Title of Invention

AN IMPLANTABLE MEDICAL DEVICE AND PROCESS OF PREPARATION THEREOF

Abstract

An implantable medical device (1) for providing controlled delivery of therapeutic agent, said implantable medical device comprising a flexible substrate material such as herein described (2) adapted for introduction into the body of a patient; said substrate material being successively coated one above the another with a polymeric base layer (3) wherein the coating comprises therapeutic agent to polymer in a ratio of 33.96 % : 66.04 %, a polymeric middle layer (4) wherein the coating comprises therapeutic agent to polymer in a ratio 26.45 %: 73.55 %, a polymeric top layer (5) wherein the coating comprises therapeutic agent to polymer ratio 24.77 % : 75.23 % and a protective layer (6) wherein the coating comprises therapeutic agent to polymer ratio 00.00 % : 100.00 %; wherein the base (3), the middle (4) and the top polymeric layers (5) comprise varying amounts of the therapeutic agent such as herein described and the polymer essentially comprises a mixture of Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) SAHAJANAND MEDICAL TECHNOLOGIES PVT. LTD. of Sahajanand House, Parsi Street, Saiyedpura, Surat 395 003, Gujarat, India The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. . ORIGINAL 497/MUM/2003 19/05/2003 GRANTED 28-12-2006 CONTROLLED DELIVERY OF THERAPEUTIC AGENT FROM IMPLANTABLE MEDICAL DEVICES FIELD OF THE INVENTION: The present invention relates to an implantable medical devices. More particularly, the present invention relates to a Paclitaxel Eluting Stent System comprising a pre-mounted 316L Stainless Steel stent coated with a blend of biodegradable polymers and Paclitaxel drug, wherein the drug content on the stent is 3.0 micrograms/mm2. BACKGROUND AND PRIOR ART TO THE INVENTION Many pharmacologic (biochemical) attempts for systemic delivery have been made to reduce the amount of restenosis. The development of coronary stents has revolutionized the practice of interventional cardiology over the past 5 years. Coronary Stents are indicated for use in-patients with symptomatic ischemic heart disease due to coronary artery lesions. Stents are now used in approximately 80% of percutaneous coronary interventions. Unfortunately, epidemiological data shows that 20-25% of coronary stents with restenose. It is clear that most effective pharmacological support to prevent restenosis is the controlled-release of anti-proliferative drugs directly to the target vessel tissue. In an effort to reduce restenosis, investigators have tried many drugs incorporated into stents. Paclitaxel (Taxol) is an antitumoral drug naturally extracted from the bark of Pacific Yew Taxus Brevifolia and purified by HPLC method without any semi-synthesis process. Its antineoplastic properties are mainly related to unique effects on the microtubular function. Paclitaxel is a white to off-white crystalline powder that is highly lipophilic and insoluble in water and melts at around 216-217°C. It has a molecular weight of 853.93 and molecular formula C47H51NO14. Paclitaxel stabilizes microtubules by shifting the dynamic equilibrium between soluble and in soluble tubulin. Thus, paclitaxel inhibits cell processes dependent on microtubule turnover including mitosis, cell proliferation and cell migration while the cells remain viable (cytostatic). Microtubules are formed by polymers of tubulin in a dynamic equilibrium of alpha and beta subunits, and their principal function is the formation of the mitotic spindle during cellular division. Furthermore, microtubules help to maintain the cell shape, and are intimately related to the functions of intracellular transport, signaling, protein secretion and motility. Paclitaxel induces abnormal polymerization of tubulin, forming stable dysfunctional microtubules and thereby disrupting these cellular processes that rely on prompt depolymerization of the microtubules. Thus, paclitaxel is an antiproliferative agent that blocks the mitotic cycle at the metaphase/anaphase transition. In experimental models of restenosis, local administration of paclitaxel led to significant neointimal reduction, with a clear dose-dependent effect. However, although associated with more pronounced neointimal inhibition, exposure to higher doses was shown to eliminate direct contact between stent struts and the medial wall, implying an enlargement of the vessel wall relative to the stent, even though no aneurysmal dilatation was observed. Unlike other antimicrotubule drugs, such as vinca alkaloids, which induce the disassembly of microtubules, paclitaxel promotes the polymerization of tubulin. At subnanomolar concentrations, paclitaxel inhibits the disassembly of microtubules, whereas it increases their mass and numbers at higher, albeit clinically achievable, concentrations. The microtubules formed in the presence of paclitaxel are extraordinarily stable and dysfunctional, thereby causing the death of the cell by disrupting the normal microtubule dynamics required for cell division and vital interphase processes. Paclitaxel also induces the expression of the gene for tumor necrosis factor a, but structure-activity studies indicate that these activities are not related to paclitaxel's effects on microtubule assembly, raising the issue of what part these cytokines play in the antitumor activity of paclitaxel. The binding site for paclitaxel is distinct from the binding sites for guanosine triphosphate, colchicine, vinblastine, and podofilox (podophyllotoxin). Paclitaxel binds to the N-terminal 31 amino acids of the beta-tubulin subunit in the microtubule, rather than to tubulin dimers. In intact cells, paclitaxel induces the bundling of microtubules, which may be a useful clinical correlate of a lethal drug effect, and the formation of large numbers of asters of mitotic spindles (Fig. 2). It also enhances the cytotoxic effects of ionizing radiation in vitro, possibly by inducing arrest in the premitotic G2 and mitotic phases of the cell cycle, which are the most radiosensitive phases. The feasibility of using paclitaxel in combination with radiation to treat patients with locally advanced lung, head and neck, and esophageal cancers, which are responsive to both kinds of treatment, is currently being evaluated. Two mechanisms of acquired resistance to the taxanes have been characterized. First, some tumors contain alpha- and beta-tubulin with an impaired ability to polymerize into microtubules and have an inherently slow rate of microtubule assembly that is normalized by the taxanes. A second mechanism involves the amplification of membrane phosphoglycoproteins that function as drug-efflux pumps. The multidrugresistant phenotype of tumor cells confers varying degrees of cross-resistance to various structurally bulky natural products, including anthracyclines, etoposide, vinca alkaloids, colchicine, and taxanes. Paclitaxel has a unique way of preventing the growth of cells: it affects the cell's skeleton (microtubules), which plays an important role in cell functions. In normal cell growth, microtubules are organized when a cell starts dividing. Paclitaxel prevents this division by stabilizing the microtubules. The AP-1 activator protein stimulates gene activation, resulting in proteins and cytokinas, important in chronic inflammation. Paclitaxel inhibits AP-1 interaction with genes that begin the process of chronic inflammation (i) proteins necessary for cell division, (ii) cell migration, and (iii) enzymes that cause tissue destruction (extracellular matrix breakdown). Objects of the present invention The main object of the present invention is to develop a novel implantable medical device for controlled delivery of therapeutic agents. Another object of the present invention is to provide a novel method for preparing the implantable medical device for controlled delivery of therapeutic agents. Yet another object of the present invention is to provide a novel stent containing paclitaxel. Brief Description of the Accompanying Drawings In the drawings accompanying the specification, Figure 1 represents the release of paclitaxel in a controlled manner from a polymer matrix bound to the stent. Figure 2 represents the In-Vitro release profile of paclitaxel from polymer-coated stents. Figure 3 represents the scanning electron microscope image showing smooth surface of crimped stent. Figure 4 represents the scanning electron microscope image showing smooth and uniform surface of infinnium paclitaxel eluting stent. Figure 5 represents the scanning electron microscope image showing thickness of drug coating layer of infinnium paclitaxel eluting stent. Figure 6 represents the scanning electron microscope