WO2013102842A2 - Device and composition for drug release - Google Patents

Device and composition for drug release Download PDF

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Publication number
WO2013102842A2
WO2013102842A2 PCT/IB2013/000010 IB2013000010W WO2013102842A2 WO 2013102842 A2 WO2013102842 A2 WO 2013102842A2 IB 2013000010 W IB2013000010 W IB 2013000010W WO 2013102842 A2 WO2013102842 A2 WO 2013102842A2
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WIPO (PCT)
Prior art keywords
heparin
polymer
active agent
poly
lactide
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PCT/IB2013/000010
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French (fr)
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WO2013102842A3 (en
WO2013102842A4 (en
Inventor
Chhaya Babubhai ENGINEER
Ankur Jaykumar RAVAL
Rahul GAYWALA
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Sahajanand Medical Technologies Private Limited
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Publication of WO2013102842A2 publication Critical patent/WO2013102842A2/en
Publication of WO2013102842A3 publication Critical patent/WO2013102842A3/en
Publication of WO2013102842A4 publication Critical patent/WO2013102842A4/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/143—Stabilizers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/18—Materials at least partially X-ray or laser opaque
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A61L2300/61—Coatings having two or more layers containing two or more active agents in different layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Definitions

  • the present invention relates to a medical device comprising the composition comprising a pharmaceutically active agent and a biodegradable polymer covalently bonded to heparin.
  • Percutaneous Transluminal Coronary Angioplasty is a procedure for treating heart disease.
  • a catheter assembly having a balloon portion is introduced into the cardiovascular system of a patient via the brachial or femoral artery.
  • the catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion.
  • the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the lumen wall.
  • the balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
  • a problem associated with the procedure includes formation of intimal flaps or torn arterial linings that can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery can develop over several months after the procedure, which can require another angioplasty procedure or a surgical bypass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, an expandable stent is implanted in the lumen to maintain the vascular patency.
  • Stents are scaffolding structures, usually cylindrical or tubular in shape, functioning to physically hold open, and if desired, to expand the wall of the passageway.
  • stents are capable of being compressed for insertion through small cavities via small catheters, and then expanded to a larger diameter once at the desired location.
  • Thrombosis is a prime concern after an implant of a drug eluting stent.
  • Various anticoagulants have been systemically used orally and/or intravenously to overcome or to minimize the risk of thrombus formation at the stented region and in the immediate neighborhood of the stent.
  • bleeding and other complications may occur from the use of anticoagulants (e.g., clopidogrel, LMW, heparin, ticlopidine, aspirin, etc). Accordingly, there remains a need for a more localized delivery of anticoagulants and other pharmaceutically active agents.
  • Heparin is an anionic, multi-sulfate, mucopolysaccharide used as an anticoagulant. Heparin acts as an anticoagulant by binding ⁇ to antithrombin III and inhibiting thrombogenesis primarily through inactivation of factors, Ila and Xa. Heparin can achieve at least one of the following functions, including inhibiting the activation of coagulation, potentiating the inhibition of the activated coagulation enzymes, and preventing platelet adhesion to the surface of the device.
  • Heparin has also been used as a systemic anti-coagulant in humans and in connection with stent coatings for local delivery for prevention of stent related thrombotic events. Accumulation of platelets at portions of an implanted stent remains a drawback that affects clinical safety and efficacy. Heparin has been evaluated as a stent coating for preventing early and late thrombosis and found to be satisfactory to inhibit sub-acute thrombosis (SAT). The morphology of blood vessels observed after coronary stenting demonstrates that thrombus occurs at an early stage in addition to acute inflammation (proliferation and migration of smooth muscle cells) followed by neointimal growth. The occurrence of increased inflammation soon after stenting is associated with medial injury and lipid core penetration by stent struts.
  • SAT sub-acute thrombosis
  • US patents 6702850 and 7638158 describe a stent having a multi-layered coating adhered to its surface which can prevent restenosis and thrombosis at the implant site.
  • the stent coating as described comprises of two layers, wherein the first layer is a polymeric coating with one or more biologically active agent dispersed therein and the second layer is comprised of a hydrophobic heparinized polymer.
  • US patent 7022334 describes therapeutic compositions comprising a polysaccharide, such as heparin or a derivative of heparin; or a cationic peptide and a method of coating the device.
  • the therapeutic composition as described comprises heparin and polymer which are physically blended in organic solvent prior to coating.
  • an implantable medical device such as a stent having a coating that can include an optional primer layer comprising a solution of polysaccharide and a solvent mixed with a polymer, a reservoir layer comprising a polymer, a polysaccharide and a therapeutic agent and an optional topcoat layer comprising a polymer alone or in combination with a polysaccharide.
  • EP1834636A1 describes compositions comprising a first polymer having pores, nanoparticles dispersed within the pores of the first polymer, the nanoparticles comprising a second polymer and at least one pharmaceutically active agent dispersed in the second polymer, and heparin covalently bonded to at least one of the first and second polymer.
  • the document also describes stents coated with the composition.
  • EP1832301 A2 describes a composition comprising at least one polymer covalently linked to heparin and at least one pharmaceutically active agent other than heparin dispersed within the ' at least one polymer and a medical device coated with the composition.
  • EP 1832289A2 describes a composition comprising at least one polymer, heparin and at least one pharmaceutically active agent specifically benzopyran-4-one compounds and an implantable device coated with the composition.
  • US patent 7785647 and US patent application 20100300903 describe a method of providing a volatile antioxidant, such as butylated hydroxytoluene (BHT) and/or butylated hydroxyahisole (BHA) to a medical device to improve the shelf life of the drug coated stent, and a kit comprising the medical device.
  • a volatile antioxidant such as butylated hydroxytoluene (BHT) and/or butylated hydroxyahisole (BHA)
  • Published US patent application 2003/0204239 describes a system for treating a vascular condition, including a catheter, a stent including a stent framework coupled to the catheter, a preservative coating including at least one antioxidant disposed on the stent framework.
  • US patent 7709049 describes coating a method, a composition for controlled release of active agent and the medical device coated with the composition, wherein the active agent release is determined by deposition rate of the coating composition.
  • US patent 8007737 describes use of antioxidant to prevent oxidation and reduce drug degradation in drug eluting medical devices and implantable medical devices coated with biocompatible materials mixed with therapeutic drugs, agents or compounds and an antioxidant. - .
  • the bare metal stent described comprises an elongated tubular structure having a luminal surface and an abluminal surface, the elongated tubular structure including a plurality of interconnected elements, a portion of the interconnected elements comprising at least one reservoir extending from the luminal surface to the abluminal surface, at least one base composition inlay comprising a polymer deposited in the at least one reservoir proximate the luminal surface of the elongated tubular structure, and at least one top composition inlay comprising a therapeutic agent deposited in the reservoir on top of the base composition inlay and below the abluminal surface of the elongated tubular structure.
  • Figure 1 shows synthesis reaction of Heparinized Poly L-Lactide
  • Figure 2 shows schematic of Reactor Used for Synthesis for Heparinized
  • Figure 3 shows histological analysis of rabbit iliac artery after 28 days of implantation
  • Figure 4 shows histological analysis of rabbit iliac artery after 90 days of implantation
  • Figure 5 shows In- Vitro Drug Release Profile of the stent coated with formulation- 1 ;
  • Figure 6 shows In- Vitro Drug Release Profile of the stent coated with formulation-2;
  • Figure 7 shows In- Vitro Drug Release Profile of the stent coated with formulation-3;
  • Figure 8 shows schematic of coating layer distribution of drug eluting stent
  • Figure 9 shows FT-IR spectra of Poly (L-Lactide).
  • Figure 10 shows FT-IR spectra of Heparin Sodium
  • Figure 11 shows FT-IR spectra of H-PLLA
  • Figure 12 shows H-NMR spectra of Poly (L-Lactide).
  • Figure 13 shows H-NMR spectra of Heparin Sodium
  • Figure 14 shows H-NMR spectra of Heparinized Poly L Lactide
  • Figure 15 shows TGA of Poly (L-Lactide).
  • Figure 16 shows TGA of Heparin Sodium
  • Figure 18 shows DSC of Poly (L-Lactide).
  • Figure 19 shows DSC of Heparin Sodium
  • Figure 20 shows DSC of Heparinized Poly L Lactide.
  • drug is used interchangeably herein with the term “pharmaceutically active agent” or “bioactive agent”.
  • the present invention provides a device comprising a base layer comprising at least one polymer covalently linked to heparin and effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer.
  • the present invention also provides a process for preparation of the device.
  • the present invention further provides a composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer and an antioxidant to stabilize the pharmaceutically active agent.
  • the present invention also provides a process of preparation of the composition as disclosed in the present invention.
  • the present invention provides a drug eluting stent having polymer covalently bonded to heparin (heparinized polymer). Coating on coronary stents comprising the heparinized polymer can be used for preventing stent thrombosis. Heparin, covalently coupled to the coating polymer, may provide anti-thrombotic effect throughout the entire period of biological degradation of the coating polymer thus maximizing the biocompatibility of the coated stent.
