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WO2008048083A1 - Compositions pharmaceutiques destinées au traitement de maladies thrombo-emboliques - Google Patents

Compositions pharmaceutiques destinées au traitement de maladies thrombo-emboliques Download PDF

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Publication number
WO2008048083A1
WO2008048083A1 PCT/MX2007/000117 MX2007000117W WO2008048083A1 WO 2008048083 A1 WO2008048083 A1 WO 2008048083A1 MX 2007000117 W MX2007000117 W MX 2007000117W WO 2008048083 A1 WO2008048083 A1 WO 2008048083A1
Authority
WO
WIPO (PCT)
Prior art keywords
clopidogrel
pharmaceutical composition
triflusal
composition according
active substances
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/MX2007/000117
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English (en)
Spanish (es)
Other versions
WO2008048083B1 (fr
Inventor
Leopoldo de Jesús ESPINOSA ABDALA
María Elena GARCÍA ARMENTA
Victor Guillermo ÁLVAREZ OCHOA
Josefina Santos Murillo
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Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to ARP070104608A priority Critical patent/AR063481A1/es
Publication of WO2008048083A1 publication Critical patent/WO2008048083A1/fr
Publication of WO2008048083B1 publication Critical patent/WO2008048083B1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/4365—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 having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the synergistic association or combination of a Tienopyridine, which is a prodrug known as Clopidogrel (+) - (6) -ex- (2- chlorophenyl) -6-7 dihydrothiene [3,2-c] pyridine-5 (4H) -methyl acetate and a platelet-derived anti-aggregator fluorinated salicylate known as Triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) for the treatment and prevention of thromboembolic diseases that They are formulated in a single dose unit, which have a synergistic effect when administered in combination than when they are administered independently, which use lower concentrations of the active ingredients, producing a better synergistic response with lower risks of collateral events such as bleeding.
  • a Tienopyridine which is a prodrug known as Clopidogrel (+) - (6) -ex- (2- chlorophenyl) -6-7 dihydrothiene [3,2-c] pyridine-5
  • Cardiovascular and cerebrovascular diseases in particular, those of thromboembolic origin represent an important cause of morbidity and mortality in developed countries.
  • a certain reduction in its prevalence and associated mortality has been observed, probably due to a better control of risk factors, tobacco, hypertension, hyperlipidemia, diabetes, etc., as well as, to the progress made in.
  • they are called platelet antiaggregants (AGP) to a group of medicines that, by different mechanisms and at different levels prevent platelet activation, preventing or minimizing the thrombotic phenomenon without causing serious hemorrhagic risk.
  • AGP platelet antiaggregants
  • the thrombus formation process is the pathological consequence of the activation of the hemostatic mechanism, which depends on a complex enzymatic system regulated by the action of various activating and inhibiting factors. Circulating elements, vascular wall structures and plasma proteins are involved in their development. Pharmacological characteristics of platelet antiaggregants
  • Clopidogrel is an AGP derived thienopyridine structurally related to ticlopidine that has a mechanism of action similar to this (selective and irreversible blocking of ADP binding to its receptors) although somewhat more potent. Additionally, it can reduce platelet response to other platelet agonists, increasing platelet cyclic AMP. Like ticlopidine, it prolongs the bleeding time (1.5-2 times after 5-7 days of treatment) and has a synergistic effect with ASA. Clopidogrel must be previously metabolized in the liver to exert its action, which manifests somewhat faster than with ticlopidine.
  • Triflusal is a drug structurally related to ASA. It is a fluorinated salicylate derivative that inhibits platelet function, increases nitric oxide production, induces a downregulation of nuclear factor-kB and reduces the synthesis of inducible nitric oxide expressed in the brain during postnatal excito-toxic damage. Its platelet antiaggregant activity consists of a reversible inhibition of cyclooxygenase, reducing plasma concentrations of trotnboxane A 2 and the activity of AMP-cyclic phosphodiesterase.
  • the triflusal discreetly inhibits thromboxane function and formation during coagulation in response to endogenously formed thrombin two hours after a single dose of 600 and 900 tng.
  • the inhibitory effect is increased during the first 3 days of treatment and after the third dose the formation of thromboxanes and platelet aggregation induced by ADP arachidonate, epinephrine and collagen are strongly or almost completely inhibited as occurs with aspirin, however, at Unlike aspirin, the triflusal does not increase bleeding time, which is important for its low risk of bleeding.
