EP0971732A1 - Nouvelle utilisation d'antithrombine iii - Google Patents

Nouvelle utilisation d'antithrombine iii

Info

Publication number
EP0971732A1
EP0971732A1 EP98909214A EP98909214A EP0971732A1 EP 0971732 A1 EP0971732 A1 EP 0971732A1 EP 98909214 A EP98909214 A EP 98909214A EP 98909214 A EP98909214 A EP 98909214A EP 0971732 A1 EP0971732 A1 EP 0971732A1
Authority
EP
European Patent Office
Prior art keywords
iii
preparation
heparin
heparins
use according
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.)
Withdrawn
Application number
EP98909214A
Other languages
German (de)
English (en)
Inventor
Hans-Peter Schwartz
Anton Philapitsch
Ludwig Pichler
Wilfried Auer
Yendra Linnau
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Baxter AG
Original Assignee
Baxter AG
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 Baxter AG filed Critical Baxter AG
Publication of EP0971732A1 publication Critical patent/EP0971732A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans

Definitions

  • the invention relates to a new use of antithrombin III.
  • Antithrombin III is a plasmatic protein that has an anticoagulant effect by inhibiting thrombin, the factors IXa, Xa, XIa, Xlla and plasmin.
  • AT III deficiency (or hereditary thrombophilia) is an autosomal dominant hereditary disease with a tendency to thrombosis or embolism due to reduced formation of AT III.
  • Acquired AT III deficiency can e.g. with consumption coagulopathy (DIC), sepsis, cirrhosis of the liver or with nephrotic syndrome.
  • DIC consumption coagulopathy
  • sepsis sepsis
  • cirrhosis of the liver or with nephrotic syndrome.
  • AT III deficiency symptoms can occur with heart valve prostheses, postoperative, thromboembolic complications, with estrogen therapy or with asparagine therapy.
  • Heparin is a coagulation-inhibiting polymer made of D-glucuronic acid and D-glucosamine that occurs in the body (lungs, liver, thymus, spleen and basophilic mast cells) and contains several molecules of sulfuric acid per structural unit. Heparin inhibits the effect of thrombin on, for example, fibrinogen by binding to AT III, which is why heparin is also referred to as a cofactor for AT III. Furthermore, heparin also inhibits the effects of thrombokinase and thereby the conversion of prothrombin to thrombin, as well as the Agglomera ⁇ tion of the platelets and the clotting reaction.
  • Heparin AT III has an inhibitory effect on the arterial coagulation factors Va, IXa, Xa and Xlla and has an activating effect on lipoprotein lipase.
  • heparin treatment can also cause serious side effects.
  • the cause of a heparin-induced thrombocytopania and the associated risk of thrombosis are assumed to be immunological reactions that are not predictable. Due to the inhibition of platelet aggregation, bleeding often occurs as part of heparin therapy.
  • heparins are routinely administered primarily for prophylaxis but also for the treatment of thrombosis and embolism. Hematomas (“bruises”) often occur especially when heparins are administered subcutaneously, which patients often find very painful.
  • the object of the present invention is therefore to provide an improved prophylaxis and therapy treatment of thromboses and embolisms, which can be used primarily for routine use in hospitals and no longer has the disadvantages of conventional heparin administration.
  • This object is achieved according to the invention by using AT III for the manufacture of a pharmaceutical preparation for preventing bleeding during anticoagulation therapy, in particular for the manufacture of a pharmaceutical preparation for prophylaxis or treatment of thrombosis.
  • the inhibition of platelet aggregation can also be prevented or treated, and the bleeding time can be shortened.
  • AT III is also provided only once ⁇ a pharmaceutical preparation with AT III as an effective component are available which may be provided for subcutaneous administration, III for the preparation of a subcutaneous medicament to be administered.
  • the present invention therefore also relates to a pharmaceutical preparation for subcutaneous injection, which preparation contains AT III as the or one of the essential active components.
  • the subcutaneous preparation contains AT III in a relatively high concentration, corresponding to at least 2 times the concentration usual for in vitro products.
  • a concentration in the range from 100 to 5000 ATH HI / ml is usually chosen, preferably between 500 and 3000 ATH HI / ml, depending on the purity of the protein used.
  • AT III is also used as an IV or IM product for Intended use suggested.
  • the AT III used according to the invention can be contained in various types of preparations, for example in combination with high-affinity heparins or heparinoids with affinity for AT III, preferably as an AT III-heparin (or heparinoid) complex (heparinoids is a collective term for natural occurring, semi-synthetic and synthetic mucopolysaccharides with heparin-like effects).
  • a preferred production process for such a complex is described in AT-PS 379 310, wherein human plasma or AT III-containing plasma fractions are mixed with heparin or heparinoid and the heparin or heparinoid complex formed is purified by adsorption on an anion exchanger.
  • Such a preparation is commercially available under the designation Atheplex ® (Fa. Immuno, AT).
  • Atheplex ® Fa. Immuno, AT.
  • this method can also be carried out with starting solutions which have been produced by the recombinant DNA technology.
  • AT III is preferably used in the context of an anticoagulation therapy which comprises a heparin treatment.
  • the pain associated with the heparin injection (as a side effect of the anticoagulation therapy) can be greatly reduced or even prevented with the combined administration of AT III and heparin or of AT III complexed with heparin.
  • patients at risk of heparin-induced thrombocytopania can be treated.
  • the preparation for subcutaneous administration according to the invention can contain different types of heparin.
  • heparins in low molecular weight with a molecular weight of about 1500 to 10,000 or in high molecular weight with a Molecular weight of about 10,000 to 30,000 daltons may be included.
