Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Patent
1994-11-10
1997-06-03
Sayala, Chhaya D.
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
424 851, A61K 4505
Patent
active
056351763
DESCRIPTION:
BRIEF SUMMARY
The present invention contemplates pharmaceutical compositions containing Interleukin-6 (IL-6), and particularly contemplates compositions based on IL-6 stabilized with nonreducing sugars. Interleukin-6 is a protein belonging to the group of cytokines, which proved to play a key role in the organism immune response and haematopoiesis stimulation (International Symposium on IL-6: Physiopathology and Clinical Potentials, Montreux, Oct. 21-23, 1991).
The prospective therapeutic applications of IL-6 are tumoral growth inhibition, treatment of thrombocytopenia caused by chemotherapy, radiotherapy, and even accidental exposure to radiations. It may also be used as a vaccine adjuvant.
According to the present invention, IL-6 may be either natural or synthetic, i.e. produced on the basis of recombinant DNA technology, the latter being preferred.
The protein of this invention is glycosylated human IL-6, prepared on the basis of the recombinant DNA technology by expression in CHO (Chinese Hamster Ovary) cells, transformed with the corresponding DNA, according to the disclosures of European Patent Application EP 0220574.
As known, purified proteins show a great tendency to become denaturated, even by normal atmospheric agents. This characteristic is even more evident in proteins produced on the basis of recombinant DNA technology. To prevent any contamination of non-human origin, they must be purified to a high degree, which makes their stability lower than that of corresponding purified natural proteins.
IL-6 formulations for injection are obtained on the basis of a process inclusive of freeze-drying for dry powder production.
As described by M. J. Pikal in Biopharm., Oct. 25-30, 1990, the protein pharmacological activity is reduced by phenomena taking place during freeze-drying.
For example, proteic aggregates, which are generally regarded as directly responsible for the onset of allergic manifestations, frequently form during the process. Furthermore, should the protein be not damaged by the various process stresses, a partial denaturation of same during storage operations would be extremely probable.
It is just because of the very easy denaturation of highly purified proteins that it is highly desirable to produce stable formulations with an as long life cycle as possible, even when stored at ambient temperature.
The expression "formulation stability" is used to mean that the protein maintains its activity both during the pharmaceutical preparation and storage.
The formulations containing highly purified proteins may be stabilized by addition of one or more excipients preventing or delaying the active ingredient degradation.
Excipients of different chemical nature were used in various proteins formulations.
High molecular weight stabilizers of biological origin, such as sea colloids, dextran, and phospholipids, are known.
Equally effective stabilizers often proved to be the formulations containing proteins, e.g. albumin, amino acids, e.g. arginine or glycine, and sugars, e.g. monosaccharides or oligosaccharides. Another cytokine, i.e. Interleukin-2 (IL-2), and particularly its recombinant form, was formulated with various stabilizers, preferably albumin and amino acids.
International patent application WO 90/00397 discloses IL-2 stabilization with arginine or carnitine or a mixture thereof, with betaine, pyridoxine, polyvinylpyrrolidone, carboxylic acids salts, and by the addition, if any, of other excipients, such as sugars and citrate buffer.
European patent application EP 158487 discloses IL-2 formulations with human albumin and a reducing compound, such as glutathione, N-acetylcysteine or ascorbic acid.
Pikal in Biopharm., Oct. 25-30, 1990, also suggests that excipients capable of bringing about amorphous and/or vitreous structures can cause protein stabilization on drying.
The amorphous structure seems to secure a considerable restriction of protein molecular mobility, with consequent decrease in chemical reactivity, as well as a long lasting protection: in fact, it is supposed to form a sort of casing where
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Rendina Filippo
Samaritani Fabrizio
Applied Research Systems ARS Holding N.V.
Sayala Chhaya D.
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