WO2007088554A1 - Préparation pharmaceutique pour le traitement de plaques athérosclérotiques vulnérables et l'inhibition de la thrombose, des molécules d'adhésion et de l'inflammation - Google Patents

Préparation pharmaceutique pour le traitement de plaques athérosclérotiques vulnérables et l'inhibition de la thrombose, des molécules d'adhésion et de l'inflammation Download PDF

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Publication number
WO2007088554A1
WO2007088554A1 PCT/IN2006/000037 IN2006000037W WO2007088554A1 WO 2007088554 A1 WO2007088554 A1 WO 2007088554A1 IN 2006000037 W IN2006000037 W IN 2006000037W WO 2007088554 A1 WO2007088554 A1 WO 2007088554A1
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WIPO (PCT)
Prior art keywords
agents
fucans
treatment
thrombosis
inflammation
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Application number
PCT/IN2006/000037
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English (en)
Inventor
Baskaran Chandrasekar
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Baskaran Chandrasekar
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Priority to PCT/IN2006/000037 priority Critical patent/WO2007088554A1/fr
Publication of WO2007088554A1 publication Critical patent/WO2007088554A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • a pharmaceutical composition for treatment of vulnerable atherosclerotic plaque and inhibition of thrombosis, adhesion molecules and inflammation is provided.
  • the present invention relates generally to a pharmaceutical composition for the treatment of vulnerable plaque in a patient with established atherosclerosis, and specifically to the prevention of thrombosis, inhibition of adhesion molecules and inflammation, and enhancing endothelial regeneration by the local delivery of fucans in the treatment of vulnerable atherosclerotic plaque.
  • the present invention also relates to the local delivery of fucans by means of any intravascular device (implantable or nonimplantable) for the prevention of restenosis following arterial injury.
  • the present invention proposes to address the need for such a treatment for vulnerable plaque.
  • U. S. Patent Nos. 5833651 and 6228845 to Donovan et al. describe the application of fucoidan as a polymer for coating the lumen-exposed surface of an intravascular stent as a barrier to minimize diffusion of DNA into the lumen of the artery (DNA is the active agent, and is coated on to the outer surface of the stent on another polymer).
  • U. S. Patent Application No. 20050186243 to Hunter William L et al. describes the application of fucoidan as a carrier to deliver active fibrosing agents (such as silk, fibrin, fibronectin, collagen, etc.) to a vulnerable plaque.
  • U. S. Patent No. 5321133 to Colliec et al. and U. S. Patent No. 5948405 to Cedro et al. describe the anti-thrombotic properties of fucoidan administered by parenteral, oral or topical route.
  • U. S. Patent No. 6828307 to Colliec- Jouault et al. describes the use of fucan for treatment of systemic arterial thrombosis by intravenous or subcutaneous administration. The same patent also describes the application of fucan delivered locally by balloon catheters for restenosis prevention following balloon angioplasty.
  • U. S. Patent Nos. 6410587 and 6734208 to Grainger et al. describe the local delivery of agents (one of which is fucoidan) in the treatment of a mammal having, or at risk of, a vascular indication which is associated with TGF-beta deficiency such as for plaque stabilization in atherosclerosis by a method of increasing the levels of TGF- beta.
  • agents one of which is fucoidan
  • TGF-beta deficiency such as for plaque stabilization in atherosclerosis by a method of increasing the levels of TGF- beta.
  • current evidence has clearly demonstrated that TGF-beta deficiency is associated with only the preliminary stage of atherosclerosis such as fatty streaks, whereas, established plaques and complicated plaques are associated with intrinsically high levels of TGF-beta (Panutsopulos D, et al.
  • the present invention describes treatment of vulnerable plaque by the local delivery of fucoidan for inhibiting thrombosis, for inhibiting adhesion molecules, and for stimulating endothelial regeneration. This new use is novel and non-obvious over the art of record.