  • the preparation according to the invention has a surprisingly high functional half-life. Due to its novel absorption and pharmacokinetics, the preparation according to the invention is characterized by an exceptional bioavailability of AT III or heparin.
  • the components of the preparation are preferably mixed and administered by the choice of the heparins or the heparinoids or their AT III affinity such that the heparins or heparinoids contained in vivo have a functional half-life of more than 10 hours, in particular of more than 20 hours, in certain cases even more than 30 hours.
  • the pharmaceutical preparation according to the invention is produced by completing a purified preparation containing AT III and optionally heparin, according to methods known per se, by combining it with suitable buffer, auxiliary, preservative and / or stabilizing substances or protease inhibitors and is filled in a form suitable for administration and is preferably stored in a stable manner, optionally in a lyophilized or frozen state.
  • the effective dosage of the preparation when used depends on the individual patient (height, body weight, condition, blood count, .
  • the AT III concentration in the preparation according to the invention or for the application according to the invention is preferably selected such that administration of a dose of 5 to 10,000 U AT HI / kg body weight in a volume of less than 20 ml, in particular less than 10 ml, preferably less than 5 ml, most preferably less than 2 ml.
  • the preparation according to the invention is preferably subjected to a method for inactivating infectious or pathogenic material, in particular viruses.
  • These inactivation treatment is preferably ensured with a surfactant and / or heat treatment, for example by a heat treatment in the solid state, in particular a steam treatment according to EP-0 159 311, or EP-0 519 901 or EP-0 674 531.
  • Treatments for inactivating viruses also include treatment with chemical or chemical / physical methods, e.g. with chaotropic substances according to W094 / 13329, DE 44 34 538 or EP-0 131 740 (solvent) or the photo inactivation.
  • Irradiation or nanofiltration is also a preferred physical method for depleting viruses in the context of the present invention.
  • the invention also relates to a kit for subcutaneous injection comprising a pharmaceutical preparation containing AT III, instructions for the use of the preparation for subcutaneous injection, and optionally an application device suitable for subcutaneous injection, preferably a syringe.
  • This syringe has one in relation to i. m. -Spray very thin needle to facilitate penetration under the skin.
  • the pharmaceutical preparation in the kit is preferably provided in a container in lyophilized form, but it can also be provided in liquid form, in which case, however, it is then preferably stored in deep-frozen form.
  • 1A and 1B the local tolerance of heparin and Atheplex ® on the mouse; 2: the pain-inducing effect of heparin in the rat paw model;
  • FIG. 4 shows the comparison of the ristocetin-dependent Plötenaggrega- tion of heparin and Atheplex ®.
  • Fig. 5 the determination of the half-life of heparin and Atheplex ® .
  • Example 1 Haematoma formation in mice after subcutaneous injection of heparin or the preparation according to the invention (currently the best way of carrying out the invention in the opinion of the applicant)
  • mice 15 male NMRI mice are a total of g in weight of 25 to 30 having heparin (I MUNO AG, Wien) or preparation according to the invention (Atheplex ®, obtainable from IMMUNO AG, Vienna.) Treated as follows:
  • the animals were sacrificed on day 4 and the subcutaneous changes were assessed pathologically and anatomically.
  • Control animals which had received isotonic saline analogue, never showed hematomas.
  • the section confirmed the visual assessment of the 4th day.
  • Example 2 Examination of the pain-triggering effect of a subcutaneous injection of heparin and the preparation according to the invention in the rat paw model
  • a mercury monometer was connected to a 10 ml syringe, the piston of which was equipped with a short, bullet-shaped plug. This syringe applied increasing pressure to the rat paw (26.7 mbar / s). The pain threshold was given as the pressure in mbar that is necessary to trigger a defense reaction of the animal.
  • mice Female Sprague-Dawley rats weighing between 250 and 350 g were used for the study.
  • the pain threshold was measured before the injection (previous value) and every hour up to 6 hours after the intraplantar injection of heparin (multiple doses) or Atheplex ® (multiple doses) or isotonic saline (100 ⁇ l, negative control).
  • the values after injection of test or control substances were expressed as a percentage of the previous value.
  • Figs. 2 heparin
  • Fig. 3 theplex ® produced (x + SJJ-).
  • the abscissa represents the time axis (hours after intraplantar injection).
  • Heparin (Fig. 2) was tested in doses 1, 3, 10, 40 and 130 IU on 10 animals each. From 10 IU, progressive, severe pain occurs, with no further dose dependency being discernible.
  • Atheplex ® (Fig. 3) was tested in doses 10, 40, 130 and 200 units of heparin (n respectively 10). Here too there is initial pain, which, however, diminishes as the duration progresses. The timing and extent of this decrease are dose-dependent:
  • Example 3 In vitro investigation of the inhibition of platelet aggregation by heparin and by the preparation according to the invention
  • the influence of the substances on the platelet aggregation takes place by means of a turbidometric method using an aggregometer (from Chronolog).
  • a turbidometric method using an aggregometer from Chronolog.
  • To 400 ⁇ l of a formaldehyde-fixed platelet preparation (250,000 cells per ⁇ l), 25 ⁇ l of an FVIII-vWF preparation and 25 ⁇ l sample or buffer to be tested are added as a control. After an incubation of 3 min at 37 ° C., the aggregation is started with 50 ⁇ l ristocetin sulfate (10 mg / ml). The aggregation is evaluated via the increase in the aggregation curve.
  • the reference value is the aggregation with buffer addition.
  • Example 4 Determination of the half-life of subcutaneously injected heparin and subcutaneously injected preparation according to the invention