image showing different layers of infinnium paclitaxel eluting stent. Figure 7 indicates that paclitaxel blocks the cell cycle between G2 and M phase by the following processes. Figure 8 represents the paclitaxel's unique way of preventing the growth of cells. Figure 9 represents the spray gun used for coating the drug on the stent. Figure 10 represents the process for preparing the paclitaxel coated stent. Figure 11 represents the cross-sectional view of the coated stent of the present invention. Statement of the Invention Accordingly, the present invention provides an implantable medical device (1) for providing controlled delivery of therapeutic agent, said implantable medical device comprising a flexible substrate material such as herein described (2) adapted for introduction into the body of a patient; said substrate material being successively coated one above the another with a polymeric base layer (3) wherein the coating comprises therapeutic agent to polymer in a ratio of 33.96 % : 66.04 %, a polymeric middle layer (4) wherein the coating comprises therapeutic agent to polymer in a ratio 26.45 %: 73.55 %, a polymeric top layer (5) wherein the coating comprises therapeutic agent to polymer ratio 24.77 % : 75.23 % and a protective layer (6) wherein the coating comprises therapeutic agent to polymer ratio 00.00 % : 100.00 %; wherein the base (3), the middle (4) and the top polymeric layers (5) comprise varying amounts of the therapeutic agent such as herein described and the polymer essentially comprises a mixture of Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone Furthermore, present invention also relates a process for preparing the implantable medical device as claimed in any one of claims 1 to 25 said process comprising the steps of: (a) obtaining a flexible substrate material (2) adapted for introduction into the body of a patient, (b) coating the said substrate material one above the another with a polymeric base layer (3), a polymeric middle layer (4), a polymeric top layer (5) and a protective layer (6), wherein the base, the middle and the top layers comprise varying amounts of the therapeutic agent and the base layer essentially comprises a mixture of Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone, and (c) drying the substrate after each layer is coated in ambient conditions for 18-24 hours and finally vacuum drying the coated substrate at 37 °C for 24 hours to obtain the implantable medical device. Detailed Description of the Invention Accordingly, the present invention provides an implantable medical device (1) providing controlled delivery of therapeutic agent, said implantable medical device comprising a flexible substrate material (2) adapted for introduction into the body of a patient; said substrate material being successively coated one above the another with a polymeric base layer (3), a polymeric middle layer (4), a polymeric top layer (5) and a protective layer (6), wherein the base, the middle and the top layers comprise varying amounts of the therapeutic agent and the base layer essentially comprises a mixture of Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone. In an embodiment of the present invention, the polymeric base layer (3) comprises 66 to 72% by wt. of Poly L-Lactide, 17 to 23% by wt. of 50/50 Poly DL-Lactide-co-Glycolide and 7 to 13 % by wt. of Poly Vinyl Pyrrolidone. In another embodiment of the present invention, the polymeric middle layer (4) comprises 24 to 30% by wt. of 50/50 Poly DL-Lactide-co-Glycolide, 64 to 70% by wt. of 75/25 Poly L-Lactide-co-Caprolactone and 2 to 8% by wt. of Poly Vinyl Pyrrolidone. In yet another embodiment of the present invention, the polymeric top layer (5) comprises 50/50 Poly DL-Lactide-co-Glycolide. In still another embodiment of the present invention, the protective layer (6) comprises Poly Vinyl Pyrrolidone. In one more embodiment of the present invention, the amount of therapeutic agent introduced in the base layer (3) is in the range of 30 to 45% by wt. of the base layer. In one another embodiment of the present invention, the amount of therapeutic agent introduced in the middle layer (4) is in the range of 25 to 30% by wt. of the middle layer. In a further embodiment of the present invention, the amount of therapeutic agent introduced in the top layer (5) is in the range of 22 to 30% by wt. of the tope layer. In further more embodiment of the present invention, the therapeutic agent-polymer ratio in various layers is preferably: Base layer (3): Therapeutic agent: 33.96 % Polymers: 66.04 % Middle layer (4): Therapeutic agent: 26.45 % Polymers: 73.55 % Top layer (5): Therapeutic agent: 24.77 % Polymer: 75.23 % Protective layer (6): Therapeutic agent: 00.00 % Polymer: 100.00 % In an embodiment of the present invention, the size of the substrate material is: Minimum Maximum Substrate diameter: 2.50 mm 4.50 mm Substrate Length: 8.00 mm 38.00 mm In another embodiment of the present invention the therapeutic agent content on the stent is 3.0 micrograms /mm . In yet another embodiment of the present invention, the therapeutic agent is selected from the group comprising of antiproliferative/antimitiric agents, antibiotics, enzymes, antiproliferative/antimitotic alkylating agents antiproliferative/antimitiric antimetabolities, hormones, anticoagulants, fibrinolytic agents, antiplatelet agents, antimigratory agents, antisecretory agents, antiinflammatory agents, immunosuppressive agents, angiogenic agents, nitric oxide donors, anti-sense oligo nucleotides and combinations thereof. In still another embodiment of the present invention, the antiproliferative / antimitotic agents are selected from natural products such as vinca alkaloids i.e. vinblastine, vincristine and vinorelbine, paclitaxel and epidipodophyllotoxins i.e. etopside, teniposide. In a further embodiment of the present invention, the antibiotics are selected from dactinomycin, actinomycin D, daunorubicin, doxorubicin and indarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin. In a further more embodiment of the present invention, the enzyme is L-asparaginase which systematically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine. In yet another embodiment of the present invention, the antiproliferative / antimitotic alkylating agents are selected from nitrogen mustards such as mechlorethamine, cyclophosphamide and analogs, melphalan and chlorambucil, ethylenimines and methylmelamines such as hexamethylmelamines and thiopeta, alkyl sulfonates-busulfan, nitrosoureas such as caramustine (BCNU) and analogs and streptozocin and trazenes-dacarbazinine (DTIC). In another embodiment of the present invention, the antiproliferative / antimitotic antimetabolites are selected from the group comprising of folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil, floxuridine and cytarabine, purine analogs and related inhibitors such as mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine), platinum coordination complexes such as cisplastin and carboplatin, procarbazine, hydroxyorea, mitotane and aminoglutethimide. In still another embodiment of the present invention, the homone is estrogen. In yet another embodiment of the present invention, the anticoagulants are selected from heparin, synthetic heparin salts and inhibitors of thrombin. In one more embodiment of the present invention, the fibrinolytic agents are selected from tissue plasminogen activator, streptokinase and urokinase. In one another embodiment of the present invention, the antiplatelet agents are selected from aspirin, dipyridamole, ticlopidine, clopidogrel and abciximab. In a further embodiment of the present invention, the antisecretory agent is breveldin. In a further more embodiment of the present invention, the antiinflammatory agent is selected from adrenocortical steroids such as Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6.alpha.