WO2003094983A1 - Formulation pharmaceutique resorbable destinee a la liberation continue de thrombine - Google Patents

Formulation pharmaceutique resorbable destinee a la liberation continue de thrombine Download PDF

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Publication number
WO2003094983A1
WO2003094983A1 PCT/EP2003/004680 EP0304680W WO03094983A1 WO 2003094983 A1 WO2003094983 A1 WO 2003094983A1 EP 0304680 W EP0304680 W EP 0304680W WO 03094983 A1 WO03094983 A1 WO 03094983A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
thrombin
formulation according
resorbable
collagen
Prior art date
Application number
PCT/EP2003/004680
Other languages
German (de)
English (en)
Inventor
Frank Gerhards
Rui-Miguel Pereira-Paz
Doris Klee
Hartwig Höcker
Original Assignee
Rheinisch-Westfälische Technische Hochschule Aachen (RWTH)
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 Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) filed Critical Rheinisch-Westfälische Technische Hochschule Aachen (RWTH)
Priority to AU2003232257A priority Critical patent/AU2003232257A1/en
Priority to EP03749866A priority patent/EP1501558A1/fr
Priority to CA002485268A priority patent/CA2485268A1/fr
Publication of WO2003094983A1 publication Critical patent/WO2003094983A1/fr

Links

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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/425—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A61L15/325—Collagen

