Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Patent
1993-10-01
1995-02-14
Kishore, G. S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
514938, 514 31, A61K 9107
Patent
active
053893735
DESCRIPTION:
BRIEF SUMMARY
The antibiotic amphotericin B is extremely beneficial in certain infectious conditions, particularly those caused by the fungal organism Candida. A common therapy is in the form of a product called Fungizone (Regd. T. M., Squibb) which consists of a solubilised formulation of amphotericin in the natural surfactant material sodium deoxycholate. This product is marketed by the Squibb Company. While helpful in combating Candida infections this product is not without its adverse reactions and side effects. It has been shown clearly that the Fungizone formulation can have a toxic effect particularly towards the kidney (see for example Reynolds et al (1963), Med. Clin. North American 47 1149-1154). The antibiotic properties of amphotericin are due to its binding to sterols in cell membranes and the subsequent formation of a membrane pore. The binding to ergosterol, the primary fungal sterol, is stronger than the binding to the mammalian sterol cholesterol. Hence the toxicity of amphotericin is only selective for fungal cells and not specific; this is the origin of the side effects in patients. Alternative strategies for administering amphotericin have been investigated and work conducted in Texas by Juliano, Lopez-Berenstein and others is particularly noteworthy (see for example Mehta et al (1984), Biochem. Biophys. Acta 770 230-234). These workers have employed a liposome formulation (phospholipid vesicle) in order to achieve benefit in terms of therapy. Others working along similar lines include the Squibb Company itself with the pro-liposome concept (see for example Payne et al (1987), J. Pharm, Pharmacol. 39 24-28). While the liposomal system might be beneficial clinically it is well known that liposomes are normally difficult to prepare reproducibly in bulk and can be unstable.
While it is possible to produce an amphotericin emulsion system by the simple admixture of a commercial fat emulsion product (Intralipid, (Regd. T. M., Kabi) with the commercial solubilised system of amphotericin (Fungizone) (see, for example, EP-A-202 837), this system is unstable in that it produces a precipitate of the drug after this admixture and also has poor stability if stored for more than a few hours. The amphotericin B apparently is not intercalated at the oil-water interface in the additive formulations.
EP-A-215 313 (American Cyanamid) discloses certain emulsions which break easily on administration to a patient. The drug is mixed with an oil phase before water is added to form an emulsion. Benzyl alcohol is used as a co-surfactant. The emulsions not only break quickly on administration but are not very stable in storage.
WO 82/01821 (Chinoin) discloses formulations which have the drug as a solid suspension dispersed throughout an emulsion. Again, the emulsions are not very stable and do not overcome the problem of toxicity of the drug; it is to be noted that all the prior formulations are for topical application.
EP-A-211258 (Abbott) discloses certain micro-emulsions, which are quite distinct from the emulsions of the present invention.
Our earlier application EP-A-296 845 describes the preparation of an oil-in water surfactant-stabilised drug emulsion in which the drug is present in the surfactant layer. This was found to reduce the problems of toxicity and stability encountered with prior formulations. However, the drug emulsion has to be sterilised, for example by heat treatment, and this may result in loss of around 10% of the drug. The resulting product is perfectly usable but it would clearly lead to cost savings if such losses could be avoided.
It is the intention of the present invention to provide a process for preparing a drug emulsion which reduces loss of activity of the drug during formulation.
The invention provides a process for preparing an oil-in-water emulsion of a drug which is poorly soluble in water wherein the drug is dissolved in a solution of high or low pH prior to the formation of the drug emulsion. A "solution of high pH" is a solution with a pH of at least 9, preferably at least pH 11. A "sol
REFERENCES:
patent: 4684633 (1987-08-01), Imagawa et al.
patent: 4707470 (1987-11-01), Kirsh et al.
patent: 4784845 (1988-11-01), Desai et al.
patent: 4816247 (1989-03-01), Desai et al.
patent: 4831018 (1989-05-01), Kirsh et al.
patent: 5118511 (1992-06-01), Horn et al.
Davis Stanley S.
Washington Clive
Hulina Amy
Kishore G. S.
The University of Nottingham
LandOfFree
Preparation of oil-in-water emulsions of drugs does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Preparation of oil-in-water emulsions of drugs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of oil-in-water emulsions of drugs will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-286019