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WO2003086497A1 - Stent vasculaire eluant un medicament et procede de traitement d'une maladie vasculaire hyperproliferative - Google Patents

Stent vasculaire eluant un medicament et procede de traitement d'une maladie vasculaire hyperproliferative Download PDF

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Publication number
WO2003086497A1
WO2003086497A1 PCT/IB2003/001230 IB0301230W WO03086497A1 WO 2003086497 A1 WO2003086497 A1 WO 2003086497A1 IB 0301230 W IB0301230 W IB 0301230W WO 03086497 A1 WO03086497 A1 WO 03086497A1
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WIPO (PCT)
Prior art keywords
vascular
stent
cells
drug
cell
Prior art date
Application number
PCT/IB2003/001230
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English (en)
Inventor
Issam Moussa
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Issam Moussa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Issam Moussa filed Critical Issam Moussa
Priority to AU2003216573A priority Critical patent/AU2003216573A1/en
Publication of WO2003086497A1 publication Critical patent/WO2003086497A1/fr

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Classifications

    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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

Definitions

  • This invention relates generally to vascular stents and, in particular, to a drug eluting vascular stent and a method of preventing or treating hyperproliferative vascular disease in a mammal by administering an antiproliferative effective amount of imatinib mesylate, alone or in combination with other compounds, via a drug eluting vascular stent.
  • the disease process is often referred to as a hyperproliferative vascular disease because of the patho- biology of this disease.
  • Intimal thickening following arterial injury can be divided into three sequential steps: 1) initiation of smooth muscle cell proliferation, 2) smooth muscle cell migration into the intimal, and 3) further proliferation of smooth muscle cells in the intima with deposition of extracellular matrix.
  • Investigation of the pathogenesis of intimal thickening has shown that the arterial injury and the loss of endothelial cell integrity (Fishman JA, et al .
  • Endothelial cell regeneration after arterial injury is particularly critical in cases of metal stent implantation in blood vessels where the continued exposure of metal surface to blood elements triggers vascular thrombosis that often leads to fatal events.
  • the recent experience with intravascular radiation therapy for hyperproliterative vascular disease clearly illustrates the danger of delaying endothelial cell regeneration after stent implantation.
  • a more favorable solution to this problem would be to identify a compound that inhibits smooth muscle cell proliferation without adversely affecting endothelial cell regeneration.
  • Abundant evidence is available to support roles for growth factors as key signaling molecules in the accelerated vascular injury following angioplasty.
  • Many features of the lesions can be readily explained by known properties of growth factors and other cytokines.
  • PDGF platelet derived growth factor
  • PDGF is important in vivo, since it is released in significantly greater amounts from intimal smooth muscle cells isolated from arteries after balloon injury.
  • the expression of PDGF occurs within sites and at times that are in accord with its potential to be a central regulator of accelerated vascular injury. Its properties as a growth factor and chemoattractant, together with its ability to transform cells, are the factors suspected to be responsible for the accelerated proliferation of smooth muscle cells and the local invasion of intimal tissues.
  • PDGF Through its ability to upregulate expression of other cytokine genes, PDGF also extends the functions that it can direct to include other functions relevant to restenosis injury that cannot be understood when it is studied in vitro.
  • PDGF is a leading candidate to play a major role in accelerated vascular injury. It is likely that many of the pathologic features of restenosis injury result from the continued high levels of expression of PDGF and related factors (Walker LN, et al. Atherosclerosis 1983; 47:123- 130; Libby P, et al. N Engl J Med 1988; 318:1493-1498; Sjolund M, et al. J Cell Biol 1988; 106:403-413; Heldin CH et al. Physiological Reviews 1999; 79(4): 1283-1316).
  • PDGF exerts its effects on target cells by activating two structurally related protein tyrosine kinase receptors (Matsui T, et al . Science 1989; 243; 800-803).
  • the binding of PDGF to these receptors initiates potent mitogenic signals that result in cell growth, chemotaxis, actin reorganization, and prevention of apoptosis, all are critical to the formation of restenosis after vascular injury (Parsons JT, et al . Curr Opin Cell Biol 1997; 9:187-192; Kundra V, et al . Nature 1994; 367:474-476).
  • Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML) .
  • CML chronic myeloid leukemia
  • imatinib is not entirely selective; it also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF) , c-Kit, and inhibits PDGF-and SCF- mediated cellular events (Buchdunger E, et al . JPET 2000; 295:139-145) .
  • PDGF platelet-derived growth factor
  • SCF stem cell factor