  • the present invention in particular provides to an implantable medical device having coatings comprising a drug and a biodegradable polymer covalently bonded to heparin for localized effect of heparin as an anticoagulation agent.
  • the medical device as disclosed in the present invention includes intraocular lenses and medical devices which often fail due to tissue in-growth or accumulation of proteinaceous material in, on and around the device, such as shunts for hydrocephalus, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, leads for pace makers and implantable defibrillators, osteointegration of orthopedic devices to enhance stabilization of the implanted device, surgical devices, sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, various types of dressings, bone substitutes, intraluminal devices, and vascular supports.
  • the medical devices as disclosed in the present invention can be used to deliver therapeutic and/or pharmaceutical active agents, such as antiproliferative/antimitotic agents including natural products, such as vinca alkaloids (i.e., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e., etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents, such as G(GP) Ilb/IIIa inhibitors and vitronectin receptor antagonists; anti-proliferative/
  • anti-coagulants heparin, synthetic heparin salts and other inhibitors of thrombin
  • fibrinolytic agents such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory; antisecretory (breveldin); antiinflammatory, such as adrenocortical steroids (Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6.alpha-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, i.e., aspirin; para- aminophenol derivatives, i.e., acetaminophen; indole and indene acetic acids (indomethacin, sulindac, and eto
  • the medical devices as disclosed in the present invention can also comprises at least one image enhancing material in one of the layer or in a separate layer, which is capable of enhancing visibility in ultra sound, magnetic resonance imaging or X-ray imaging.
  • stents there are various types of stents that may be utilized following PTCA. Although any number of stents may be utilized in accordance with the present invention, the present invention describes a limited number of stents in exemplary embodiments of the present invention. The person skilled in the art will know that any number or types of stents may be utilized in connection with the invention. In addition, as stated above, other medical devices may be utilized.
  • a stent is a tubular structure left inside the lumen of a duct to relieve an obstruction.
  • stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ.
  • a typical method of expansion occurs through the use of a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
  • Many drugs and polymers are unstable and subject to degradation during processing, packaging, sterilization, or storage of a drug-polymer coated devices.
  • the present invention provides a solution to this problem by providing a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent and anti-oxidant; and a top layer comprising at least one polymer alone or in combination with heparin, wherein heparin is covalently linked to at least one polymer.
  • Poly L-lactide being the biodegradable polymer when coupled with Heparin, provide anti-thrombotic effect throughout its degradation period of 6 to 18 months when coated on stents. Further, anti-oxidant can be added in top and intermediate layer also to prevent drug degradation.
  • biodegradable polymer Poly L lactide is covalently coupled with heparin molecule ⁇ enhancing the biocompatibility as well as hemocompatibility.
  • a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein heparin is covalently linked to at least one polymer.
  • Another embodiment of the present invention relates to a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising poly-L-Lactide (PLLA) covalently linked to heparin, polyvinyl pyrrolidone (PVP), poly (D,L-lactide-co-glycolide) (PLGA), sirolimus and/or butylated hydroxyl toluene and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer.
  • PLLA poly-L-Lactide
  • PVP polyvinyl pyrrolidone
  • PLGA poly (D,L-lactide-co-glycolide)
  • sirolimus and/or butylated hydroxyl toluene
  • a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to
  • Another embodiment of the present invention relates to ⁇ a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising polyvinyl pyrrolidone alone or in combination of heparin covalently linked to poly-L-Lactide.
  • a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently- linked to heparin and an effective amount of at least one pharmaceutically active agent; an intermediate layer comprising at least one pharmaceutical active agent admixed with at least one biodegradable polymer alone or in combination with a polymer covalently linked with heparin, and a top layer comprising at least one polymer alone or in combination with a polymer covalently linked with heparin.
  • Another embodiment of the present invention relates to the device capable of delivering pharmaceutically active agent as disclosed in the present invention, wherein ratio of the polymer to the pharmaceutically active agent is in the range of 90: 10 to 50:50.
  • the device as disclosed in the present invention comprising a base layer, a top layer, and with or without an intermediate layer, wherein all layers comprises an antioxidant.
  • the device as disclosed in the present invention comprising a base layer, a top layer and with or without an intermediate layer, wherein all layers comprises an antioxidant, wherein ratio of antioxidant to the pharmaceutically active agent is in the range of 5 % (w/w) to 0.05 % (w/w).
  • a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer, wherein the device further comprises at least one image enhancing material selected from a group consisting of ultra sound, magnetic resonance imaging or X-ray imaging material.
  • a device capable of delivering pharmaceutically active agent, wherein .the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer, wherein thickness of the base layer is in the range of 1 to 10 micrometer.
  • a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein heparin is covalently linked to at least one polymer, wherein thickness of the top layer is in the range of 0.5 to 5 microns.
  • a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; an intermediate layer comprising at least one pharmaceutical active agent admixed with at least one biodegradable polymer alone or in combination with a polymer covalently linked with heparin, and a top layer comprising at least one polymer alone or in combination with heparin, wherein thickness of the intermediate layer is in the range of 0.5 to 5 microns.
  • the device as disclosed in the present invention is an implantable device, such as stent, balloons, sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports.
  • implantable device such as stent, balloons, sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports.
  • One embodiment of the present invention relates to the device as disclosed in the present invention which is a stent.
  • a stent capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer.
  • a stent capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one, polymer, wherein the dose of pharmaceutical agent is about 0.1 ⁇ g/mm2 to 4.0 ⁇ g/mm2 of the stent surface area.
  • the polymer as described or used in the device as disclosed is biodegradable and biocompatible, such as poly-L-Lactide(PLLA), polyvinyl pyrrolidone (PVP), poly(D,L-lactide-co-glycolide) (PLGA) racemic polylactide, poly(l - lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co- caprolactone poly(d,l-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate).
  • PLLA poly-L-Lactide
  • PVP polyvinyl pyrrolidone
  • PLGA racemic polylactide
  • poly(l - lactide-co-glycolide) racemic poly(l-lactide-co-glycolide)
  • One embodiment of the present invention relates to the pharmaceutically active agent selected from the group consisting of antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, anti-inflammatories, antimitotics, anti restenotic agents, smooth muscle cell inhibitors, antibiotics, fibrinolytics, immunosuppressives, flavonoids, antimicrobial agents, antineoplastic agents, cytostatic agents, antiplatelet agent, and anti-antigenic agents.
  • the pharmaceutically active agent selected from the group consisting of antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, anti-inflammatories, antimitotics, anti restenotic agents, smooth muscle cell inhibitors, antibiotics, fibrinolytics, immunosuppressives, flavonoids, antimicrobial agents, antineoplastic agents, cytostatic agents, antiplatelet agent, and anti-antigenic agents.
  • flavonoids which includes but are not limited to chalcones, dihydrochalcones, flavanones, flavonols, dihydroflavonols, flavones, flavanols, isoflavones, neoflavones, aurones, anthocyanidins, proanthocyanidins, genistein, isoflavanes, narigenin, naringin, eriodictyol, hesperetin, hesperidin (esperidine), kampferol, quercetin, rutin, cyanidol, meciadonol, catechin, epi-gallocatechin-gallate, taxifolin (dihydroquercetin), genistein, genistin, daidzein, biochanin, glycitein, chrysin, diosmin, luetolin, apigenin
  • the pharmaceutically active agents as used in the present invention includes but are not limited to Sirolimus or analogs thereof, paclitaxel or analogs thereof, Heparin and Dexamethasone.
  • One embodiment of the present invention provides a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising coating of the composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer and an antioxidant to stabilize the pharmaceutically active agent, wherein ratio of pharmaceutically active agent to the antioxidant is in the range of 0.05 % (w/w) to 5 % (w/w), wherein ratio of polymer to pharmaceutically active agent is in the range of 90: 10 to 50:50; and a top layer coating, the base layer, said top layer comprising a polymer alone or in combination with at least one polymer covalently linked to heparin, wherein the device may or may not comprise an intermediate layer.
  • Another embodiment of the present invention provides a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent, wherein said effective amount of pharmaceutically active agent is in the range of 0.1 ⁇ / ⁇ 2 to 5 g /mm2 of total surface area of the device; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer.
  • Still another embodiment of the present invention provides a composition
  • a composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer and an antioxidant to stabilize the pharmaceutically active agent, wherein ratio of pharmaceutically active agent to the antioxidant is in the range of 0.05 % (w/w) to 5 % (w/w).
  • Still another embodiment of the present invention provides a composition
  • a composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer, and an antioxidant to stabilize the pharmaceutically active agent, wherein ratio of pharmaceutically active agent to the antioxidant is in the range of 0.05 % (w/w) to 5 % (w/w), and ratio of the pharmaceutically active agent to the polymer is in the range of 90:10 to 50:50.
  • Another embodiment of the present invention relates to an antioxidant selected from a group consisting of butylated hydroxyl toluene (BHT) and Butylated Hydroxanisole (BHA).
