Stable lyophilized pharmaceutical preparations of G-CSF

Details Stable lyophilized pharmaceutical preparations of G-CSF Stable lyophilized pharmaceutical preparations of G-CSF

1995-06-15

1999-07-06

Sayala, Chhaya D.

Drug, bio-affecting and body treating compositions

Lymphokine

530351, A61K 4505

Patent

active

059194430

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns lyophilized pharmaceutical preparations of G-CSF which contain maltose, raffinose, sucrose, trehalose or amino sugars as stabilizers. In addition the invention concerns a process for the production of these stabilized lyophilisates and the use of maltose, raffinose, sucrose, trehalose or amino sugars as stabilizers of pharmaceutical agents containing G-CSF.
Various pharmaceutical preparations which contain G-CSF (granulocyte colony stimulating factor) are already known from the state of the art.
A pharmaceutical agent containing G-CSF is described in DE 37 23 781 (GB 2,193,631) which contains at least one pharmaceutically acceptable surface-active agent, saccharide, protein or a high-molecular compound for stabilizing G-CSF. Preparations are proposed there which contain human serum albumin as a stabilizing agent. In particular preparations are stated to be advantageous which contain surface-active agents in parts by weight which correspond to 1-10000-fold the amount of G-CSF used.
Stabilized preparations of G-CSF are described in EP 0 373 679 which are characterized essentially by an acidic pH value of the solution, wherein the solutions should have as low a conductivity as possible. The solutions have a pH value of 3-3.7 in the case that the solutions contain further pharmaceutical auxiliary substances such as for example buffers or mannitol. If no buffer substances are present in the pharmaceutical formulation, pH ranges of 2.75-4 are described as being advantageous.
Furthermore, stabilized lyophilisates of human protein preparations are described in EP 0 306 824 in which stabilization is achieved by adding a mixture of urea, amino acids and detergent.
In the earlier PCT Patent Application PCT/EP92/01823 a process is described for the production of well-tolerated pharmaceutical agents containing G-CSF for infusion or injection purposes. The liquid forms of administration are characterized in particular by a low titration acidity and low buffer capacity. The pH values of the described infusion and injection solutions containing G-CSF are in an acidic range of about 3.8-4.5.
Processes for the production of liquid drug administration forms containing G-CSF which additionally contain preservatives are known from PCT/EP92/01822. The pH values of the aqueous pharmaceutical solutions are in the acidic range of 2.5-4.5. In this case the stabilization of G-CSF is essentially achieved by setting an acidic pH value which is favourable for G-CSF and by adding a mixture of various amino acids.
The previously known drug administration forms for G-CSF do, however, have some disadvantages. It was found that liquid G-CSF preparations can in some cases be sensitive towards freezing and thawing. The uncontrolled freezing and thawing of such preparations can lead to the formation of dimers, oligomers and aggregates; insoluble precipitates may also be formed. Such properties of pharmaceutical agents containing protein are questionable from a medical-pharmaceutical point of view since it is not possible to absolutely avoid an accidental freezing of the pharmaceutical solution and thus there is a risk of administering a qualitatively changed preparation.
A disadvantage of the preparations described in DE 37 23 781 is moreover that they contain pharmaceutical additives or auxiliary substances which, from a medical point of view, cannot simply be judged as harmless. Polymers and proteins have a certain potential risk with regard to their suitability as pharmaceutical additives due to their origin and their physicochemical properties. Proteins of human or animal origin as well as proteins obtained from cell cultures bear a potential residual risk of viral contaminations. Other protein-like impurities which are analytically difficult to detect can also cause immunological reactions in humans due to their antigenic properties. Moreover proteins of animal origin can generally trigger immunological reactions in humans due to their species-specific properties. Long-term reactions after a later readminist

REFERENCES:
patent: 5503827 (1996-04-01), Woog et al.
patent: 5591713 (1997-01-01), Igari et al.
patent: 5597562 (1997-01-01), Nomura et al.

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