  • Imatinib mesylate is designated chemically as 4-[(4- Methyl-1-piperazinyl) methyl] -N- [4-Methyl-3- [ [4- (3- pyridinyl) -2-pyrimidinyl] amino] -phenyl]benzamide methanesulfonate.
  • Imatinib mesylate is a white to off- white to brownish or yellowish tinged crystalline powder. Its molecular formula is C 29 H 3 1N 7 O • CH4SO 3 and its relative molecular mass is 589.7.
  • Imatinib mesylate is very soluble in water and soluble in aqueous buffers ⁇ pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers.
  • the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol and ethanol, but is insoluble in n-octanol, acetone and acetonitrile.
  • the following U.S. patents describe various drug eluting stents and methods of manufacture. These and all other patents referred to herein are hereby incorporated by reference in their entirety.
  • FIGS 1A and IB, FIGS 2A and 3B, and FIGS 3A and 3B are graphs illustrating the experimental results from in vitro experiments comparing the effects of Imatinib Mesylate, Rapamycin and Paclitaxel on human aortic smooth muscle cells (AoSMC) and human umbilical vein endothelial cells (HUVEC) .
  • AoSMC aortic smooth muscle cells
  • UAVEC human umbilical vein endothelial cells
  • FIG 1A is a graph of comparative growth curves of untreated AoSMC cells and AoSMC cells treated with three different concentrations of Imatinib Mesylate.
  • FIG IB is a graph of comparative growth curves of untreated HUVEC cells and HUVEC cells treated with three different concentrations of Imatinib Mesylate.
  • FIG 2A is a graph of comparative growth curves of untreated AoSMC cells and AoSMC cells treated with three different concentrations of Rapamycin.
  • FIG 2B is a graph of comparative growth curves of untreated HUVEC cells and HUVEC cells treated with three different concentrations of Rapamycin.
  • FIG 3A is a graph of comparative growth curves of untreated AoSMC cells and AoSMC cells treated with three different concentrations of Paclitaxel.
  • FIG 3B is a graph of comparative growth . curves of untreated HUVEC cells and HUVEC cells treated with three different concentrations of Paclitaxel.
  • This invention provides a method for preventing or treating hyperproliferative vascular disease in a mammal in need thereof by administering an antiproliferative effective amount of Imatinib Mesylate via a vascular stent impregnated with imatinib mesylate alone or in combination with other compounds.
  • this drug may be delivered intravascularly, intranasaly, intrabronchially, transdermally.
  • imatinib mesylate is useful in treating intimal smooth muscle cell hyperplasia, restenosis, and vascular occlusion, particularly following either biologically or mechanically mediated vascular injury.
  • Biologically mediated vascular injury includes, but is not limited to injury attributed to infectious disorders, atherosclerosis, and vascular injury resulting from hypothermia, and irradiation.
  • Mechanical mediated vascular injury includes, but is not limited to vascular injury caused by percutaneous transluminal coronary angioplasty, atherectomy, laser, stent implantation, vascular surgery, transplantation surgery and other invasive procedures which disrupt the integrity of the vascular intima or the endothelium.
  • Treating includes retarding the progression, arresting the development, as well as palliation. Preventing includes inhibiting the development of and prophylacticly preventing of hyperproliferative vascular disease at the time of inducing vascular injury.
  • Imatinib mesylate was compared to rapamycin and paclitaxel in an in vitro standard pharmacological test procedure, which emulates the intimal smooth muscle cell proliferation observed following vascular injury. Also, we evaluated the effect of these drugs on endothelial cell proliferation since the ability of endothelial cells to regenerate is a key feature to preserve the biologic integrity of the vessel wall. The experimental protocol and results of the experiment are described below.
  • the apparatus and methods of the present invention may be utilized with any of the numerous vascular, stent designs and configurations known in the industry.
  • any of the various methods known in the industry for manufacturing and coating or impregnating stents with drugs or other biologically active substances may be utilized for the manufacture of the drug impregnated stent of the present invention.
  • the three study drugs (rapamycin, paclitaxel, Drug X) were acquired from professional sources and dissolved in solvent to make stock solutions, which were then serially diluted in media to three study concentrations (lOnM, lOOnM, and lOOOnM) (refer to Section V below)
  • AoSMCs Cell Source -Human aortic smooth muscle cells
  • SMGM contained: 500 ml SMBM-2 basal media, 5% FBS, and all recommended singlequot growth supplements (provided with SMGM-2 bulletkit)
  • EGM contained: 500 ml EBM basal media, 2% FBS, and all recommended singlequot growth supplements (provided with EGM-bulletkit)
  • Source cells were selected at 70-80 % confluency of the second or third population doubling since initial thaw
  • source cells were removed from culture • dishes by trypsinization (0.05 x 1-2 min) , quantified by hemacytometer after centrifuge (800 RPM x 5 min) , and re-suspended in media to obtain a stock solution of 25,000 cells/ml
