Solution containing IGF-1

Details Solution containing IGF-1 Solution containing IGF-1

1995-10-16

1998-07-21

Tsang, Cecilia J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 21, A61K 3808, A61K 3822

Patent

active

057835594

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a stable solution containing Insulin-like Growth factor I (IGF-1 ) in a phosphate buffer in an amount of 50 mmol or less, giving a pH of 5.5 to 6.5, which is isotonic and suitable for injection.


INTRODUCTION

Insulin-like Growth Factor I (IGF-1) is a peptide present in plasma and other body fluids as well as many cells/tissues. It comprises 70 amino acids, including 3 disulphide bonds, and can stimulate proliferation of a wide range of cell types and it mediates some of the effects of growth hormone. Human IGF-1 has been purified from plasma and its complete amino acid sequence is established. (Rinderknecht E et al. "The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin" J. Biol. Chem 253; 2769-76, 1978) Sequences with extensive homologies to human IGF-1 are present in IGF-1 purified from plasma of other species.
It has both systemic and local effects and appears mostly associated with different specific binding proteins, four of which have been sequenced and are termed IGFBP1, IGFBP2, IGFBP3 and IGFBP4. These appear to modulate the biological functions and availability of IGF-1 in both a positive and negative manner. Analogues with changed affinities for the binding proteins have been produced and changes of biological activities related to sequence variation have been found. IGF-1 appears to act mainly by interactions with the IGF-type 1 receptor exposed on the outer surface of plasma membranes in many different cell types. However, binding to IGF type 2- and insulin receptors also seems to be of importance.
Because of the scarcity of purified plasma IGF-1 there was a great necessity to develop methodology for the commercial scale production of IGF-1. Nowdays, such large scale production can readily be achieved by using recombinant DNA techniques.
As a result of studies with preparations of recombinant DNA IGF-1 it has been demonstrated that it promotes skeletal growth and skeletal muscle protein synthesis. IGF-1 has been shown to act both as an endocrine factor as well as a paracrine/autocrine factor. (Skottner et al, Endocrinology, Vol.124, No 5, 1989 and Cook et al, J Clin Invest 81; 206-212; 1988)
Moreover, IGF-1 is also effective for the treatment or prevention of catabolic states in patients (Swedish patent application SE 9002731-9) and improves the regeneration of transected peripheral nerves (EP 0 308 386). It has previously been demonstrated in vitro that IGF-1 also can promote actin synthesis in myocytes in culture (Florini, J R, Muscle and Nerve 10 (1987) 577-598 and contractility of neonatal rat cardiocytes in vitro (Vetter, U et al, Basic Res. Cardiol. 83 (1988)647-654).
The stability of proteins is generally a problem in the pharmaceutical industry.
A formulation with a low amount of protein will generally lose activity during purification, sterile manufacturing, storage and during the administration.
It has often been solved by drying of the protein in different drying processes, such as freeze-drying. The protein has thereafter been distributed and stored in dried form. The patient necessarily has to reconstitute the dried protein in a solvent before use, which of course is a disadvantage and is an inconvenience for the patient. For a patient, who needs daily injections of IGF-1, and especially when the patient is a child, it is of importance that the product is easy to handle, to dose and inject. The reconstitution of a freeze-dried product demands prudence and carefulness and should therefore preferably be avoided.
The freeze-drying process is also a costly and time consuming process step, and it would be of great advantage if this step could be avoided, when preparing a commercial product of a protein.
Another possibility is to add human albumin, which generally reduces the activity loss of the active protein considerably. If the protein is freeze-dried, human albumin functions as a general stabilizer during the purification, sterile manufacture and freeze-drying. It is, however, not desirable to add

REFERENCES:
patent: 4853224 (1989-08-01), Wong

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