown in Fig.15 operates in such a way that "cold ends" medical device 10200 prevent double dosage of a therapeutic substance in a region overlapping segments devices 9900, 10200.

Fig.16 performance�shows an alternative embodiment of the invention, where different therapeutic substances are placed in various holes expandable medical device 11300. The first therapeutic substance is placed in the holes 11330a at the ends of the device, and the second therapeutic substance is placed in the holes 11330b in the Central part of the device. Therapeutic substance may contain various drugs, the same drug in different concentrations, or different variants of the same drug. An example of execution shown in Fig.16, can be used to create expandable medical device with 11300 "hot ends" or "cold."

In a preferred embodiment, each end portion of the device 11300 containing holes 11330a filled with a first therapeutic agent should be indented from the edge, equal in magnitude at least one hole and up to about fifteen holes from the edge. This distance corresponds approximately 0.127-2.54 mm (about 0.005 to 0.1 inch) from the edge of the device in an unexpanded condition. The distance from the edge of the device 11300 comprising a first therapeutic substance, preferably should correspond to one section, and under section refers to the gap between the connecting elements.

Various therapeutic substances containing various medicinal CPE�PTS can be placed in different holes in the stent. It allows to deliver two or more different therapeutic agents with one stent according to any desired scheme. In an alternative embodiment, various medicinal substances that contain the same therapeutic agent in various concentrations, can be placed in different holes. This allows you to evenly distribute the drug in the tissue with non-uniform structure of the device itself.

Two or more different therapeutic material disposed in the device described herein may include (1) different drugs; (2) different concentrations of the same drug; (3) the same drug with different release kinetics, i.e. different rates of erosion of the matrix; or (4) different forms of the same drug. Options various therapeutic substances containing the same drug with different release kinetics, can be used in combination with various carriers to obtain elution profiles of different shapes. Some examples of different forms of the same drug include forms of drugs having different hydrophilicity and lipophilicity.

In one embodiment, the device 1130, shown in Fig.16, hole 11330a at the ends of the device filled with a first therapeutic substance containing a drug with high lipophilicity, whereas the holes 11330b in the Central part of the device is filled with a second therapeutic substance containing a drug with a lower lipophilicity. First vysokololtnoe therapeutic substance on the "hot ends" much faster diffuses into the surrounding tissue, reducing the formation of edge restenosis.

The device 11300 may have a sharp transition line, where the first therapeutic substance is replaced with a second therapeutic substance. For example, all openings in the range of 1.27 mm (0.05 inch) from the edge device may contain a first substance, while the rest of the holes contain a second substance. In an alternative embodiment, the device can have a gradual transition between the first and second substances. For example, the concentration of the drug in the holes may progressively increase (or decrease) towards the end of the device. In another embodiment, the number of the first means in the holes is increased, while the number of funds in the second hole decreases toward the ends of the device.

Fig.17 shows an alternative embodiment of an expandable medical device 12400, where various medical�training substance placed in different holes 12430a, 12430b in the device in peremejayutsya or multiple order. This method gives the opportunity to deliver a variety of therapeutic substances to the tissue over the entire area or only part of the area supported by the device. This example implementation may be used to deliver multiple therapeutic agents where the combination of several substances in a single composition for placement in the unit is not possible due to the reaction of interaction of therapeutic substances to each other or stability problems.

In addition to a host of different therapeutic agents in different openings to receive different media in different concentrations of certain areas of the fabric, the placement of different therapeutic agents in different openings can serve to improve the spatial distribution of therapeutic substance in cases where the holes are distributed on an expandable medical device in the expanded state is uneven.

The use of different drugs in different openings in an alternating or multiple procedure allows for the delivery of two different drugs, the delivery of which is composed of the same matrix composition polymer/drug impossible. For example, if choose medicines interact with each other in undesirable.�m. Or two of the drug substance may not be combined with the same polymer to form the matrix or with the same solvents for the delivery of the matrix polymer/drug in the holes.

Further, an implementation option, shown in Fig.17, with various medicinal substances, placed in different holes arranged in a dispersed manner, allows the delivery of different drugs with completely different desired release kinetics from the same medical device or stent and to optimize the release kinetics depending on the mechanism of action and properties of individual substances. For example, the solubility of a substance has a significant impact on the release of a substance from a polymer or other matrix. Compounds with a high degree of water solubility, usually delivered from a polymer matrix very quickly, whereas for the delivery of lipophilic substances from the same matrix requires a longer period of time. Thus, if delivery of a hydrophilic substance and a lipophilic substance in the form of a double-drug combination with one medical device, it is difficult to obtain the desired release profile of two such substances to be delivered from the same polymer matrix.

The system shown in Fig.17, makes it easy to deliver hydrophilic and lipophilic substances with a single stent. In addition, the system shown in Fig.17, allows the delivery of two substances with different kinetics and/or different periods of the administration of funds. The initial release of each of the funds during the first days, the rate of release through the day, the total period of administration of funds and any other characteristic of the release of the two drugs can be regulated separately. For example, the rate of release of the first therapeutic substance can be set so that at least forty percent (in the preferred embodiment, fifty percent) of the funds were delivered during the first twenty-four hours, and the rate of release of the second substance can be set so that during the first twenty-four hours was delivered less than twenty per cent (in the preferred embodiment, less than ten percent) funds. During administration of the first therapeutic substance may be about three weeks or less (in the preferred embodiment, two weeks or less), and during administration of the second therapeutic agent may be about four weeks or more.

Restenosis, or recurrence of occlusion after surgery contains combinatio�Yu or a series of biological processes. These processes include activation of platelets and macrophages. Cytokines and growth factors promote proliferation of smooth muscle cells and enhances gene expression regulation and metalloproteinases, leading to cell growth, remodeling of extracellular matrix and migration of smooth muscle cells. Drug therapy using a combination of drugs aimed at these processes is perhaps the most effective means of combating restenosis. The present invention provides the means to implement such an effective combination of medication therapy.

The examples discussed below illustrate some systems, using a combination of medicines that will provide the best effect when you use the ability to release a variety of drugs in different holes or cells. An example of such an effective system for delivery of two drugs from vents located in the scattered or alternate order is the delivery of anti-inflammatory agent or immunosuppressant in combination with an anti-proliferative agent, or anti-immigration agent. Other combinations of these agents can also be used for targeting multiple biological processes,�actuosa in the formation of restenosis. Anti-inflammatory agent inhibits primary inflammatory reaction receptacles angioplasty and stenting and is delivered at high speed in the initial period of introduction; followed by a slower delivery within approximately a two week period to coincide with the peak in the response of macrophages, stimulating the development of the inflammatory response. Antiproliferative agent is delivered with fairly even rate over a long period of time in order to reduce the migration and proliferation of smooth muscle cells.

In addition to the examples given below, the following table 7 reflects some options for successful therapy using combinations of two drugs, where the positive effect is achieved by placing funds in different holes of the medical device.

Table 7
Paclitaxel (PTX)Cladribine (2-chloromethoxypropyl)Epothilone DGleevec (imatinib mesilate)The rapamycin analoguePimecrolimusPKC-412 (protein kinase C) DexamethasoneFarglitazarInsulinVasoactive intestinal peptide (VIP)Apoa Milan
Paclitaxel (PTX)xxxxxxxx
Cladribine (2-chloromethoxypropyl)xxxxxs
Epothilone Dxxxx xx
Imatinibxxxx
Mesilate
Gleevec
Rapamycin xxxxx
Analogue
Pimecrolimusxxxxx
PKC-412 (protein kinase C)xx x
Dexamethasonexx
Farglitazarxx
Insulinx
Vasoactive intestinal peptide (VIP) x
Apoa-I Milan

Placing drugs in different holes allows you to specify the kinetics of the release of each individual agent regardless of hydrophobic or lipophobic the aphrodisiac properties. Examples of some accommodation options for the delivery of lipophilic funds mainly constant or linear release rate is described in the international patent application WO 04/110302 issued on 23 December 2004, which is fully incorporated into this description by reference. Examples of some accommodation options for the delivery of hydrophilic means described in international patent application WO 04/043510, published may 27, 2004, which �totally incorporated into this description by reference. Hydrophilic materials described above, include cladribine (2-chloromethoxypropyl), Gleevec, vasoactive intestinal peptide (VIP), insulin and Apoa-1 Milano. Lipophilic funds, referred to above, include paclitaxel, epothilone D, rapamycin, pimecrolimus, PKC-412 (protein kinase C) and dexamethasone. Farglitazar is partially and partially lipophilic hydrophilic agent.

In addition to delivering multiple drugs that have a directional influence on various biological processes involved in the formation of restenosis, the present invention can be used to delivery one stent two different drugs for the treatment of various diseases. For example, the stent can serve for the delivery of antiproliferative funds, such as Paclitaxel or family of funds Limonov, from one group of holes for the treatment of restenosis, and to give means for the prevention of myocardial infarction, such as insulin, from other holes for the treatment of acute myocardial infarction.