  • Clopidogrel a thienopyridine a platelet antiaggregant agent is a prodrug known as a dextrogyric isomer of Clopidogrel, it is a substance structurally related to ticlopidine, another platelet antiaggregant.
  • Clopidogrel has been used in the preventive treatment of diseases thromboembolic, currently marketed in oral pharmaceutical forms (tablets).
  • Clopidogrel has been under investigation in combination with acetylsalicylic acid, a platelet antiaggregant with a mechanism of action different from Clopidogrel, in order to produce synergy;
  • acetylsalicylic acid increases bleeding time.
  • Clopidogrel-aspirin combination has shown its synergistic activity of the two active ingredients and is described in US Patent 5989578. However, studies have shown that the combination of Clopidogrel-Aspirin does not reduce the size of the infarct or improve ventricular function anymore that or there is improvement of endothelial function (Heart 2005. Dec. 30. Yuejin et al). On the other hand, in order to interpret data from studies of combinations of platelet antiaggregants, it is important to consider whether information on the 'bleeding time can be extrapolated to clinical bleeding events. In an exhaustive review based on different studies involving human animals, trying to find an answer to this question, they concluded that there is no evidence that supports bleeding time as a predictor of bleeding risk, but not all researchers have accepted This statement.
  • bleeding time is a very popular test method to evaluate primary hemostasis and is unquestionably useful for investigations (Atherosclerosis supplements 6 (2006) 13-19, Anthony J. Comerota).
  • Clopidogrel in 75 mg and Triflusal in 300 mg in a single dose unit we made a combination of 2 active ingredients known as Clopidogrel in 75 mg and Triflusal in 300 mg in a single dose unit.
  • Clopidogrel 75 mg and Triflusal 600 mg in a single dose unit evaluating its effectiveness, synergistic activity, bleeding time and adverse events.
  • the combinations according to the invention can be used in daily doses and are preferably made to be administered orally in the form of tablets, sublingual tablets, soft gelatin capsules, solutions and oral suspensions.
  • Clopidogrel 10 mg / kg was administered daily for 7 days.
  • Group 2 was given Triflusal 20 mg / kg daily for 7 days.
  • Group 3 was given the combination of Clopidogrel 10 mg / kg + Triflusal 20 mg / kg daily for 7 days
  • the baseline results showed that the bleeding time in the experimental animals was an average of 2 to 7 seconds.
  • the group 1 that received Clopidogrel had a change in bleeding time at 7 days of 10 seconds.
  • Group 2 that received the Triflusal showed no change in bleeding time at 7 days of treatment.
  • the group 3 that received the combination of clopidogrel + triflusal showed a modification of the bleeding time at 7 days of 10 seconds, without undergoing a modification by the combination and like the administration of clopidogrel alone.
  • Example 2 Different studies were conducted in rabbits to evaluate bleeding time and observe a possible increase in it. 6 rabbits were used per experimental point and were divided into three groups. Blood samples were taken from all three groups to assess baseline bleeding time. Once the samples were taken and the baseline data was given to group 1, Clopidogrel 10 mg / kg was administered daily for 7 days.
  • Group 2 was given Triflusal 40 mg / kg daily for 7 days.
  • Group 3 was given the combination
  • the group 1 that received Clopidogrel had a change in bleeding time at 7 days of 10 seconds.
  • the group 3 that received the combination of clopidogrel + triflusal showed a modification of the bleeding time at 7 days of 10 seconds, without undergoing a modification by the combination and like the administration of clopidogrel alone.
  • the invention comprises two active substances, one of which is Clopidogrel 75 mg and the other Triflusal 300 mg in a single dose unit.
  • the invention comprises two active substances, one of which is Clopidogrel 75 mg and the other is Triflusal 600 mg in a single dose unit.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une combinaison formée par un isomère dextrogyre de clopidogrel et du trifusal en monodose, destinée au traitement, à la prévention et à l'élimination des maladies thrombo-emboliques, réduisant le risque d'effets indésirables, tels que des hémorragies gastro-intestinales et cérébrovasculaires.
PCT/MX2007/000117 2006-10-17 2007-10-15 Compositions pharmaceutiques destinées au traitement de maladies thrombo-emboliques Ceased WO2008048083A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
ARP070104608A AR063481A1 (es) 2006-10-17 2007-10-17 Composiciones farmaceuticas para el tratamiento de enfermedades tromboembolicas