  • BHT butylated hydroxyl toluene
  • BHA Butylated Hydroxanisole
  • Still another embodiment of the present invention provides a composition
  • a composition comprising 15 % to 50 % (w/w) sirolimus admixed with heparin covalently linked to 25 % to 75 % (w/w) poly-L-Lactide (PLLA), 1 % to 20 % (w/w) polyvinyl pyrrolidone (PVP), 5-35 % (w/w) poly (D, L-lactide-co-glycolide) (PLGA), and 0.05-5 % (w/w)) butylated hydroxyl toluene (BHT).
  • PLLA poly-L-Lactide
  • PVP polyvinyl pyrrolidone
  • PVP polyvinyl pyrrolidone
  • PLGA L-lactide-co-glycolide
  • BHT butylated hydroxyl toluene
  • compositions as disclosed in the present invention, wherein the composition can be used for the manufacture of a medicament for treating at least one disease or condition associated with vascular injury or angioplasty, wherein the medicament is administered by implanting in a subject in need thereof a medical device having a coating for at least a portion thereof comprising the medicament.
  • Another embodiment of the present invention relates disease or the condition associated with vascular injury angioplasty, wherein the disease may be a proliferative disorder, thrombosis, embolism, or platelet accumulation, an inflammatory disease, an autoimmune disease, disease or condition is neointima and neointimal hyperplasia.
  • Yet another embodiment of the present invention relates to the proliferative disorder, such as restenosis, tumor, or proliferation of smooth muscle cells.
  • Figure 1 illustrates the synthesis reaction of Heparinized Poly L-Lactide.
  • the Heparin sodium-conjugated PLLA was prepared by a direct coupling reaction using DCC/DMAP chemistry called "Steglich Esterification".
  • a reactor 200 used for carrying . out the synthesis reaction is shown in figure 2.
  • Heparin and Poly L-Lactide in the molar ratio of 0.5 to 5 were used for preparation of Heparinized PLLA (H-PLLA).
  • Heparin sodium was dissolved in N, N- Dimethyl formamide.
  • Poly L-Lactide (PLLA) was dissolved in Dichloromethane.
  • Heparin sodium solution was heated in a glass reactor vessel 202 ( Figure 2) at 30°C to 70°C with constant agitation.
  • the coupling agent, DCC (1.0 M solution in DCM) and catalyst, DMAP (0.1 M Solution in DMF) were added to Heparin sodium solution.
  • PLLA solution was dropped in to the reaction mixture. Nitrogen gas was purged to create inert atmosphere.
  • Heparinized Poly L- Lactide was purified by dissolving precipitates in chloroform and deionized water to remove unreacted Heparin. Mass dissolved in organic solvent was separated by separating funnel. Water washing process was repeated three times. Organic mass was re-precipitated by addition of excess methanol. Precipitates were filtered through the whatman filter paper using Buckner funnel with vacuum pump.
  • H- PLLA Heparinized Poly L-Lactide
  • Table A illustrates the FT-IR spectra of - Heparin sodium, Poly (L-Lactide) and their conjugate H-PLLA;
  • FT-IR Spectra 90.0 and 1000 are illustrated in Figure 9 and 10.
  • FT-IR spectra 900 and 1000 of pure PLLA and Heparin sodium, respectively, show all the characteristic absorption bands as per the structure and functional groups in these compounds.
  • the FT-IR spectra 1100 of conjugate H-PLLA demonstrated that both Heparin sodium and PLLA with carbonyl stretching vibration at 1755 cm-1, with new broader absorption bands at 3500-3600 cm-1, which can be identified by characteristic N-H bond stretching adsorption and/or hydrogen-bonded hydroxy 1 groups of conjugated Heparin.
  • IR spectra of H-PLLA display the new absorption bands near 1234 and 1664 cm-1 compared to that of PLLA, which are characteristic adsorption peaks of sulfonated group (-S03 stretching) and amino group (N-H bending) of conjugated heparin. These results indicate the formation of PLA-Heparin. Low. intensity of peak at 1234 and 1664 cm-1 further indicate content of heparin is relatively small.
  • Table B illustrates the Nuclear Magnetic Resonance (1H-NMR) spectra of Poly (L-Lactide), Heparin sodium and their conjugate H-PLLA:
  • figure 12 and 13 illustrate the 1H- NMR Spectra 1200 and 1300.
  • 1H-NMR spectra 1200 and 1300 of pure PLLA and Heparin sodium, respectively, show all characteristic absorption band as per the structure of the compounds.
  • Table C illustrates the main thermal degradation pattern indicating % amount of compound.
  • thermogravimetric analysis 1500 pure PLLA starts degrading at around 250°C (refer to Table C). Major degradation step is involved in the temperature range 300°C to 373°C, leaving behind 1.7 % residue at 373°C.
  • thermogravimetric analysis 1600 in Figure 16 in Heparin sodium, side groups -S03 and decarboxylation, etc., starts degrading at 230°C -250°C (refer to Table C), losing almost 19 % weights. In the temperature range 300-500 °C, it degrades only about 9 % due to stable ring structure of heparin. TGA pattern of conjugate demonstrate the combined properties of both PLLA and Heparin.
  • thermogravimetric analysis 1700 shown in Figure 17. First indicating slow degradation around 230-250°C due to heparin and 300- 370 °C due to PLLA. Thus from TGA of conjugate it is inferred that both PLLA and Heparin sodium units are present in H-PLLA.
  • FIG. 18 illustrates the differential scanning calorimetry analysis 1800.
  • DSC thermogram of PLLA indicates melting temperature 188°C close to literature values of 177°C. The melting temperature depends upon molecular weight and crystanility of polymer sample. No glass temperature Tg is indicated in the curve.
  • DSC analysis 1900 illustrated in Figure 19 DSC thermogram of Heparin sodium indicates Tg at 91 °C, and exotherm around 257°C indicates decomposition.
  • PLLA is modified due to conjugation and slightly different DSC thermogram of conjugate was observed. The same is also shown in the DSC analysis 2000 of Figure 20. It has a two melting temperatures 165°C and 177°C. Exotherm is seen after 250°C. DSC thermogram of conjugate demonstrates that conjugation has taken place.
  • Table D illustrates the elemental analysis of the Heparinized PLLA:
  • Table E illustrates molecular weight data of Heparinized PLLA:
  • Table G illustrates the contact angle data of HPLLA
  • H-PLLA Heparin-conjugated polymer
  • stent coating 800 is carried out in two layers. Only base layer 802 contains Sirolimus blended in heparinized biodegradable polymeric matrix. Base layer 802 contains Sirolimus drug and heparinized Poly L- Lactide, Poly Lactide-co-Glycolide and Polyvinylpyrrolidone in solvent (dichloromethane). Butylated Hydroxytoluene (BHT) is added in the solution to increase the stability of drug.
  • BHT Butylated Hydroxytoluene
  • the coated stent undergoes many post-coating treatments, which may involve heat, moisture, pressure, sterilized gas, etc.
  • Sirolimus is oxidation-sensitive; this characteristic can adversely impact the shelf life and efficacy of Drug Eluting Stent.
  • One of the commonly used methods to overcome these shortcomings is to include one or more antioxidants, such as Butylated Hydroxytoluene (BHT) in the stent coating formulation.
  • BHT Butylated Hydroxytoluene
  • Top layer 804 contains either Poly vinylpyrolidone alone or in combination with Heparinized Poly L-Lactide in solvent dichloromethane. It is meant for protection from light and moisture and also to prevent premature drug release from the underneath layers.
  • This top layer 804, which serves as the protective layer, is completely removed within 2 to 3 hours after implantation.
  • the slippery nature of this coating (Lubricious hydrophilic coating) provides smooth navigation of the stent, inside the_arterial system, without damage to intima.
  • Neointimal thickness and percentage of stenosis was lower in stents coated with 0.45 ⁇ g/mm2 drug compare to Control BMS group at 28 days as shown in Table 3 below and in the Figure 3.
  • the surface of a stent was spray coated with a drug coating solution of the base layer 802, which comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer (all polymers including heparinized polymer) weight ratio was 30:70.
  • the base layer 802 comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer (all polymers including heparinized polymer) weight ratio was 30:70.
  • the base layer 802 was vacuum dried for 1 hour; subsequent to drying the base layer 802 was coated with a composition of top layer 804 comprising Polyvinyl Pyrolidone and vacuum dried for 1 hour at room temperature.
  • the stent thus obtained was incubated in phosphate buffer saline (pH 6.4) at 37°C and in-vitro drug release was estimated by HPLC.
  • the graph 500 in Figure 5 and Table 5 represents in-vitro drug release results of stents coated with formulation- 1.
  • the surface of a stent was spray coated with a drug coating solution of the base layer 802, which comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer weight ratio was 30:70.
  • the base layer 802 is vacuum dried for 1 hour.
  • the base layer 802 was coated with a composition of the top layer 804 comprising Polyvinyl Pyrolidone and Heparinized Poly L-Lactide in a weight ratio of 1 : 1 and vacuum dried for 1 hour at room temperature.