Most of the known expandable device, and the device shown in Fig.18, the density of the coating device 13500 in parts of the cylindrical tube 13512 device more than on the connecting elements (bridges) 13514. Coating density is defined as the ratio of the surface area� device to the area of the lumen, in which the device is placed. If the device with varying coating used to deliver a therapeutic agent contained in the holes of the device, the concentration of therapeutic agent delivered to the tissue adjacent to the cylindrical tube parts 13512, higher than the concentration of therapeutic agent delivered to the tissue adjacent to the connecting elements (bridges) 13514. In order to directionally adjust the longitudinal variability in the structure of the device and other fluctuations in the coating device, which lead to uneven concentrations of the delivered therapeutic agent, the concentration of therapeutic agent may vary in the holes on different parts of the device to achieve a more uniform distribution of therapeutic agent throughout the tissue. In the case of the example of implementation shown in Fig.18, hole 13530a in tubular parts 13512 contain therapeutic agent with a lower concentration of drug than the holes 13530b located on the connecting elements (bridges) 13514. The uniformity of the delivery agent can be achieved in various ways, including by varying the concentration of funds, diameter and shape of the holes, the number of agent in the hole (i.e., the percentage of fill hole), the matrix material or form of the drug.

If�'erom of the invention to use various medicinal agents in different openings is expandable medical device 14600, as shown in Fig.19 intended for use in place of a bifurcation in a vessel. Bifurcation devices include a side opening 14610, which is thus to skip the blood flow through the side branch vessel. An example of bifurcation devices are described in U.S. patent No. 6293967, fully incorporated in the description by reference. Bifurcation device 14600 contains a side opening 14610, interrupting the regular structure of the cross-beams, forming the remainder of the device. Due to the fact that the area around the bifurcation is extremely problematic in terms of the possible formation of restenosis, the concentration of the antiproliferative funds can be increased in the holes 14630a in the area surrounding the side opening 14610 device 14600, for the delivery of higher concentrations of the drug where it is needed. The remaining holes 14630b in the field, remote from the side openings, contain therapeutic agent with a lower concentration of antiproliferative funds. Increasing the dose of antiproliferative funds delivered to the area surrounding the hole bifurcation, can be achieved by using various therapeutic agents containing various tools or therapeutic agent containing an increased concentration of one means.

In addition to the delivery of various Le�bnyh agents to parietal or abdominales side expandable medical device for treatment of the vessel wall, therapeutic agents can be delivered to the luminal side of the expandable medical devices to prevent or reduce thrombosis. Drugs that are delivered to the bloodstream from the luminal surface of the device, can be placed at the proximal end of the device or at the distal end of the device.

Methods to accommodate different therapeutic agents in different openings in the expandable medical device may include known techniques, such as dipping and coating, and also known a method of piezoelectric microinjection. Microinjection device can have computer control to deliver a known manner the exact number of two or more liquid therapeutic agents to a precisely defined location on the expandable medical device. For example, the injection device of the double agent can deliver in the holes of the two agents simultaneously or sequentially. When therapeutic agents are placed through holes in the expandable medical device in the boot process luminal side of the through holes can be closed by means of a flexible mandrin, which will allow delivery of therapeutic agents in liquid form, for example in the form of solvent. Loading therapeutic agents can also be performed using the hand-held injection device.

Fig.20 shows a stent, providing two medicinal substances�and, 15700, where delivery of anti-inflammatory agent and antiproliferative agent is carried out from various holes in the stent to provide an independent release kinetics of each of the two drugs, the kinetics of release of each drug substance is specifically programmed to coincide in time with the biological processes leading to restenosis. In accordance with this embodiment of the stent, providing two drugs that includes anti-inflammatory agent - pimecrolimus - in the first series of holes 15710 in combination with the antiproliferative agent paclitaxel in the second series of openings 15720. Each agent is placed in a matrix material within the holes of the stent, in particular a mosaic manner designed to achieve the release kinetics shown in Fig.21. Each medicinal substance is delivered mainly parietal for the treatment of restenosis.

As shown in Fig.20, pimecrolimus is placed in the stent for the targeted delivery to the mural side of the stent by applying a barrier 15712 on the luminal side of the hole. Barrier 15712 formed from biodegradable polymer. Pimecrolimus is loaded into the holes in such a way, through which is formed a two-phase release kinetics. The first phase� release of pimecrolimus is provided parietal layer lying 15716 matrix, which contains rapid release connection including pimecrolimus and biodegradable polymer (copolymer of lactic and glycolic acids (PLGA)) with a high percentage of the drug substance is about ninety percent of the drug and about ten percent of the polymer. The second phase release of pimecrolimus is provided by a Central layer 15714 matrix containing pimecrolimus and biodegradable polymer (copolymer of lactic and glycolic acids (PLGA)) in a ratio of about fifty percent of the drug substance to fifty percent of the polymer. As can be seen from the graph in Fig.21, as a result of the first phase of the release of pimecrolimus delivered about fifty percent of the loaded drug during the first twenty-four hours. As a result of the second phase of the release are delivered the remaining fifty percent within two weeks. Such a release profile is specially programmed to match with the progression of the inflammatory process following angioplasty and stenting. In addition or alternatively to the use of different concentrations of the drug substance in two layers to achieve a two-phase release, in order to obtain different release rate in two different�'s layers you can use different ratios of polymers or copolymers of the same polymer.

Paclitaxel is placed inside openings 15720 in this way, through which is formed the kinetics of release with a predominantly linear release after the first twenty-four hours, as shown in Fig.21. Opening with paclitaxel 15720 loaded three layers, including a base layer 15722, consisting mainly of a polymer with a minimal addition of the drug to the luminal side of the hole, the Central layer 15724 with paclitaxel and a polymer (copolymer of lactide and glycolide (PLGA)) having a concentration gradient, and the covering layer 15726 containing mainly polymer that controls the release of paclitaxel. The release of paclitaxel as follows: initial release on the first day is from five to fifteen percent of the total amount of the loaded drug substance, followed by a predominantly linear release for from twenty to ninety days. Additional examples of the order of placement of paclitaxel in the holes concentration gradient is described in international patent application WO 04/110302 mentioned above.

Fig.20 to facilitate understanding of the medicinal substance, barrier and capping�e layers are shown as individual layers inside the hole. It should be understood that these layers do not have clear boundaries and are formed by mixing different areas. Thus, although the barrier layers mainly composed of a polymer and does not include any medicinal substance, depending on the applied production technologies, a certain amount of medicinal substance from the next layer can get into the barrier layer.

The number of delivered drugs may vary depending on the size of the stent. The stent size 3 mm 6 mm number of pimecrolimus is from fifty to three micrograms, in the preferred embodiment, from one hundred to two hundred fifty micrograms. The amount of paclitaxel delivered with such a stent, is from 5 to 50 micrograms, in a preferred embodiment from 10 to 30 micrograms. In one example implementation is delivered about two hundred micrograms of pimecrolimus and about twenty micrograms of paclitaxel. Medicinal substances can be accommodated in alternate holes of the stent. However, due to the large difference in the dose of two drugs that must be delivered, it is more expedient to place paclitaxel in every third or every fourth hole in the stent. In an alternative embodiment, the openings to deliver low doses of medicinal substances (paclitaxel) can bituminise, than openings for high doses.

Layer of the polymer/drug substance form using a computer-controlled piezoelectric injection, as described in the international patent application WO 04/026182, published 1 April 2004, fully incorporated in the description of the present invention by reference. First formed layer of the first agent, then using a piezoelectric injector form a layer of the second agent. In an alternative embodiment, the system described in the international patent application WO 04/02182, can be equipped with dual piezoelectric dosimeter for dosed introduction of the two agents at the same time.

In accordance with this embodiment of the stent, providing two medicinal substances, contains Gleevec in the first series of holes 15710 in combination with the antiproliferative agent paclitaxel in the second series of openings 15720. Each agent included in the matrix material within the holes of the stent, in particular a mosaic manner designed to achieve the release kinetics shown in Fig.21.

Gleevec delivered by a two-phase release, initially with a high rate of release during the first day, and then by slow release over a period of one to two weeks. The first phase of the release Glivec provides �you around fifty percent loaded the funds within the first twenty-four hours. The second phase of the release delivers the remaining fifty percent for one to two weeks. Paclitaxel is placed inside openings 15720 way through which is formed the kinetics of release with a predominantly linear release after the first twenty-four hours, as shown in Fig.21 and as set forth above.

The number of delivered drugs may vary depending on the size of the stent. The stent size 3 mm 6 mm number of Gleevec is from two hundred to five hundred micrograms, in the preferred embodiment, from three hundred to four hundred micrograms. The amount of paclitaxel delivered with such a stent, is from five to fifty micrograms, in the preferred embodiment, from ten to thirty micrograms. As with the previous embodiments, the drug substance may be placed in alternate holes of the stent, or distributed in any order. Layer of the polymer/drug formed by the method described above.