Definitions

  • the present invention relates to a resorbable pharmaceutical formulation for continuous local thrombin release comprising thrombin which is embedded in resorbable spheres of polymers, the spheres being incorporated in a sponge.
  • the formulation according to the invention provides a resorbable hamostatic agent for use in surgery, in particular dental surgery / in dento alveolar interventions.
  • anticoagulation due to various diseases, the number of patients requiring therapeutic anticoagulation (anticoagulation) is increasing. These include, for example, patients with artificial heart valve prostheses or patients who have had a stroke or venous thrombosis.
  • vitamin K antagonists coumarin derivatives such as e.g.
  • Warfarin® Form of Warfarin®
  • heparin has a significantly shorter half-life, which makes it easier to control the anticoagulant if bleeding complications occur, without having to forego the necessary protection against thrombosis.
  • postoperative bleeding is also caused by the piasmin system.
  • the piasmin system the physiological antagonist of the blood coagulation system, ensures a dissolution of at a systemic level Blood clots. However, this function is not desirable if there is an increased risk of bleeding after surgery.
  • the optimal local wound care is the same for both concepts: after the extraction of the teeth or after a smaller dental intervention, the bone wound is tamponized with a collagen vial (e.g. Lyostypt) or a gelatin sponge (e.g. Topostatin).
  • a collagen vial e.g. Lyostypt
  • a gelatin sponge e.g. Topostatin
  • the mechanical compression of the bone wound brought about by this can achieve an initial hemostasis.
  • a local hemostatic agent based on thrombin or fibrin glue preparation can also be applied to the bone wound.
  • the mucosal wound is then closed with saliva-tight atraumatic sutures.
  • a wound protection plate made of plastic is often used in patients and attached to the remaining teeth.
  • the object of the present invention is therefore to provide a pharmaceutical formulation with which the active end product of the blood coagulation cascade, thrombin, can be made available over a limited period of time.
  • the period until stable intraoral wound healing is considered to be the required period of time. This corresponds to 7 to 10 days. After this period, stable wound healing has occurred, which means that external mechanical influences on the wound can no longer have any effect.
  • thrombin is embedded in resorbable spheres, preferably from commercially available polymers that are already used for other medical devices (e.g. surgical sutures) (see Figure 1).
  • spheres in the context of the invention is understood to mean particles, capsules or liposomes which contain the active ingredient embedded, enclosed, dispersed or dissolved, as described, for example, in Voigt, Pharmaceutical Technology, Deutscher maschinerverlag Stuttgart, 2000, pages 467-471.
  • spheres in the sense of the present invention is understood in particular to mean microparticles or nanoparticles which contain an active ingredient embedded in a polymer matrix without the formation of a separate capsule skin
  • Spheres with a size of 0.1 to 1000 / ym are preferred, very particularly with a size of 10 to 150 ⁇ m.
  • the loading of the spheres can be 0.1 to 20%, depending on the corresponding thrombin preparation, and the loading of the collagen sponge can be 0.1 to 50%.
  • the total dose should be 1 I.U. up to 2000 IU, preferably 250 IU up to 1000 IU Thrombin per implant.
  • the spheres can be produced with the aid of known processes, in particular emulsion techniques (w / o; o / w; w / o / w - emulsion evaporation or extraction method) or spray drying.
  • emulsion techniques w / o; o / w; w / o / w - emulsion evaporation or extraction method
  • spray drying emulsion techniques
  • the methods are described in the prior art.
  • EP 0 330 180 describes microspheres of the polylactic acid type containing physiologically active substances and processes for their production.
  • Other manufacturing processes include Müller RH and Hildebrand GE, Pharmaceutical Technology: Modern Pharmaceutical Forms, Stuttgart, pp. 243-258 and S339-355, Eldrigé J. et al., J. Controlled Release 1990, 11, 205 -214; Jeffery J. et al. Pharm. Res.
  • Resorbable polymers used according to the invention for producing the resorbable spheres include poly sugar and their derivatives, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polylactic acid (PLA), polylactides, polyhydroxybutyrate (PHB), poly-L-lysine, their homologues and cocondensates, lactic acid Glycolic acid copolymer (PLG), in particular Resomer RG 504 and 505 from Boehringer Ingelheim.
  • PVA polyvinyl alcohol
  • PVP polyvinyl pyrrolidone
  • PLA polylactic acid
  • PHB polyhydroxybutyrate
  • PEG poly-L-lysine
  • Other usable polymers are disclosed, inter alia, in Müller RH and Hildebrand GE, Pharmaceutical Technology: Modern Pharmaceutical Forms,ticianliche Verlagsgesellschaft Stuttgart, 1998, pp. 243-258 and S339-355.
  • the spheres thus obtained are in turn incorporated into resorbable sponges, in particular collagen sponges.
  • This is done, for example, by freeze-drying an aqueous collagen or an aqueous collagen suspension or gelatin solution in which the spheres are uniformly dispersed.
  • the production of collagen sponges is e.g. in US 4,515,637, EP 562862 and by Chvapil, J. Biomed. Mater. Res. H, 721-741 (1977).
  • the collagen used according to the present invention should preferably be soluble in vivo by enzymatic degradation or other biological processes.
  • Preferred is native collagen in its potentially soluble form or natural insoluble collagen which is inherently cross-linked and is insoluble in either an acidic or alkaline medium such as e.g. also described in US 4,515,637.
  • the collagen used is preferably type 1 collagen.
  • the origin of the collagen for use in the present invention is not particularly limited.
  • collagen is used which is derived from the skin, bone, cartilage, tendons, internal organs, etc. of a mammal such as e.g. comes from humans, horses, cattle, pigs, sheep, rabbits, mice.
  • Collagen-like protein derived from birds, fish or the like can also be used.
  • Genetically engineered collagen can also be used, and genetic engineering is currently in progress (e.g. ZymoGenetics, WA, U.S.A.)
  • the thrombin used in the present invention can be obtained from a variety of sources, e.g. pooled human or animal plasma.
  • Bovine thrombin is e.g. available from a variety of commercial sources.
  • Recombinant thrombin can also be used in accordance with the invention (e.g. ZymoGenetics, WA, U.S.A.).
  • thrombin-like compounds such as proteolytic snake venom, and thrombin precursors such as prothrombin can be used as sources for thrombin.
  • thrombin as used here also includes thrombin precursors and thrombin-like compounds and refers to all proteins and amino acid polymers of natural or synthetic origin which are able to catalyze the formation of fibrin clots from fibrinogen and / or to activate the blood platelets other coagulation factors such as factor VIII can also be used
  • This formulation according to the invention has various advantages since, on the one hand, the use of collagen sponges for mechanical wound compression and the platelet aggregation induced by collagen, the existing therapy concept is only slightly changed and, on the other hand, the healing of the wound is supported over a period of 7-10 days by the released thrombin , The platelet aggregation caused by collagen, through the release of mediators, activates plasmatic blood coagulation.
  • the release is preferably 0 to 14 days, particularly preferably 7 to 10 days.
  • the preparation can be supplemented with therapy-supporting antifibrinolytics such as tranexamic acid, ⁇ -amino caproic acid, 4- (aminomethyl) benzoic acid, aprotinin, EPO, acetaminonaphtone, thromboplastin, menadione sodium bisulfonate sulfonate sulfonate sulfonate sulfonate sulfonate, and add become.
  • antifibrinolytics such as tranexamic acid, ⁇ -amino caproic acid, 4- (aminomethyl) benzoic acid, aprotinin, EPO, acetaminonaphtone, thromboplastin, menadione sodium bisulfonate sulfonate sulfonate sulfonate sulfonate, and add become.
  • antifibrinolytics such as tranexamic acid,
  • Figure 2 shows a release profile of thrombin from poly (DL-lactide-co-glycolide) 50:50 (Boehringer Ingelheim RG 504) at 37 ° C in PBS buffer. The time-dependent cumulative thrombin release is shown, determined by means of the Bradford test measured in vitro over the release period of 28 days.
  • Figure 3 shows a release profile of thrombin from poly (DL-lactide-co-glycolide) 50:50 (Boehringer Ingelheim RG 504) at 37 ° C in PBS buffer.
  • the time-dependent cumulative thrombin release is shown, which is measured by the elimination of p-nitroaniline from the chromogenic substrate, in vitro over the release period of 28 days.
  • 1 NIH thrombin corresponds to 0.324 +/- 0.073 ⁇ g thrombin.
  • the amount of p-nitroaniline released is proportional to the active thrombin, the thrombin used had an activity of 50 NIH / mg.
  • the present invention further provides the use of the pharmaceutical formulation according to the invention as a local hemostatic agent, in particular for local hemostasis in blood-clot-inhibited / blood-coagulation-incompetent patients.
  • the cause of the anticoagulation can be iatrogenic, i.e. due to an inhibition of blood clotting due to the administration of vitamin K antagonists such as phenprocoumon or coumadin, platelet aggregation inhibitors such as acetylsalicylic acid, tirofiban, dipyramidol, ticiopidine or eptifibatide or is endogenously caused as in patients with a congenital defect in blood clotting in a mild form.
  • vitamin K antagonists such as phenprocoumon or coumadin
  • platelet aggregation inhibitors such as acetylsalicylic acid, tirofiban, dipyramidol, ticiopidine or eptifibatide
  • the frequency of postoperative bleeding in coagulation-incompetent patients is approximately 30% and the required duration of hospitalization is several days (on average 5 days).
  • the clinical use of the pharmaceutical formulation according to the invention significantly reduces the frequency of subsequent bleeding and thereby shortens the duration of hospitalization. It also enables certain outpatient procedures Interventions. In addition to a significantly reduced risk for the patients, this also means considerable cost savings in the healthcare system.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Materials Engineering (AREA)
  • Dispersion Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des formulations pharmaceutiques résorbables destinées à la libération continue locale de thrombine. La thrombine est enrobée dans des sphères en polymère résorbable, les sphères étant incorporées dans une éponge de collagène. La formulation selon l'invention propose un hémostyptique résorbable destiné à être utilisé en chirurgie, notamment en chirurgie dentaire dans le cas d'interventions dento-alvéolaires.
PCT/EP2003/004680 2002-05-08 2003-05-05 Formulation pharmaceutique resorbable destinee a la liberation continue de thrombine WO2003094983A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2003232257A AU2003232257A1 (en) 2002-05-08 2003-05-05 Resorbable pharmaceutical formulation for the continuous release of thrombin
EP03749866A EP1501558A1 (fr) 2002-05-08 2003-05-05 Formulation pharmaceutique resorbable destinee a la liberation continue de thrombine
CA002485268A CA2485268A1 (fr) 2002-05-08 2003-05-05 Formulation pharmaceutique resorbable destinee a la liberation continue de thrombine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10220030.0 2002-05-08
DE10220030 2002-05-08