  • HUVEC were plated at three different densities (2000 cells/cm 2 , 5000 cells/cm 2 , and 10,000 cells/cm 2 ) using aseptic technique in the culture hood, and as detailed in the diagram below
  • rapamycin and paclitaxel were dissolved in the appropriate amount of standard DMSO/media freezing solution to yield a 10 nrM stock solution
  • Imatinib mesylate was less soluble in the DMSO/media solution, requiring a stock concentration of 1 mM for full solubility
  • Cell Preparation -Source cells were selected at 70-80 % confluency of the third or fourth population doubling since initial thaw •In order to synchronize cell cycle, source cells were changed from standard growth media to media containing 1% serum 24 hours prior to experiment (other growth factors were unchanged) and media containing 1% serum was used for the remainder of the experiment
  • source cells were removed from culture dishes by trypsinization (0.05 x 1-2 min), quantified by hemacytometer after centrifuge (1000 RPM x 5 min) , and resuspended in media to obtain a stock solution of 25,000 cells/ml
  • IX Viability and Proliferation Assay 'For consecutive 24 hour time-periods, from Day 0 to Day 5, four 96-well plates were removed from the incubator (2 plates each for AoSMCs and HUVECs)
  • FIGS 1A and IB, FIGS 2A and 3B, and FIGS 3A and 3B are graphs illustrating the experimental results from in vitro experiments according to the experimental protocol described above comparing the effects of Imatinib Mesylate, Rapamycin and Paclitaxel on human aortic smooth muscle cells (AoSMC) and human umbilical vein endothelial cells (HUVEC) .
  • AoSMC aortic smooth muscle cells
  • UAVEC human umbilical vein endothelial cells
  • FIG 1A is a graph of comparative growth curves of untreated AoSMC cells and AoSMC cells treated with three different concentrations of Imatinib Mesylate. The graph shows inhibition of smooth muscle cell proliferation by
  • Imatinib Mesylate at a concentration of 1000 nM.
  • FIG IB is a graph of comparative growth curves of untreated HUVEC cells and HUVEC cells treated with three different concentrations of Imatinib Mesylate. The graph shows no inhibition of endothelial cell growth at all concentrations of Imatinib Mesylate.
  • FIG 2A is a graph of comparative growth curves of untreated AoSMC cells and AoSMC cells treated with three different concentrations of Rapamycin. The graph shows inhibition of smooth muscle cell proliferation at all concentrations of Rapamycin.
  • FIG 2B is a graph of comparative growth curves of untreated HUVEC cells and HUVEC cells treated with three different concentrations of Rapamycin. The graph shows inhibition of endothelial cell growth at all concentrations of Rapamycin.
  • FIG 3A is a graph of comparative growth curves of untreated AoSMC cells and AoSMC cells treated with three different concentrations of Paclitaxel. The graph shows inhibition of smooth muscle cell proliferation at all concentrations of Paclitaxel.
  • FIG 3B is a graph of comparative growth curves of untreated HUVEC cells and HUVEC cells treated with three different concentrations of Paclitaxel.
  • the graph shows inhibition of endothelial cell growth at all concentrations of Paclitaxel .
  • this in vitro study illustrates that imatinib mesylate inhibits smooth muscle cell proliferation at a concentration of 1000 nM without affecting endothelial cell viability.
  • both rapamycin and paclitaxel inhibit both smooth muscle cells and endothelial cells even at lower concentrations.
  • This differential effect of imatinib mesylate makes it a unique drug that may decrease intimal proliferation without, affecting endothelial healing. This effect makes it preferable to the other agents under investigation.
  • imatinib mesylate When employed alone or in combination with other compounds in the prevention or treatment of hyperproliferative vascular disease, it can be formulated neat or with a pharmaceutical carrier to a mammal in need thereof .
  • the pharmaceutical carrier may be solid or liquid.
  • a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins .
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, chickening agents, colors, viscosity regulators, stabilizers or osmo-regulators .
  • Imatinib mesylate alone or in combination with other compounds can be administered intravascularly or via a vascular stent impregnated with imatinib mesylate, alone or in combination with other compounds, during balloon dilatation and stent implantation to provide localized effects immediately following injury.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un stent vasculaire éluant un médicament, ainsi qu'un procédé de prévention ou de traitement d'une maladie vasculaire hyperproliférative chez un mammifère, ce procédé consistant à administrer une quantité d'imatinib-mesylate seul ou en combinaison avec d'autres composés, par l'intermédiaire d'un stent vasculaire.
PCT/IB2003/001230 2002-04-16 2003-04-04 Stent vasculaire eluant un medicament et procede de traitement d'une maladie vasculaire hyperproliferative WO2003086497A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003216573A AU2003216573A1 (en) 2002-04-16 2003-04-04 Drug eluting vascular stent and method of treating hyperproliferative vascular disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37310702P 2002-04-16 2002-04-16
US60/373,107 2002-04-16