In accordance with this embodiment of the stent, providing two drugs that contain PKC-412 (regulator of cell growth) in the first series of holes in combination with the antiproliferative agent paclitaxel in the second series of holes. Each agent vkluchen matrix material within the holes of the stent in particular mosaic fine, designed to achieve the release kinetics discussed above.

PKC-412 is delivered with a mainly constant rate of release that comes after about the first twenty-four hours, the release occurs during the period from four to sixteen weeks, in the preferred embodiment, six to twelve weeks. Paclitaxel is placed inside a hole in a special way, through which is formed the kinetics of release with a predominantly linear release is achieved after approximately the first twenty-four hours, after which the release continues for a period of from four to sixteen weeks, in the preferred embodiment, six to twelve weeks.

The number of delivered drugs may vary depending on the size of the stent. The stent size 3 mm to 6 mm, the amount of PKC-412 ranging from one hundred to four hundred micrograms, in a preferred embodiment of one hundred fifty to two hundred fifty micrograms. The amount of paclitaxel delivered with such a stent, is from five to fifty micrograms, in the preferred embodiment, from ten to thirty micrograms. As with the previous embodiments, the drug substance may be placed in alternate holes of the stent or distributed in domesti�loosely. Layer of the polymer/drug formed by the method described above.

Some of the agents described herein can be combined with additives that support their activity. For example, additives containing surfactants, antacids, antioxidants and detergents, can be used to the maximum possible reduction of the denaturation and aggregation of protein means. Perhaps the use of anionic, cationic or nonionic surfactants. Examples of non-ionic excipients include the following compounds, but are not limited to: sugars, including sorbitol, sucrose, trehalose; dekstrana, including dextran, carboxymethylchitin (km), diethylaminoethylamine (ؤ]❊]); derivatives of sugars, including D-glucosamina acid and D-gluconacetobacter; synthetic polyethers including polyethylene glycol (PEO) and polyvinylpyrrolidone (PVP); carboxylic acids including D-lactic acid, glycolic acid and propionic acid; surfactants with affinity to hydrophobic surfaces of the partition including n-dodecyl-beta-D-maltoside, n-octyl-beta-D-glucoside, PEO-esters of fatty acids (e.g. stearate (myrj 59) or oleate), PEO esters of sorbitol and fatty acids (e.g., tween 80, PEO-20 sorbitan monooleate), esters of sorbitol and fatty puss�located the whereabouts (for example, SPANN 60, servicemonitor), PEO esters of glycerol and fatty acids; esters of glycerol and fatty acids (e.g., glycerylmonostearate), PEO-hydrocarbon-ethers (for example, PEO-10 oleyl ether; Triton X-100; and lubrol. Examples of ionic surfactants include the following compounds, but are not limited to: salts of fatty acids, including calcium stearate, magnesium stearate, and zinc stearate; phospholipids including lecithin and phosphatidyl choline; (PC) CM-PEG; cholic acid; sodium dodecyl sulfate; docusate (AOT); and tauroholeva acid.

In accordance with another embodiment of the stent or intraluminal frame described herein may be coated with an antithrombotic substance, in addition to one or more therapeutic means is placed in the holes or cells. In one embodiment of the stent can contain holes; before adding or deposition of therapeutic agents in the holes on the stent or to any of its parts can be fixed antithrombotic substance, together with the vehicle for delivery of this substance (polymer or polymer matrix) or without it. In this embodiment of the luminal and abdominalgia the surface of the stent can be coated with an antithrombotic substance or coating, and the surface of the walls of the hole or holes. In Alta�native embodiment of the stent is first coated with an antithrombotic substance or coating, then bore holes or holes. In this embodiment, the implementation of only the luminal and abdominally's surface is covered antithrombotic substance or coating, but not the walls of the holes or openings. In each of these embodiments any number of antithrombotic substances may be mounted on the surface of the stent or its parts. In addition, any number of known techniques may be used to secure antithrombotic substance on the stent, such as the technique used to secure the substance in the coating under the brand name HEPACOAT™ coronary stent Bx Velocity® company Cordis Corporation. In an alternative embodiment, the surface of the stent may be rough or microporous, which enhances cell attachment and endothelization, regardless of or in addition to antithrombotic coating. In addition, any number of therapeutic agents can be deposited inside the holes or openings, while various means can be applied on different parts of the stent.

Now let us turn to Fig.22A, 22B and 22C: here is a schematic view of part of the stent.

As shown in Fig.22A, the stent 17900 contains many, mostly, round holes 17902. In this example implementation a lot, mostly, round hole�rd 17902 passes through the wall of the stent 17900. In other words, lots of round holes 17902 passes through from abdominales the surface of the stent 17904 to abdominales the surface of the stent 17906, where the wall thickness is defined as the distance between the luminal and abdominales surfaces. In other embodiments, however, it is not necessary that the holes passed through the wall of the stent 17900. For example, the holes or reservoirs may extend partially from both the luminal and abdominales surface or from both surfaces. The stent 17900 Fig.22A has a rough surface 17904 17906 and and blank openings 17902.

Fig.22B, at least one surface is coated with a therapeutic agent 17908. Therapeutic agent in a preferred embodiment contains antithrombotic substance, such as heparin; however, the use of any antithrombotic substances. The antithrombotic agent may be recorded by any method, as briefly described above. In this example, the implementation of both the luminal and abdominally's surface is covered recorded antithrombotic substance. In addition, as many mainly circular openings 17902 on the connecting element does not have a filling, the walls of the holes 17902 may also contain some amount of anti�tromboticheskoe substances recorded on them. The number of antithrombotic substances are fixed on the walls of the hole 17910, depends on the method of fixation of the substance. For example, if the substance is xed by immersion, on the walls of the hole will be fixed more matter than in the case for fixation of a substance, a method of spraying. As described here, in this example, the implementation of all the open (unprotected) surface have recorded antithrombotic coating; however, in alternative embodiments, the antithrombotic coating is fixed only on certain surfaces. For example, in one embodiment, the implementation of only the surface that is in contact with the blood, may be treated with antithrombotic substance. In another embodiment, the implementation of one or both surfaces can be coated with an antithrombotic substance, whereas the walls of the holes of the coating does not have. This can be achieved in various ways, including by plugging holes before coating or in that case, if the holes after fixing antithrombotic substances.

Fig.22C presents the filled stent in accordance with this example implementation. As shown in this figure, many, mostly, round holes 17902 filled�; and one or more therapeutic agents for the treatment of pathological conditions of blood vessels, such as restenosis and inflammation, or any other diseases as described herein. Each hole 17902 may be filled with a single therapeutic agent or by various means, as described in detail above. As shown in the figure, the holes are filled with different drug substances 17912, 17914, and 17916 in a specific order; however, as described above, the allowable use of any combination, and the use of one substance in different concentrations. Drugs, such as rapamycin, may be deposited in openings 17902 by any suitable method. Methods of deposition of the drug substance include a method of dispensing a pipette and/or the method of jet injection. In one embodiment of the filling of the drug substance can be performed so that the level of the drug substance and/or matrix drug/polymer in the hole will be below the surface of the stent so that the contact with the surrounding tissue is absent. Alternatively, the holes can be filled so that the medicinal substance and/or the matrix of the drug/polymer can come into contact with the surrounding tissue. In addition, if you are using multiple drugs, the dose of each drug substance can be calculated in max�but a wide range. In addition, the rate of release of each drug substance can be controlled individually. For example, hole lying closer to the ends, can contain a greater number of drugs for the treatment of edge restenosis.

In accordance with this example implementation, the holes can be configured not only to implement the most effective drug therapy, but also for the formation of the physical separation of various medicinal substances. This physical separation can help in preventing the interaction of various drugs with each other.

In accordance with another exemplary embodiment of a polymeric structure comprising the layered distribution of stereospecific polymers, can be used as a transport depot of the drug substance or a therapeutic agent or as coatings used in conjunction with medical devices. Under medical devices in the present context mean any device for local or regional delivery of drug substances described herein. In fact, such a polymer structure can be used with any of therapeutic agents described herein, or a combination thereof, with any device described herein for delivery of medical�CSOs substances and described here with any implantable medical devices. In addition, as mentioned above, the polymer structure can be used as a coating to cover some or all of the surfaces of the implantable medical device or as a vehicle to fill the tanks in implantable medical devices. Polymer design can take many forms, as described in detail below.

