Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Patent
1996-08-21
1998-05-05
Lankford, Jr., Leon B.
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
424 943, 424 9463, A61K 3848, A61K 3854
Patent
active
057470308
DESCRIPTION:
BRIEF SUMMARY
The invention relates to pharmaceutical preparations containing plasminogen activators or derivatives of same as the active substances and to related pharmaceutical forms of administration in the form of lyophilisates or injection and infusion solutions, respectively.
The human tissue plasminogen activator (t-PA) is of immense therapeutic importance in dissolving blood clots, e.g., in cardiac infarctions. t-PA causes dissolving of blood clots by activation of plasminogen to plasmin. Plasmin, in turn, dissolves fibrin which is the major component of the protein matrix of clotted blood.
Natural t-PA is composed of multiple functional domains F, E, K1, K2, and P. Domain P involves the proteolytically active centre causing cleavage of plasminogen to plasmin. The preparation of plasminogen activators (PA) by genetic engineering, in particular, of t-PA or various t-PA muteins in eukaryotic and prokaryotic cells is already known. Here, in contrast to natural t-PA, t-PA derivatives are synthesised from prokaryotes in non-glycosylised form.
In the meaning of the invention, in principle, such derivatives of t-PA, particularly those prepared by recombination, are possible as the plasminogen activators, which essentially comprise those protein regions of natural protein that are responsible for the fibrinolysis of the thrombi. Here, such t-PA derivatives may also be used which have deletions or substitutions of single or multiple amino acids in the t-PA sequence.
According to the invention, the following plasminogen activators may be employed, for example: t-PA (e.g., Alteplase), LY 210825 (K2P available from "Syrian hamster" cell lines, Circ. 1990, 82, 930-940); .DELTA.FE3x and .DELTA.FE1x (K1K2P, Blood 1988, 71, 216-219); .DELTA.FEK1 (K2P from C127 mouse cells, J. Cardiovasc. Pharmacol. 1990, 16, 197-209); E-6010 (Jap. Circ. J. 1989, 53, p. 918); t-PA variants (Thromb. Haemost. 1989, 62, p. 542); K2P and D-K2P (Thromb. Haemost. 1989, 62, p. 393); MB-1018 (FK2K2P, Thromb. Haemost. 1989, 62, p. 543); FK2P (FASEB J. 1989, 3, A1031, abstract 4791); .DELTA.1x (Circulation 1988, 4, II-15); K1K2P (Thromb. Res. 1988, 50, 33-41); FK1K2P (J. Biol. Chem. 1988, 263, 1599-1602); TNK variant of t-PA (WO 93/24635); bat-PA (Witt et al., Blood 1992, 79, 1213-1217, and Mullot et al., Arterioscler. Thrombos. 1992, 12, 212-221). In particular, those plasminogen activators are possible which contain the cringle 2 domain ("K2") of the t-PA and/or the serine protease domain ("P"). In this respect, one may exemplify the K2P type t-PA mutein "r-PA" described in EP 0 382 174 (WO 90/09437).
More specifically, the present invention relates to K2P, K1K2P, FK1K2P, and FK2K2P type plasminogen activators as described in the following printings: Protein Engineering 5(1), 93-100 (1992); DE-OS-39 23 339.1; Circ. 1990, 82, 930-940; J. Cardiovasc. Pharmacol. 1990, 16, 197-203; Blood 1988, 71, 216-219; J. Biol. Chem. 1988, 263, 1599-1602; Thromb. Haemost. 1989, 62, p. 543. In particular, recombinant K2P type plasminogen activators are employed as described in EP-A-0 382 174 and in Protein Engineering Vol. 5(1), p. 93-100 (1992). Further t-PA muteins of this type are described in the following patent applications: U.S. Pat. No. 4,970,159, EP-A-0 196 920, EP-A-0 207 589, AU 61804/86, EP-A-0 231 624, EP-A-0 289 508, JP 63133988, EP-A-0 234 051, EP-A-0 263 172, EP-A-0 241 208, EP-A-0 292 009, EP-A-0 297 066, EP-A-0 302 456, EP-A-0 379 890.
The substantial influence of the sugar proportion on solubility and aggregation of proteins is known from prior art (J. Biol. Chem. 263 (1988), 8832-8837). Thus, it has been determined in EP-B-458 950 that, e.g., a non-glycosylated recombinant plasminogen activator of domain composition K2P has a substantially poorer solubility than glycosylated t-PA derivatives, for example. As a rule, non-glycosylated plasminogen activators such as r-PA dissolve only to a slight extent in buffers conventionally used for the solubilisation of proteins, such as 50 mmoles/l of Na citrate pH 6, 50 mmoles/l of phosphate buffer or physiologic
REFERENCES:
patent: 5068106 (1991-11-01), Paques et al.
patent: 5352452 (1994-10-01), Kohnert et al.
patent: 5352453 (1994-10-01), Kohnert et al.
Fischer Stephan
Kohnert Ulrich
Markl Hans-Jorg
Woog Heinrich
Boehringer Mannheim GmbH
Lankford , Jr. Leon B.
Tate Christopher R.
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