  • Fucans (fucoidan, sulfated fucans, fucoidin), and exemplified by fucoidan, have properties of inhibition of thrombosis, inhibition of adhesion molecules thereby suppressing inflammation, and of enhancing endothelial regeneration. These properties make fucans an ideal candidate for the treatment, by local delivery, of vulnerable plaque in established atherosclerosis. Additionally, fucans have properties of inhibiting vascular smooth muscle cell proliferation. This effect, along with their ability to inhibit inflammation and to enhance endothelial regeneration, may be utilized to reduce restenosis after arterial injury by delivering fucans locally by means of any intravascular device (implantable or nonimplantable).
  • Vulnerable plaques are atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression. These have been well described in the literature as, (1) rupture-prone plaque with large lipid core and thin fibrous cap infiltrated by macrophages, (2) ruptured plaque with subocclusive thrombus and early organization, (3) erosion-prone plaque with proteoglycan matrix in a smooth muscle cell-rich plaque, (4) eroded plaque with subocclusive thrombus, (5) plaque with intra- plaque hemorrhage, (6) plaque with calcific nodule protruding into the vessel lumen, and (7) chronically stenotic plaque with severe calcification, old thrombus, and eccentric lumen (Naghavi M, et al. From vulnerable plaque to vulnerable patient. Circulation 2003;108:1664).
  • Fucans are potent anti-thrombotic agents. Fucans exert their anti-thrombotic effect by catalysis of the serpins anti-thrombin and heparin cofactor II (Millet J, et al. Anti-thrombotic and anticoagulant activities of a low molecular weight fucoidan by the subcutaneous route. Thromb Haemost 1999;81:391- 5). Fucans release tissue factor pathway inhibitor from endothelial cells, further contributing to their anti-thrombotic activity (Giraux JL, et al. Fucoidan, as heparin, induces tissue factor pathway inhibitor release from cultured human endothelial cells. Thromb Haemost 1998;80:692-5).
  • Erosion of endothelial lining with resultant loss of endothelial cells is an important histological feature of vulnerable plaque. Regeneration of the damaged endothelial cell lining is an important constituent in the treatment of vulnerable plaque. Fucans have been demonstrated in experimental studies to stimulate the growth and migration of endothelial cells (Giraux JL, et al. Modulation of human endothelial cell proliferation and migration by fucoidan and heparin. Eur J Cell Biol 1998;77:352-9; Matou S, et al. Effect of fucoidan on fibroblast growth factor-2 induced angiogenesis in vitro. Thromb Res 2002;106:213-21; Matsubara K, et al. Effects of middle molecular weight fucoidans on in vitro and ex vivo angiogenesis of endothelial cells. Int J MoI Med 2005; 15:695-9).
  • vulnerable plaques demonstrate a high local concentration of adhesion molecules such as P-selectin (Tenaglia AN, et al. Levels of expression of P-selectin, E-selectin and intercellular adhesion molecule- 1 in coronary atherectomy specimens from patients with stable and unstable angina pectoris. Am J Cardiol. 1997;79:742-747) crucial for the recruitment of inflammatory cells. Inflammatory cell infiltration plays an important role in pathogenesis of a vulnerable plaque (Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med 1999;340: 115-26; Tiong AY, et al.
  • Fucans exert their anti-inflammatory effect by binding to P-selectin and potently inhibiting P-selectin function (Berteau O, et al. Sulfated fucans, fresh perspectives: structures, functions, and biological properties of sulfated fucans and an overview of enzymes active towards this class of polysaccharides. Glycobiology 2003;13:29R-40R).
  • Systemic administration of fucoidan may not achieve a local concentration of the agent sufficient to produce a significant effect. Administration of higher systemic doses to produce the desired effect may result in intolerance or adverse effects.
  • fucoidan Locally delivering fucoidan directly to the desired site would eliminate any adverse effects associated with systemic administration. As the fucoidan is delivered directly to the desired site of action, the dose required to produce the desired effect is also markedly reduced, further decreasing the incidence of any possible adverse effect.
  • the molecular weight of fucoidan intended to be used in the present invention will range from 8 kDa to less than 30 kDa.
  • the fucoidan may be administered locally . in a dose ranging from 0.1 mg/kg to 50 mg/kg.