Publications (1)

Publication Number Publication Date
WO2003094983A1 true WO2003094983A1 (fr) 2003-11-20

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PCT/EP2003/004680 WO2003094983A1 (fr) 2002-05-08 2003-05-05 Formulation pharmaceutique resorbable destinee a la liberation continue de thrombine

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EP (1) EP1501558A1 (fr)
AU (1) AU2003232257A1 (fr)
CA (1) CA2485268A1 (fr)
WO (1) WO2003094983A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9265858B2 (en) 2012-06-12 2016-02-23 Ferrosan Medical Devices A/S Dry haemostatic composition
US9283187B2 (en) 2011-04-27 2016-03-15 Biom'up Hemostatic compositions
US9533069B2 (en) 2008-02-29 2017-01-03 Ferrosan Medical Devices A/S Device for promotion of hemostasis and/or wound healing
US9724078B2 (en) 2013-06-21 2017-08-08 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
US10111980B2 (en) 2013-12-11 2018-10-30 Ferrosan Medical Devices A/S Dry composition comprising an extrusion enhancer
US10653837B2 (en) 2014-12-24 2020-05-19 Ferrosan Medical Devices A/S Syringe for retaining and mixing first and second substances
US10918796B2 (en) 2015-07-03 2021-02-16 Ferrosan Medical Devices A/S Syringe for mixing two components and for retaining a vacuum in a storage condition
US11046818B2 (en) 2014-10-13 2021-06-29 Ferrosan Medical Devices A/S Dry composition for use in haemostasis and wound healing
US11052172B2 (en) 2016-08-12 2021-07-06 Biom'up France SAS Hemostatic flowable
US11109849B2 (en) 2012-03-06 2021-09-07 Ferrosan Medical Devices A/S Pressurized container containing haemostatic paste
CN114159623A (zh) * 2020-12-12 2022-03-11 复旦大学 一种自抗凝弹性体材料及其制备方法
US11801324B2 (en) 2018-05-09 2023-10-31 Ferrosan Medical Devices A/S Method for preparing a haemostatic composition