In one example implementation structure consists of alternating layers of identical chemical composition of biodegradable polymers with different optical rotations. In this example, the implementation of biodegradable polymers include poly-D-lactic acid (PDLA) and poly-L-lactic acid (PLLA). Poly-D-lactic acid synthesized from stereospecific RR-dimer lactide using a catalyst, which preserves chiral configuration in the process of polymerization with ring opening. Conversely, poly-L-lactic acid synthesized from SS-dimer lactide by polymerization with ring opening. The conditions of polymerization with ring opening known to specialists in this field. These alternating layers, lying in close proximity to each other, form stereocomplex that provides the best results in relation to local or regional delivery of the drug substance or a therapeutic agent. In other words, the identical chemical properties of two stereospecific polymers with different physical properties allow the use of a wide range of controls stability of therapeutic agents and release. In addition, changes in the rheological properties of these stereocomplex biodegradable polymers makes these materials more dense and allow the use of thinner thickness of the coating and the polymer with lower molecular weight, are achieved similar or better results than when using Nestorianism polymers. Such a thinner coating in the preferred embodiment, should improve long biological compatibility of the coating and to reduce the period of resorption. Actually are layered poly-D-lactic acid and poly-L-lactic acid to form stereocomplex in situ, which provide better control of pharmakinetic release of therapeutic agents with fewer matrix of the carrier of drugs.

Polymer-polymer complexes can be formed by mixing the polymers with different chemical compositions in suitable conditions. Such complexes comprise a polyelectrolyte complex between the polycation and anionic complex with the formation of hydrogen bonds between poly�arbonboy acid and polyester or polyol and complex with charge transfer between the polymer donor and acceptor. However, there are only limited examples where the formation of the complex may occur between the polymers with identical formulas but different spatial structures. Believed to be the first such complex was obtained Ikada, Y., et al., Sterocomplex formation Between Enantiomeric poly(lactides), Marcomolecter, 1987, 20, 904-906, in 1987, as a result of interaction between poly-L-lactic acid and poly-D-lactic acid. It is known that polymers derived from D,L-lactides are disordered and are optically active, whereas polymers derived from L-lactide and D-lactide are partially crystallized and optically active. L-lacheny polymer is crystallized to a greater extent than the polymer-based D - lactide, and can be more hydrophobic and therefore more slowly decomposes. The study Ikada also showed that if you mix equal gram-molecules of poly-L-lactic acid and poly-D-lactic acid, a mixture of polymers has a common melting temperature equal to two hundred thirty degrees Celsius, which is above the melting temperature of each polymer, taken individually, approximately one hundred eighty degrees Celsius. Crystal structure of poly-L-lactide formed from SS-lactide, as shown in Fig.23A, consists of levovrashchajushchij spiral chains, and poly-D-lactide formed from RR-lactide, �AK shown in Fig.23B, has a clockwise rotating spiral crystalline structure. Fig.23C presents meso-lactide, which upon polymerization forms a disordered, racemic polymer.

Observations received Ikada et al., can be important if such dimer-lactide used in the stereospecific synthesis of polylactide, as shown in Fig.24 poly-L-lactide and Fig.25 poly-D-lactide. For the reasons described here, stereocomplex formed between poly-D-lactic acid and poly-L-lactic acid, contributes to the implementation of more effective control over the elution of the drug substance, with application of a relatively small number of medium or thinner, or, alternatively, low-molecular coating. Stereocomplex formed between poly-D-lactic acid and poly-L-lactic acid, the result may have a greater physical stability due to its overall higher melting temperature, and can also contribute to a better depositing a therapeutic agent or means contained therein. In addition, lower molecular weight poly-D-lactic acid and poly-L-lactic acid used in stereocomplex that may lead to reduction of the time of resorption and improved biocompatibility compared to higher molecular weight of each�th of a single polymer.

An example of the technological process with the use of such stereocomplex poly-D-lactic acid and poly-L-lactic acid involves mixing one of stereospecific and optically pure polylactic acids with therapeutic agent or combination of means, and coating at least a portion of the surface of the medical device by a conventional coating process, such as coating by spraying. You may use any of the methods of coating, such as those described here. The next step is the mixing of different stereospecific and optically pure polylactic acid with opposite optical rotation with a therapeutic agent or combination of funds and the application of this coating on top of the previous layer; alternatively, the coating can not wait until the previous layer has dried. These polymers possessing opposite stereospecificity, contact in situ for the formation of stereocomplex and retaining a therapeutic agent or combination of therapeutic agents in place for local or regional delivery. The process described above can be repeated any number of times until, until you reach the required level of maintenance of a therapeutic agent or a combination of therapeutics�their funds. The top layer or covering of any of the two optically active polymers or combination of polymers can be used for further controlling the speed of release of therapeutic agent or combination of funds from the coatings.

This technology can be applied on at least part of the surface or surfaces of any of the medical devices described herein using any of therapeutic agents described herein, or combinations of these means, for using any of the techniques described herein for coating. In addition, the above process can carried out with the use of therapeutic agents and without them.

In an alternative embodiment of therapeutic agent can be added after each layer to the surface of the device, not mixing a therapeutic agent with a polymer layer.

In another alternative embodiment of the combination of optically pure polylactic acid called PLA and/or therapeutic agents described above can be mixed and placed in the container, for example into the hole inside the medical device to form a layered configuration of a therapeutic agent.

Relative to Fig.26A, 26B and 26C: here is an example of a coating or Deposit schemes using alternating�I layers of poly-D-lactic acid and poly-L-lactic acid, optional with therapeutic substance or therapeutic means, sprayed between them. Specifically, Fig.26A shows a section 11102 of the medical device in section with applied layer-by-layer stereocomplex coating. In this example implementation, one or more therapeutic agents 11104 mixed with poly-D-lactic acid 11106 and fixed on the surface of section 11102 medical device. The second layer containing poly-L-lactic acid 11108, is fixed over the first layer, thereby forming a basic structural element of the layered structure. It is important to note that it is possible to use additional layers containing the same or other therapeutic agent 1110, provided that the polymers used, identical in chemical composition, but having different physical properties. As shown, one or more additional therapeutic agents 11110 fixed on the polymer layer a basic constructive element, and then on top of a therapeutic agent or means is fixed to the second layer of the basic constructive element containing poly-D-lactic acid 11106 and poly-L-lactic acid 11108.

Fig.26B shows the tank in section 11112 11114 a medical device with a layer-by-layer stereocomplex coating deposited in it. This example is p�effect to the first bottom barrier layer poly-D-lactic acid 11116 and poly-L-lactic acid 11118 standard applied by deposition, such as jet injection. Poly-D-lactic acid and poly-L-lactic acid is premixed in a universal solvent and placed in a tank in sequential order, thus forming stereocomplex barrier layer. The number of poly-D-lactic acid and poly-L-lactic acid preferably should be the same. Then poly-D-lactic acid 11116, mixed with therapeutic agent 11120 or a combination of therapeutic agents 11120, placed in the tank with the subsequent premises poly-D-lactic acid 11118 for the formation in situ of stereocomplex and the polymer matrix with the drug substance. The second layer of stereocomplex poly-D-lactic acid and poly-L-lactic acid, optionally mixed with either the same or different therapeutic agent 11122, can be placed on the first layer, once again, forming a layered structure. The alternating layers can be repeated any number of times. To control the release of drug substance from the top of the tank can be coated with optional upper barrier layers containing poly-D-lactic acid and poly-L-lactic acid 1118.

As described above, a therapeutic agent or means can be mixed with polymers, or simply deposited, or applied as a coating between the polymer�I.

Fig.26C presents layer-by-layer deposition of poly-D-lactic acid 11130 and poly-L-lactic acid 11132 used as a drug diffusion barrier for therapeutic means or combination of means 11128 on the surface of the section chair 11126 medical device.

Fig.27A and 27B presents the coating scheme or the Deposit with the use of polymer solutions 11202 containing both poly-D-lactic acid and poly-L-lactic acid in a molar ratio of one to one, optionally also containing a therapeutic agent or means 11204, dispersed in the solution and fixed on the surface 11206 device or deposited in the reservoir 11208 device.

In accordance with another exemplary embodiment of the present invention relates to a vascular stent, providing two medicines that have the tanks, as described above, where a portion of these tanks contains a composition which releases sirolimus (rapamycin), mainly in intraparietal or alumininum direction, and in the rest of the tanks contains a composition that produce Cilostazol primarily in a luminal direction. More specifically, after the stent implantation, providing two drugs into the artery of the patient sirolimus eluated locally in the tissue of the artery and provide�AET therapeutic effect, suppressing the development of restenosis in the artery, whereas Cilostazol eluated directly into the bloodstream and provides an antiplatelet effect between the lumen of the stent, providing two drugs, and a section of artery wall adjacent to the stent, releasing the medicinal substance. Thus, dual antithrombotic effect; that is, inhibition of clot formation in the area or near the implanted stent, providing two medicinal substances, and inhibition of platelet aggregation and deposition in the area or near the stent, providing two medicinal substances. In addition, if the stent providing two drugs, used in the treatment of a patient suffering acute myocardial infarction, Cilostazol doing with the blood restored artery may provide a cardioprotective effect against myocardial tissue, limiting the state "unrecovered blood flow after stenting, mitigating reperfusion lesion and/or reducing infarct size. The stent providing two medicinal substances, also can improve the outcome of disease in patients, which are characterized by slow healing of wounds, such as patients with diabetes.

