Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1997-08-12
2001-05-22
Chin, Christopher L. (Department: 1641)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S001110, C424S190100, C424S191100, C424S192100, C424S193100, C424S199100, C424S200100, C424S201100, C424S278100, C424S283100, C514S785000
Reexamination Certificate
active
06235282
ABSTRACT:
The present invention mainly relates to entirely metabolizable injectable water-in-oil emulsions intended to stimulate the immune response induced by active principles, which may be viruses, bacteria, parasites or fractions of the latter, toxins, polysaccharides but also recombinant proteins, or else small antigen molecules, for example peptides, coupled to carrier molecules.
Knowledge restatement
Vaccination, by stimulating the immune defense system, is a means for the preventive control of infectious agents. Vaccines currently use as antigens either living microorganisms whose pathogenic power has been attenuated or killed microorganisms, or indeed even purified fractions from these microorganisms. The sub-units or inactivated vaccines very often contain an adjuvant substance which is intended to increase the immune response. The function of the adjuvant is to increase, on the one hand, the level of the humoral and cellular immune response and, on the other hand, the duration of this response. Consequently, the adjuvant makes it possible to reduce the number of injections and the antigen dose included in the vaccine, thus keeping the vaccination at an acceptable cost. In addition to the desired effect on the immune response, the adjuvant substances can induce local or general toxicity: inflammatory edema, abscess, fibrosis at the point of injection, pain, fever or stimulation of a hyper-sensitivity state. An adjuvant must be effective but must also be acceptable as regards toxicity.
Mention may be made, among the many immunity adjuvant substances, of gels derived from aluminum (hydroxide, phosphate), which are only used in human medicine, saponins, which are complex heterosides and which are employed in the veterinary field, and also emulsions which seem to be one of the most active excipients. In particular, emulsions containing mycobacteria in mineral oil and Arlacel A®, which is defined as a dianhydromannitol monooleate, as surface-active agents are widely used under the name of Freund's complete adjuvant for laboratory animal immunization. Nevertheless, the use of killed mycobacteria has two major drawbacks: local reactions at the point of injection are very significant and the animals are sensitized to tuberculin; this leads to this adjuvant being rejected in veterinary medicine. The same adjuvant without mycobacteria, known as Freund's incomplete adjuvant, is less poorly tolerated and is still widely used in laboratories for producing hyperimmune sera. However, emulsions prepared with the Freund adjuvants are very viscous and have little stability, which prevents their industrial development. Research into the substances responsible for the adjuvant effect of mycobacteria has led to the characterization of peptidoglycans (MDP) and glycolipids (TMD), and then to their use (or that of their derivatives) in emulsions in place of mycobacteria, so as to reduce the toxicity of these emulsions (Woodward L. F., 1990, Surface Chemistry and Classification of Vaccine Adjuvants and Vehicles, in Bacterial Vaccines, pp. 281-306, Alan R. Liss, New York).
The use of emulsions in vaccines has remained anecdotal for a long time; tests which were carried out, in man in particular, with, on the one hand, an influenza vaccine with an adjuvant of Freund incomplete type and, on the other hand, an emulsion containing groundnut oil, Arlacel A® and aluminum stearate, known under the name of “adjuvant 65”, finally led to the banning of such formulae from human medicine.
The development on an industrial scale of water-in-oil emulsion vaccines had to await the work of Cessi and Nardelli (Develop. Biol. Standard., 1973, 25, 325-328). These vaccines were intended to protect laying hens against Newcastle disease, which is caused by a Paramyxovirus, throughout the whole period of egg laying; conventional vaccines, whose lower immunity was reflected by a fall in egg laying during passage of the virus through the poultry farm, were incapable of doing this. Vaccines of this type were quickly developed in the world of poultry farming, at least in Europe, for many avian diseases (for example infectious avian bronchitis, Gumboro disease). Emulsion-based vaccines, the emulsions being more particularly of oil-in-water type, for preventing many mammalian diseases, of bacterial origin (brucellosis in ruminants, enterotoxemia in ovines, colibacillosis) or viral origin (swine aphthous fever, swine influenza, Aujeszky's disease, and the like), also appeared on the market. However, although they generally have an immunogenic activity which is much greater than that of non-oily vaccines, these vaccines can cause local reactions at the injection site of the vaccine. These reactions, whose intensity depends on the formulation employed (water-in-oil or oil-in-water) and also on the nature of the antigens, are conventionally attributed to the presence of the mineral oil. In fact, the latter does not seem to be metabolized by the organism and in part remains close to the injection sites. It was therefore desirable to replace the mineral oil with a metabolizable oil.
Metabolizable oil must be understood to mean natural hydrocarbons present in nature, such as squalene, vegetable oils belonging to the category of triglycerides, semisynthetic triglycerides, such as triolein and medium-chain (C8/C10) triglycerides, fatty acid esters and more particularly oleyl oleates, propylene glycol dioleate or diesters of capric/caprylic acids and propylene glycol.
At this stage, one difficulty is that the emulsions must be injectable and therefore fairly fluid; the result is to favor medium-chain triglycerides and certain esters, rather than vegetable oils, whose viscosity at 25° C. is already appreciable (50 to 70 mpa•s).
However, the major difficulty is to obtain stable water-in-oil emulsions with these oils and in particular vegetable oils. To do this, the use of monoglycerides is widespread in the food industry but, in general, the emulsions sought for and obtained are thick, which promotes their stability.
A number of emulsion formulae of water-in-oil type based on metabolizable oils have already been published: groundnut oil and lecithin (Brugh M. et al., Am. J. Vet. Res., 1983, 44, 72-75), oil enriched in modified phospholipids and diglycerides (Patent Application EP-A-0,417,562) and triglycerides or fatty esters in combination with hydrocarbons and with surface-active agents (French Patent No. 2,649,013). None of these emulsion formulae corresponds to the present invention.
International Patent Application WO 91/00107 describes the preparation of emulsions from a mixture of metabolizable oil and non-metabolizable oil (from 2 to 95%) and emulsifying surface-active agents obtained by condensation of a liquid fatty acid at 20° C. with a sugar, such as mannitol, glucose or sucrose, or with glycerol. The surface-active agents chosen do not make it possible to produce an emulsion based solely on metabolizable oil.
Moreover, in Patent Application EP-A-0,174,377, polyglyceryl polyricinoleates were used as emulsifying agents in a very specific application for the preparation of water-oil-water double emulsions intended to have high resistance to heat, to freezing and to storage in the field of cosmetic and medical products for external use and conventional medicaments, for example insulin. The technical problem which this prior application was targeted at solving was especially that of preventing denaturation of the emulsion during final sterilization treatments or the like, which has no point in common with the search for adjuvant emulsions according to the invention.
We have surprisingly discovered that the use of polyglyceryl ricinoleate or of polyglyceryl polyricinoleate, alone or in combination with other surface-active agents such as monoglycerides, optionally hydrogenated polyoxyethylenated castor oils or else sorbitan esters, leads to fluid and very stable water-in-oil emulsions, both with, as oil, a triglyceride, which can be a vegetable oil or so-called medium-chain triglycerides (glyceryl tricaprylate/trica
Riviere Michel Emile Albert
Roulet Claude
Chin Christopher L.
Larson and Taylor
Nguyen Bao-Thuy L.
Rhone Merieux
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