Injectable multi-phase emulsions

Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector

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4242781, 514785, A61K 3939, A61K 9113

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active

054240670

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BRIEF SUMMARY
The present invention relates to multi-phase emulsions usable for administering active substances or antigens by injectable route; such emulsions constitute new well tolerated vehicles permitting a gradual release of the active substances or antigens.
The invention finds a particular application in multi-phase vaccines, in the immunity adjuvants contained therein, and in their preparation processes.
Immunity adjuvants are products which increase the reactions of the immunity system when they are administered in the presence of antigens of virus, bacterial or synthetic origin: they cause a massive appearance of macrophages on the injection site, in the lymphatic nodules, they increase the production of specific immunoglobulins (antibodies) and stimulate a great number of cells implied in the immunity defense mechanisms.
Among these adjuvants, it is recognized that those resulting from the association of a mineral oil with a mannitol ester, optionally containing a dead mycobarterium and known under the name of Freund's adjuvants (FIA) are the most efficient.
Vaccines produced by mixing equal quantities of Freund's adjuvant and antigenic medium remain a reference throughout the world for immunological research in laboratories. These vaccines are in the form of emulsions with continuous oily phase (W/O), which are very viscous (about 5000 mPas at 20.degree. C.), hence difficult to inject and moreover with poor stability: dephasing is observed after a few days.
Said vaccines are very badly tolerated and cause in animals, at the injection site, very serious local reactions with oedemae, abscesses and necroses, which are unacceptable to the Public Health authorities and which render cattle meat unfit for consumption.
In humans, anti-diphtheric vaccines produced with the Freund's complete adjuvant have caused severe intolerances, and in some cases even abortions.
To improve the injectability of such vaccines, a method consisting in re-dispersing them in an aqueous phase containing a hydrophilic surface-active agent (Polysorbate 80) has been described by HERBERT (The LANCET 16, 771, 1965).
The resulting double emulsions are fluid, but their stability only lasts a few days.
The hydrophilic surface-active agent used is toxic towards the cells since it is known to be widely used in biology for eliminating lipids from cellular membranes.
The preparation of this type of multiple emulsions is delicate: it is dependent not only on the composition of the phases but also on the operational method used: authors, using the ultrasonic stirring method described by HERBERT, have obtained a multiple emulsion by sonication for 10 secs, whereas the same formula is of W/O type if sonication is continued for 30 secs.
Such great variability in the parameters of the method which, moreover, requires two steps, is not readily acceptable at the industrial level.
From an immunity standpoint, the vaccines obtained with this method have proved less efficient than the W/O type vaccines. (ANDERSON. Res. Vet. Sci 12, 18, (1971) HERBERT. Immunological standardization. Symposium series 6, 29, (1967)).
It would therefore be advantageous to obtain emulsions that are fluid, readily injectable, stable and of W/O/W type at room temperature and which could be transformed, at the temperature of the human or animal body into a more efficient W/O type preparation.
Such transformation, called phase inversion, has been studied at great length by SHINODA and his team. The temperature at which form W/O passes to form W/O/W is the phase inversion temperature. It is determined by following the electric conductivity of an emulsion produced under heat and cooled in an ice bath.
The phase inversion occurs with a lot of non-ionic surface-active agents although it has been mainly studied with products of ethoxylated alkyl phenol type, which are incompatible with medical or veterinary applications.
The emulsions object of the present invention are produced in one operation, from pharmaceutically acceptable emulsifyiers which, when dissolved in an injectable oil, form

REFERENCES:
patent: 3983228 (1976-09-01), Woodhour et al.
patent: 4069313 (1978-01-01), Woodhour et al.
patent: 4795635 (1989-01-01), Peleg et al.
patent: 4803070 (1989-02-01), Cantrell et al.
Al-Dabbass et al., "Immunizing Activity of Oil Adjuvant Attenuated Spore Vaccine of Bacillus anthracis in Sheep, " J. Vet. Med. B 33, 340-345 (1986).
Woodard, L., "Adjuvant Activity of Water-Insoluble Surfactants," Lab. Animal Sci., vol. 39, No. 3, pp. 222-225 (1989).
Yamamoto et al (1978) Abstract only, Jpn J Med Sci Biol 31(3): 263-276.
Yamamoto et al (1978) Abstract only, Jpn J Med Sci Biol 31(5-6): 393-406.
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