Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1999-01-06
2000-07-04
Russel, Jeffrey E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530385, 536105, A61K 3842, C07K 14805, C08B 3118
Patent
active
060839090
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new oxygen transfer agents which comprises haemoglobin-hydroxyethylstarch conjugates, and processes for their preparation. The invention furthermore relates to the use of the oxygen transfer agents as a blood substitute, plasma expander, perfusion agent, haemodilution agent and/or cardioplegic solution.
The development of stroma-free haemoglobin solutions, so-called "haemoglobin-based oxygen carriers" (HBOCs), which can be used as a blood substitute has for a long time been an urgent aim of pharmaceutical research and development.
Blood loss, for example as a consequence of an accident or an operation, is in most cases treated with an allogenic blood donation. The associated problems of uncontrolled transfer of pathogenic organisms, in particular of viruses such as HIV or hepatitis pathogens, and the need for blood group typing before the transfusion have been known the expert for a long time and are described comprehensively in the literature.
An HBOC product which can be used as a standard blood substitute would not only solve these problems, but could furthermore be used as a plasma expander, perfusion agent, haemodilution agent and/or cardioplegic solution.
Although the need for such a product was already recognized early on (cf. Rabiner, J. Exp. Med. 126, (1967) 1127), none of the known HBOC products has so far achieved the status of an approved medicament.
The natural oxygen transfer agent is the blood pigment haemoglobin, a chromoprotein with a molecular weight (MW) of 64 kilodaltons (kDa). The protein comprises two .alpha. and .beta. peptide chains, each of which has a haem bonded as a prosthetic group. This is a porphyrin ring with a central iron atom. Isolated haemoglobin molecules are very unstable and rapidly dissociate into the more stable .alpha.,.beta.-dimers (MW 32 kDa). The biological half-life of isolated haemoglobin in the blood circulation is about 1 hour, since the dimers are rapidly excreted via the kidneys. The dimers cause nephrotoxic side effects here (cf. Bunn & Jandl, J. Exp. Med. 129, (1967) 925-934).
The HBOC products initially developed also had a nephrotoxic potential, which was attributed to contamination of the products with cell constituents (cf. Relihan, Ann. Surg. 176, (1972) 700).
Furthermore, an isolated haemoglobin composition lacks 2,3-diphosphoglycerate (2,3-DPG), which is the naturally occurring allosteric activator of oxygen bonding. This results in an increased oxygen-bonding affinity of the isolated haemoglobin, and accompanying this a reduced oxygen release capacity of such compositions.
Development work on derivatized haemoglobin molecules was therefore primarily directed at improving the oxygen transfer properties thereof, and by-passing the nephrotoxic symptoms. In this work, haemoglobin was crosslinked intramolecularly, linked intermolecularly to form polymeric HBOC forms and/or coupled to polymers to provide conjugated HBOC forms. In this work, mixed forms of intra- and intermolecularly crosslinked haemoglobin derivatives have also been prepared and investigated for the planned use.
Crosslinking of haemoglobin by means of bi- or polyfunctional crosslinking agents can take place selectively or non-selectively. In one form of selective crosslinking, two protein chains of the haemoglobin are bonded intramolecularly with one another, as a result of which the natural tetrameric form of the isolated haemoglobin molecule is stabilized. By choosing a suitable crosslinking agent, the oxygen affinity of the haemoglobin can bond oxygen reversibly under physiological conditions. Examples of such crosslinking agents are pyridoxal phosphate and diaspirin, and derivatives thereof. Processes for crosslinking haemoglobin are described, for example, in Benesch (Meth. Enzymol., vol. 231 (1994), 267-274), Keipert et al. (Transfusion, vol. 29 (1989), 767-773), Synder et al. (Proc. Natl. Acad. Sci. USA, 84, (1987), 7280-7284) and in Rogers et al. (Biochim. et Biophys. Acta, 1248 (1995), 135-142).
In a non-selective crosslinking, intermolecularly
REFERENCES:
patent: 4064118 (1977-12-01), Wong
patent: 5110909 (1992-05-01), Dellacherie et al.
Eichner Wolfram
Sommermeyer Klaus
Fresenius AG
Russel Jeffrey E.
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