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Publication Number Publication Date
WO2003086497A1 true WO2003086497A1 (fr) 2003-10-23

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005049021A1 (fr) * 2003-11-03 2005-06-02 Oy Helsinki Transplantation R & D Ltd Substances et procedes pour inhiber l'hyperplasie neointime
US7361691B2 (en) * 2002-12-02 2008-04-22 Arqule, Inc. Method of treating cancers using β-lapachone or analogs or derivatives thereof
US8815260B1 (en) 2005-10-20 2014-08-26 University Of South Florida Treatment of restenosis and stenosis with dasatinib

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003854A1 (fr) * 1997-07-18 1999-01-28 Novartis Ag Modification de la forme cristalline d'un derive n-phenyl-2-pyrimidineamine, procede de preparation et d'utilisation de ce dernier
US20010032014A1 (en) * 1999-07-02 2001-10-18 Scimed Life Sciences, Inc. Stent coating

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003854A1 (fr) * 1997-07-18 1999-01-28 Novartis Ag Modification de la forme cristalline d'un derive n-phenyl-2-pyrimidineamine, procede de preparation et d'utilisation de ce dernier
US20010032014A1 (en) * 1999-07-02 2001-10-18 Scimed Life Sciences, Inc. Stent coating

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7361691B2 (en) * 2002-12-02 2008-04-22 Arqule, Inc. Method of treating cancers using β-lapachone or analogs or derivatives thereof
WO2005049021A1 (fr) * 2003-11-03 2005-06-02 Oy Helsinki Transplantation R & D Ltd Substances et procedes pour inhiber l'hyperplasie neointime
US8815260B1 (en) 2005-10-20 2014-08-26 University Of South Florida Treatment of restenosis and stenosis with dasatinib

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Publication number Publication date
AU2003216573A1 (en) 2003-10-27

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