Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1998-09-21
2001-05-15
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S204100, C424S206100, C424S208100, C424S209100, C424S211100, C424S212100, C514S053000, C514S059000, C514S588000
Reexamination Certificate
active
06231860
ABSTRACT:
The present invention relates to stabilizing agents for monovalent or multivalent live vaccines, to the stabilized vaccines containing these agents, and to the processes for preparing such vaccines.
Vaccines which comprise live viruses and, more especially, attenuated live viruses are markedly sensitive to the conditions under which they are prepared and stored. Substantial losses of viral titre are observed during the lyophilization stages, during storage and also during the stages of harvesting the virus following culture. Given the importance of viral titre for immunization efficiency, it is found to be essential to use stabilizing agents in order to safeguard the viral titre to the greatest possible extent. Stabilizing agents are chemical and/or biological compounds which can be added to vaccines at different stages in their preparation with a view to ensuring that the efficiency of the vaccine is at a maximum when it is used, which can sometimes be several years after it was initially stored.
A large number of compounds have been tested for their ability to stabilize different vaccines containing attenuated live viruses. The compounds which have been tested in the prior art (cf., for example, U.S. Pat. No. 3,783,098, U.S. Pat. No. 3,915,794 and EP 028,563), one of the first of which was SPGA, mainly contain bovine or human serum albumin, casein which is hydrolysed to a greater or lesser extent, or gelatin, where appropriate an alkali metal salt of glutamic acid, a sugar (glucose, sucrose or dextran), and a monometallic or dimetallic alkali metal phosphate, or one of their mixtures. EP 065,905 describes a stabilizing compound for the vaccine against yellow fever which is composed of one or more amino acids selected from a group of eleven amino acids, lactose, sorbitol and a phosphate buffer solution (PBS).
However, all these compositions suffer from major drawbacks. In the first place, they contain proteins or protein hydrolysates of animal or human origin (albumins, etc.) which represent a potential biological risk and do not constitute chemically defined components. Furthermore, the compositions of the state of the art do not confer adequate stability on attenuated live vaccines, thereby limiting the possibilities of storing such vaccines and rendering hazardous any possible exposure of the vaccines to elevated temperatures while they are being stored or shipped. Thus, the loss in the activity of these vaccines results in inefficient vaccination and therefore in a vaccination which does not protect in the case of an actual infection. In addition, the efficiency of the known compositions is still more limited when it is a matter of stabilizing the different valencies of a multivalent vaccine containing different viruses. Thus, the tetravalent vaccine MMRV (measles/mumps/rubella/varicella) represents an example of a multivalent vaccine for which is there currently no stabilizer which is adequate for the four valencies.
The stabilizing agents of the invention do not suffer from the abovementioned drawbacks. These stabilizing agents for compositions, in particular vaccines, containing one or more attenuated live viruses, comprise one or more components selected from each of the groups consisting of amino acids, disaccharides, polyalcohols and buffer solutions, with the proviso that one component selected from the disaccharide group is sucrose. In the stabilizing agent of the invention, the component(s) selected from the disaccharide group can be present in a proportion of from 2 to 6%. Advantageously, the component(s) selected from the disaccharide group can be present in a proportion of 2.5%.
The polyalcohol group, which is a component of the stabilizing agent of the invention, can, in particular, include sorbitol and mannitol. The stabilizing agent of the invention can comprise sorbitol and mannitol. When the stabilizing agent of the invention comprises sorbitol, the latter is preferably present in a proportion of from 2 to 6%. When the stabilizing agent of the invention comprises sorbitol, the latter is advantageously present in a proportion of from 3 to 5%. Particularly advantageously, the sorbitol can be present in a proportion of 5%. When the stabilizing agent of the invention comprises mannitol, the latter is preferably present in a proportion of from 1 to 2.5%. When the stabilizing agent of the invention comprises mannitol, the latter is advantageously present in a proportion of 1.5%.
The buffer solution group, which is a component of the stabilizing agent of the invention, can, in particular, include phosphate buffers and ethylenediaminetetraacetic acid (EDTA). Advantageously, the stabilizing agent of the invention comprises a phosphate buffer. The stabilizing agent of the invention can additionally comprise dextran. When the stabilizing agent of the invention comprises dextran, the latter is preferably present in a proportion of from 1 to 4%. When the stabilizing agent of the invention comprises dextran, the latter is advantageously present in a proportion of 3%.
The stabilizing agent of the invention can additionally comprise urea, a urea derivative, or a mixture thereof. Examples of urea derivatives which can be employed are allylurea, acetamide, methyl carbamate or butyl carbamate. When the stabilizing agent of the invention comprises urea, a urea derivative or a mixture thereof, the latter is/are preferably present in a proportion of from 0.125 to 2%. When the stabilizing agent of the invention comprises urea, a urea derivative or a mixture thereof, the latter is/are advantageously present in a proportion of 0.5%.
The pH of the compositions of the invention is preferably adjusted in dependence on the virions to be stabilized. It is particularly advantageous to adjust the pH to 7.
The stabilizing agents of the invention can be used to stabilize a large number of compositions, in particular monovalent vaccines which basically contain one viral strain or species, or multivalent vaccines which contain several viral strains or species. The invention also relates to the compositions, in particular the vaccines, which are stabilized using the abovementioned stabilizing agents.
Such vaccines which have been stabilized in accordance with the invention can, for example, comprise at least one virus of the Herpesviridae family. The Herpesviridae family comprises, in particular, varicella virus, cytomegalovirus and herpes simplex virus. Varicella virus is particularly delicate and thermolabile as compared with other viruses. The stabilizing agents of the invention are therefore of particular relevance when it is a matter of stabilizing a virus which is as unstable as varicella virus.
The stabilizing agents of the invention can be applied to other viruses, which viruses can be selected, in particular, from the Paramyxoviridae (
morbillivirus,
including measles, the mumps virus,
parainfluenza
viruses of types 1, 2, 3 and 4, and
pneumoviruses
), Togaviridae (rubella) and the
influenza
(A, B and C) viruses.
The mixtures which are obtained from the abovementioned viruses or from other viruses and which constitute multivalent vaccines can advantageously be stabilized using the stabilizing agents of the invention. A conceivable multivalent vaccine which may be mentioned is the measles/mumps/rubella vaccine. Within the context of valency combinations, the stabilizing agents of the invention exhibit favourable properties, in addition to the abovementioned advantages, in that their ability to stabilize each of the valencies enables these valencies to be combined. Thus, combining infectious agents for different diseases represents an economic and practical advance to the extent that one prophylactic treatment protects against several diseases, contrary to the situation with monovalent vaccines. However, the coexistence of different infectious agents poses substantial problems of compatibility between these agents, which problems make it difficult to carry out an effective simultaneous polyvaccination. The stabilizing agents of the invention provide a solution to these problems.
Fanget Bernard
Francon Alain
Burns Doane Swecker & Mathis L.L.P.
Pasteur Merieux Serums & Vaccins
Stucker Jeffrey
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