  • the stent thus obtained was incubated in phosphate buffer saline (pH 6.4) at 37°C and in-vitro drug release was estimated by HPLC.
  • the graph 600 in Figure 6 and Table 6 represents in-vitro drug release results of stents coated with formulation-2.
  • the surface of a stent was spray coated with a drug coating solution of the base layer 802, which comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer weight ratio was 25:75.
  • the base layer 802 was vacuum dried for 1 hour. Subsequent to vacuum drying the base layer 802 is coated with a composition of the top layer 804 comprising Polyvinyl Pyrolidone and vacuum dried for 1 hour at room temperature.
  • the stent thus obtained was incubated in phosphate buffer saline (pH 6.4) at 37°C and in-vitro drug release was estimated by HPLC.
  • the graph 700 shown in Figure 7 and Table 7 represents in-vitro drug release results of stents coated with formulation-3.
  • the surface of a stent was spray coated with a drug coating solution of the base layer 802, which comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer weight ratio was 25:75.
  • the base layer 802 was vacuum dried for 1 hour. Subsequent to vacuum drying the base layer 802 was coated with a composition of the top layer 804 comprising Polyvinyl Pyrolidone and Heparinized Poly L-Lactide in a weight ratio of 50:50.
  • the stent thus obtained was incubated in phosphate buffer saline (pH 6.4) at 37°C and in- vitro drug release was estimated by HPLC.

Abstract

A device having a coating (800) comprising a base layer (802) comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent, and a top layer (804) comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer. Further, a composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer and an antioxidant to stabilize the pharmaceutically active agent is provided herein.

Description

DEVICE AND COMPOSITION FOR DRUG RELEASE FIELD OF INVENTION
[0001] The present invention relates to a medical device comprising the composition comprising a pharmaceutically active agent and a biodegradable polymer covalently bonded to heparin.
BACKGROUND OF THE INVENTION
[0002] Percutaneous Transluminal Coronary Angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the lumen wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
[0003] A problem associated with the procedure includes formation of intimal flaps or torn arterial linings that can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery can develop over several months after the procedure, which can require another angioplasty procedure or a surgical bypass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, an expandable stent is implanted in the lumen to maintain the vascular patency.
[0004] Stents are scaffolding structures, usually cylindrical or tubular in shape, functioning to physically hold open, and if desired, to expand the wall of the passageway. Typically stents are capable of being compressed for insertion through small cavities via small catheters, and then expanded to a larger diameter once at the desired location.
[0005] To treat the damaged vasculature tissue and further fight against, thrombosis and restenosis, there is a need to administer therapeutic substances to the treatment site. For example, anticoagulants, anti-platelets, and cytostatic agents are commonly used to prevent thrombosis of the coronary lumen, to inhibit development of restenosis, and to reduce post-angioplasty proliferation of the vascular tissue. To provide an efficacious concentration to the treated site and to prevent toxic side effects, local drug delivery is preferred over a systemic administration. One commonly applied technique for the local delivery of the drugs is through the use of drug eluting stents.
[0006] Thrombosis is a prime concern after an implant of a drug eluting stent. Various anticoagulants have been systemically used orally and/or intravenously to overcome or to minimize the risk of thrombus formation at the stented region and in the immediate neighborhood of the stent. However, bleeding and other complications may occur from the use of anticoagulants (e.g., clopidogrel, LMW, heparin, ticlopidine, aspirin, etc). Accordingly, there remains a need for a more localized delivery of anticoagulants and other pharmaceutically active agents.
[0007] Heparin is an anionic, multi-sulfate, mucopolysaccharide used as an anticoagulant. Heparin acts as an anticoagulant by binding · to antithrombin III and inhibiting thrombogenesis primarily through inactivation of factors, Ila and Xa. Heparin can achieve at least one of the following functions, including inhibiting the activation of coagulation, potentiating the inhibition of the activated coagulation enzymes, and preventing platelet adhesion to the surface of the device.
[0008] Heparin has also been used as a systemic anti-coagulant in humans and in connection with stent coatings for local delivery for prevention of stent related thrombotic events. Accumulation of platelets at portions of an implanted stent remains a drawback that affects clinical safety and efficacy. Heparin has been evaluated as a stent coating for preventing early and late thrombosis and found to be satisfactory to inhibit sub-acute thrombosis (SAT). The morphology of blood vessels observed after coronary stenting demonstrates that thrombus occurs at an early stage in addition to acute inflammation (proliferation and migration of smooth muscle cells) followed by neointimal growth. The occurrence of increased inflammation soon after stenting is associated with medial injury and lipid core penetration by stent struts.
[0009] A variety of coating compositions, medical devices coated with the composition and methods of coating the composition have been reported.
[0010] US patents 6702850 and 7638158 describe a stent having a multi-layered coating adhered to its surface which can prevent restenosis and thrombosis at the implant site. The stent coating as described comprises of two layers, wherein the first layer is a polymeric coating with one or more biologically active agent dispersed therein and the second layer is comprised of a hydrophobic heparinized polymer.
[0011] US patent 7022334 describes therapeutic compositions comprising a polysaccharide, such as heparin or a derivative of heparin; or a cationic peptide and a method of coating the device. The therapeutic composition as described comprises heparin and polymer which are physically blended in organic solvent prior to coating. The document also describes an implantable medical device, such as a stent having a coating that can include an optional primer layer comprising a solution of polysaccharide and a solvent mixed with a polymer, a reservoir layer comprising a polymer, a polysaccharide and a therapeutic agent and an optional topcoat layer comprising a polymer alone or in combination with a polysaccharide.
[0012] EP1834636A1 describes compositions comprising a first polymer having pores, nanoparticles dispersed within the pores of the first polymer, the nanoparticles comprising a second polymer and at least one pharmaceutically active agent dispersed in the second polymer, and heparin covalently bonded to at least one of the first and second polymer. The document also describes stents coated with the composition.
[0013] EP1832301 A2 describes a composition comprising at least one polymer covalently linked to heparin and at least one pharmaceutically active agent other than heparin dispersed within the' at least one polymer and a medical device coated with the composition. [0014] EP 1832289A2 describes a composition comprising at least one polymer, heparin and at least one pharmaceutically active agent specifically benzopyran-4-one compounds and an implantable device coated with the composition.
[0015] US patent 7785647 and US patent application 20100300903 describe a method of providing a volatile antioxidant, such as butylated hydroxytoluene (BHT) and/or butylated hydroxyahisole (BHA) to a medical device to improve the shelf life of the drug coated stent, and a kit comprising the medical device.
[0016] Published US patent application 2003/0204239 describes a system for treating a vascular condition, including a catheter, a stent including a stent framework coupled to the catheter, a preservative coating including at least one antioxidant disposed on the stent framework.
[0017] US patent 7709049 describes coating a method, a composition for controlled release of active agent and the medical device coated with the composition, wherein the active agent release is determined by deposition rate of the coating composition.
[0018] US patent 8007737 describes use of antioxidant to prevent oxidation and reduce drug degradation in drug eluting medical devices and implantable medical devices coated with biocompatible materials mixed with therapeutic drugs, agents or compounds and an antioxidant. - .
[0019] Published US Patent application 2011/0137407 describes a bare metal stent with drug eluting reservoirs for implantation into a tubular organ of a living organism. The bare metal stent described comprises an elongated tubular structure having a luminal surface and an abluminal surface, the elongated tubular structure including a plurality of interconnected elements, a portion of the interconnected elements comprising at least one reservoir extending from the luminal surface to the abluminal surface, at least one base composition inlay comprising a polymer deposited in the at least one reservoir proximate the luminal surface of the elongated tubular structure, and at least one top composition inlay comprising a therapeutic agent deposited in the reservoir on top of the base composition inlay and below the abluminal surface of the elongated tubular structure.
[0020] Accordingly, there exists a need for medical devices for local delivery of drug which is capable of delivering the drug in more efficient way with fewer side effects.
OBJECTS OF THE INVENTION
[0021] It is a primary object of the present invention to provide a coating composition comprising at least one active agent to prevent, reduce, and/or treat thrombosis, restenosis, or other adverse reactions related to vascular diseases.
[0022] It is another object of the present invention to provide a medical device capable of delivering the active agent at the desired target and effectively preventing, treating and/or reducing thrombosis, restenosis, or other adverse reactions related to vascular diseases.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0023] The foregoing and other features of the present invention will be apparent from the accompanying drawings.
