Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1998-02-09
1999-03-30
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 12, A61K 3816, A61K 3800
Patent
active
058889671
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP96/03345 filed Jul. 30, 1996.
The invention concerns the use of plasminogen activators to prepare drugs for the local formation of bone as well as pharmaceutical compositions that are suitable for this application. The local formation of bone mass is for example necessary for the healing of bone fractures, in the case of bone destruction caused by tumours, for cosmetic surgery, for the implantation of materials for dental prostheses or for bone replacement materials such as artificial hips or knee joints or to support the incorporation of auxiliary materials such as nails and screws.
It is known that growth factors such as transforming growth factory-.beta. (TGF-.beta.), basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF) can positively influence osteogenesis (Pierce et al., J. Cell. Biol. 109 (1989) 429-440).
The object of the invention is to provide further agents which when applied locally support bone growth and bone healing (osteogenesis).
The invention concerns the use of plasminogen activators to produce a drug for local osteogenesis. The plasminogen activator is preferably administered locally at the site in the body to be treated as a solution (injection or infusion) or in a carrier-bound form.
A plasminogen activator is understood as a protein enzyme which activates the zymogen plasminogen by cleavage between arginine 506 and valine 561 to form the serine protease plasmin. Plasmin can cleave numerous proteins including fibrin. Plasminogen activators are for example urokinase (uPA), tissue plasminogen activator (t-PA) and streptokinase. Urokinase is composed of 411 amino acids which can be divided into three domains (epidermal growth factor like domain (EGF), kringle domain and serine protease domain). Urokinase was already purified and characterized in 1982. The recombinant production has been described by Holz, W. E. et al., Biotechnology 3 (1985) 923-929.
t-PA is a protein which is composed of 527 amino acids. It also contains various domains which are referred to as the finger region, EGF-like domain, 2 kringle region and serine protease region. t-PA was purified and characterized by Collen, D. et al., Thromb. Haemostas. 43 (1980) 77-89. The recombinant production is described in Pennica, D. et al., Nature 301 (1983) 214-220. Derivatives and muteins of urokinase and t-PA are described by Harris T. J. R., Protein Engineering 1 (1987) 449-458.
Plasminogen activators are preferably used which have similar properties to human t-PA in particular with regard to plasminogenolytic and immunological properties and with regard to fibrin binding.
Plasminogen activators are particularly preferably used which have a low fibrin binding. Such plasminogen activators are described for example in WO 90/09437 and are preferably composed of the kringle 2 and the protease domain of t-PA.
The application of the plasminogen activator to the site in the body to be treated, preferably bones, can either be achieved in solution and expediently by infusion or injection (preferably local injection) or bound to a carrier. Carrier-bound plasminogen activators can for example be applied to implants as gels, pastes or as a coating.
Biocompatible and preferably biodegradable materials are used as carriers. Preferably the materials themselves also additionally induce wound healing or osteogenesis.
For the application it is preferable to embed the plasminogen activator in polymeric gels or films, to immobilize it in this manner and to apply this preparation directly onto the site on the bones to be treated. Such polymeric base gels or films are for example composed essentially of glycerol, methyl cellulose, hyaluronic acid, polyethylene oxides and/or polyoxamers. Collagen, gelatin and alginate are also suitable and are described for example in WO 93/00050 and WO 93/20859. Other polymers are polylactic acid (PLA) and copolymers of lactic acid and glycolic acid (PLPG) (Hollinger et al., J. Biomed. Mater. Res. 17 (1983) 71-82) as well as the bone derivative "Demineraliz
REFERENCES:
patent: 5290692 (1994-03-01), Suzuki et al.
patent: 5422340 (1995-06-01), Dammann et al.
patent: 5491082 (1996-02-01), Suzuki et al.
Database Biosis, 84:252958, Hajduk et al., "The Effect of Streptase Traskolan and Sefril on the Development of Experimental Osteitis 2 . . ." (1981).
Database Medline, 82105103, Hajduk et al., "Effect on Streptokinase, Traskolan and Sefril on the Development of Experimental Osteomyelitis . . ." (1981).
International Publication No. WO 94/07537 published Apr. 14, 1994.
International Publication No. WO 94/15653 published Jul. 21, 1994.
Honold Konrad
Kling Lothar
Lang Kurt
Leser Ulrike
Boehringer Mannheim GmbH
Criares Theodore J.
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