Drug formulations for parenteral use

Details Drug formulations for parenteral use Drug formulations for parenteral use

1994-07-07

1996-11-05

Cintins, Marianne M.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

424488, 424493, 424499, 514646, A61K 914

Patent

active

055715346

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FI92/00339, filed Dec. 10, 1992 and published as WO93/11757 Jun. 24, 1992.


DRUG FORMULATIONS FOR PARENTERAL USE

This invention relates to drug formulations of antiestrogens, particularly antiestrogens comprising a triphenylbutene moiety, for use in parenteral administration. Toremifene, desmethyl toremifene, desmethyl tamoxifen and tamoxifen are all examples of substituted triphenylbutenes useful in cancer therapy. Reference is made to U.S. Pat. No. 4,696,949, U.S. Pat. No. 4,990,538 and U.S. Pat. No. 4,356,516. They can all be described with the formula ##STR1## in which R.sub.1 is CH.sub.3 or H and R.sub.2 is H or Cl.
The compounds mentioned above have the following values of R.sub.1 and R2;


______________________________________ R.sub.1 R.sub.2 ______________________________________ toremifene CH.sub.3 Cl desmethyl toremifene H Cl tamoxifen CH.sub.3 H desmethyl tamoxifen H H ______________________________________
A common feature of these antiestrogens is their poor solubility in water. Thus, parenteral administration of these drugs cannot be accomplished simply by an aqueous solution of the active ingredients.
There is a clear need for parenteral formulations of the anticancer antiestrogens. Injectable high-concentration toremifene formulations will have important clinical benefit necessary especially when combinations of toremifene with cytotoxic drugs are given to a patient. As shown by DeGregorio et al (J Clinical Oncology, vol 7, No 9,1989: 1359-1364.) high plasma concentrations are more effective in reversing multidrug resistance than low concentrations. An injectable formulation enables high peak concentrations in blood and tissues without exposing the patient to long-term treatment; concentration in the tumor to be achieved; mastalgia, where toremifene can be injected directly into a painful cyst; breast cancer metastases; superficial bladder cancer. In this indication toremifene may well be used together with other anticancer drugs to enhance their efficacy; types of overian cancer; antiestrogen.
The parenteral drug formulations according to this invention include emulsions, aqueous solutions of cyclodextrin--drug complexes and liposomes.
Dissolution properties of drugs can be significantly improved by complexation of the drug substance with cyclodextrins. Cyclodextrins (including .alpha., .beta. and .GAMMA. cyclodextrins and their derivatives) are all cyclic oligomers of glucose. The cyclodextrins can form inclusion complexes with drugs in that the drug molecule is included in the lipophile-seeking cavities of the cyclodextrin molecule. Therefore the cyclodextrins effectively solubilize lipophilic drugs into aqueous media. The use of cyclodextrins in the pharmaceutical field has been described e.g. in Drug Development and Industrial Pharmacy, 17(11), 1503-1549, 1991.
With respect to the antiestrogens mentioned above, however, no parenteral drug formulations based on complexation of the active drug substance with 2-hydroxypropyl cyclodextrins are known in the art. One object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably 2-hydroxypropyl .beta.-cyclodextrin or 2-hydroxypropyl-.GAMMA.-cyclodextrin, complex including an active drug substance selected from the group consisting of toremifene, desmethyltoremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being present in an aqueous solution.
Emulsions of the antiestrogens mentioned above can be made by dispersing the drug or a cylodextrin complex of said drug into a pharmaceutically acceptable emulsifier, and optionally adding a stabilizing agent.
Parenteral administration of the drugs mentioned above may also be accomplished by aqueous solutions of liposomes containing said drug or a salt thereof. Liposomes are spherical particles in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. The lipid surface may be either unilamellar or multilamellar. The liposomes

REFERENCES:
CA116:15328 Shah et al, "Human Albumin binding of tamoxifen in the presence of a perfluorochemical erythrocyte substitute", J. Pharm. Pharmocology 43(11), pp. 790-793. 1991.
CA(114)88647, 1990. Abstract only.
CA(104)139720, 1985. Abstract only.
Chemical Abstracts, vol. 116, No. 16, 20 Apr. 1992, p. 442, Abstract No. 158718p, "Solubilization and Stabilization of Drugs Through Cyclodextrin Complexation", Thorsteinn Loftsson et al.
Acta Pharm. Nord. 3 (4)215-217 (1991), "Solubilization and Stabilization of Drugs Through Cyclodextrin Complexation", Thorsteinn Loftsson et al.
Journal of Chromatography, 414, No. 1 (1987), 192-196, Biomedical Applications, "Seperation of Tamoxifen Geometric Isomers and Metabolites by Bonded-Phase .beta.-Cyclodexrin Chromatography", R. Douglas Armstrong et al.
FEBS Letters, vol. 274, No. 1,2, Nov. 1990, pp. 107-110, "Mechanism of Inhibition of Lipid Peroxidation by Tamoxifen and 4-hydroxytamoxifen Introduced into Liposomes", Helen Wiseman et al.
Journal of Clinical Oncology, vol. 7, No. 9, (Sep.), 1989, pp. 1359-1364, "Toremifene: Pharmacologic and Pharmacokinetic Basis of Reversing Multidrug Resistance", Michael W. DeGregorio et al.
Drug Development and Industrial Pharmacy, 17(11), 1503-1549 (1991), "Cyclodextrins in the Pharmaceutical Field", O. Bekers et al.

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