  • the dosage of fucoidan intended to be delivered locally may be determined by the attending physician taking into account factors such as, body weight of the patient, the number of vulnerable plaques to be treated, and other parameters. In experimental studies no adverse effects were observed when doses of 300 mg/kg per day of fucoidan were administered systemically for as long as six months (Li N, et al. Toxicological evaluation of fucoidan extracted from Laminaria japonica in Wistar rats. Food Chem Toxicol 2005 ;43:421-6).
  • the dose of fucoidan intended to be delivered locally in the present invention is only a fraction of the dose used for systemic administration in animal studies, and, more importantly, will be administered to the patient only at the time of the procedure, and not everyday.
  • the local delivery of fucans at the desired site can be performed with the help of a variety of drug delivery catheters.
  • various drug delivery catheters for local drug delivery are well described and is known to those skilled in the art (Chandrasekar B, et al. Local delivery in coronary artery disease: an overview for the interventional cardiologist. Indian Heart Journal 1999; 51: 21-6).
  • These include, but are not limited to a double-balloon catheter, porous balloon catheter, infusion sleeve catheter, coil balloon catheter (Dispatch catheter), iontophoretic balloon catheter, the infiltrator, and the hydrogel-coated balloon catheter.
  • an aqueous solution of fucans (1 ml to 10 ml) may be delivered using designated drug delivery catheters.
  • fucans can be delivered in the form of a viscous material or gel using a hydrogel-coated balloon catheter.
  • fucans can be delivered using iontophoresis.
  • the fucans may also be administered in the form of a suspension, such as a suspension of bio-degradable polymers releasing fucans.
  • fucans may be delivered locally at the desired site by means of any intravascular implantable device, such as a stent.
  • the drug-eluting stent may be metallic, made of metal alloy, non-metallic, or biodegradable.
  • the fucan may be released from the drug-eluting stent either with or without the use of polymers or other bio-degradable materials as drag carriers. Alternatively, the fucan may be released directly from a bare drug-eluting stent.
  • the use of drug-eluting stents for local drug delivery is well known to those skilled in the art (de Scheerder I, et al. The Elutes clinical study: 12 -month clinical follow-up.
  • the present invention provides a pharmaceutical composition for treatment of vulnerable atherosclerotic plaque and for the inhibition of thrombosis, adhesion molecules and inflammation, and for enhancing endothelial regeneration comprises fucans and / or its functional equivalents having a molecular weight in the range of 8 kDa to less than 30 kDa either alone or in combination with a drug capable of synergistically acting with fucans such as hormones, genetic materials, peptides, antithrombotic agents, inhibitors of oxidative stress, agents to decrease plaque size, statins, HDL-cholesterol mimetic agents, fibrinolytic agents, anti-inflammatory agents, and antiproliferative agents.
  • a drug capable of synergistically acting with fucans such as hormones, genetic materials, peptides, antithrombotic agents, inhibitors of oxidative stress, agents to decrease plaque size, statins, HDL-cholesterol mimetic agents, fibrinolytic agents, anti-inflammatory agents, and antiproliferative agents
  • the present invention also provides a method of treating vulnerable atherosclerotic plaque and for inhibiting thrombosis, adhesion molecules and inflammation, and for enhancing endothelial regeneration comprising the step of administering locally and intramurally a pharmaceutical composition containing fucans and / or its functional equivalents having a molecular weight of 8Kda to less than 30 kDa either alone or in combination with a drug capable of synergistically acting with said fucans such as hormones, genetic material, peptides, antithrombotic agents, oxidative stress inhibiting agents, agents to decrease plaque size, statins, HDL- cholesterol mimetic agents, fibrinolytic agents, anti-inflammatory agents, and antiproliferative agents.