-methylprednisolone, triamcinolone, betamethasone, and dexamethasone; non-steroidal agents selected from salicylic acid derivatives such as aspirin; para-aminophenol derivatives such as acetominophen; Indole and indene acetic acids such as indomethacin, sulindac, and etodalac; heteroaryl acetic acids such as tolmetin, diclofenac, and ketorolac; arylpropionic acids such as ibuprofen and derivatives; anthranilic acids such as mefenamic acid, and meclofenamic acid; enolic acids such as piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone; nabumetone and gold compounds such as auranofin, aurothioglucose and gold sodium thiomalate. In one further embodiment of the present invention, the immunosuppressive agent is selected from cyclosporine, tacrolimus (FK-506), sirolimus such as rapamycin, azathioprine and mycophenolate mofetil. In a further more embodiment of the present invention, the Angiogenic agents are selected from vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). The present invention also provides a process for preparing the implantable medical device as claimed in any one of claims 1 to 25, said process comprising the steps of: (a) obtaining a flexible substrate material (2) adapted for introduction into the body of a patient, (b) coating the said substrate material one above the another with a polymeric base layer (3), a polymeric middle layer (4), a polymeric top layer (5) and a protective layer (6), wherein the base, the middle and the top layers comprise varying amounts of the therapeutic agent and the base layer essentially comprises a mixture of Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone, and (c) drying the substrate after each layer is coated and finally drying the coated substrate to obtain the implantable medical device. In an embodiment of the present invention, the polymeric base layer (3) comprises 66 to 72% by wt. of Poly L-Lactide, 17 to 23% by wt. of 50/50 Poly DL-Lactide-co-Glycolide and 7 to 13 % by wt. of Poly Vinyl Pyrrolidone. In another embodiment of the present invention, the polymeric middle layer (4) comprises 24 to 30% by wt. of 50/50 Poly DL-Lactide-co-Glycolide, 64 to 70% by wt. of 75/25 Poly L-Lactide-co-Caprolactone and 2 to 8% by wt. of Poly Vinyl Pyrrolidone. In still another embodiment of the present invention, the polymeric top layer (5) comprises 50/50 Poly DL-Lactide-co-Glycolide. In yet another embodiment of the present invention, the protective layer (6) comprises Poly Vinyl Pyrrolidone. In a one more embodiment of the present invention, the amount of therapeutic agent introduced in the base layer (3) is in the range of 30 to 45% by wt. of the base layer. In one another embodiment of the present invention, the amount of therapeutic agent introduced in the middle layer (4) is in the range of 25 to 30% by wt. of the middle layer. In a further embodiment of the present invention, the amount of therapeutic agent introduced in the top layer (5) is in the range of 22 to 30% by wt. of the tope layer. In a further more embodiment of the present invention, the therapeutic agent-polymer ratio in various layers is preferably: Base layer (3): Therapeutic agent: 33.96 % Polymers: 66.04 % Middle layer (4): Therapeutic agent: 26.45 % Polymers: 73.55 % Top layer (5): Therapeutic agent: 24.77 % Polymer: 75.23 % Protective layer (6): Therapeutic agent: 00.00 % Polymer: 100.00 % In one further embodiment of the present invention, the size of the substrate material is: Minimum Maximum Substrate diameter: 2.50 mm 4.50 mm Substrate Length: 8.00 mm 38.00 mm In an embodiment of the present invention, the therapeutic agent content on the stent is 3.0 micrograms /mm2. In another embodiment of the present invention, the therapeutic agent is selected from the group comprising of antiproliferative/antimitiric agents, antibiotics, enzymes, antiproliferative/antimitotic alkylating agents antiproliferative/antimitiric antimetabolities, hormones, anticoagulants, fibrinolytic agents, antiplatelet agents, antimigratory agents, antisecretory agents, antiinflammatory agents, immunosuppressive agents, angiogenic agents, nitric oxide donors, anti-sense oligo nucleotides and combinations thereof. In yet another embodiment of the present invention, the antiproliferative / antimitotic agents are selected from natural products such as vinca alkaloids i.e. vinblastine, vincristine and vinorelbine, paclitaxel and epidipodophyllotoxins i.e. etopside, teniposide. In still another embodiment of the present invention, the antibiotics are selected from dactinomycin, actinomycin D, daunorubicin, doxorubicin and indarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin. In one more embodiment of the present invention, the enzyme is L-asparaginase which systematically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine. In one another embodiment of the present invention, the antiproliferative / antimitotic alkylating agents are selected from nitrogen mustards such as mechlorethamine, cyclophosphamide and analogs, melphalan and chlorambucil, ethylenimines and msthylmelamines such as hexamethylmelamines and thiopeta, alkyl sulfonates-busulfan, nitrosoureas such as caramustine (BCNU) and analogs and streptozocin and trazenes-dacarbazinine (DTIC). In a further embodiment of the present invention, the antiproliferative / antimitotic antimetabolites are selected from the group comprising of folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil, floxuridine and cytarabine, purine analogs and related inhibitors such as mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine), platinum coordination complexes such as cisplastin and carboplatin, procarbazine, hydroxyorea, mitotane and aminoglutethimide. In a further more embodiment of the present invention, the homone is estrogen. In one further embodiment of the present invention, the anticoagulants are selected from heparin, synthetic heparin salts and inhibitors of thrombin. In an embodiment of the present invention, the fibrinolytic agents are selected from tissue plasminogen activator, streptokinase and urokinase. In another embodiment of the present invention, the antiplatelet agents are selected from aspirin, dipyridamole, ticlopidine, clopidogrel and abciximab. In yet another embodiment of the present invention, the antisecretory agent is breveldin. In still another embodiment of the present invention, the antiinflammatory agent is selected from adrenocortical steroids such as Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6.alpha.-methylprednisolone, triamcinolone, betamethasone, and dexamethasone; non-steroidal agents selected from salicylic acid derivatives such as aspirin; para-aminophenol derivatives such as acetominophen; Indole and indene acetic acids such as indomethacin, sulindac, and etodakc; heteroaryl acetic acids such as tolmetin, diclofenac, and ketorolac; arylpropionic acids such as ibuprofen and derivatives; anthranilic acids such as mefenamic acid, and meclofenamic acid; enolic acids such as piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone; nabumetone and gold compounds such as auranofin, aurothioglucose and gold sodium thiomalate. In one more embodiment of the present invention, the immunosuppressive agent is selected from cyclosporine, tacrolimus (FK-506), sirolimus such as rapamycin, azathioprine and mycophenolate mofetil. In one another embodiment of the present invention, the angiogenic agent is selected from vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). The Inventors have developed a novel implantable medial device containing Paclitaxel (Taxol), an antiproliferative drug. More particularly, the present invention relates to a novel paclitaxel eluting stent that has been shown to significantly reduce binary restenosis, repeat target lesion revascularization, and angiographic late loss at six months, when compared to an uncoated stent. The stent is made up of SS 316L tube. The tubes are first cut with laser machines according to programmed design. The cut stents are electropolished for surface smoothness. These stents are transferred to clean room where quality check is carried out and further proceed to coating room where they are coated with Paclitaxel. The coated stents are crimped on balloons. The packed stents are sterilized with ETO. Quality check is carried out at each and every stage and non-confirmed stents are rejected. The process for preparing the stent coated with paclitaxel is described in detail in the following paragraphs. The process of preparing the stent comprised of: (1) Preparation of Solutions, (2) Spray Coating Technique, (3) In-vitro Drug Elution Studies, (4) In-vivo Studies, and (5) Clinical Data. SELECTION OF POLYMERS: Polymers that can be used for coating on the stent should essentially be able to form microspheres and should be biodegradable. Such polymers include poly (lactic acid), poly (lactic-co-glycolic acid), poly (caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyortho esters, polyacetals, polycyanoacrylates and biodegradable polyurethanes and non-erodible polymers such as polyacrylates, ethylene-vinyl acetate copolymers and other acyl substitutes cellulose acetates and derivatives thereof, non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonated polyolefins and polyethylene oxide. In addition to the polymers described, almost any type of polymer can be used provided the appropriate solvent and non-solvent are found which have the desired melting points. Polymers such as Poly (L-lactide) (PLLA), Poly (D,L-lactide) (PLA), Polyglycolide (PGA), Poly (L-lactide-co-D,L-lactide) (PLLA/PLA), Poly (L-lactide-co-glycolide) (PLLA/PGA), Poly (D,L-lactide-co-glycolide) (PLA/PGA), Poly (D,L-lactide-co-caprolactone) (PGA/PCL), and their copolymers and Polyanhydrides (PAN) such as polyvinylpyrrolidone are also suitable for use. The Inventors would like to highlight here that different polymers and their copolymer will have different degradation rate. Further, such different polymers should be compatible with the body and should be non-toxic with the body. Only those polymers and their copolymers can be used whose degradation rate match the specific release property as shown in Figure 1. Further, such polymers should be not be inflammatory and irritant to arterial cells. Keeping in view all the aforesaid parameters, the polymers for coating different layers should be chosen. MATERIALS: Paclitaxel is obtained from Bioxel Pharma Inc, Canada and used without further purification. Paclitaxel was dried to constant weight at ambient temperature in a vacuum oven equipped with an external pump. Paclitaxel is stored at 25.0 ± 0.5°C in desiccator jars over saturated solution of CaCl2.2H20, NaNC«2 and KNO3 Four different polymers Poly L-Lactide (PLLA) 70kD (Purac, Inc), 50/50 Poly DL-Lactide-co-Glycolide (PDLLA/PGA) 74kD (Alkermes, Inc), 75/25 Poly L-Lactide-co-Caprolactone (PLLA/PCL) (Alkermes, Inc) and Poly Vinyl Pyrrolidone (PVP) 90kD (ISP Technologies Inc) were used as such. They were selected by known medical application and favorable screening in vitro and in vivo. [1-5] All solvents used in this study were HPLC grade. METHODS: Stainless steel stents (16-mm Matrix™, Sahajanand Medical Tech. Pvt. Ltd. Surat) were left bare and coated with polymers with or without paclitaxel 200 pg per stent (Total 3.0 pg/mm2). After sterilization, drug content for each stent was assessed gravimetrically using the known mass proportions of paclitaxel and polymers in the coating. Stents with calculated paclitaxel content >220 pg or The bare stent is placed in a bath of deionized water. The water is then heated to boiling temperature and the stent is retained therein for from fifteen minutes to forty-five minutes. Thereafter, the stent is removed from the bath and placed in a sealed chamber in which nitrogen gas is purged and temperature within the range of 40°C to 50°C. This drying step is carried out for a period of six to eight hours. The process for preparing the stent is here below described in detail. Preparation of Solutions: Four different types of solutions are prepared. A sufficient quantity of polymers is weighted directly into a 100ml amber colour volumetric flask and sufficient DCM (HPLC grade) is added. The flask is then capped and mixed by hand in order to dissolve the polymers. An appropriate amount of drug is then added to the solution and dissolved by hand shaking. The prime coat can contain about 42.5 % (w/v) of paclitaxel drug in coating composition. The middle coat can contain about 27.5 % (w/v) of drug in the coating solution. The third upper layer contains about 30.0 % w/v of drug in the solution. A sufficient quantity of polyvinyl pyrrolidone is weighted directly into a 100ml amber colour volumetric flask and sufficient DCM added in order to achieve a 0.125 % (w/v) solution. The flask is then capped and mixed by hand in order to dissolve the polymer. This solution does not contain drug and used as protective layer on the top of all the four drugs coated layers. The stent of the present invention is coated with four different biodegradable polymers. They are, 1. Poly L-Lactide (PLLA) 70kD (Purac, Inc), 2. 50/50 Poly DL-Lactide-co-Glycolide (PDLLA/PGA) 74kD (Alkermes, Inc), 3. 75/25 Poly L-Lactide-co-Caprolactone (PLLA/PCL) (Alkermes, Inc) and 4. Poly Vinyl Pyrrolidone (PVP) 90kD (ISP Technologies Inc) were used. More particularly, in the present invention the stent is coated in four layers. The Inventors have for the first time used a combination of different polymers for coating the base and the middle layers. Each of these two layers consists of different polymeric compositions in combination with the drug. Except for the fourth layer, all the other layers contain the drug, the fourth i.e. the protective layer contains only one polymer and has no drug. Base Layer A: Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone + Drug. Middle Layer B: 75/25 Poly L-Lactide-co-Caprolactone, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone + Drug. Upper Layer C: 50/50 Poly DL-Lactide-co-Glycolide + Drug. Top Protective Layer D; Poly Vinyl Pyrrolidone. The weight percentage of the various ingredients in various layers is given below: Layers Polymers (wt %) Total Poly L-Lactide 50/50 Poly DL Lactide -co-Glycolide 75/25 Poly DL Lactide -co-Caprolactone Poly Vinyl Pyrrolidone A 69.37 (66-72) 20.41 (17-23) 0.0 10.22 (7-13) 100 B 0.0 27.41 (24-30) 67.45 (64-70) 5.14 (2-8) 100 C 0.0 100.0 0.0 0.0 100 D 0.0 0.0 0.0 100.0 100 Spray Coating Technique The drug coating is done with the help of indigenously developed spraying machine. The spray machine is placed in Amber color glass box to eliminate air currents and to slow down the evaporation rate. The spray-coating machine is composed of, 1. Spray Gun 2. Spray Gun Oscillation Assembly 3. Stent Holding & Rotating Assembly 4. Isolation Valve The spray gun is provided with the gas inlet and the 0.1 -mm diameter nozzle outlet. The special grade nitrogen gas is supplied via an isolation valve to the gas inlet. The stents are hooked vertically to the stent holding assembly with the help of thin S.S. wires. The spray gun oscillating assembly will give the oscillations to the spray gun in the vertical plane with a constant frequency and constant amplitude. The working of the entire Drug Coating Machine depends on the programmable controller box. Once the box is switched ON it is programmed in such a way that it gives supply to the machine for 50 seconds, then it remains OFF for 20 seconds and again it gives supply for next 50 seconds. This cycle continues till the controller box is not switched OFF. The purpose of giving 20 second rest between ON periods is to give the sufficient drying time for the coating. Stents would be positioned 4.8 - 5.0 cm distance from the spray gun. Using an automatic pipette, a suitable volume of drug & polymer solution is taken and transferred to the spray gun. Spraying is continued until a suitable amount of drug and polymer is deposited on the stents. To determine the amount, weigh the stent after spraying has been completed and the stent has dried. Subtract the original weight of the stent from the finished weight and this produces the amount of polymer + drug applied to the stent. To understand the working mechanism of the Drug Coating Machine, first of all we have to be familiar with its different important components. The following data will explain this. Spray Gun: The Spray Gun is made up of the whole metallic body with a gas supply inlet and the nozzle outlet. It has a fluid cup on its top in which the drug solution is poured. The outlet nozzle diameter is of 0.1 mm. There is a sharp pointed steel rod by which we can adjust the optimized flow of drug solution. Also there is an arrangement for the flow of the gas. This gas helps in the formation of fine microparticles of the drug solution and it carries these particles towards the stent surface. From the experiments we have seen that the 0.1-mm diameter nozzle spray gun gives the best microparticles formation for our purpose. Spray Gun Oscillation Assembly: As the experiment results suggests that it is necessary to give the movement to the Spray gun to cover the entire surface area of the stent for uniform drug distribution. By keeping these results in the mind the machine is designed in such a way that the Spray Gun is given vertical oscillating movement. By precise technology we have succeeded to convert the rotary motion of D.C. motor into an oscillatory motion. The Spray Gun is attached to this arrangement to solve our purpose. As the length of stent varies from about 11 mm to about 29 mm, it is necessary that the developed mechanism should also be flexible and it is essential that the vertical motion of the spray gun should be variable so that depending upon the length of the stent the vertical motion can be adjusted. The Applicants have for the first time arrived at a novel design which is also very flexible. The Applicants have been able to change the oscillation angle by doing minor changes in its mechanical arrangement. The Applicants have been able to move the spray gun holding assembly through different length depending upon the length of the stent and more particularly, between 