Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1997-05-21
1999-01-12
Scheiner, Toni R.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4242041, A61K 3913, A61K 3912
Patent
active
058583750
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to stabilised pharmaceutical compositions and to their preparation.
Biological agents such as proteins, nucleic acids and live attenuated or inactivated viruses can be formulated in a number of ways for pharmaceutical use. They may be formulated as aqueous solutions or dispersions. Such solutions or dispersions should, however, have a shelf-life of several months or, better, a year or more to take account of the time that may elapse between manufacture and use.
It is impossible to store solutions or dispersions of many biological agents at room temperature for prolonged periods of time without deterioration. This problem is overcome in some instances by freeze-drying to form a lyophilisate. The lyophilisate then has to be reconstituted prior to use which can itself be a difficulty. Alternatively, solutions or dispersions may be stored at a reduced temperature such as in a refrigerator in order to reduce degradation.
We have now found that solutions or dispersions of biological agents can be better stabilised by using deuterium oxide as the principal diluent in combination with a number of other components. Especially, live virus vaccines can be better stabilised.
Accordingly, the present invention provides a pharmaceutical composition which comprises a solution or suspension of a biological agent in a diluent comprising D.sub.2 O, which solution or suspension contains sufficient amounts of a sugar, phosphate, glutamic acid or a physiologically acceptable salt thereof and, optionally, a non-toxic protein, a peptone or a mixture of two or more amino acids besides glutamic acid to enhance the stability of the agent.
The invention can be applied to biological macromolecules such as proteins and nucleic acids. It may be applied to recombinant proteins. The proteins may be cytokines, enzymes or antibodies such as interferons, interleukins, antigens and enzymes. The protein may be erythropoetin, blood clotting factor VIII, insulin, human growth hormone or another growth factor. The nucleic acid may be DNA or RNA.
The invention can also be applied to viruses, in particular to live attenuated or inactivated viruses. Such viruses may be used in vaccines. They are not therefore virulent. The invention is particularly applicable to live virus vaccines.
The virus may be a RNA virus or a DNA virus. The virus may be influenza virus or poliovirus. The invention can thus be applied to live attenuated or inactivated poliovirus types 1, 2 or 3. A preferred composition of the invention is a suspension of a live attenuated poliovirus or of an inactivated poliovirus of each of poliovirus types 1, 2 and 3.
Any vaccine strain of poliovirus may be employed. The strain may therefore be a Sabin strain type 1, 2 or 3 poliovirus. Sabin strains are live attenuated polioviruses. Further, attenuated polioviruses can be constructed by genetic mutation, for example by genetic mutation of the 5' non-coding region of the poliovirus genome. Alternatively, the invention can be applied to Salk type 1, 2 and 3 polioviruses. Salk vaccines are poliovirus vaccines containing inactivated poliovirus.
The sugar in the pharmaceutical composition of the invention is typically a mono-, di-saccharide or tri-saccharide such as glucose, fructose, sucrose, lactose, maltose or cellobiose Preferably it is sucrose.
The phosphate is typically an orthophosphate. It may be potassium dihydrogen orthophosphate, KH.sub.2 PO.sub.4, and/or dipotassium hydrogen orthophosphate, K.sub.2 HPO.sub.4. The phosphate can act as a buffer, for example to ensure that a solution or suspension according to the invention has a pH of from 6.2 to 7.2 such as from 6.5 to 7.0.
Preferably the glutamic acid is L-glutamic acid. The preferred salt is the monosodium salt.
The optional non-toxic protein, peptone or mixture of two or more amino acids other than glutamic acid is generally albumin. The albumin can be bovine serum albumin or preferably human serum albumin.
The biological agent is dissolved or dispersed in a diluent comprising D.sub.2 O. The diluent th
REFERENCES:
Jenson et al., Diagn. Microbiol. Infect. Dis., vol. 19, pp. 137-142, 1994.
WPI Acc. No. 94-307582/38 & JP-624659 (ZH-Handai Biseibutsubyok) 23 Aug. 1994.
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Furminger Ian George Stephen
Sizer Philip James
Medeva Europe Limited
Scheiner Toni R.
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