  • a drug capable of synergistically acting with said fucans such as hormones, genetic material, peptides, antithrombotic agents, oxidative stress inhibiting agents, agents to decrease plaque size, statins, HDL- cholesterol mimetic agents, fibrinolytic agents, anti-inflammatory
  • the present invention further relates to a method of administering a pharmaceutically effective dosage of a composition containing fucans and / or its functional equivalents directly and locally to the desired site either alone or in combination with one or more drug capable of synergistically acting with said fucans such as hormones, genetic material, peptides, antithrombotic agents, oxidative stress inhibiting agents, agents to decrease plaque size, statins, HDL-cholesterol mimetic agents, fibrinolytic agents, anti-inflammatory agents, and antiproliferative agents.
  • a drug capable of synergistically acting with said fucans such as hormones, genetic material, peptides, antithrombotic agents, oxidative stress inhibiting agents, agents to decrease plaque size, statins, HDL-cholesterol mimetic agents, fibrinolytic agents, anti-inflammatory agents, and antiproliferative agents.
  • the local administration of fucan may be performed in combination with the local delivery of another drug, hormone, chemical, pharmaceutical agent, genetic material, or peptide, that may have one or more functions as an anti-thrombotic, or, anti-inflammatory, or, that facilitates endothelial regeneration.
  • the second agent to be administered combined with fucans is such that its effect will be complimentary to, or additive or synergistic with the effect of fucans in the treatment of vulnerable plaque.
  • Such combinations may include but are not limited to combination of fucan with either anti-thrombotic agents, fibrinolytic agents, anti-proliferative agents, immunosuppressive agents, antiinflammatory agents such as but not limited to dexamethasone, or agents that enhance endothelial proliferation and function, hormones such as 17beta-estradiol, agents to decrease plaque size, statins, HDL-cholesterol mimetic agents, inhibitors of extracellular matrix synthesis, inhibitors of oxidative stress, etc.
  • fucans may be administered locally in the form of, for example but not limited to, any implantable intravascular device such as a drug-eluting stent for the prevention of restenosis following arterial injury, in view of its documented effects on inhibition of smooth muscle cell proliferation and inhibition of intimal hyperplasia after arterial injury (Religa P, et al. Fucoidan inhibits smooth muscle cell proliferation and reduces mitogen-activated protein kinase activity. Eur J Endovasc Surg 2000;20:419-26; Weg JF, et al. Low molecular weight fucoidan prevents neointimal hyperplasia in rabbit iliac artery in-stent restenosis model.
  • any implantable intravascular device such as a drug-eluting stent for the prevention of restenosis following arterial injury
  • Estradiol accelerates functional endothelial recovery after arterial injury. Circulation 1997;95:1768-72; Chandrasekar B, et al. Coronary artery endothelial protection following local delivery of 17- ⁇ estradiol during balloon angioplasty in a porcine model: a potential new pharmacological approach to improve endothelial function. J Am Coll Cardiol 2001 ;38: 1570-6).
  • the local delivery of fucans to enhance endothelial regeneration and to inhibit inflammation as a method to prevent restenosis is novel, and non-obvious over the art of record.
  • the drug-eluting stent may be metallic, made of metal alloy, non-metallic, or bio-degradable.
  • the fucan may be released from the drug-eluting stent either with or without the use of polymers or other bio-degradable materials as drug carriers. Alternatively, the fucan may be released directly from a bare drug-eluting stent.
  • the local administration of fucan for the prevention of restenosis may be performed in combination with the local delivery of another drug, hormone, chemical, pharmaceutical agent, genetic material, or peptide that is effective in the prevention of restenosis.
  • suitable combinations may include but are not limited to combination of fucan with either anti-proliferative agents, or immunosuppressive agents, or agents that enhance endothelial proliferation and function, hormones such as 17beta-estradiol, inhibitors of extracellular matrix synthesis, inhibitors of oxidative stress (the redox process) after arterial injury, etc.
  • fucans may be administered locally either alone or in combination as described above for the treatment of vulnerable plaques in peripheral arteries such as the arteries supplying the limbs, renal arteries or carotid arteries.
  • fucans may be administered locally either alone or in combination with another agent as discussed above for the prevention of restenosis in peripheral arteries such as the arteries supplying the limbs, renal arteries or carotid arteries following arterial injury.