In this example, the implementation of the stent, providing two drugs, used�ü tanks for the targeted delivery of two different therapeutic agents or drugs from the stent. The composition of the polymer and sirolimus provided for controlled prolonged local delivery of sirolimus from the portion of the reservoirs of the stent abdominale to the tissue of the artery of the patient. The composition of the polymer and Cilostazol is designed for controlled prolonged delivery of Cilostazol luminal different from and separate reservoirs of the stent or directly into the bloodstream recoverable artery, or later, after the stent implantation in biological tissue that grows and covers the luminal surface of the stent.

It should be noted that, although described here isolated and separate reservoirs, in practice, can be used any other suitable mechanism of targeted delivery.

Fig.28 shows the graphical side image of a portion of the stent, providing two medicinal substances, in accordance with the present invention. Although the scheme of delivery of therapeutic agents or pharmaceutical substances can be individually designed for a number of different situations or clinical scenarios, for ease of understanding, it appears that allied tanks contain various medicinal substances. The stent 2800 providing two drugs, the figure has two reservoir 2802 and 2804, one tank is filled composition with sirolimus 2806, and jugozapaden composition with Cilostazol 2808.

The composition contains sirolimus sirolimus and a matrix copolymer of lactide and glycolide (PLGA). In the exemplary embodiment of the mixture consists of 162 micrograms of sirolimus and 93 micrograms copolymer of lactide and glycolide (PLGA). The process of mixing and filling of the reservoir are described in detail below. To ensure the release of the greater part of sirolimus in the direction of the edge or abdominales side of the stent 2800 providing two medicinal substances, as indicated by arrow 2810, the basic structure 2812 is used as a tube in the hole in the reservoir 2802 with luminal side. This basic structure 2812 may be composed of any suitable biocompatible material. In the exemplary embodiment of the basic structure consists of 2812 copolymer of lactide and glycolide (PLGA). The formation of the basic structure 2812 detailed below.

Composition with Cilostazol contains Cilostazol and a matrix copolymer of lactide and glycolide (PLGA). In the exemplary embodiment of the mixture consists of 120 micrograms of Cilostazol and 120 micrograms copolymer of lactide and glycolide (PLGA). The process of mixing and filling of the reservoir are described in detail below. To ensure the release of the greater part of Cilostazol in the direction of luminal stent 2800 providing two medicinal substances, as indicated by arrow 2814, the upper covering structure 2816 is used to�the number of tubes in the vessel opening with 2804 abdominales side. This upper covering structure 2816 may be composed of any suitable biocompatible material. In the exemplary embodiment of the upper covering structure 2816 consists of a copolymer of lactide and glycolide (PLGA). The formation of an upper covering structure 2816 detailed below.

The amount of the drug substance and polymer, as mentioned above, are the total for stent 3.5 millimeters by 17 millimeters. The range of dosages for each drug substance are described in detail further. In addition, the weight of the polymer is the sum of the weight of the polymer in the matrix and the weight of polymer in the base or top paryaya structure. The amount of the polymer used is also explained in detail next.

As stated above, the reservoirs of the stent can be completed or downloaded in a variety of ways. In the exemplary embodiment of the reservoirs or openings are filled with compositions in two separate and consecutive stages, including, first, depositing the liquid composition of the solution in the tanks and, secondly, the evaporation of the greater part, if not all, of the solvent filling solution. Ideally, the solvent is absent. Compositions in accordance with the present invention, as described above, are solid materials that remain in the tanks after removal of the n�akticheski all, while in the preferred embodiment, all of the solvent from the composition of the filling solution.

The liquid composition used for formation of solid compositions comprising sirolimus include bioresorbable or bioabsorbable polymer, in a preferred embodiment the copolymer of lactide and glycolide (PLGA) polymer, a suitable solvent, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), sirolimus, and optional stabilizer, or an antioxidant, such as butyloctyl (BHT). In a preferred embodiment at least one of the liquid filling compositions of the solutions used during deposition to create a final composition with sirolimus in the reservoirs of the stent containing butylacetyl (BHT). Alternatives for butylacetyl (BHT) include butylated hydroxyanisole (BHA), esters of Gallic acid, such as propylgallate or esters of adsorbate, such as Palmitoyl ascorbate. Preferably, the use of butylacetyl (BHT) because of its high level of effectiveness in the stabilization of sirolimus, low toxicity and hydrophobicity. Butylacetyl (BHT) is eluated from the tanks at approximately the same speed as sirolimus, thus, together with sirolimus is always present butylacetyl (BHT). Alternatives to dimethylsulfoxide (LCA�) and N-methylpyrrolidone (NMP) include dimethylacetamide (DMAc) or dimethylformamide (DMF). Preferably, the use of dimethyl sulfoxide (DMSO) as sirolimus in the presence of DMSO exhibits greater stability.

Each sequentially applied liquid composition may contain the same components, or consistently applied filling solutions can be prepared with a filling of solutions consisting of different components. In a preferred embodiment, the first series of sediment from filling solutions contains only the polymer and the solvent, after each stage of filling solutions dried. This part of the process as a result leads to the formation of basic design patterns 2812. Once the basic structure 2812 is formed, add the following solutions containing the polymer, solvent, sirolimus, and preferably butylacetyl (BHT), these solutions and dried after each filling stage. Thanks to this technological sequence of operations in the reservoir formed by the composition of sirolimus in the area of the luminal surface of the vessel is present in a lower concentration, and in the parietal surface of each reservoir sirolimus present in relatively high concentrations. This configuration, as described above, forms a longer path or a higher resistance to elution of medicines�tively substances in the luminal direction compared with the elution of the drug in parietal direction, and, thus, contributes to almost all of sirolimus was delivered to the mural side of the stent and the artery tissue. In other words, some of the tanks that delivers sirolimus mainly parietal, will be designed, where the capacity of the reservoir on the luminal surface of the stent or near it will contain primarily polymer and a minor amount of sirolimus, whereas the capacity of the same tank on the parietal side of the stent or near it will contain mainly sirolimus and a minor proportion of the polymer.

The composition of sirolimus within the tank will mostly include sirolimus, bioresorbable polymer, a stabilizing agent and the solvent in proportion to each other. In the preferred embodiment, the total dose or amount of sirolimus coming from eluting stent substance, is from 0.6 to 3.2 micrograms per square millimeter square tissue of the artery, where the area of the tissue of the artery is defined as theoretical surface area of a cylinder, the diameter and length of which correspond to the diameter and length of the expandable stent implanted in an artery. In a more preferred embodiment, the total dose or amount of sirolimus coming from eluting stent substances�, is from of 0.78 to 1.05 micrograms per square millimeter square tissue artery.

As mentioned above, the bioresorbable polymer used in the composition includes a copolymer of lactide and glycolide (PLGA). In a more preferred embodiment, the composition includes a copolymer of lactide and glycolide (PLGA), where the molar ratio of lactide to glycolide residues (L:G) in the polymer chain is in the range from about 85:15 to about 65:35. In an even more preferred embodiment, the composition must contain a copolymer of lactide and glycolide (PLGA), where the molar ratio of lactide to glycolide residues (L:G) in the polymer chain is in the range from about 80:20 to about 70:30. Copolymer of lactide and glycolide (PLGA) should preferably have internal viscosity in the range from about 0.3 to about 0.9. In an even more preferred embodiment, the copolymer of lactide and glycolide (PLGA) must have the internal viscosity in the range from approximately 0.6 to approximately 0.7. The weight ratio of sirolimus and a copolymer of lactide and glycolide (PLGA), denoted as D/P ratio preferably should be between about 50/50 to about 70/30, and still more preferably from about 54/46 to about 66/34. All ratios are given in percentage by weight. In an alternative embodiment, �otnositelnye weight ratio of sirolimus and a copolymer of lactide and glycolide (PLGA) can be expressed in normalized form, D:P. Thus, the preferred D:P ratio ranges from about 1:0.4 to about 1:1.2 and more preferably in the range from about 1:0.52 to about 1:0.85 to.

Also, as described above, the composition of sirolimus preferably contains butylacetyl (BHT). The number of added butylacetyl (BHT) is preferably from about 1% by weight to about 3% by weight of the total amount of sirolimus. In an even more preferred embodiment, the number of butylacetyl (BHT) is from about 1.2% by weight to approximately 2.6% by weight of the total amount of sirolimus.

To prepare the filling solution of the above components require suitable solvent. Dimethyl sulfoxide (DMSO) is the preferred solvent and in the preferred embodiment is used in an amount of from about 1% to about 20%, as percentage by weight to the weight of sirolimus. In an even more preferred embodiment, dimethyl sulfoxide (DMSO) is used in an amount of from about 1% to about 15%, as percentage by weight to the weight of sirolimus. In an even more preferred embodiment, the amount of dimethyl sulfoxide (DMSO) is from about 4% to about 12%, as percentage by ve�have to weight sirolimus.