[0024] Figure 1 shows synthesis reaction of Heparinized Poly L-Lactide;
[0025] Figure 2 shows schematic of Reactor Used for Synthesis for Heparinized
Polymer;
[0026] Figure 3 shows histological analysis of rabbit iliac artery after 28 days of implantation;
[0027] Figure 4 shows histological analysis of rabbit iliac artery after 90 days of implantation;
[0028] Figure 5 shows In- Vitro Drug Release Profile of the stent coated with formulation- 1 ;
[0029] Figure 6 shows In- Vitro Drug Release Profile of the stent coated with formulation-2; [0030] Figure 7 shows In- Vitro Drug Release Profile of the stent coated with formulation-3;
[0031] Figure 8 shows schematic of coating layer distribution of drug eluting stent;
[0032] Figure 9 shows FT-IR spectra of Poly (L-Lactide);
[0033] Figure 10 shows FT-IR spectra of Heparin Sodium;
[0034] Figure 11 shows FT-IR spectra of H-PLLA;
[0035] Figure 12 shows H-NMR spectra of Poly (L-Lactide);
[0036] Figure 13 shows H-NMR spectra of Heparin Sodium;
[0037] Figure 14 shows H-NMR spectra of Heparinized Poly L Lactide;
[0038] Figure 15 shows TGA of Poly (L-Lactide);
[0039] Figure 16 shows TGA of Heparin Sodium;
[0040] Figure 17 TGA of Heparinized Poly L Lactide;
[0041] Figure 18 shows DSC of Poly (L-Lactide);
[0042] Figure 19 shows DSC of Heparin Sodium; and
[0043] Figure 20 shows DSC of Heparinized Poly L Lactide.
DETAILED DESCRIPTION OF THE INVENTION
[0044], Definitions
[0045] The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
[0046] The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise.
[0047] The term "drug" is used interchangeably herein with the term "pharmaceutically active agent" or "bioactive agent".
[0048] The present invention provides a device comprising a base layer comprising at least one polymer covalently linked to heparin and effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer. The present invention also provides a process for preparation of the device.
[0049] The present invention further provides a composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer and an antioxidant to stabilize the pharmaceutically active agent. The present invention also provides a process of preparation of the composition as disclosed in the present invention.
[0050] Furthermore, the present invention provides a drug eluting stent having polymer covalently bonded to heparin (heparinized polymer). Coating on coronary stents comprising the heparinized polymer can be used for preventing stent thrombosis. Heparin, covalently coupled to the coating polymer, may provide anti-thrombotic effect throughout the entire period of biological degradation of the coating polymer thus maximizing the biocompatibility of the coated stent.
[0051] The present invention in particular provides to an implantable medical device having coatings comprising a drug and a biodegradable polymer covalently bonded to heparin for localized effect of heparin as an anticoagulation agent.
[0052] While exemplary embodiments of the invention will be described with respect to the treatment of restenosis, thrombosis and related complications following PTCA, it is important to note that the local delivery of active agent be utilized to treat a wide variety of conditions utilizing any number of medical devices, or to enhance the function and/or life of the device.
[0053] The medical device as disclosed in the present invention includes intraocular lenses and medical devices which often fail due to tissue in-growth or accumulation of proteinaceous material in, on and around the device, such as shunts for hydrocephalus, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, leads for pace makers and implantable defibrillators, osteointegration of orthopedic devices to enhance stabilization of the implanted device, surgical devices, sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, various types of dressings, bone substitutes, intraluminal devices, and vascular supports.
[0054] The medical devices as disclosed in the present invention can be used to deliver therapeutic and/or pharmaceutical active agents, such as antiproliferative/antimitotic agents including natural products, such as vinca alkaloids (i.e., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e., etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents, such as G(GP) Ilb/IIIa inhibitors and vitronectin receptor antagonists; anti-proliferative/antimitotic alkylating agents, such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); anti-proliferative/antimitotic antimetabolites, such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine{cladribine}); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen); anti-coagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory; antisecretory (breveldin); antiinflammatory, such as adrenocortical steroids (Cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6.alpha-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, i.e., aspirin; para- aminophenol derivatives, i.e., acetaminophen; indole and indene acetic acids (indomethacin, sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF); angiotensin receptor blockers; nitric oxide donors; antisense oligionucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor receptor signal transduction kinase inhibitors; retenoids; cyclin/CDK inhibitors; HMG co-enzyme reductase inhibitors (statins); and protease inhibitors.
[0055] The medical devices as disclosed in the present invention can also comprises at least one image enhancing material in one of the layer or in a separate layer, which is capable of enhancing visibility in ultra sound, magnetic resonance imaging or X-ray imaging.
[0056] There are various types of stents that may be utilized following PTCA. Although any number of stents may be utilized in accordance with the present invention, the present invention describes a limited number of stents in exemplary embodiments of the present invention. The person skilled in the art will know that any number or types of stents may be utilized in connection with the invention. In addition, as stated above, other medical devices may be utilized.
[0057] A stent is a tubular structure left inside the lumen of a duct to relieve an obstruction. Commonly, stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ. A typical method of expansion occurs through the use of a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen. [0058] Many drugs and polymers are unstable and subject to degradation during processing, packaging, sterilization, or storage of a drug-polymer coated devices. During sterilization, oxidation of the drug or polymer may occur in some cases leading to degradation by cleavage of the polymeric bonds and breakdown of the polymer and/or drug. The lack of drug stability may cause decreased efficacy. The present invention provides a solution to this problem by providing a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent and anti-oxidant; and a top layer comprising at least one polymer alone or in combination with heparin, wherein heparin is covalently linked to at least one polymer. Poly L-lactide being the biodegradable polymer when coupled with Heparin, provide anti-thrombotic effect throughout its degradation period of 6 to 18 months when coated on stents. Further, anti-oxidant can be added in top and intermediate layer also to prevent drug degradation.
[0059] Moreover, current drug eluting stents (prior art stent) majorly utilizes the non-degradable polymer for drug delivery and there are evidences that they hinder normal healing process therefore biodegradable polymers are preferable. In the current invention, biodegradable polymer Poly L lactide is covalently coupled with heparin molecule^ enhancing the biocompatibility as well as hemocompatibility.
[0060] In accordance with the present invention in one embodiment there is provided a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein heparin is covalently linked to at least one polymer.
[0061] Another embodiment of the present invention relates to a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising poly-L-Lactide (PLLA) covalently linked to heparin, polyvinyl pyrrolidone (PVP), poly (D,L-lactide-co-glycolide) (PLGA), sirolimus and/or butylated hydroxyl toluene and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer.
[0062] Another embodiment of the present invention relates to^a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising polyvinyl pyrrolidone alone or in combination of heparin covalently linked to poly-L-Lactide.
[0063] In one embodiment of the present invention there is provided a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently- linked to heparin and an effective amount of at least one pharmaceutically active agent; an intermediate layer comprising at least one pharmaceutical active agent admixed with at least one biodegradable polymer alone or in combination with a polymer covalently linked with heparin, and a top layer comprising at least one polymer alone or in combination with a polymer covalently linked with heparin.
[0064] Another embodiment of the present invention relates to the device capable of delivering pharmaceutically active agent as disclosed in the present invention, wherein ratio of the polymer to the pharmaceutically active agent is in the range of 90: 10 to 50:50.
[0065] The device as disclosed in the present invention comprising a base layer, a top layer, and with or without an intermediate layer, wherein all layers comprises an antioxidant.
[0066] Further, the device as disclosed in the present invention comprising a base layer, a top layer and with or without an intermediate layer, wherein all layers comprises an antioxidant, wherein ratio of antioxidant to the pharmaceutically active agent is in the range of 5 % (w/w) to 0.05 % (w/w).
[0067] In another embodiment of the present invention there is provided a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer, wherein the device further comprises at least one image enhancing material selected from a group consisting of ultra sound, magnetic resonance imaging or X-ray imaging material.
[0068] In another embodiment of the present invention there is provided a device capable of delivering pharmaceutically active agent, wherein .the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer, wherein thickness of the base layer is in the range of 1 to 10 micrometer.
[0069] In yet another embodiment of the present invention there is provided a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein heparin is covalently linked to at least one polymer, wherein thickness of the top layer is in the range of 0.5 to 5 microns. ,
[0070] In one embodiment there is provided a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; an intermediate layer comprising at least one pharmaceutical active agent admixed with at least one biodegradable polymer alone or in combination with a polymer covalently linked with heparin, and a top layer comprising at least one polymer alone or in combination with heparin, wherein thickness of the intermediate layer is in the range of 0.5 to 5 microns.
[0071] The device as disclosed in the present invention is an implantable device, such as stent, balloons, sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports.
[0072] One embodiment of the present invention relates to the device as disclosed in the present invention which is a stent.
[0073] In yet another embodiment of the present invention there is provided a stent capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer.
[0074] In yet another embodiment of the present invention there is provided a stent capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one, polymer, wherein the dose of pharmaceutical agent is about 0.1 μg/mm2 to 4.0 μg/mm2 of the stent surface area.
[0075] The polymer as described or used in the device as disclosed is biodegradable and biocompatible, such as poly-L-Lactide(PLLA), polyvinyl pyrrolidone (PVP), poly(D,L-lactide-co-glycolide) (PLGA) racemic polylactide, poly(l - lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co- caprolactone poly(d,l-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate).
