HAS-active ingredient conjugates

Abstract

The invention relates to compounds comprising a conjugate of hydroxyalkyl starch (HAS) and an active agent, whereby the hydroxyalkyl starch is either directly covalently bonded to the active agent, or by means of a linker. The invention further relates to methods for the production of a covalent HAS-active agent conjugate, whereby HAS and an active agent are reacted in a reaction medium, characterised in that the reaction medium is water or a mixture of water and an organic solvent, comprising at least 10 wt. % water.

Description

[0001] The present invention relates to compounds comprising a conjugate of hydroxyalkyl starch (HAS) and an active ingredient, wherein the hydroxyalkyl starch is coupled to the active ingredient either directly or via a linker. The invention further relates to processes for the preparation of a covalent HAS-active ingredient conjugate in which HAS and an active ingredient are reacted with each other in a reaction medium, wherein the reaction medium is water or a mixture of water with an organic solvent, having at least 10 weight-% water. The invention further relates to the medical use of the conjugates. TECHNICAL BACKGROUND [0002] The clinical use of many active ingredients of pharmaceuticals is adversely affected by a number of problems (e.g. Delgado et al., Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 9 (3, 4), (1992) pp. 249-304). Parenterally administered native proteins are subject for example to excretion by the reticuloendothelial system, the liver, the kidney...

AI Technical Summary

Benefits of technology

[0028] The object of the present invention is thus to provide improved hydroxyalkyl starch-active ingredient conjugates and processes for their preparation which lead to biologically active conjugates which can be used in everyday clinical practice. A further object of the present invention is to provide a process for the preparation of hydroxyalkyl starch-active ingredient conjugates wherein by-products are not produced in significant quantities, as these by-products also adversely affect the subsequent purification of the product to a significant extent.

Problems solved by technology

The clinical use of many active ingredients of pharmaceuticals is adversely affected by a number of problems (e.g. Delgado et al., Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 9 (3, 4), (1992) pp.

Proteins expressed by bacteria as well as other recombinant proteins can have an increased immunogenicity and provoke life-threatening hypersensitivity reactions.

Corresponding reactions naturally prevent the medical use of these products.

The process of coupling the active ingredients proved to be problematic however, as the active group of the protein was inactivated by coupling to PEG or the reactions did not provide the reaction product in a suitable yield.

However, although the demand for such a product was recognized early on (e.g. Rabiner, J. Exp. Med. 126, (1967) 1127), none of the known HBOC products has as yet achieved the status of an approved drug.

Isolated haemoglobin molecules are however very unstable and rapidly break down into the more stable α,β dimers (MW 32 kDa).

Thus, the protein-HES conjugates known in the state of the art result from a non-selective coupling of Bromcyan-activated HES to haemoglobin (e.g. DE 26 16 086, hereby incorporated by reference) Corresponding processes can lead to polydisperse products with non-uniform properties and potentially toxic side effects.

In every case, a costly removal of the organic solvent is necessary, as even residual proportions of organic solvents may not be acceptable for the intended medical use.

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