Liquid compositions used for forming solid compositions containing Cilostazol include bioresorbable or bioabsorbable polymer, preferably a copolymer of lactide and glycolide (PLGA) polymer, a suitable solvent, such as dimethylsulfoxide (DMSO), or N-methylpyrrolidone (NMP) and Cilostazol. Permissible use in the composition of the same alternatives of dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP), however, preferred is the use of dimethyl sulfoxide (DMSO).

Each sequentially applied liquid composition may contain the same components, or consistently applied filling solutions can be prepared with a filling of solutions consisting of different components. In a preferred embodiment, the first series of sediment from filling solutions contains polymer, Cilostazol and solvent after each stage of filling solutions are dried, and the last series filling solutions contains only the polymer and the solvent, after each of the filling phase solutions are dried. This process leads to the formation of structure the upper structure 2816. Thanks to this technological sequence of operations in the vessel composition is formed in which Cilostazol in the area of the wall surface reserve�RA is present in a lower concentration, and in the luminal surface of each tank Cilostazol is present in relatively high concentrations. This configuration, as described above, forms a longer path or a higher resistance to elution of the drug in parietal direction compared with the elution of the drug in the luminal direction and, thus, helps to ensure that virtually the entire Cilostazol been transported to the luminal side of the stent and into the bloodstream and/or tissues of the arteries. In other words, some of the tanks that delivers Cilostazol primarily in a luminal direction, will be so designed, where the capacity of the reservoir on the parietal surface of the stent or near it will contain primarily polymer and a minor amount of Cilostazol, whereas the capacity of the same tank at the luminal surface or near it will contain mainly Cilostazol and a minor proportion of the polymer.

The composition of Cilostazol inside the tank will mostly consist of Cilostazol, camerascamera polymer and solvent in proportion to each other. In the preferred embodiment, the total dose or the number of Cilostazol coming from eluting stent substance, is from 0.4 to 2.5 microg�AMM per square millimeter square tissue artery where the area of the tissue of the artery is defined as theoretical surface area of a cylinder, the diameter and length of which correspond to the diameter and length of the expandable stent implanted in an artery. In a more preferred embodiment, the total dose or the number of Cilostazol coming from eluting stent substance, ranges from 0.56 to 1.53 micrograms per square millimeter square tissue artery.

As described above, the bioresorbable polymer used in the composition comprises a copolymer of lactide and glycolide (PLGA). In a more preferred embodiment, the composition includes a copolymer of lactide and glycolide (PLGA), where the molar ratio of lactide to glycolide residues (L:G) in the polymer chain is in the range from about 90:10 to about 25:75. In an even more preferred embodiment, the composition must contain a copolymer of lactide and glycolide (PLGA), where the molar ratio of lactide to glycolide residues (L:G) in the polymer chain is in the range from about 80:20 to about 45:55. Copolymer of lactide and glycolide (PLGA) should preferably have internal viscosity in the range from about 0.1 to about 0.9. In an even more preferred embodiment, the copolymer of lactide and glycolide (PLGA) must have the internal viscosity in the range from about 0.4 to about 7. The weight ratio of Cilostazol and copolymer of lactide and glycolide (PLGA), denoted as D/P ratio preferably should be from about 35/65 to about 95/5, and still more preferably from about 47/53 to approximately 86/14. All ratios are given in percentage by weight. In an alternative embodiment, the relative weight ratio of Cilostazol and copolymer of lactide and glycolide (PLGA) can be expressed in normalized form, D:P. Thus, the preferred D:P ratio ranges from about 1:0.05 to about 1:2.0, and more preferably in the range from about 1:0.16 to about 1:1,20.

To prepare the filling solution of the above components require suitable solvent. Dimethyl sulfoxide (DMSO) is the preferred solvent and in the preferred embodiment is used in an amount of from approximately 0.01% to approximately 20%, as percentage by weight to the weight of Cilostazol. In an even more preferred embodiment, dimethyl sulfoxide (DMSO) is used in an amount of from about 1% to about 15%, as percentage by weight to the weight of Cilostazol. In an even more preferred embodiment, the amount of dimethyl sulfoxide (DMSO) is from about 3% to approx�till then 12% as a percentage by weight to the weight of Cilostazol.

As described above, the stents may be made of any suitable biocompatible material. In this embodiment of the stent preferably is made of a cobalt alloy. In addition, the ratio of polymers in the composition of the copolymer of lactide and glycolide (PLGA) may vary. For example, a copolymer of lactide and glycolide (PLGA) may have a ratio of L:G from about 100:0 to about 0:100, in a more preferred embodiment, from about 50:50 to about 85:15, and even more preferably from about 60:40 to about 80:20.

Unique performance or design of the stent, providing two medicinal substances described by the present invention provides a completely independent speed selection sirolimus and Cilostazol. In addition, this unique design ensures the delivery of sirolimus mainly in parietal or alumininum direction and delivery of Cilostazol primarily in a luminal direction.

Relative to Fig.29: total interest expressions of release of drugs in vivo for each medicinal substance within the thirty-day period. Curve 2902 shows the release profile of Cilostazol, whereas the curve 2904 shows the release profile of sirolimus. Fig.30 count�Cesky displays the number of each drug, micrograms, released in vivo. Curve 3002 displays a profile of Cilostazol, and curve 3004 displays the profile of sirolimus. Curves in the figure show that both drug substances are released independently from each other, and their interaction with each other is minimized or non-existent. About sixty (60) to seventy (70) percent release of both tools was observed during the first thirty (30) days. Due to the fact that in appropriate reservoirs contains a different number of medicinal substances (by weight), the total amount released within thirty (30) days of the drug substance above for sirolimus than for Cilostazol.

It is important to note that the laying means or the dosage of each agent can be expressed in a variety of ways, including those listed above. In a preferred embodiment of the ranges of doses can be expressed in the form of grouped absolute weight ranges of the drug, based on a standard stent size 3,5×17 mm. Thus, the range of doses is determined by the size of the stent and corresponds to the number of tanks. For example, in the stent, size 3.5 x 17 mm number of holes or reservoirs is equal to 585. In other embodiments, the number of tanks for the specified size of the stent can vkljucitev yourself 211 tanks stent 2.5 x 8 mm, 238 the stent of 3.0×8 mm, 290 tanks stent of 3.5×8 mm, 311 tanks stent of 2.5×12 mm, 347 tanks stent of 3.0×12 mm, 417 reservoirs of the stent, a 3.5×12 mm, 431 tanks stent 2.5 x 17 mm, 501 tanks stent of 3.0×17 mm, 551 tanks stent 2.5 x 22 mm, 633 tanks stent of 3.0×22 mm, 753 tanks stent 3,5×22 mm, 711 reservoirs of the stent, a 2.5×28 mm, 809 tanks stent of 3.0×28 mm, 949 tanks stent of 3.5×28 mm, 831 tanks stent of 2.5×33 mm, 963 tanks stent of 3.0×33 mm and 1117 tanks stent 3,5×33 mm. Ranges of doses reported here cover the ratio of tanks containing sirolimus, and tanks containing Cilostazol 20%/80% to 80%/20%. The dosage of sirolimus for use in stent size 3,5×17 mm lies in the range from about 30 micrograms to about 265 micrograms, in a more preferred embodiment from about 130 micrograms to about 200 micrograms, and still more preferred dosage range is from about 150 micrograms to about 180 micrograms. It is important to note here that given the approximate size and number of tanks. Dosage Cilostazol the stent, the size of 3.5×17 mm is from about 50 micrograms to about 200 micrograms, in a more preferred embodiment, from about 90 micrograms to appr� 200 micrograms, even more preferred dosage range from about 100 micrograms to about 150 micrograms. As mentioned above, the dose ranges are determined by the size of the stent and tanks. These doses are given for the final product sterilized stent.

The stent providing two medicinal substances, the present invention can be used to treat a number of pathological conditions, in accordance with the above description, including restenosis, thrombosis, acute myocardial infarction, reperfusion injury, a phenomenon unrestored capillary blood flow, coronary artery disease, and/or to enhance the effect of the application of sirolimus to prevent restenosis in diabetic patients. In addition to sirolimus and Cilostazol with the device can be used with other medicines. For example, as mentioned above, it is possible to add an antithrombotic agent such as heparin. Additional funds can be included in the coating and placed in the tanks. It is important to note that any number of drugs and combinations of tanks, as well as coatings can be applied in order to adapt the device to a specific pathological condition.

In the framework of the present invention, rapamycin includes rapamycin and all analogs, production�s and conjugates, that bind to FKBP12, and other immunophilins, and possesses the same pharmacologic properties as rapamycin including inhibition of TOR. Other drugs in the class of Cilostazol include milrinone, vesnarinone, enoximone, pimobendan, inamrinone, cilostamide, Catherine, motapizone, oxazine, imazodan, Pletal, Primacor, Inamrinone Lactate and merienda.

It is also important to note that the period of release can be calculated individually. For example, in vitro release of sirolimus ranges from approximately 7 to approximately 120 days and more preferred is from about 14 to about 90 days, whereas in vitro the release of Cilostazol can vary from approximately 5 to approximately 61 days. The status of the release can be specifically designed for each individual drug.