10 mm to 30 mm so that all available stents can be coated using this machine. Stent Holding & Rotating Assembly: The results of different experiments show that it is necessary to rotate the stent for better drug distribution on the entire area. By keeping this thing in mind we combined the two arrangements in one assembly, that is we hold the stent in the hooks and it rotates by the help of a D.C. motor. The rotation is given to the stent to cover the both surfaces i.e., the outer and the inner surface. So we are able to coat the drug to the outer and inner surfaces with uniform distribution. This is done by synchronizing the rotary motion of the stent and the oscillatory motion of the Spray Gun. The Inventors have able to achieve this for the first time and to the best knowledge of the applicants, no one has been able to arrive at this novel stent coating technique using which the drug is coated on both the surfaces of the stent and an uniform coating is obtained. Isolation Valve: This is basically a solenoid valve. It acts as a switch to supply the gas to the Spray Gun. When 230 V A.C. supply is given to this valve the solenoid energizes and allows the gas to pass. Collates and Hooks: It is necessary here to explain the hanging arrangement of the stent. The Applicants have designed this arrangement in a unique pattern. The stent is hung on to the hooks. These hooks are made up of thin S.S. wires. This wire is flexible and strong enough to withstand the load. It is usually assumed that the wires that are used should be big enough to withstand the load. However, the Applicants have found that use of big wires adversely effect the stent. Hence, the Applicants have for the first time used a very thin wire so that minimum contact of the wire with the stent is present. The upper hook is fixed to the brass collate and the lower hook is fixed to the aluminum collate. While keeping the lower collate made up of aluminum, it was in the mind that its weight should be minimum because in working, the lower collate will remain hanging. Working of the Machine: The entire working of the Drug Coating Machine depends on the programmable controller box. Once the box is switched ON it is programmed in such a way that it gives supply to the machine for 50 seconds, then it remains OFF for 20 seconds and again it gives supply for next 50 seconds. This cycle continues till the controller box is not switched OFF. The purpose of giving 20 second rest between ON periods is to give the sufficient drying time for the coating. When we switch ON the controller box, the oscillating motion of the Spray Gun and the rotating motion of the stent will start. Simultaneously the magnetic valve will also start and it gives the gas supply to the Spray Gun. The Drug Coating Machine will work as per the programmable controller box. General Coating Details on the Drug Coating Machine: • Running the Drug Coating Machine without Drug & Polymer Load (Solvent: Dichloro Methane) > It takes 290-300 seconds for 2.0 ml DCM. • Running the Drug Coating Machine with Drug & Polymer (Solvent DCM) > It takes 290-300 seconds for 2.0 ml Drug & polymer solution. NOTE: Time given above includes 20 second drying period per every 50 seconds. This procedure is repeated until all the solution has been sprayed. Stored the coated stent in a sealed container. Air pressure =30 psi, Burst duration = 5.0 second, Nozzle to stent distance = 4,8-5.0 cm, Time between bursts = 10-12 seconds, Ambient temperature and humidity = 22° ± 2° C and 60 ± 2 %. After at least 4 hours of air drying, the stents were fixtured at the other end and the second half was coated. After overnight vacuum drying at 37°C, the stents were weighed. Additional coatings were applied using the same conditions to bring each stent up to the target weight. The completed stents were vacuum dried at 37°C for 24 hours. The stent would then be dried in ambient conditions for 18-24 hrs and subseq'iently vacuum dried at 37 °C for 24 hours. (Freeze-drying techniques not necessary). When we switch ON the controller box, the oscillating motion of the Spray Gun and the rotating motion of the stent will start. Simultaneously the magnetic valve will also start and it gives the gas supply to the Spray Gun. The Drug Coating Machine will work as per the programmable controller box. Working: Stents would be positioned 4.8-5.0 cm distance from the spray gun. Using an automatic pipette, a suitable volume of drug + polymer solution is taken and transferred to the spray gun. Then the machine is switched ON, Initially the stent is rotated clockwise for 50 seconds, then it remains OFF for 20 seconds and again it is rotated anti¬clockwise for 50 seconds and it is kept ON until the targeted amount of drug + polymer solution is sprayed on the stent. To determine the amount of drug, weigh the stent after spraying has been completed and the stent has dried. Subtract the original weight of the stent from the finished weight and this produces the amount of drug + polymer applied to the stent. Store the drug-coated Stent in a sealed container. Ambient temperature = 22° ± 2° C, Humidity = Protective layer is a protective polyvinyl pyrrolidone polymer layer and it is removed within two hours after implantation. This layer does not contain any drug. The top protective layer contains only Poly Vinyl Pyrrolidone is a fastest release layer and it is completely removed within 2 to 3 hours after insertion of coated stent into the artery. The other advantage is that it also gives slippery surface (Lubricious like hydrophilic coating) to the coated stent, so the stent can easily moves in artery easily without damaging soft tissues of artery. Present invention involves contacting a medical device having a lubricious. Top layer contains (60 pg) 30.0 % of total paclitaxel drug and is release 15 to 18 pg of drug per day. This layer is completely released within four days. As indicated above, the top layer contains 50/50 Poly DL-Lactide-co-Glycolide along with the drug. Middle layer is loaded with (55 p.g) 27.5 % of paclitaxel and it is release 8.0 to 10.0 pg of drug per day. This layer is completely disappeared with in next six days. As indicated above, the top layer comprises 75/25 Poly L-Lactide-co-Caprolactone, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone. Base (Prime) layer is coated with remaining (85 p,g) 42.5 % of drug and it is release 2.5 to 3.5 pg of drug per day. This layer is completely released within next 28 days. As indicated above, the base layer comprises Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone. Drug-Polymer Ratio in different layers: Base (Prime) layer: Paclitaxel -> 33.96% Middle layer: Paclitaxel -> 26.45 % Top layer: Paclitaxel -> 24.77 % Protective layer: Paclitaxel -> 00.00 % Polymers: 66.04 % Polymers: 73.55 % Polymers: 75.23 % Polymer: 100.00% After at least 4 hours of air drying at 37°C, the stents were weighed. If the weight is not as per the targeted amount, additional coatings should be applied using the same conditions to bring each stent up to the target weight. The completed stents were vacuum dried at 37°C for 24 hours. The stent would then be dried in ambient conditions for 18-24 hrs and subsequently vacuum dried at 37 °C for 24 hours. Figure 1 indicates Release of Paclitaxet per day in a controlled manner from a Polymer matrix bound to the stent, that is released from Upper Layer C (fast release), Middle Layer B (medium release) and Base Layer A (slow release) respectively. Product Type: Our Paclitaxel Coated Eluting Stent has only one model with different length and diameter for placement in various sizes of Coronary Artery. Drug Eluting Coronary Stent System: .J. . ... : - i ■„■■- ... Minimum Maximum Stent Diameter (mm)* 2.5 4.5 Stent Length (mm) 8.00 38.00 *Step between two consecutive stent diameters: 0.25mm or 0.5mm. The drug content on the stent is 3.0 microgram/mm2. This is a constant quantity of drug per square area of stent, however as the stent length varies from 8.00 mm to 38.00 mm, the total drug loading on each stent varies from 110 microgram to 523 microgram per stent. Amount of Medicinal Substance (Paclitaxel) Incorporated into Medicinal Device (Infinnium-Paclitaxel Drug Eluting Stent) Total Loading (Drug + Polymer) on various size of Stents: Sr. No. Stent Length mm Base Layer (A) pg Middle Layer (B) pg Upper Layer (C) pg Protective Layer (D) pg Total Loading pgS Total Drug Content pg 1 08 120 100 120 60 400 100 (90-110) 2 11 170 140 170 80 560 138 (124-152) 3 14 220 180 210 120 730 175 (157-193) 4 16 250 210 240 150 850 200 (180-220) 5 19 300 250 290 170 1010 238 (214-262) 6 23 360 300 350 200 1210 287 (258-316) 7 29 460 380 450 250 1540 362 (326-398) 8 38 590 490 570 350 2000 475 (427-523) Amount of Medicinal Substance (Paclitaxel) Incorporated into Medicinal Device (Infinnium-Paclitaxel Drug Eluting Stents Drug Loading on various size of Stents: Sr. No. Stent Length Mm Base Layer (A) Middle Layer (B) pg Upper Layer (C) pg Total Drug Content pg 1 08 42.50 (38.2-46.7) 27.50 (24.7-30.2) 30 (27.0-33.0) 100 (90-110) 2 11 58.65 (52.7-64.6) 37.95 (34.1-41.8) 41.40 (37.2-45.6) 138 (124-152) 3 14 74.37 (66.7-82.0) 48.13 (43.2-53.1) 52.50 (47.1-57.9) 175 (157-193) 4 16 85.00 (76.5-93.5) 55.00 (49.5-60.5) 60.00 (54-66) 200 (180-220) 5 19 101.15 (91.0-111.4) 65.45 (58.9-72.0) 71.40 (64.2-78.6) 238 (214-262) 6 23 121.98 (109.6-134.3) 78.93 (70.9-86.9) 86.10 (77.4-94.8) 287 (258-316) 7 29 153.85 (138.5-169.1) 99.55 (89.6-109.4) 108.60 (97.8-119.4) 362 (326 - 398) 8 38 201.87 (181.6-222.1) 130.63 (117.5-143.6) 142.50 (128.2-156.7) 475 (427 - 523) Drug Elution Studies: In-Vitro assays were preformed to assess the kinetics of paclitaxel elution from polymer-coated stent over 40 days. Fifteen stents were coated with polymers loaded with paclitaxel, sterilized and had initial paclitaxel load calculated (200 ±20 pg) gravimetrically. Each stent was incubated in 15 ml of Phosphate Buffered Saline (PBS, Sigma) (pH 7.4) at 37°C with constant agitation at 120 rpm. PBS was changed twice daily for one day and every one to two days thereafter to ensure sink conditions. Three stents each at 1, 7, 14, 28 and 38 days were removed from their release vials and analyzed for residual paclitaxel content. Residual drug was extracted using the bellowed mentioned method. The resultant supernatant was analyzed for paclitaxel content by HPLC and the percent of initial paclitaxel released from each stent was calculated. The work was performed at Chemo-Test Laboratories, Mumbai a commercial laboratory using HPLC (Waters) equipped with an UV detector. High Pressure Liquid Chromatography (HPLC): The Paclitaxel eluting stents are tested to assess the loading / content and release kinetics over 38-days. The stents are coated with polymers loaded with paclitaxel, sterilized and had initial paclitaxel load calculated gravimetrically (200 ± 20 pg) on 16-mm stents. The exact loading/content and release kinetics methods are given below. Paclitaxel Loading/Content: Take- 1 stent in 10-ml volumetric flask + 8 ml DCM, Stir intermittently every five minutes for 20 minutes. Make up volume to 10 ml with DCM and Mix it. Evaporate DCM under Nitrogen (10 min), add 4 ml Acetonitrile, and inject it to the HPLC column. Standard treated in similar manner. To determine concentration in sample, Compare the peak area of standard with that of sample and multiply it by 4. Paclitaxel Release Kinetics: Prepare Phosphate Buffer Saline having pH 7.4 (U.S.P/E.P) or Bovine serum according to U.S.P/E.P Procedure. Take 10 ml of above buffer in 10-ml volumetric flask and place 1 stent in it. Keep for 24, 48, 72 hrs...Transfer total amount in extraction flask containing 2 ml DCM. Replace same amount of buffer (10 ml) in volumetric flask. Extract the whole quantity of drug by extracting it three times using 2 ml of DCM at each step. Separate the organic layer (DCM) and place it in 10-ml volumetric flask. Evaporate DCM under nitrogen (10 min). Add 1 ml Acetonitrile to the volumetric flask then inject it to the HPLC column. All apparatus should be amber colored. Taking aseptic precautions carried out all the above procedures. Paclitaxel analysis by HPLC: Column: C-18 (ODS, Octyl Deyl Scheme) Make: SGE (5 microns) — Packing size of particles Dimension: 25 cm x 4.6 cm Mobile Phase: Acetonitrile (58): Methanol (5): H20 (37) Flow Rate: 1.0 ml/min Amax: 227 nm — 232 nm The results of drug elution from stent contain approximately 200 p.g of Paclitaxel. Residual ETO: The residual ETO in the sterile stent system is analyzed by extracting residues in solvent and analyzing by using head space analyzer attached to Gas Chromatograph. The reference is injected and estimation is carried out by area normalization method. The limits are as per Pharmacopoeia requirements for Medical Devices sterilized using ETO. TABLE: In-Vitro Release Profile of Paclitaxel from polymer-coated Stents Days Drug Release, pg Cumulative Release, pg Cumulative Percentage 1 15 15 07.57 2 15 30 15.15 3 15 45 22.72 4 15 60 30.30 5 9 69 34.84 6 9 78 39.39 7 9 87 43.93 8 9 96 48.48 9 9 105 53.03 10 9 114 57.57 11 3 117 59.09 12 3 120 60.60 13 3 123 62.12 14 3 126 63.63 15 3 129 65.15 16 3 132 66.66 17 3 135 68.18 18 3 138 69.69 19 3 141 71.21 20 3 144 72.72 21 3 147 74.24 22 3 150 75.75 23 3 153 77.27 24 3 156 78.78 25 3 159 80.30 26 3 162 81.81 27 3 165 83.33 28 3 168 84.84 29 3 171 86.36 30 3 174 87.87 31 3 177 89.39 32 3 180 90.90 33 3 183 92.42 34 3 186 93.93 35 3 189 95.45 36 3 192 96.96 37 3 195 98.48 38 3 198 100.00 Total 198 Paclitaxel content on 16-mm stent 3.0 (pg/mm2 Total Paclitaxel content: 200 meg (A=85 meg, B=55 meg, C=60 meg). Before putting the sample for observation under SEM, imperfections were created by means of a sharp scalpel over the coated stents to see the thickness and the different layers of the coating. The thickness of coating is in between 10 and 20 microns. (See Fig. 5&6). Successful development of drug-eluting stent designed to inhibit cell proliferation and control the growth of smooth muscle cells. The stent also enhance the "healing" process and regrowth of endothelial cells. Kinetic studies confirm the controlled release properties of the drug and polymers. CLINICAL DOCUMENTATION: Dr. Gambhir's data Clinical Summary: The study was undertaken to evaluate the safety and efficacy of the Infinnium stent in¬patients with symptomatic Coronary Artery Disease (CAD). The Infinnium stent has a semi-open-cell design with low metal to artery ratio (11% - 19%) and optimal scaffolding properties. Total 221 stents were implanted in 205 patients, out of whom 167 were males (81.46%) and 38 were females (18.54%). One stent was used in 51.5% of patients, two stents were used in 37.0% of patients and three or more stents were used in 11.5% of patients. The arterial diameter ranged from 2.5 to 3.5 mm, and the average length of the stent was 1S.2 mm. Following were the details of arteries in which Infinnium were implanted: Target Site No. of Patients implanted with Infinnium Percentage of Patients implanted with Infinnium LAD 130 58.82% LCx 28 12.67% RCA 46 20.81% OM 7 3.17% Diagonal 4 1.81% LMCA 1 0.45% Ramus 2 0.90% PDA 3 1.36% The procedural success rate was 100%. There was one abrupt occlusion and 1 in-hospital death reported. The 30 days MACE includes 2 non-cardiac deaths and 3 repeat procedures due to stent thrombosis. There were no events at 3 months clinical follow-up and 6 months check angiogram. Till date 25 six month check angiogram have been conducted all of which have shown good results with the Infmnium DES. Also no side effects like Palpitation, Ischemia, hair loss, skin rashes etc. were reported in these patients. The stents were deployed in calcific lesions as well as total occlusions, in diabetics and instent restenotic lesions also. Since the study was an open registry/ real world trial there was no inclusion and exclusion criteria involved. All types of patients were enrolled in the study irrespective of their medical status. Stent implantation is associated with endovascular injury followed by a healing response. High degrees of injury appear to translate into more restenosis in the long term presumably because of more robust fibrotic healing responses (which induce the formation of clots (sub-acute thrombosis) and cause blockage of the vessel). For drug-eluting stents, the delivery vehicle must release the drug into the vessel in a manner that is consistent with the drug's mode of action. [Comment (h)] Combining paclitaxel with the carrier system provides controlled release of the drug into the vessel wall, Paclitaxel interacts with arterial tissue (transfer to tissue with greater efficiency) elements as it moves under the forces of diffusion and convection and can establish substantial partitioning and spatial gradients across the tissue [Creel et al 2000]. Initial local high dose release of anti-proliferative drug paclitaxel to have immediate contact with the vessel wall (immediate response to injury), favoring its rapid accumulation by arterial tissue. This strategy of fast release resembles short-term irradiation by optimizing the conditions for blocking the earliest cellular events triggered by injury. Results show largest reduction in Neointimal encroachment at the initial high dose release from Upper Layer C (fast release). Thus this immediate response of drug prevent restenosis. Another concern from