Reconstitution medium for protein and peptide formulations

Abstract

Compositions useful for reconstitution of concentrated formulations containing protein / peptide pharmaceuticals are provided. The composition generally includes one or more lipids, as well as one or more alcohols that promote and stabilize the formation of (a) lipid molecular assemblies with greater protein encapsulation; (b) protein-lipid complexes and (c) protein and lipid solutions. The reconstitution medium improves the protein-lipid association that in turn alters the pharmaceutical properties.

Description

FIELD OF THE INVENTION This invention relates to compositions for reconstitution of freeze-dried formulations and more particularly provides a composition and method for reconstitution of freeze-dried formulations comprising proteins and lipids. BACKGROUND OF THE INVENTION Advances in protein engineering and biotechnology, have led to large scale production of proteins and peptides for pharmaceutical purposes such as replacement therapies and vaccines. However, due to their complex structure and folding dynamics, proteins undergo physical and chemical instability. These instabilities present unique difficulties in the production, formulation, storage and administration of protein pharmaceuticals (1,2). Chemical instability is related to covalent modification of the protein that leads to loss of activity. One strategy to overcome this difficulty and to prolong the shelf life, is to freeze dry protein products and reconstitute them prior to the administration. The reconstitution buf...

AI Technical Summary

Benefits of technology

In order to prevent physical instability, a strategy has been proposed to add lipidic particles to stabilize the intermediate structures. With this invention, we report the composition of a reconstitution medium which promotes the association of protein and lipid, in solution, to form stabilized lipidic molecular assemblies (cochleate, laminar, or other tertiary structures), protein-lipid bilayer complexes and protein-lipid solutions (in which lipids associate with hydrophobic protein domains without forming larger structures) by promoting protein-lipid interactions. Compositions and buffer conditions for preparing the reconstitution solution are disclosed. An example is low concentration of ethanol (less than about 60%, preferably 5-10% vol / vol) in various buffer systems. Another example is a solution comprising 0.5 to 10 mM CaCl2. The reconstitution of the protein in such medium promotes the interaction of protein with lipidic structures, improving pharmaceutical properties such as stability, pharmacokinetic / pharmacodynamic characteristics and immune response. Such stabilized solutions have many biotechnology applications including replacement therapies and vaccines.

Problems solved by technology

However, due to their complex structure and folding dynamics, proteins undergo physical and chemical instability.

These instabilities present unique difficulties in the production, formulation, storage and administration of protein pharmaceuticals (1,2).

Chemical instability is related to covalent modification of the protein that leads to loss of activity.

Such instabilities complicate the safety of protein products as the presence of aggregates evokes undesired immune response (4).

The loss of protein due to surface adsorption and binding to vial and syringes complicates the therapy.

In order to avoid surface adsorption, it is a general practice to include large quantities of albumin but inclusion of such excipients presents other pharmaceutical problems including the safety related to the source of albumin.

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