Although shown and described herein options for implementation are considered to be the most practical and preferred embodiments, it is clear that the experts in this field of technology are presented the possibilities to deviate from the established performance and methods shown and described herein, which may find practical application without departing from the scope of the claims and without disturbing its essence. The present invention is not limited to the� specific designs, described and shown here, but all the structures of the invention should be consistent with all modifications that may fall within the formula of the present invention.

1. The device of the drug delivery that contains:
implantable intraluminal frame having a luminal surface and abdominally surface;
a set of through holes in the intraluminal frame, where each of the plurality of through holes comprises a composition selected from the group consisting of:
the composition of the mTOR inhibitor and a base structure having a configuration that allows the mTOR inhibitor in the composition is an inhibitor of mTOR to elyuirovaniya mainly in alumininum direction of seven (7) to one hundred twenty (120) days, wherein the composition is an inhibitor of mTOR contains a polymer in combination with an mTOR inhibitor, and the basic structure contains multiple layers of the polymer in the absence of the mTOR inhibitor; and
the composition of an inhibitor of phosphodiesterase III and the upper covering structure having a configuration that allows the inhibitor of phosphodiesterase III in the composition is an inhibitor of phosphodiesterase III to buyouts, mainly in the luminal direction from five (5) to sixty-one (61) day,
the composition of an inhibitor of phosphodiesterase III contains the polymer in combination with an inhibitor of phosphodiesterase III, � upper covering structure contains multiple layers of the polymer in the absence of an inhibitor of phosphodiesterase III;
so that at least one of the plurality of holes comprises a composition of mTOR inhibitor in an amount of from 0.6 to 3.2 micrograms per square millimeter square tissue artery and the underlying structure in the absence of an inhibitor of phosphodiesterase III, and at least another of the plurality of holes comprises a composition of an inhibitor of phosphodiesterase III in an amount of from 0.4 to 2.5 micrograms per square millimeter square tissue artery and the upper covering structure in the absence of the mTOR inhibitor.

2. The device of the drug delivery according to claim 1, where the composition of the mTOR inhibitor comprises a composition of rapamycin.

3. The device of the drug delivery according to claim 2, where the composition of rapamycin comprises a composition of sirolimus.

4. The device of the drug delivery according to claim 1, where the composition is an inhibitor of phosphodiesterase III contains Cilostazol.

5. The device of the drug delivery according to claim 1, where the composition is an inhibitor of phosphodiesterase III contains at least one substance of the following: milrinone, vesnarinone, enoximone, pimobendan and merienda.

6. The device of the drug delivery according to claim 1, wherein the implantable intraluminal frame contains the stent.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to application of composition for preparation of medications aimed at secondary prevention of cardiac infarction. Application of composition based on substances, applied in Chinese medicine, for preparation of medications aimed at secondary prevention of cardiac infarction, with composition, based on substances, applied in Chinese medicine, is prepared from composition, which contains Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae, taken in specified ratio.

EFFECT: composition makes it possible to prepare medication, which is effective for secondary prevention of cardiac infarction, prevents stenocardia, improves coronary blood flow.

14 cl, 8 dwg, 74 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with a crystalloid cardioplegic solution, which contains salt solution, including sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydrogen carbonate, water for injections and a structural analogue of natural apelin X-Arg(NGY)-Pro-Arg-Leu-Ser-His-Lys-Cly-Pro-Nle-Pro-Phe-Z, where X=CH3, Y=H, Z=OH. The group of inventions also deals with the crystalloid cardioplegic solution, containing salt solution, including sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydrogen carbonate, water for injections and structural analogue of natural apelin X-Arg(NGY)-Pro-Arg-Leu-Ser-His-Lys-Cly-Pro-Nle-Pro-Phe-Z, where X=H, Y=NO2, Z=NH2.

EFFECT: group of inventions provides the recovery of the coronary flow, cardiac contractile and pump function in case of the reperfusion and the reduction of injury to membranes of cardiomyocytes.

2 cl, 2 dwg, 8 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiac surgery, and represents cardioplegic solution, which contains sodium chloride - 3.41-3.62, potassium chloride - 1.092-1.156 g, magnesium chloride - 3.190-3.485 g, calcium gluconate - 0.0105-0.0130 g, mannite - 4.365-4.520 g, L-carnosine - 20.1504-24.1650 g, N-acetylcarnosine - 8.056-11.032 g, L-histidine - 0.705-0.820 g, water for injections to 1000 ml.

EFFECT: invention ensures prevention of reduction of amplitude, speed of front and speed of pulse-wave reduction, as well as increase of diastolic pressure in left heart ventricle during reperfusion with preservation of buffer capacity and osmolarity of cardioplegic solution with physiological pH parameters.

4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel derivatives of pyrazole pyridine of formula , as well as to its tautomers, geometrical isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, where G1 represents H; G2 represents -CHR1R2; R1 and R2 independently on each other are selected from H; C1C6-alkoxy-C1C6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or -CHR1R2 together form a ring, selected from an optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3 is selected from an optionally substituted C1C6-alkoxy -C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1C6-alkyl; G4 is selected from a substituted acyl-C1C6-alkyl, where acyl represents a group -CO-R and R stands for H or morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridine- or furanyl-C1C6-alkyl; morpholine- or piperidine-C1-C6-alkyl; G5 represents H; where the term "substituted" stands for the groups, substituted with 1 to 5 substituents, selected from the group, which includes a "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "acylamino", which stands for the group NRCOR", where R represents H and R" represents a C1-C6-alkyl, "phenyl", "fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6-alkoxycarbonyl", "halogen". The invention also relates to a pharmaceutical composition based on the formula (I) compound and particular compounds.

EFFECT: obtained are the novel derivatives of pyrasole pyridine, useful for the treatment and/or prevention of disorders or states, associated with NADPH-oxidase.

12 cl, 3 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine.

SUBSTANCE: group of inventions relates to field of therapy and/or prevention of diseases in mammals, in particular humans. Group of inventions includes medication for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis by increasing content of polyunsaturated fatty acids in mammal's blood, representing dairy product of ruminants with reduced cholesterol content, where cholesterol content constitutes from 10 mg/100 g of fat to 150 mg/100 g of fat, as well as application of dairy product of ruminants with reduced cholesterol content, in which cholesterol content constitutes from 10 mg/100 g of fat to 150 mg/100 g of fat, for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis by increasing content of polyunsaturated fatty acids in mammal's blood.

EFFECT: obtaining medication for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis.

18 cl, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, wherein R1 and R2 are identical or different and specified in an alkyl or alkenyl hydrocarbon chain; the R3 group values split by lipase are specified in the patient claim. R4 and R5 are independently hydrogen or C1-C7alkyl; R6 represents hydrogen or C1-C7alkyl; and R7 and R8 are independently hydrogen or C1-C7alkyl. The invention also refers to using compounds of formulas ,

which are introduced into the mammalian biological system and increase the cell concentrations of specific sn-2 substituted ethanolamine-plasmalogens.

EFFECT: compounds are applicable in treating or preventing the age-related disorders associated with high membrane cholesterol, high amyloids and low plasmalogens, such as neurodegeneration, cognitive disorder, dementia, cancer, osteoporosis, bipolar disorder and vascular diseases.

11 cl, 18 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to cardiology, and represents a method of the drug treatment of patients in late rehabilitation period after aortocoronary bypass surgery, consisting in the combined administration to the patient of medications thrombo ASS 100 mg, atorvastatin 20 mg and additionally amlodipine in a daily dose from 5 to 10 mg and losartan in a daily dose from 25 to 100 mg.

EFFECT: invention ensures the long-term preservation of results of surgical myocardium revascularisation.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to fluorinated aminotriazole derivatives of formula

,

wherein A represents a group specified in furanyl, oxazolyl and thiazolyl, wherein two attachment points of the above group are found in 1,3-position; R1 represents phenyl, which is unsubstituted, mono- or disubstituted, wherein the substitutes are independently specified in a group consisting of halogen, methyl, methoxy group, trifluoromethyl, trifluormethoxy group and dimethylamino group; and R2 represents hydrogen, methyl, ethyl or cyclopropyl. Besides, the invention refers to a pharmaceutical composition containing the compound of formula (I), and to using the compound of formula (I) for preparing a therapeutic agent.

EFFECT: compounds of formula (I) possessing the agonist activity in relation to ALX receptor.

26 cl, 2 tbl, 36 ex

FIELD: medicine.

SUBSTANCE: method involves taking general baths and prescribing mud applications on lower extremities with underlying standard drug therapy. The patient takes prepared silicate-carbonate baths with the concentration of sodium salt of metasilicic acid of 100-150 mg/l and the content of carbon dioxide of 1.2 g/l. The bath water temperature is 36°-37°C. The length of the procedure is 10-15 minutes. Taking the baths is followed by having a 30-40-minute rest. Sulphide silt mud sock- or boot-like applications are performed. The mud temperature is 32°-36°C; the length of procedure is 8-20 minutes. The procedures are performed 2 days running, with a pause on the 3rd day. The therapeutic course makes 6-10 procedures.

