WO2020101627A1 - Solution développée pour être appliquée à une greffe de veine saphène - Google Patents

Solution développée pour être appliquée à une greffe de veine saphène Download PDF

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Publication number
WO2020101627A1
WO2020101627A1 PCT/TR2019/050946 TR2019050946W WO2020101627A1 WO 2020101627 A1 WO2020101627 A1 WO 2020101627A1 TR 2019050946 W TR2019050946 W TR 2019050946W WO 2020101627 A1 WO2020101627 A1 WO 2020101627A1
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WO
WIPO (PCT)
Prior art keywords
solution
saphenous vein
antiplatelet
agents
vein graft
Prior art date
Application number
PCT/TR2019/050946
Other languages
English (en)
Inventor
Ercan AKSIT
Basak BUYUK
Original Assignee
Canakkale Onsekiz Mart Universitesi Rektorlugu
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
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Application filed by Canakkale Onsekiz Mart Universitesi Rektorlugu filed Critical Canakkale Onsekiz Mart Universitesi Rektorlugu
Publication of WO2020101627A1 publication Critical patent/WO2020101627A1/fr

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Classifications

    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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

Definitions

  • the invention relates to the development of a solution comprising a locally effective antiplatelet and anticoagulant agent to reduce thrombus formation and the application of this solution to the saphenous vein graft before performing bypass operation to the artery.
  • CVDs cardiovascular diseases
  • CVDs cardiovascular diseases
  • peripheral arterial bypass surgery for three-vessel disease and left main coronary artery disease, and for end-stage peripheral arterial disease
  • coronary artery bypass surgery is the first treatment option [2-4].
  • the survival rate of artery grafts taken for a single lesion is good, vein grafts are still being used for multi-vessel disease and peripheral artery disease.
  • percutaneous coronary interventions and stents 400,000 people still have a coronary bypass operation in the United States per year [5].
  • Vein graft disease occurs with three mechanisms: the first one is thrombosis in the first month, the other two mechanisms are intimal hyperplasia within 1 month to 1 year and atherosclerosis seen after 1 year. After bypass surgery, up to 10% of the vein grafts are lost due to acute thrombosis within the first one month. Platelet activation and thrombin are the triggers of early graft loss. In 10 years, about half is lost due to intimal hyperplasia and atherosclerosis [14-17]. The researchers conducted experimental studies to overcome saphenous vein disease through these mechanisms. Most of these studies are experimental studies in animals to reduce intimal hyperplasia.
  • ASA saphenous vein graft disease
  • the researchers operated the patients without interrupting their antiplatelet regimens, and continued to give the antiplatelet agent orally within 6 hours after the operation, but they experienced bleeding complications so much so that they needed transfusion.
  • ADP receptor inhibitors from other antiplatelet agents such as ticagrelor should be discontinued for 3 days, clopidogrel 5 days and prasugrelin 7 days in advance, all antiplatelet agents are discontinued in the perioperative period because of the fear of bleeding in daily practice and antiplatelet agents are started one day after the operation if there is no bleeding complication [27-30].
  • biodegradable polymer coated embolic protection stents suitable for implantation into the patient's body lumen, such as a vessel or coronary artery.
  • Anti-thrombic and anti-platelet drugs are selected from the group consisting of sodium heparin, low molecular weight heparin, hirudin, argatroban, sippogralate, recombinant hirudin, forskolin, vapiprost, prostacyclin.
  • the United States patent document numbered US2012277726 of the prior art refers to a method for the treatment of acute myocardial infarction (AMI), Thrombus-Containing Lesion (TCL) and Saphenous Vein Graft Lesion (SVGL), and a drug-eluting implantable medical device. More particularly, the invention relates to a drug-eluting implantable medical device that releases a drug, coated with Nano-carriers for releasing the drug at different rates to address late thrombus formation associated with acute thrombus formation, lower acute thrombus formation and AMI, TCL treatment.
  • AMI acute myocardial infarction
  • TCL Thrombus-Containing Lesion
  • SVGL Saphenous Vein Graft Lesion
  • the method consist of following steps; implanting a medicament-releasable implantable medical device with nano carriers, at least one drug encapsulated with the first biological agent; releasing the nano-carriers from the drug-releasable insertion device at the target site, and at least one drug in the target site, the nano-carriers at the first release rate, and release of the second biological agent.
  • the drug contains anti-thrombogenic and anti-inflammatory agents.
  • US7416558 of the prior art refers to a stent system for delivering a therapeutic agent into the body lumen.
  • the system comprises; a stent configured to contact the wall of the body lumen to maintain the opening of the lumen; a stent cap made of a mesh and defining a distribution sleeve disposed on the stent; the delivery envelope comprises at least one therapeutic agent in quantities sufficient to release it at the treatment site.
  • the aim of the invention is to develop a solution comprising a locally effective antiplatelet and anticoagulant agent to reduce thrombus formation and to apply this solution to the natural saphenous vein graft prior to conducting a bypass operation to the artery.
  • Another aim of the invention is to reduce the occlusion rates of saphenous vein grafts after coronary artery bypass surgery with the application of the developed solution to the saphenous vein graft.
  • Another aim of the invention is to perform a bypass to the artery after administration of the solution containing acetylsalicylic acid, ticagrelor, and unfractionated heparin, which may affect the saphenous vein locally.
  • Another aim of the invention is to provide tunica adventitious coating on the outer layer of the saphenous vein graft by means of pluronic gel.
  • Figure 1 A schematic view of the application of the solution according to the invention.
  • Figure 2 A schematic view of the application of the solution according to the invention from different angles.
  • the invention is a solution (1) comprising a locally effective antiplatelet and anticoagulant agent to reduce thrombus formation; wherein, before bypassing the artery, the solution (1) is applied to the tunica adventitia (4) which is the outer layer of the saphenous vein graft (5).
  • the invention is a solution comprising local effective antiplatelet and anticoagulant agents to reduce thrombus formation; comprising any of the agents of cangrelor, ticagrelor, prasugrel, clopidogrel which are ADP receptors in addition to the acetylsalicylic acid which is an antiplatelet agent, and one of unfractionated heparin, enoxaparin sodium, bivalirudin, fondaparinux, dabigatran, apixaban, rivaroxaban or edoxaban agents as the anticoagulant agent.
  • the solution (1) comprises tirofiban, abciximab or eptifibatide which inhibits glycoprotein lib / Ilia.
  • the invention is a solution (1) comprising local effective antiplatelet and anticoagulant agents to reduce thrombus formation; it comprises; the antiplatelet agent, pg/kg or mI/L acetylsalicylic acid by weight pg / kg or pi [L cangrelor or ticagrelor by weight, pg/kg or U/L unfractionated heparin by weight as the anticoagulant agent according to the patient's weight in certain proportions.
  • the solution (1) covers the tunica adventitia (4), which is the outer layer of the saphenous vein graft (5) with the help of pluronic gel (6) as a local delivery agent.
  • the solution (1) can also be distributed by encapsulation of the nanoparticles.
  • Nanoparticles have several advantages as a delivery system for the local delivery of therapeutic agents. These advantages are; subcellular size, good suspension, easy penetration and continuous intracytoplasmic release capacity without causing trauma to the vessel wall [31,32]. Therefore, two antiplatelets and one anticoagulant loaded nanoparticles will be an innovative treatment strategy to prevent vein graft failure. A study has been shown to prevent stent thrombosis by combining perfluorocarbon nanoparticles with a direct thrombin inhibitor agent [33]
  • the tunica adventitia (4) is coated with pluronic gel (6).
  • Pluronic gel (6) is ideal as a local delivery agent as it can provide
  • each molecule may be prepared as separate nanoparticles.
  • the drugs may be introduced into the vein by a combination of locally effective microparticles/hydrogel. The additional advantage of this combination is that it can be released for longer periods of time [34,35]. Since the saphenous vein graft is also detached from its natural environment, the "organ storage solutions" can be added to the drug solution in addition to the drug solution before being bypassed into the artery in nanoparticles or hydrogel.
  • Coronary bypass graft fate and patient outcome angiographic follow-up of 5065 grafts related to survival and reoperation in 1388 patients during 25 years. J Am Coll Cardiol. 1996;28:616-26.

