Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1997-03-19
2002-01-29
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S283100, C424S093100, C424S614000, C424S639000, C514S04400A
Reexamination Certificate
active
06342234
ABSTRACT:
BACKGROUND OF THE INVENTION
(i) Field of the Invention
The present invention relates to a therapeutic composition comprising at least one antigen, in particular an antigen of viral, bacterial or parasitic origin, or at least one in vivo generator of a compound comprising an amino acid sequence, and at least one adjuvant.
(ii) Description of Related Art
The use of adjuvants in therapeutic compositions of the vaccine type has been known for a long time. The main objective of these adjuvants is to allow an increase in the immune response. These adjuvants are diverse in nature. They may, for example, consist of liposomes, oily phases, for example the Freund type of adjuvants, generally used in the form of an emulsion with an aqueous phase, or, more commonly, may consist of water-insoluble inorganic salts. These inorganic salts may consist, for example, of aluminum hydroxide, zinc sulfate, colloidal iron hydroxide, calcium phosphate or calcium chloride. Aluminum hydroxide (Al(OH)
3
) is the most commonly used adjuvant. These adjuvants are described in particular in the article by Rajesh K. Gupta et al “Adjuvants, balance between toxicity and adjuvanticity”, Vaccine, Vol. 11, issue 3, 1993, pages 993-306.
The adjuvants mentioned above have the drawback of limited efficiency. Moreover, they may induce a certain toxicity with regard to individuals treated. More particularly, when these therapeutic compositions are injected, the formation of lesions and other local reactions such as granulomae is observed at the point of injection. These drawbacks are less pronounced when the adjuvant in aluminum hydroxide. Accordingly, the latter compound is one of the most commonly used adjuvants. Recently, however, aluminum hydroxide, like all aluminum-based compounds, has come to be suspected of being a factor promoting the appearance of certain diseases, such as renal dysfunctions or Alzheimer's disease. In addition, it is known that aluminum hydroxide efficiently induces only humoral immunity and not cell immunity.
SUMMARY AND OBJECTS OF THE INVENTION
A first object of the invention is to provide therapeutic compositions comprising an adjuvant which allows an increase in the immune response which is at least equal to that imparted by aluminum hydroxide, without causing lesions or local reactions of the granuloma type and which is not liable to promote the appearance of diseases in the individual treated.
Another object of the invention is to provide a therapeutic composition comprising an adjuvant which efficiently induces both cell immunity and humoral immunity.
Yet another object of the invention is to provide a method for making a therapeutic composition using the adjuvant of the invention.
In a first aspect, the present invention relates to a therapeutic composition comprising (i) at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence and (ii) at least one adjuvant comprising at least one pharmaceutically acceptable and water-soluble salt of an organic anion and a metal cation.
In a second aspect, the present invention relates to a method of making a composition intended for the prevention or treatment of infectious diseases comprising combining (a) at least one adjuvant comprising at least one pharmaceutically acceptable and water-soluble salt of an organic anion and a metal cation and (b) at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence.
In a third aspect, the present invention relates to a method for treating a functional disease comprising administering to a patient the therapeutic composition as described above.
In another aspect, the invention relates to an adjuvant composition comprising a pharmaceutically acceptable and water-soluble salt and (a) an oily adjuvant. (b) a surfactant and/or (c) an oily adjuvant combined with a surfactant.
With the foregoing as well as other objects advantages and features of the invention that will become hereinafter apparent. The nature of the invention may be better understood by reference to the following detailed description of the preferred embodiments and to the appended claims.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In the sense of the present invention, a water-soluble salt may be such that its solubility in water is greater than or equal to 10 g/l, preferably between 10 and 2000 g/l.
The metal cation constituting said pharmaceutically acceptable salt is preferably a divalent cation. This cation is advantageously a cation of a metal chosen from the group consisting of manganese, calcium and zinc. Manganese is a very particularly preferred metal within the context of the present invention. The reason for this is that it has been observed that pharmaceutically acceptable and water-soluble salts according to the invention comprising an Mn
2+
cation allow the induction of a particularly large immune response, while at the same time being low in toxicity.
The organic anion constituting said pharmaceutically acceptable salt is advantageously an anion of a compound comprising at least one oxygenated functional group, preferably a phosphoric group —PO
4
H
2
, or a carboxylic group —COOH.
Glycerophosphoric acid is a preferred anion containing a phosphoric group.
The preferred anions comprising at least one carboxylic group are derived from compounds chosen from:
acid saccharides, preferably acid saccharides having from 5 to 7 carbon atoms, more preferably those having 6 or 7 carbon atoms,
mono- or polycarboxylic acids,
amino acids.
The preferred mono- or polycarboxylic acids are fumaric acid and the compounds of the formula (I):
where: R represents COOH, CH
3
CO, CH
3
or CH
2
OH, R′ represents H or COOH and s, t and u, which may be identical or different, are between 0 and 3.
Preferred compounds of formula (I) are acetic acid, lactic acid, tartaric acid, malic acid, citric acid and pyruvic acid.
In the sense of the present invention, an acid saccharide is of a saccharide comprising at least one carboxylic function, a saccharide being a glucide consisting of reducing sugars. These acid saccharides are advantageously aldose derivatives obtained by oxidation of the primary alcohol function or of the aldehyde function into a carboxylic function. Such compounds may most particularly include of gluconic acid, glucuronic acid, fructoheptonic acid, gluconoheptonic acid and glucoheptonic acid. When the organic anion is derived from an amino acid, this amino acid may be an &agr;-amino acid such as glutamic acid, methionine and, most particularly, aspartic acid.
A pharmaceutically acceptable, water-soluble salt according to the invention may comprise a polyvalent cation, especially a divalent cation, combined with an organic anion or with several organic anions of different nature. Thus, by way of example, a divalent cation such as the calcium cation may be combined with an anion derived from gluconoheptonic acid and an anion derived from gluconic acid.
A water-soluble adjuvant most particularly preferred within the context of the present invention consists of manganese gluconate.
A therapeutic composition according to the present invention may comprise between 0.01 and 1000 mc/ml, preferably between 0.1 and 150 mg/ml. of an adjuvant as defined above.
A therapeutic composition according to the invention may be prepared by simple mixing of an aqueous suspension containing the antigen or said in vivo generator with an aqueous solution of the salt defined above.
Besides the adjuvant comprising a pharmaceutically acceptable and water-soluble salt as defined above, the therapeutic composition according to the invention may also comprise an oily adjuvant. In such a case, the therapeutic composition according tc the invention is advantageously in the form of an emulsion combining at least one aqueous phase and at least one oily phase.
This emulsion may be of the water-in-oil (W/O) type or, preferably, of the oil-in-water (O/W), water-in-oil-in-water (W/O/W) or microemulsion type. Such an emulsion may be prepared according to the standard methods f
Societe d'Exploitation de Produits Pour les Industries Chem
Wortman Donna C.
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