EFFECT: method provides the further development of the symptom-free involvement of target organs: heart, kidneys, vessels by taking the antihypertensive, antianginal and antiarrhythmic effects, promotes the energetic and adaptation possibilities of the body.

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula or , where Ar1 represents phenyl group, optionally substituted with one or several identical or non-identical halogen atoms; R1 represents hydrogen atom; R4, R5, R6a, R6b represent hydrogen atoms; Y, Z independently represent linear C1-4 alkylene group, optionally substituted with one linear C1-4 alkyl group; Ar2 stands for condensed with benzene 5-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, substituted with one linear C1-4 alkyl group, or derivative of 5- or 6-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, condensed with heteroaromatic 6-memebered ring, containing one or two nitrogen atoms, substituted with one linear C1-4 alkyl group, linear C1-4 alkoxygroup or group -NR7R8, where R7 and R8 independently stand for hydrogen atom, linear or branched C1-4 alkyl group, or R7 and R8 together with nitrogen atom form group of general formula , where R2, R3 represent linear C1-4 alkyl groups, A stands for group -CHR12, oxygen atom or group -NR9, where R12 and R9 stand for hydrogen atom or linear C1-4 alkyl group, m has value 1 or 2, n has value 1 or 2, o has value 0 or 1, p has value 0 or 1, Q stands for group -O-, group -N--H or group -N--CO-R10, where R10 stands for linear C1-4 alkyl group or -NH-R11 group, where R11 represents linear C1-4 alkyl group; and to their salts. Invention also relates to methods of obtaining therein and to based on them pharmaceutical composition, possessing antagonistic activity with respect to receptor CCR3.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions, which can be applied in medicine for obtaining medication, intended for treating asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory intestinal diseases, ulcerous colitis, Crohn's disease, allergic conjunctivitis, multiple sclerosis or HIV-infection and AIDS-associated diseases.

14 cl, 3 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new polycyclic compounds, pharmaceutically acceptable salts thereof of general formula wherein R1 -phenyl, pyridyl, optionally substituted, or C3-7-cycloalkyl; R2 -H, -CH2R3, -C(=O)R3, -C(=O)N(R4)R3, and -SO2-pyridyl, wherein R3-H, C1-6 alkyl, C2-6 alkenyl, C3-7-cycloalkyl, -(CH2)m-phenyl -(CH2)m-(5-, 6- or 9-member heterocyclyl with 1-3 heteroatoms N, O or S); m is equal to 0-6; R4 -H; X represents O or S; the alkyl, alkenyl, cycloalkyl, phenyl and heterocyclyl groups may be substituted by one or more substitutes. A together with atoms whereto attached forms phenyl or heteroaryl with 1 or 2 nitrogen atoms, optionally substituted; B-C means -CH2-(CH2)z-, wherein z is equal to 1 or 2; D represents -CRIIIRIV-, wherein RIII and RIV are identical, and mean CH3 or H; or RIII and RIV together with the atom C whereto attached form a 3-member cycloalkyl ring, a pharmaceutical composition containing them, and the use of the above compounds for treating viral RSV infections.

EFFECT: new polycyclic compounds are described.

24 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a composition of a rapamycin analogue for immunomodulation and antiproliferation that involves a crystalline form of the rapamycin analogue having at least one of the following structures: and a pharmaceutically acceptable carrier. What is also described a method for preparing the crystalline form of the rapamycin analogue.

EFFECT: what is described is a new form of rapamycin, which can be used in the therapeutic treatment.

38 cl, 30 ex, 11 tbl, 21 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel isoquinolinone derivatives of formula (I) , wherein R1 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (CH2)a-X-Ar and (CR101R102)a-X-Ar, where said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from -(C1-C6)alkoxy, -halogen, -OH, -heterocycloalkyl, (C3-C7)cycloalkyl and -NR8R9; R2 is selected from H and (C1-C6)alkyl; R is selected from H, (C1-C6)alkyl and (CH2)d-Y; provided that when R3 is (CH2)d-Y, R2 is selected from H; R4 and R5 are independently selected from H, (C1-C6)alkyl and halogen; R is (C3-C7)cycloalkyl; R7 is H; Ar is phenyl or heteroaryl, optionally substituted with 1, 2 or 3 groups independently selected from -(C1-C6)alkyl, -(CH2)e-O-(C1-C6)alkyl, -(CH2)e-S(O)f(C1-C6)alkyl, -(CH2)e-N(R10)-(C1-C6)alkyl, -(CH2)e-Z-(C1-C6)alkyl, -halogen, heterocycloalkyl, -C(O)NR8R9, -NR8R9 and -C(O)OH, where (C1-C6)alkyl in each case is independently optionally substituted with 1, 2 or 3 groups, independently selected from -NRI2R13; X is selected from a single bond; Y is NR16R17, where R16 and R17 together with a nitrogen atom with which they are bonded form a 5-7-member ring, optionally containing an additional heteroatom NR27, where said ring is optionally substituted on the carbon atom with 1 or 2 substitutes independently selected from -(C1-C6)alkyl, where said -(C1-C6)alkyl is optionally substituted with -OH; and where R27 is selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with -OH; Z is selected from C(O)N(R18); R8 and R9 are independently selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups, independently selected from NR19R20; or R8 and R9 together with the nitrogen atom with which they are bonded form a 5-6-member ring, optionally containing an additional heteroatom, selected from NR21; R12 and R13 are independently selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with -(C1-C6)alkoxy, -OH; or R12 and R13 together with the nitrogen atom with which they are bonded form a 5-6-member ring optionally containing an additional heteroatom selected from NR24; R10, R18, R19, R20, R21, R22, R23 and R24 are independently selected from H and (C1-C6)alkyl; a is selected from 1, 2, 3, 4, 5 and 6; d equals 0 or 1; e equals 0; f is independently selected from 1 and 2; where the heterocycloalkyl is a 5-6-member non-aromatic cyclic ring bonded at a C atom, having 1-2 NR28 atoms; optionally having one double bond; the heteroaryl is a 6-member aromatic ring containing 1 N atom; R is selected from H, (C1-C6)alkyl and -C(O)O-(C1-C6)alkyl; R101 is (C1-C6)alkyl; R102 is H; or pharmaceutically acceptable salts thereof or N-oxides. The invention also relates to methods of producing said compounds and use thereof as a p38 kinase inhibitor.

EFFECT: improved method.

13 cl, 4 dwg, 1 tbl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and biotechnology and represents a therapeutic antimalaria drug containing an antimalaria agent and excipients differing by the fact that it additionally contains a biomass of the Bacillus subtilis probiotic strains in the amount of CFU not less than 1×108 cell/tablet (dose) with the ingredients in the preparation taken in certain proportion, wt %.

EFFECT: invention provides antiprotozoal action with probiotic effect.

7 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes the pyrrolo- and thiazolopyridinium compounds and their pharmaceutically acceptable salts covered by general structural formula I: wherein the values A, B, R1, R2, R3, R4, R5, R6, R7 and R8 are those as presented in cl.1, and a pharmaceutical composition based on the given compound for inhibition of hypoxia-inducible factor (HIF) hydroxylase activity.

EFFECT: there are produced and described new compounds able to modulate hypoxia-inducible factor (HIF) stability and/or activity.

29 cl, 178 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmaceutics and medicine and pharmaceutical composition for treatment of reperfusion disorders, which contains inert auxiliary substances and as active component compounds of general formula I-Iva.

EFFECT: obtaining pharmaceutical composition for treatment of reperfusion disorders.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazolopyridin-4-amines, pyrazoloquinoline-4-amines, pyrazolonaphthyridine-4-amines and 6,7,8,9-tetrahidropyrazoloquinoline-4-amines, pharmaceutical compositions based on said compounds, which can be used as immunomodulators for inducing or suppressing biosynthesis of cytokines in aminals and when treating viral and malignant diseases.

EFFECT: obtaining novel biologically active compounds.

24 cl, 197 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: there are involved local hyperthermia, teletherapy and chemotherapy. The chemotherapy is two-staged and follows the schedule: paclitaxel 175 mg/m2 intravenously drop-by-drop for 3 hours and carboplatin AUC 6 intravenously drop-by-drop on the 1st and 22nd days. The teletherapy starts from the 3rd day in the multi-fractionation mode for 5 weeks in a dose of 1.3 Gy × 2 times a day to reach a total boost dose of 66 isoGy. The hyperthermia is conducted from the 1st to 33rd days of the chemotherapy 3 times a day, 15 sessions in all, 3 hours before administering the chemopreparations or conducting the radiation session to temperature 42 to 44°C for 60 min.

EFFECT: higher patient's survival rate ensured by reducing incidence of local recurrences and remotes metastases accompanied by improving acceptability of the treatment and quality of life.

1 ex

Up!