[0076] One embodiment of the present invention relates to the pharmaceutically active agent selected from the group consisting of antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, anti-inflammatories, antimitotics, anti restenotic agents, smooth muscle cell inhibitors, antibiotics, fibrinolytics, immunosuppressives, flavonoids, antimicrobial agents, antineoplastic agents, cytostatic agents, antiplatelet agent, and anti-antigenic agents. [0077] Another embodiment of the present invention relates to the flavonoids which includes but are not limited to chalcones, dihydrochalcones, flavanones, flavonols, dihydroflavonols, flavones, flavanols, isoflavones, neoflavones, aurones, anthocyanidins, proanthocyanidins, genistein, isoflavanes, narigenin, naringin, eriodictyol, hesperetin, hesperidin (esperidine), kampferol, quercetin, rutin, cyanidol, meciadonol, catechin, epi-gallocatechin-gallate, taxifolin (dihydroquercetin), genistein, genistin, daidzein, biochanin, glycitein, chrysin, diosmin, luetolin, apigenin, tangeritin and nobiletin.
[0078] The pharmaceutically active agents as used in the present invention includes but are not limited to Sirolimus or analogs thereof, paclitaxel or analogs thereof, Heparin and Dexamethasone.
[0079] One embodiment of the present invention provides a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising coating of the composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer and an antioxidant to stabilize the pharmaceutically active agent, wherein ratio of pharmaceutically active agent to the antioxidant is in the range of 0.05 % (w/w) to 5 % (w/w), wherein ratio of polymer to pharmaceutically active agent is in the range of 90: 10 to 50:50; and a top layer coating, the base layer, said top layer comprising a polymer alone or in combination with at least one polymer covalently linked to heparin, wherein the device may or may not comprise an intermediate layer.
[0080] Another embodiment of the present invention provides a device capable of delivering pharmaceutically active agent, wherein the device comprising a base layer comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent, wherein said effective amount of pharmaceutically active agent is in the range of 0.1 μ§/ιοαιή2 to 5 g /mm2 of total surface area of the device; and a top layer comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer. [0081] Still another embodiment of the present invention provides a composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer and an antioxidant to stabilize the pharmaceutically active agent, wherein ratio of pharmaceutically active agent to the antioxidant is in the range of 0.05 % (w/w) to 5 % (w/w).
[0082] Still another embodiment of the present invention provides a composition comprising at least one pharmaceutically active agent admixed with heparin covalently linked to at least one polymer, and an antioxidant to stabilize the pharmaceutically active agent, wherein ratio of pharmaceutically active agent to the antioxidant is in the range of 0.05 % (w/w) to 5 % (w/w), and ratio of the pharmaceutically active agent to the polymer is in the range of 90:10 to 50:50.
[0083] Another embodiment of the present invention relates to an antioxidant selected from a group consisting of butylated hydroxyl toluene (BHT) and Butylated Hydroxanisole (BHA).
[0084] Still another embodiment of the present invention provides a composition comprising 15 % to 50 % (w/w) sirolimus admixed with heparin covalently linked to 25 % to 75 % (w/w) poly-L-Lactide (PLLA), 1 % to 20 % (w/w) polyvinyl pyrrolidone (PVP), 5-35 % (w/w) poly (D, L-lactide-co-glycolide) (PLGA), and 0.05-5 % (w/w)) butylated hydroxyl toluene (BHT). .
[0085] Further embodiment of the present invention provides a process of making an implantable medical device capable of delivering pharmaceutically active agent, wherein the process comprising coating the device surface with a composition comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent to form a base layer; drying the base layer; and coating the base layer with a composition comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer to form a top layer.
[0086] The process of making an implantable medical device capable of delivering pharmaceutically active agent as disclosed in the present invention, wherein drying of the base layer, an intermediate layer and/or the top layer is carried put by using vacuum or heat drying method.
[0087] Further embodiment of the present invention relates to the use of the composition as disclosed in the present invention, wherein the composition can be used for the manufacture of a medicament for treating at least one disease or condition associated with vascular injury or angioplasty, wherein the medicament is administered by implanting in a subject in need thereof a medical device having a coating for at least a portion thereof comprising the medicament.
[0088] Another embodiment of the present invention relates disease or the condition associated with vascular injury angioplasty, wherein the disease may be a proliferative disorder, thrombosis, embolism, or platelet accumulation, an inflammatory disease, an autoimmune disease, disease or condition is neointima and neointimal hyperplasia.
[0089] Yet another embodiment of the present invention relates to the proliferative disorder, such as restenosis, tumor, or proliferation of smooth muscle cells.
[0090] . Preparation of Heparinized Poly-L-Lactide
[0091] Figure 1 illustrates the synthesis reaction of Heparinized Poly L-Lactide. The Heparin sodium-conjugated PLLA was prepared by a direct coupling reaction using DCC/DMAP chemistry called "Steglich Esterification". A reactor 200 used for carrying . out the synthesis reaction is shown in figure 2.
[0092] Heparin and Poly L-Lactide in the molar ratio of 0.5 to 5 were used for preparation of Heparinized PLLA (H-PLLA). Heparin sodium was dissolved in N, N- Dimethyl formamide. Poly L-Lactide (PLLA) was dissolved in Dichloromethane. Heparin sodium solution was heated in a glass reactor vessel 202 (Figure 2) at 30°C to 70°C with constant agitation. The coupling agent, DCC (1.0 M solution in DCM) and catalyst, DMAP (0.1 M Solution in DMF) were added to Heparin sodium solution. Then PLLA solution was dropped in to the reaction mixture. Nitrogen gas was purged to create inert atmosphere. Temperature of the reactor 200 was maintained at 30°C to 70°C and agitator speed at 50 to 80 RPM for 12 to 20 hrs under nitrogen atmosphere After the coupling reaction, the reaction mixture was precipitated in excess methanol. The precipitates (H-PLLA) were filtered and crude H-PLLA was collected into Petri disc.
[0093] Heparinized Poly L- Lactide was purified by dissolving precipitates in chloroform and deionized water to remove unreacted Heparin. Mass dissolved in organic solvent was separated by separating funnel. Water washing process was repeated three times. Organic mass was re-precipitated by addition of excess methanol. Precipitates were filtered through the whatman filter paper using Buckner funnel with vacuum pump.
[0094] Further purification is done to remove excess solvent and coupling agent. Precipitates were transferred in a beaker containing the excess quantity of Methanol. Stirring was applied for 20-40 minutes. Precipitates were filtered. The final product was vacuum dried for 24 hrs.
[0095] Physico-chemical characterization of Heparinized Poly L-Lactide (H- PLLA)
[0096] The Physico-chemical characterization of Heparinized Poly L-Lactide (H- PLLA) was done using various analytical, thermal, and spectroscopic techniques.
[0097] FT-IR Spectra
[0098] The following table, referred to as Table A, illustrates the FT-IR spectra of - Heparin sodium, Poly (L-Lactide) and their conjugate H-PLLA; ,
Figure imgf000018_0001
[0099] In addition, the FT-IR Spectra 90.0 and 1000 are illustrated in Figure 9 and 10. As shown in Figure 9 and 10; FT-IR spectra 900 and 1000 of pure PLLA and Heparin sodium, respectively, (refer to Table A) show all the characteristic absorption bands as per the structure and functional groups in these compounds. The FT-IR spectra 1100 of conjugate H-PLLA (refer to Figure 1 1, Table A) demonstrated that both Heparin sodium and PLLA with carbonyl stretching vibration at 1755 cm-1, with new broader absorption bands at 3500-3600 cm-1, which can be identified by characteristic N-H bond stretching adsorption and/or hydrogen-bonded hydroxy 1 groups of conjugated Heparin. In addition, IR spectra of H-PLLA display the new absorption bands near 1234 and 1664 cm-1 compared to that of PLLA, which are characteristic adsorption peaks of sulfonated group (-S03 stretching) and amino group (N-H bending) of conjugated heparin. These results indicate the formation of PLA-Heparin. Low. intensity of peak at 1234 and 1664 cm-1 further indicate content of heparin is relatively small.
[00100] NMR Spectra
[00101] The following table, referred to as Table B, illustrates the Nuclear Magnetic Resonance (1H-NMR) spectra of Poly (L-Lactide), Heparin sodium and their conjugate H-PLLA:
Figure imgf000019_0001
[00102] In addition, figure 12 and 13 illustrate the 1H- NMR Spectra 1200 and 1300. As shown in Figure 12 and 13; 1H-NMR spectra 1200 and 1300 of pure PLLA and Heparin sodium, respectively, (refer to Table B) show all characteristic absorption band as per the structure of the compounds.
[00103] In addition, as shown in figure 14, the 1H-NMR 1400 of conjugate H- PLLA (as also shown in Table B) with chemical shift 1.57-1.59, 5.12-5.20 (m) ppm, and shifts at 1.2 and 3.7 ppm seen on enlargement demonstrated that both Heparin sodium and PLLA units are present in conjugate.
[00104] Thermogravimetric Analysis [00105] The following table, referred to as Table C, illustrates the main thermal degradation pattern indicating % amount of compound.