Abstract

L'invention concerne l'application d'une solution (1) comprenant un agent antiplaquettaire et anticoagulant, efficace localement, pour réduire la formation de thrombus, ainsi que l'application de cette solution (1) sur la greffe de veine saphène (5) avant d'effectuer une opération de pontage sur l'artère.
PCT/TR2019/050946 2018-11-14 2019-11-14 Solution développée pour être appliquée à une greffe de veine saphène WO2020101627A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201817207 2018-11-14
TR2018/17207 2018-11-14

Publications (1)

Publication Number Publication Date
WO2020101627A1 true WO2020101627A1 (fr) 2020-05-22

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Family Applications (1)

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PCT/TR2019/050946 WO2020101627A1 (fr) 2018-11-14 2019-11-14 Solution développée pour être appliquée à une greffe de veine saphène

Country Status (1)

Country Link
WO (1) WO2020101627A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050142202A1 (en) * 2001-02-12 2005-06-30 Roorda Wouter E. Compositions for achieving a therapeutic effect in an anatomical structure
US20070202140A1 (en) * 2005-12-22 2007-08-30 Veltri Enrico P Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery
WO2008134600A1 (fr) * 2007-04-27 2008-11-06 Cydex Pharmaceuticals, Inc. Préparations contenant du clopidogrel et de la sulfoalkyl-éther cyclodextrine et méthodes d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050142202A1 (en) * 2001-02-12 2005-06-30 Roorda Wouter E. Compositions for achieving a therapeutic effect in an anatomical structure
US20070202140A1 (en) * 2005-12-22 2007-08-30 Veltri Enrico P Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery
WO2008134600A1 (fr) * 2007-04-27 2008-11-06 Cydex Pharmaceuticals, Inc. Préparations contenant du clopidogrel et de la sulfoalkyl-éther cyclodextrine et méthodes d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TORSNEY, E. ET AL.: "Thrombosis and neointima formation in vein grafts are inhibited by locally applied aspirin through endothelial protection", CIRCULATION RESEARCH, vol. 94, no. 11, 2004, pages 1466 - 1473, XP055123021, DOI: 10.1161/01.RES.0000129570.06647.00 *
WIEDEMANN, D. ET AL.: "Perivascular administration of drugs and genes as a means of reducing vein graft failure", CURRENT OPINION IN PHARMACOLOGY, vol. 12, no. 2, 2012, pages 203 - 216, XP028512490, DOI: 10.1016/j.coph.2012.02.012 *

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