Landscapes

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

Abstract

L'invention concerne l'utilisation d'antithrombine III (AT III) pour produire une préparation pharmaceutique servant à empêcher les hémorragies pendant un traitement anticoagulant, ainsi qu'une préparation pharmaceutique pour injection sous-cutanée contenant l'AT III comme principe actif.
EP98909214A 1997-03-25 1998-03-24 Nouvelle utilisation d'antithrombine iii Withdrawn EP0971732A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AT51797A AT405905B (de) 1997-03-25 1997-03-25 Neue verwendung von antithrombin iii
AT51797 1997-03-25
PCT/AT1998/000078 WO1998042371A1 (fr) 1997-03-25 1998-03-24 Nouvelle utilisation d'antithrombine iii

Publications (1)

Publication Number Publication Date
EP0971732A1 true EP0971732A1 (fr) 2000-01-19

Family

ID=3492718

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98909214A Withdrawn EP0971732A1 (fr) 1997-03-25 1998-03-24 Nouvelle utilisation d'antithrombine iii

Country Status (5)

Country Link
EP (1) EP0971732A1 (fr)
AT (1) AT405905B (fr)
AU (1) AU6385298A (fr)
CA (1) CA2284820A1 (fr)
WO (1) WO1998042371A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112012012460B1 (pt) * 2009-11-24 2020-06-23 Grifols Therapeutics Inc. Método de liofilização de uma composição

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3170001D1 (en) * 1980-09-30 1985-05-23 Bayer Ag Method for the production of an antithrombin-heparin complex and pharmaceutical compositions containing the complex
US4689323A (en) * 1983-09-26 1987-08-25 Miles Laboratories, Inc. Covalently bound heparin--antithrombin-III complex
JP3494667B2 (ja) * 1992-10-02 2004-02-09 アベンティス ファーマ株式会社 アンチトロンビンｉｉｉ製剤
JP3820607B2 (ja) * 1995-11-10 2006-09-13 三菱ウェルファーマ株式会社 アンチトロンビン−ｉｉｉの液状製剤およびその保存安定化方法
US6562781B1 (en) * 1995-11-30 2003-05-13 Hamilton Civic Hospitals Research Development Inc. Glycosaminoglycan-antithrombin III/heparin cofactor II conjugates
JPH09176040A (ja) * 1995-12-27 1997-07-08 Green Cross Corp:The ヘパリンコファクターｉｉの医薬用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9842371A1 *

Also Published As

Publication number Publication date
AT405905B (de) 1999-12-27
WO1998042371A1 (fr) 1998-10-01
AU6385298A (en) 1998-10-20
ATA51797A (de) 1999-05-15
CA2284820A1 (fr) 1998-10-01

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