Figure imgf000020_0001
[00106] As is also shown in Figure 15, which illustrates the thermogravimetric analysis 1500, pure PLLA starts degrading at around 250°C (refer to Table C). Major degradation step is involved in the temperature range 300°C to 373°C, leaving behind 1.7 % residue at 373°C. On the contrary as shown in the thermogravimetric analysis 1600 in Figure 16, in Heparin sodium, side groups -S03 and decarboxylation, etc., starts degrading at 230°C -250°C (refer to Table C), losing almost 19 % weights. In the temperature range 300-500 °C, it degrades only about 9 % due to stable ring structure of heparin. TGA pattern of conjugate demonstrate the combined properties of both PLLA and Heparin. The same is illustrated in the thermogravimetric analysis 1700 shown in Figure 17. First indicating slow degradation around 230-250°C due to heparin and 300- 370 °C due to PLLA. Thus from TGA of conjugate it is inferred that both PLLA and Heparin sodium units are present in H-PLLA.
[00107] Differential Scanning Calorimetry analysis
[00108] Figure 18 illustrates the differential scanning calorimetry analysis 1800. As shown in Figure 18, DSC thermogram of PLLA indicates melting temperature 188°C close to literature values of 177°C. The melting temperature depends upon molecular weight and crystanility of polymer sample. No glass temperature Tg is indicated in the curve. As shown in the DSC analysis 1900 illustrated in Figure 19; DSC thermogram of Heparin sodium indicates Tg at 91 °C, and exotherm around 257°C indicates decomposition. PLLA is modified due to conjugation and slightly different DSC thermogram of conjugate was observed. The same is also shown in the DSC analysis 2000 of Figure 20. It has a two melting temperatures 165°C and 177°C. Exotherm is seen after 250°C. DSC thermogram of conjugate demonstrates that conjugation has taken place.
[00109] Elemental Analysis
[00110] The following table, referred to as Table D, illustrates the elemental analysis of the Heparinized PLLA:
Figure imgf000021_0001
*ND-Not detected
[00111] In Heparin sodium, Nitrogen content was 1.25% and in conjugate H-PLLA it was found to be 0.19% (refer to Table D). This indicates conjugation reaction has worked well.
[00112] Molecular Weight Distribution Analysis
[00113] The following table, referred to as Table E, illustrates molecular weight data of Heparinized PLLA:
Figure imgf000021_0002
* The weight average molecular weight (Mw) of Heparin sodium
[00114] There is a small change in MW of conjugate H-PLLA from pure PLLA, which may be due to involvement of Heparin in conjugate. This definitely indicates no destruction of PLLA during conjugation reaction. Polydispersity (PDI) is almost same indicating no change in PLLA structure due to conjugation reaction (Table E).
[00115] Surface bounded Heparin analysis by Toluidine Blue colorimetric method [00116] The following table, referred to as Table F, illustrates the amount of surface bounded Heparin by Toluidine Blue colorimetric method:
Figure imgf000022_0001
[00117] On quantitative analysis of heparin from HPLLA surface by Toludien blue colorimetric method, it is reported that amount of surface exposed heparin associated with H-PLLA is 0.012 mg/mg (refer to Table F).
[00118] Surface Contact angle (SCA) measurement Analysis
[00119] The following table, referred to as Table G, illustrates the contact angle data of HPLLA
Figure imgf000022_0002
[00120] The Surface Contact angle (SCA) of H-PLLA (82°) was decreased by 4° when compared with PLLA (86°), suggesting that the exposure of conjugated heparin on surface contribute to increased wettability of H-PLLA surface (Table G).
[00121] Considering the detailed chemical and physical analysis based on FT-IR, 1H-NMR, 13C-NMR, TGA, DSC, elemental analysis, surface contact angle measurement, colorimetric data of Heparin sodium, Poly (L-Lactide) (PLLA) and their conjugate (H-PLLA), it can be safely inferred that Heparin-conjugated polymer (H- PLLA) has been synthesized by the direct coupling of Heparin to PLLA through the reaction shown in Figure 1. The conjugation has taken place through the formation of ester link between free hydroxyl -OH group of PLLA and carboxylate -COO- group of Heparin sodium. The formation of ester link was demonstrated through increase in the intensity of band at 1755 cm-1 in FT-IR of H-PLLA.
[00122] Stent Coating
[00123] The coating layer distribution of a drug eluting stent is shown in the schematic of figure 8. As shown in figure 8, stent coating 800 is carried out in two layers. Only base layer 802 contains Sirolimus blended in heparinized biodegradable polymeric matrix. Base layer 802 contains Sirolimus drug and heparinized Poly L- Lactide, Poly Lactide-co-Glycolide and Polyvinylpyrrolidone in solvent (dichloromethane). Butylated Hydroxytoluene (BHT) is added in the solution to increase the stability of drug.
[00124] In manufacturing of Drug Eluting Stent, the coated stent undergoes many post-coating treatments, which may involve heat, moisture, pressure, sterilized gas, etc. As Sirolimus is oxidation-sensitive; this characteristic can adversely impact the shelf life and efficacy of Drug Eluting Stent. One of the commonly used methods to overcome these shortcomings is to include one or more antioxidants, such as Butylated Hydroxytoluene (BHT) in the stent coating formulation.
[00125] Top layer 804 contains either Poly vinylpyrolidone alone or in combination with Heparinized Poly L-Lactide in solvent dichloromethane. It is meant for protection from light and moisture and also to prevent premature drug release from the underneath layers. This top layer 804, which serves as the protective layer, is completely removed within 2 to 3 hours after implantation. In addition, the slippery nature of this coating (Lubricious hydrophilic coating) provides smooth navigation of the stent, inside the_arterial system, without damage to intima.
[00126] Table 1 and 2 given below, illustrate the different drug-polymer composition used in coating composition.
[00127] Table 1 : Drug-Polymer Composition in Coating Layers
Figure imgf000023_0001
Heparinized Poly L-Lactide
Base Layer Poly DL-Lactide-co-Glycolide Sirolimus 10/90 to 50/50
Polyvinyl Pyrrolidone
Top Layer Polyvinyl Pyrrolidone No Drug 0/100
[00128] Table 2: Drug-Polymer Composition in Coating Layers
Figure imgf000024_0001
[00129] During the spray coating process and micro-sized spray particles are deposited on the surface of the stent. The stent was hung between two collate with the help of hooks and solution of the base layer 802 having drug Sirolimus, Heparinized Poly L-Lactide, Poly Lactide-co-Glycolide and Polyvinyl was sprayed on the stent at an optimum flow rate at 0.5-2.5 bar of nitrogen pressure. During coating, the flow rate was maintained (0.1 to 1 ml/minute). The coating layer was vacuum dried for 60 minutes for complete solvent evaporation. Top layer coatings were performed in the same manner.
[00130] Experimental data related to cell line-(in-vivo) and animal study to confirm the functionality of the claimed composition and the stent coated with the composition
[00131] Vascular response and re-endothelialization after implantation of the Sirolimus eluting stent as described above with a novel biodegradable heparinized polymer in the rabbit iliac artery was evaluated. Total 37 animals (New Zealand White Rabbit) were implanted with control (uncoated stent, Heparinized polymer coated stent) and test (Sirolimus and Heparinized polymer coated stent) stents (total 74 stents). The animals were sacrificed at 14, 28, and 90 days after implantation.
[00132] Neointimal thickness and percentage of stenosis was lower in stents coated with 0.45 μg/mm2 drug compare to Control BMS group at 28 days as shown in Table 3 below and in the Figure 3.
[00133] Table 3: Preclinical Evaluation after 28 Days of Implantation
Figure imgf000025_0001
[00134] While at 90 days also it was comparable with Hepamer coated stents as shown below in Table 4, and Figure 4. Stents coated with 1.4 μg/mm2 drug shows favorable response at 90 days. More than 90 % endothelialization is observed after 28 days. No granulomatous reaction was observed in any experimental stent at any stage, as shown in Figure 3 and Figure 4.
[00135] Table 4: Preclinical Evaluation after 90 Days of Implantation
Figure imgf000025_0002
[00136] In-vitro drug release data in phosphate buffer saline (PBS) from the drug coated stent coated with composition comprising Sirolimus and polymer
[00137] In vitro release study using coating compositions and with varying ratio of drug to polymer were studies (Formulation 1, 2, 3 and 4). The details are provided below.
[00138] Formulation 1
[00139] The surface of a stent was spray coated with a drug coating solution of the base layer 802, which comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer (all polymers including heparinized polymer) weight ratio was 30:70.
[00140] The base layer 802 was vacuum dried for 1 hour; subsequent to drying the base layer 802 was coated with a composition of top layer 804 comprising Polyvinyl Pyrolidone and vacuum dried for 1 hour at room temperature. The stent thus obtained was incubated in phosphate buffer saline (pH 6.4) at 37°C and in-vitro drug release was estimated by HPLC.
[00141] The graph 500 in Figure 5 and Table 5 represents in-vitro drug release results of stents coated with formulation- 1.