the standpoint (medium and slow release) of therapeutic (paclitaxel) is to maintain the prevention of resurgence of neointimal growth over longer periods of time (weeks, months). We have to use drugs that interrupt the molecular cascade leading to in-stent restenosis. Further drug delivery to be at precise area at the time of implant and due to this injury. Action of slow release (low level release) is that it gives ongoing delivery through phases of healing. It was shown through experiments that while the level of macrophages, which inhibited stent induced proliferation, dropped within two months when bare stents were used, this level remained very high even after 6 months, when slow paclitaxel release were used. It was found that though the release of paclitaxel by the coated stent stopped within two months, the drug prevented cell proliferation and restenosis for six months. This indicated that the drug persisted in the blood vessel and continued to have effect. Studies have also shown that since restenosis was inhibited by paclitaxel for six months, it was unlikely for the process of cell proliferation and restenosis to begin after the drug had stopped taking effect (7). The Applicants have found that the novel stent prepared by the aforesaid process and having the novel releases characteristics of paclitaxel provide the best results. There are only chances of release + 5-mcg paclitaxel per day. The total loading 3.0 mcg/mm2 is very low dose and it is not toxic if total drug will release in a single day. (i) as per our study given release graph is best release characteristics, (ii) The dose finding study by ELUTES to determine a safe and effective dose of paclitaxel on the stent platform in-patients with de novo lesions by comparing four different dose densities (0.2, 0.7, 1.4 and 2.7 mcg/mm2) with uncoated control stents. The results shows that 2.7 mcg/mm2 is more effective than uncoated and other low dose stents. And our coating is 3.0 mcg/mm2 have excellent results in clinical trials. The Applicants have also found that thickness of the coating should be maintained in between 10 and 20 microns. The coating on the stent should be very thin and uniform. Above is the range of our coating thickness and it does not effect stent's working efficiency. The active drug that can be delivered for acting on these recipients includes antiinflammatories. However, almost all kind of drugs can be used that can give beneficial effect to the injured artery like prevent thrombosis, prevent thickenning of neointimal layer stop proliferation of smooth muscle cell etc| Paclitaxel gives the best results in above points. We Claim: 1. An implantable medical device (1) for providing controlled delivery of therapeutic agent, said implantable medical device comprising a flexible substrate material such as herein described (2) adapted for introduction into the body of a patient; said substrate material being successively coated one above the another with a polymeric base layer (3) wherein the coating comprises therapeutic agent to polymer in a ratio of 33.96 % : 66.04 %, a polymeric middle layer (4) wherein the coating comprises therapeutic agent to polymer in a ratio 26.45 %: 73.55 %, a polymeric top layer (5) wherein the coating comprises therapeutic agent to polymer ratio 24.77 % : 75.23 % and a protective layer (6) wherein the coating comprises therapeutic agent to polymer ratio 00.00 % : 100.00 %; wherein the base (3), the middle (4) and the top polymeric layers (5) comprise varying amounts of the therapeutic agent such as herein described and the polymer essentially comprises a mixture of Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone 2. An implantable medical device as claimed in claim 1, wherein the polymeric base layer (3) comprises 66 to 72% by wt. of Poly L-Lactide, 17 to 23% by wt. of 50/50 Poly DL-Lactide-co-Glycolide and 7 to 13 % by wt. of Poly Vinyl Pyrrolidone. 3. An implantable medical device as claimed in claim 1, wherein the polymeric middle layer (4) comprises 24 to 30%) by wt. of 50/50 Poly DL-Lactide-co-Glycolide, 64 to 70% by wt. of 75/25 Poly L-Lactide-co-Caprolactone and 2 to 8% by wt. of Poly Vinyl Pyrrolidone. 4. An implanatable medical device as claimed in claim 1, wherein the polymeric top layer (5) comprises 50/50 Poly DL-Lactide-co-Glycolide. 5. An implantable medical device as claimed in claim 1, wherein the protective layer (6) comprises Poly Vinyl Pyrrolidone. An implanatable medical device as claimed in claim 1, wherein the amount of therapeutic agent introduced in the base layer (3) is in the range of 30 to 45% by wt. of the base layer. An implanatable medical device as claimed in claim 1, wherein the amount of therapeutic agent introduced in the middle layer (4) is in the range of 25 to 30% by wt. of the middle layer. An implanatable medical device as claimed in claim 1, wherein the amount of therapeutic agent introduced in the top layer (5) is in the range of 22 to 30% by wt. of the top layer. An implanatable medical device as claimed in claim 1, wherein the therapeutic agent-polymer ratio in various layers is preferably: Base layer (3): Therapeutic agent: 33.96% Polymers: 66.04 % Middle layer (4): Therapeutic agent: 26.45 % Polymers: 73.55 % Top layer (5): Therapeutic agent: 24.77 % Polymer: 75.23 % Protective layer (6): Therapeutic agent: 00.00 % Polymer: 100.00 % An implanatable medical device as claimed in claim 1, wherein the size of the substrate material is: Minimum Maximum Substrate diameter: 2.50 mm 4.50 mm Substrate Length: 8.00 mm 38.00 mm An implantable medical device as claimed in claim 1, wherein the therapeutic agent content on the stent is 3.0 micrograms /mm2. An implantable medical device as claimed in claim 1, wherein the therapeutic agent is selected from the group comprising of antiproliferative/antimitiric agents, antibiotics, enzymes, antiproliferative/antimitotic alkylating agents antiproliferative/antimitiric antimetabolities, hormones, anticoagulants, fibrinolytic agents, antiplatelet agents, antimigratory agents, antisecretory agents, antiinflammatory agents, immunosuppressive agents, angiogenic agents, nitric oxide donors, anti-sense oligo nucleotides and combinations thereof. 13. An implantable medical device as claimed in claim 1, wherein the antiproliferative / antimitotic agents are selected from natural products such as vinca alkaloids i.e. vinblastine, vincristine and vinorelbine, paclitaxel and epidipodophyllotoxins i.e. etopside, teniposide. 14. An implantable medical device as claimed in claim 1, wherein the antibiotics are selected from dactinomycin, actinomycin D, daunorubicin, doxorubicin and indarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin. 15. An implantable medical device as claimed in claim 1, wherein the enzyme is L-asparaginase which systematically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine. 16. An implantable medical device as claimed in claim 1, wherein the antiproliferative / antimitotic alkylating agents are selected from nitrogen mustards such as mechlorethamine, cyclophosphamide and analogs, melphalan and chlorambucil, ethylenimines and methylmelamines such as hexamethylmelamines and thiopeta, alkyl sulfonates-busulfan, nitrosoureas such as caramustine (BCNU) and analogs and streptozocin and trazenes-dacarbazinine (DTIC). 17. An implantable medical device as claimed in claim 1, wherein the antiproliferative / antimitotic antimetabolites are selected from the group comprising of folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil, floxuridine and cytarabine, purine analogs and related inhibitors such as mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine), platinum coordination complexes such as cisplastin and carboplatin, procarbazine, hydroxyorea, mitotane and aminoglutethimide. 18. An implantable medical device as claimed in claim 1, wherein the homone is estrogen. 19. An implantable medical device as claimed in claim 1, wherein the anticoagulants are selected from heparin, synthetic heparin salts and inhibitors of thrombin. 20. An implantable medical device as claimed in claim 1, wherein the fibrinolytic agents are selected from tissue plasminogen activator, streptokinase and urokinase. 21. An implantable medical device as claimed in claim 1, wherein the antiplatelet agents are selected from aspirin, dipyridamole, ticlopidine, clopidogrel and abciximab. 22. An implantable medical device as claimed in claim 1, wherein the antisecretory agent is breveldin. 23. An implantable medical device as claimed in claim 1, wherein the antiinflammatory agent is selected from adrenocortical steroids such as Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6.alpha.