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MXPA/A/2006/011974 2006-10-17
MXPA06011974 2006-10-17

Publications (2)

Publication Number Publication Date
WO2008048083A1 true WO2008048083A1 (fr) 2008-04-24
WO2008048083B1 WO2008048083B1 (fr) 2008-06-12

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/MX2007/000117 Ceased WO2008048083A1 (fr) 2006-10-17 2007-10-15 Compositions pharmaceutiques destinées au traitement de maladies thrombo-emboliques

Country Status (3)

Country Link
AR (1) AR063481A1 (fr)
CL (1) CL2007002981A1 (fr)
WO (1) WO2008048083A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017810A1 (fr) * 2009-08-14 2011-02-17 Kardiatech, Inc. Polythérapie pour traiter des troubles vasculaires
US20120178777A1 (en) * 2009-10-15 2012-07-12 Guizhou Liansheng Parmaceutical Co., Ltd. Medicaments for Inhibiting Thrombus Formation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5989578A (en) * 1996-02-19 1999-11-23 Sanofi Associations of active principles containing clopidogrel and an antithrombotic agent
CN1887284A (zh) * 2006-07-21 2007-01-03 陈文展 一种三氟柳和氯吡格雷的药物组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5989578A (en) * 1996-02-19 1999-11-23 Sanofi Associations of active principles containing clopidogrel and an antithrombotic agent
CN1887284A (zh) * 2006-07-21 2007-01-03 陈文展 一种三氟柳和氯吡格雷的药物组合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BADIA X. ET AL.: "Short and Long-term cost-effectiveness analysis of adding clopidogrel to standard therapy in acute coronary syndrome patients in spain", REVISTA SPANISH OF CARDIOLOGIA, vol. 58, no. 12, 2005, pages 1385 - 1395, XP005648122 *
CRUZ-FERNANDEZ J.M. ET AL.: "Randomized comparative trial of trifusal and aspirin following acute myocardial infarction", EUROPEAN HEART JOURNAL, vol. 21, 2000, pages 457 - 465 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017810A1 (fr) * 2009-08-14 2011-02-17 Kardiatech, Inc. Polythérapie pour traiter des troubles vasculaires
US20120178777A1 (en) * 2009-10-15 2012-07-12 Guizhou Liansheng Parmaceutical Co., Ltd. Medicaments for Inhibiting Thrombus Formation
EP2489352A4 (fr) * 2009-10-15 2012-09-05 Guizhou Liansheng Pharmaceutical Co Ltd Médicaments inhibiteurs de thrombose
US8921390B2 (en) * 2009-10-15 2014-12-30 Guizhou Liansheng Pharmaceutical Co. Ltd. Medicaments for inhibiting thrombus formation

Also Published As

Publication number Publication date
WO2008048083B1 (fr) 2008-06-12
CL2007002981A1 (es) 2008-03-24
AR063481A1 (es) 2009-01-28

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