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104163779B (zh) * 2014-06-06 2016-04-13 浙江工业大学 一种管式连续化制备亚硫酸氢钠甲萘醌的方法
CN111053944B (zh) * 2019-11-28 2021-05-28 中国科学院大学温州研究院(温州生物材料与工程研究所) 一种载凝血酶微球-膨胀海绵复合止血材料及其制备方法及应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4515637A (en) * 1983-11-16 1985-05-07 Seton Company Collagen-thrombin compositions
WO1997037694A1 (fr) * 1996-04-04 1997-10-16 Immuno Aktiengesellschaft Eponge hemostatique a base de collagene
EP1053753A1 (fr) * 1999-05-19 2000-11-22 Resorba Chirurgisches Nahtmaterial Franz Hiltner GmbH & Co. Support de médicaments à utilisation locale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4515637A (en) * 1983-11-16 1985-05-07 Seton Company Collagen-thrombin compositions
WO1997037694A1 (fr) * 1996-04-04 1997-10-16 Immuno Aktiengesellschaft Eponge hemostatique a base de collagene
EP1053753A1 (fr) * 1999-05-19 2000-11-22 Resorba Chirurgisches Nahtmaterial Franz Hiltner GmbH & Co. Support de médicaments à utilisation locale

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9533069B2 (en) 2008-02-29 2017-01-03 Ferrosan Medical Devices A/S Device for promotion of hemostasis and/or wound healing
US9283187B2 (en) 2011-04-27 2016-03-15 Biom'up Hemostatic compositions
US9662374B2 (en) 2011-04-27 2017-05-30 Biom'up Hemostatic compositions
US10046034B2 (en) 2011-04-27 2018-08-14 Biom'up Hemostatic compositions
US10342856B2 (en) 2011-04-27 2019-07-09 Biom'up Hemostatic compostions
US11109849B2 (en) 2012-03-06 2021-09-07 Ferrosan Medical Devices A/S Pressurized container containing haemostatic paste
US10799611B2 (en) 2012-06-12 2020-10-13 Ferrosan Medical Devices A/S Dry haemostatic composition
US9265858B2 (en) 2012-06-12 2016-02-23 Ferrosan Medical Devices A/S Dry haemostatic composition
US9999703B2 (en) 2012-06-12 2018-06-19 Ferrosan Medical Devices A/S Dry haemostatic composition
US9724078B2 (en) 2013-06-21 2017-08-08 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
US10595837B2 (en) 2013-06-21 2020-03-24 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
US11103616B2 (en) 2013-12-11 2021-08-31 Ferrosan Medical Devices A/S Dry composition comprising an extrusion enhancer
US10111980B2 (en) 2013-12-11 2018-10-30 Ferrosan Medical Devices A/S Dry composition comprising an extrusion enhancer
US11046818B2 (en) 2014-10-13 2021-06-29 Ferrosan Medical Devices A/S Dry composition for use in haemostasis and wound healing
US10653837B2 (en) 2014-12-24 2020-05-19 Ferrosan Medical Devices A/S Syringe for retaining and mixing first and second substances
US10918796B2 (en) 2015-07-03 2021-02-16 Ferrosan Medical Devices A/S Syringe for mixing two components and for retaining a vacuum in a storage condition
US11052172B2 (en) 2016-08-12 2021-07-06 Biom'up France SAS Hemostatic flowable
US11801324B2 (en) 2018-05-09 2023-10-31 Ferrosan Medical Devices A/S Method for preparing a haemostatic composition
CN114159623A (zh) * 2020-12-12 2022-03-11 复旦大学 一种自抗凝弹性体材料及其制备方法

Also Published As

Publication number Publication date
CA2485268A1 (fr) 2003-11-20
AU2003232257A1 (en) 2003-11-11
EP1501558A1 (fr) 2005-02-02

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