-methylprednisolone, triamcinolone, betamethasone, and dexamethasone; non steroidal agents selected from salicylic acid derivatives such as aspirin; para-aminophenol derivatives such as acetominophen; Indole and indene acetic acids such as indomethacin, sulindac, and etodalac; heteroaryl acetic acids such as tolmetin, diclofenac, and ketorolac; arylpropionic acids such as ibuprofen and derivatives; anthranilic acids such as mefenamic acid, and meclofenamic acid; enolic acids such as piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone; nabumetone and gold compounds such as auranofin, aurothioglucose and gold sodium thiomalate. 24. An implantable medical device as claimed in claim 1, wherein the immunosuppressive agent is selected from cyclosporine, tacrolimus (FK-506), sirolimus such as rapamycin, azathioprine and mycophenolate mofetil. 25. An implantable medical device as claimed in claim 1, wherein the Angiogenic agents are selected from vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). 26. A process for preparing the implantable medical device as claimed in any one of claims 1 to 25 said process comprising the steps of: (a) obtaining a flexible substrate material (2) adapted for introduction into the body of a patient, (b) coating the said substrate material one above the another with a polymeric base layer (3), a polymeric middle layer (4), a polymeric top layer (5) and a protective layer (6), wherein the base, the middle and the top layers comprise varying amounts of the therapeutic agent and the base layer essentially comprises a mixture of Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Poly Vinyl Pyrrolidone, and (c) drying the substrate after each layer is coated in ambient conditions for 18-24 hours and finally vacuum drying the coated substrate at 37 °C for 24 hours to obtain the implantable medical device. 27. The process as claimed in claim 26, wherein the polymeric base layer (3) comprises 66 to 72% by wt. of Poly L-Lactide, 17 to 23% by wt. of 50/50 Poly DL-Lactide-co-Glycolide and 7 to 13 % by wt. of Poly Vinyl Pyrrolidone. 28. The process as claimed in claim 26, wherein the polymeric middle layer (4) comprises 24 to 30% by wt. of 50/50 Poly DL-Lactide-co-Glycolide, 64 to 70% by wt. of 75/25 Poly L-Lactide-co-Caprolactone and 2 to 8% by wt. of Poly Vinyl Pyrrolidone. 29. The process as claimed in claim 26, wherein the polymeric top layer (5) comprises 50/50 Poly DL-Lactide-co-Glycolide. 30. The process as claimed in claim 26, wherein the protective layer (6) comprises Poly Vinyl Pyrrolidone. 31. The process as claimed in claim 26, wherein the amount of therapeutic agent introduced in the base layer (3) is in the range of 30 to 45% by wt. of the base layer. 32. The process as claimed in claim 26, wherein the amount of therapeutic agent introduced in the middle layer (4) is in the range of 25 to 30% by wt. of the middle layer. 33. The process as claimed in claim 26, wherein the amount of therapeutic agent introduced in the top layer (5) is in the range of 22 to 30% by wt. of the tope layer. 34. The process as claimed in claim 26, wherein the therapeutic agent-polymer ratio in various layers is preferably: Base layer (3): Therapeutic agent: 33.96 % Polymers: 66.04 % Middle layer (4): Therapeutic agent: 26.45 % Polymers: 73.55 % Top layer (5): Therapeutic agent: 24.77 % Polymer: 75.23 % Protective layer (6): Therapeutic agent: 00.00 % Polymer: 100.00 % 35. The process as claimed in claim 26, wherein the size of the substrate material is: Minimum Maximum Substrate diameter: 2.50 mm 4.50 mm Substrate Length: 8.00 mm 38.00 mm 36. The process as claimed in claim 26, wherein the therapeutic agent content on the stent is 3.0 micrograms /mm2. 37. The process as claimed in claim 26, wherein the therapeutic agent is selected from the group comprising of antiproliferative/antimitiric agents, antibiotics, enzymes, antiproliferative/antimitotic alkylating agents antiproliferative/antimitiric antimetabolities, hormones, anticoagulants, fibrinolytic agents, antiplatelet agents, antimigratory agents, antisecretory agents, antiinflammatory agents, immunosuppressive agents, angiogenic agents, nitric oxide donors, anti-sense oligo nucleotides and combinations thereof. 38. The process as claimed in claim 26, wherein the antiproliferative / antimitotic agents are selected from natural products such as vinca alkaloids i.e. vinblastine, vincristine and vinorelbine, paclitaxel and epidipodophyllotoxins i.e. etopside, teniposide. 39. The process as claimed in claim 26, wherein the antibiotics are selected from dactinomycin, actinomycin D, daunorubicin, doxorubicin and indarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin. 40. The process as claimed in claim 26, wherein the enzyme is L-asparaginase which systematically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine. 41. The process as claimed in claim 26, wherein the antiproliferative / antimitotic alkylating agents are selected from nitrogen mustards such as mechlorethamine, cyclophosphamide and analogs, melphalan and chlorambucil, ethylenimines and methylmelamines such as hexamethylmelamines and thiopeta, alkyl sulfonates- busulfan, nitrosoureas such as caramustine (BCNU) and analogs and streptozocin and trazenes-dacarbazinine (DTIC). 42. The process as claimed in claim 26, wherein the antiproliferative / antimitotic antimetabolites are selected from the group comprising of folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil, floxuridine and cytarabine, purine analogs and related inhibitors such as mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine), platinum coordination complexes such as cisplastin and carboplatin, procarbazine, hydroxyorea, mitotane and aminoglutethimide. 43. The process as claimed in claim 26, wherein the homone is estrogen. 44. The process as claimed in claim 26, wherein the anticoagulants are selected from heparin, synthetic heparin salts and inhibitors of thrombin. 45. The process as claimed in claim 26, wherein the fibrinolytic agents are selected from tissue plasminogen activator, streptokinase and urokinase. 46. The process as claimed in claim 26, wherein the antiplatelet agents are selected from aspirin, dipyridamole, ticlopidine, clopidogrel and abciximab. 47. The process as claimed in claim 26, wherein the antisecretory agent is breveldin. 48. The process as claimed in claim 26, wherein the antiinflammatory agent is selected from adrenocortical steroids such as Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6.alpha.-methylprednisolone, triamcinolone, betamethasone, and dexamethasone; non-steroidal agents selected from salicylic acid derivatives such as aspirin; para-aminophenol derivatives such as acetominophen; Indole and indene acetic acids such as indomethacin, sulindac, and etodalac; heteroaryl acetic acids such as tolmetin, diclofenac, and ketorolac; arylpropionic acids such as ibuprofen and derivatives; anthranilic acids such as mefenamic acid, and meclofenamic acid; enolic acids such as piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone; nabumetone and gold compounds such as auranofin, aurothioglucose and gold sodium thiomalate. 49. The process as claimed in claim 26, wherein the immunosuppressive agent is selected from cyclosporine, tacrolimus (FK-506), sirolimus such as rapamycin, azathioprine and mycophenolate mofetil. 50. The process as claimed in claim 26, wherein the angiogenic agent is selected from vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). 51. An implantable medical device for providing controlled delivery of therapeutic agent such as herein described with reference to the accompanying drawings. 52. A process for preparing the implantable medical device for providing controlled delivery of therapeutic agent such as herein described with reference to the accompanying drawings. Dated this 17th day of August, 2004 D.C. GABRIEL Of K&S Partners Agent for the Applicant

Documents:

497-mum-2003 claims(granted)-(28-12-2006).doc

497-mum-2003-cancelled pages(28-12-2006).pdf

497-mum-2003-claims(granted)-(28-12-2006).pdf

497-mum-2003-correspondence(28-12-2006).pdf

497-mum-2003-correspondence(ipo)-(3-5-2007).pdf

497-mum-2003-drawing(28-12-2006).pdf

497-mum-2003-form 1(19-5-2003).pdf

497-mum-2003-form 1(28-12-2006).pdf

497-MUM-2003-FORM 15(09-12-2010).pdf

497-mum-2003-form 18(7-6-2005).pdf

497-mum-2003-form 2(granted)-(28-12-2006).doc

497-mum-2003-form 2(granted)-(28-12-2006).pdf

497-mum-2003-form 26(28-12-2006).pdf

497-mum-2003-form 3(19-5-2003).pdf

497-mum-2003-form 4(19-08-2004).pdf

497-mum-2003-form 5(19-8-2004).pdf

497-mum-2003-petition under rule 138(29-12-2006).pdf

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