[00142] Table 5: Drug Release Data with Stents Coated with Formulation 1
Figure imgf000026_0001
[00143] Formulation 2
[00144] The surface of a stent was spray coated with a drug coating solution of the base layer 802, which comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer weight ratio was 30:70. The base layer 802 is vacuum dried for 1 hour. Subsequent to vacuum drying the base layer 802 was coated with a composition of the top layer 804 comprising Polyvinyl Pyrolidone and Heparinized Poly L-Lactide in a weight ratio of 1 : 1 and vacuum dried for 1 hour at room temperature. The stent thus obtained was incubated in phosphate buffer saline (pH 6.4) at 37°C and in-vitro drug release was estimated by HPLC.
[00145] The graph 600 in Figure 6 and Table 6 represents in-vitro drug release results of stents coated with formulation-2.
[00146] Table 6: Drug Release Data with Stents Coated with Formulation 2
Figure imgf000027_0001
[00147] Formulation 3
[00148] The surface of a stent was spray coated with a drug coating solution of the base layer 802, which comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer weight ratio was 25:75. The base layer 802 was vacuum dried for 1 hour. Subsequent to vacuum drying the base layer 802 is coated with a composition of the top layer 804 comprising Polyvinyl Pyrolidone and vacuum dried for 1 hour at room temperature. The stent thus obtained was incubated in phosphate buffer saline (pH 6.4) at 37°C and in-vitro drug release was estimated by HPLC.
[00149] The graph 700 shown in Figure 7 and Table 7 represents in-vitro drug release results of stents coated with formulation-3.
[00150] Table 7: Drug Release Data with Stents Coated with Formulation 3 Days % In- Vitro Drug Release
1 10
2 18
3 25
7 43
14 . 49
[00151] Formulation 4
[00152] The surface of a stent was spray coated with a drug coating solution of the base layer 802, which comprises Sirolimus, Heparinized Poly L-Lacide, Poly Lactide- co-Glycolide and Polyvinyl Pyrolidone, wherein drug to polymer weight ratio was 25:75. The base layer 802 was vacuum dried for 1 hour. Subsequent to vacuum drying the base layer 802 was coated with a composition of the top layer 804 comprising Polyvinyl Pyrolidone and Heparinized Poly L-Lactide in a weight ratio of 50:50. The stent thus obtained was incubated in phosphate buffer saline (pH 6.4) at 37°C and in- vitro drug release was estimated by HPLC.
[00153] Conclusion
[00154] Upon a comparison of the graphs 500, 600, and 700 in Figures 5, 6, and 7, respectively, it is concluded that in-vitro drug release decrease significantly by decreasing drug to polymer ratio. Top layer 804 also has impact on drug release. Adding hydrophobic polymer Heparinized PLLA in the top layer 804 has reduced the burst release of drug.
[00155] Although shown and described herein is what is believed to be the preferred embodiments of the present invention and best mode of performing the present invention, it is apparent that the departure from specific designs and processes described is obvious to a person skilled in the art. Thus, the present invention is not restricted to the particular embodiment, description, and illustration and should be construed to encompass all the medications that may fall within the scope of the present invention.

Claims

I/We Claim:
1. A device having a coating (800) comprising: a base layer (802) comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent; and a top layer (804) comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to the at least one polymer.
2. The device as claimed in claim 1, wherein the base layer (802) comprises poly-L- Lactide (PLLA) covalently linked to heparin, polyvinyl pyrrolidone (PVP), poly(D,L-lactide-co-glycolide) (PLGA), sirolimus, analogs of sirolimus, and/or butylated hydroxyl toluene.
3. The device as claimed in claim 1 , wherein the top layer (804) comprises polyvinyl pyrrolidone alone or in combination of heparin covalently linked to poly-L-Lactide.
4. The device as claimed in claim 1, wherein the coating (800) further comprises an intermediate layer.
5. The device as claimed in claim 1, wherein ratio of the polymer to the pharmaceutically active agent is in the range of 90:10 to 50:50.
6. The device as claimed in claim 1, wherein the base layer (802) further comprises an antioxidant.
7. The device as claimed in claim 6, wherein _rati'o of antioxidant to the pharmaceutically active agent is in the range of 5 % (w/w) to 0.05 % (w/w).
8. The device as claimed in claim 1, wherein thickness of the base layer (802) is in the range of 1 to 10 microns.
9. The device as claimed in claim 1 , wherein thickness of the top layer (804) is in the range of 0.5 to 5 microns.
10. The device as claimed in claim 4, wherein thickness of the intermediate layer is in the range of 0.5 to 5 microns.
11. The device as claimed in claim 1, wherein the device is an implantable device.
12. The device as claimed in claim 1 , wherein the device further comprises at least one image enhancing material selected from a group consisting of ultra sound, magnetic resonance imaging or X-ray imaging material.
13. The device as claimed in claim 1, wherein the device is selected from a group consisting of stent, sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports.
14. The device as claimed in claim 1, wherein the device is a stent.
15. The device as claimed in claim 14, wherein surface area of about 0.1 μg/mm2 to 4.0 μg/mm of the stent is covered with the base layer (802).
16. The 'device as claimed in claim 1, wherein the polymer is biodegradable and biocompatible.
17. The device as claimed in claim 1, wherein the polymer is selected from the group consisting of poly-L-Lactide(PLLA), polyvinyl pyrrolidone (PVP), poly(D,L- lactide-co-glycolide) (PLGA) racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-capro lactone poly(d,l- lactide-co-capro lactone), poly(l-lactide-co-trimethylene carbonate), and poly(dJ- lactide-co-trimethylene carbonate).
18. The device as claimed in claim 1, wherein the pharmaceutically active agent is selected from the group consisting of antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, anti-inflammatories, antimitotics, anti restenotic agents, smooth muscle cell inhibitors, antibiotics, fibrinolytics, immunosuppressives, flavonoids, antimicrobial agents, antineoplastic agents, cytostatic agents, antiplatelet agent, and anti-antigenic agents.
19. The device as claimed in claim 18, wherein the flavonoid is selected from a group consisting of chalcones, dihydrochalcones, flavanones, flavonols, dihydroflavonois, flavones, flavanols, isoflavones, neoflavones, aurones, anthocyanidins, proanthocyanidiris, genistein, isoflavanes, narigenin, naringin, eriodictyol, hesperetin, hesperidin (esperidine), kampferol, quercetin, rutin, cyanidol, meciadonol, catechin, epi-gallocatechin-gallate, taxifolin (dihydroquercetin), genistein, genistin, daidzein, biochanin, glycitein, chrysin, diosmin, luetolin, apigenin, tangeritin, and nobiletin.
20. The device as claimed in claim 1, wherein the pharmaceutically active agent is selected from a group consisting of Sirolimus or analogs thereof, paclitaxel or analogs thereof, Heparin, and Dexamethasone.
21. The device as claimed in claim 1, wherein said effective amount of pharmaceutically active agent is in the range of Q.1 g/mm2 to 5 μg /mm2 of total surface area of the device.
22. A composition comprising at least one pharmaceutically active agent, heparin covalently linked to at least one polymer and an antioxidant to stabilize the pharmaceutically active agent, wherein ratio of pharmaceutically active agent to the antioxidant is in the range of 0.05 % (w/w) to 5 % (w/w).
23. The composition as claimed in claim 22, wherein ratio of the pharmaceutically active agent to the polymer is in the range of 90:10 to 50:50.
24. The composition as claimed in claim 22, wherein the antioxidant is selected from a group consisting of butylated hydroxyl toluene (BHT) and Butylated Hydroxanisole (BHA).
25. The composition as claimed in claim 22, wherein the composition comprises 15 % to 50 % (w/w) sirolimus, 25 to 75 % (w/w), poly-L-Lactide (PLLA), 1 to 20 % (w/w) polyvinyl pyrrolidone (PVP), 5-35 % (w/w) poly (D, L-lactide-co-glycolide) (PLGA), and 0.05-5 % (w/w)) butylated hydroxyl toluene (BHT).
26. A process of making an implantable medical device capable of delivering pharmaceutically active agent, wherein said process comprises coating the implantable medical device surface with a composition comprising at least one polymer covalently linked to heparin and an effective amount of at least one pharmaceutically active agent to form a base layer (802); drying the base layer (802); and coating the base layer (802) with a composition comprising at least one polymer alone or in combination with heparin, wherein the heparin is covalently linked to at least one polymer to form a top layer (804).
27. The. process as claimed in claim 26, wherein the base layer (802) is dried using vacuum or heat drying method.
28. Use of the composition as claimed in claim 22 for the manufacture of a medicament for treating at least one disease or condition associated with vascular injury or angioplasty, wherein the medicament is administered by implanting in a subject in need thereof a medical device having a coating for at least a portion thereof comprising the medicament.
29. The use as claimed in claim 28, wherein the disease or the condition associated with vascular injury angioplasty is a proliferative disorder, thrombosis, embolism, or platelet accumulation, an inflammatory disease, an autoimmune disease, disease or condition is neointima and neointimal hyperplasia.
30. The use as claimed in claim 29, wherein the proliferative disorder is restenosis, tumor, or proliferation of smooth muscle cells.
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