  • Natural, semi-synthesized, or synthesized substances, or, their derivatives that contain L-fucose branches (sulfated or non-sulfated), with or without varying concentrations of other monosaccharides such as but not limited to galactose, mannose, xylose, or uronic acid are considered as functional equivalents of fucans and are included within the scope of this invention.
  • Drugs, chemicals, pharmaceutical agents, genetic material, peptides that are considered functional equivalents of fucans are also intended to be included within the scope of this invention. The description of functional equivalence to fucans will be easily obvious to those skilled in the art.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une préparation pharmaceutique pour le traitement de plaques athérosclérotiques vulnérables et l'inhibition de la thrombose, des molécules d'adhésion et de l'inflammation, ainsi que pour l'amplification de la régénération endothéliale. Une préparation à usage local comprend des fucanes et/ou leurs équivalents fonctionnels de masse moléculaire comprise entre 8 kDa et moins de 30 kDa, seuls ou en combinaison avec au moins un autre médicament susceptible d'agir de façon synergique avec eux, tel que des hormones, du matériel génétique, des peptides, des agents antithrombotiques, des inhibiteurs de stress oxydant, des agents diminuant la taille des plaques, des statines, des agents mimétiques du cholestérol HDL, des agents fibrinolytiques, des agents anti-inflammatoires et des agents antiprolifératifs. Cette préparation est administrée directement et localement par des moyens et des dispositifs classiques d'administration de médicaments, tels qu'un stent. Dans un autre mode d'application de l'invention, les fucanes peuvent être libérés localement par le biais de n'importe quel dispositif intravasculaire (implantable ou non) pour prévenir la resténose qui suit une lésion artérielle.
PCT/IN2006/000037 2006-01-31 2006-01-31 Préparation pharmaceutique pour le traitement de plaques athérosclérotiques vulnérables et l'inhibition de la thrombose, des molécules d'adhésion et de l'inflammation WO2007088554A1 (fr)

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PCT/IN2006/000037 WO2007088554A1 (fr) 2006-01-31 2006-01-31 Préparation pharmaceutique pour le traitement de plaques athérosclérotiques vulnérables et l'inhibition de la thrombose, des molécules d'adhésion et de l'inflammation

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PCT/IN2006/000037 WO2007088554A1 (fr) 2006-01-31 2006-01-31 Préparation pharmaceutique pour le traitement de plaques athérosclérotiques vulnérables et l'inhibition de la thrombose, des molécules d'adhésion et de l'inflammation

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111836833A (zh) * 2017-12-14 2020-10-27 卡尔罗伊健康科学公司 通过硫酸化多糖稳定并逆转动脉粥样硬化病变的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4512762A (en) * 1982-11-23 1985-04-23 The Beth Israel Hospital Association Method of treatment of atherosclerosis and a balloon catheter for same
US5948405A (en) * 1996-12-18 1999-09-07 Crinos Industria Farmacobiologica S.P.A. Fucans with low molecular weight having anticoagulant, antithrombinic and antithromobic activity
US6475210B1 (en) * 2000-02-11 2002-11-05 Medventure Technology Corp Light treatment of vulnerable atherosclerosis plaque
US20050222191A1 (en) * 2004-03-31 2005-10-06 Robert Falotico Solution formulations of sirolimus and its analogs for CAD treatment

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4512762A (en) * 1982-11-23 1985-04-23 The Beth Israel Hospital Association Method of treatment of atherosclerosis and a balloon catheter for same
US5948405A (en) * 1996-12-18 1999-09-07 Crinos Industria Farmacobiologica S.P.A. Fucans with low molecular weight having anticoagulant, antithrombinic and antithromobic activity
US6475210B1 (en) * 2000-02-11 2002-11-05 Medventure Technology Corp Light treatment of vulnerable atherosclerosis plaque
US20050222191A1 (en) * 2004-03-31 2005-10-06 Robert Falotico Solution formulations of sirolimus and its analogs for CAD treatment

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111836833A (zh) * 2017-12-14 2020-10-27 卡尔罗伊健康科学公司 通过硫酸化多糖稳定并逆转动脉粥样硬化病变的方法

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