Complexes and their compositions

Details Complexes and their compositions Complexes and their compositions

1997-08-01

2002-08-13

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S103000

Reexamination Certificate

active

06432928

ABSTRACT:

The invention relates to the inclusion complexes or mixtures of Taxol {[2aR-[2a&agr;,4&bgr;,4&agr;&bgr;,6&bgr;,9&agr;(&agr;R*,&bgr;S*a11&agr;,12&agr;,12a&agr;,12b&agr;]]-&bgr;-(benzoylamino)-&agr;-hydroxy-benzene-propanoic acid 6,12-b-bis(acetyloxy)-12-(benzoyloxy)-2a,3-4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4a,8,13,13-tetra-methyl-5-oxo-7,11-methano-1H-cyklodeca[3,4]-benz-[1,2-b]-oxeth-9-yl-ester]} or Taxotere (butoxycarbonyl-10-desacetyl-N-debenzoyl-Taxol) or Taxus extracts (containing other diterpene Taxane derivatives besides Taxolon like cephalomannin 10-desacetyltaxol, desacetyl-baccatine III, baccatine III, baccatine III, cinnamoyl taxines, taxusine) formed with a cyclodextrin derivative and a co-solvent, process for their preparation and pharmaceutical compositions containing them, further their pharmaceutical application.
Although Taxol shows promising biological effect and significant anti-tumor activity, its pharmaceutical use is accompanied by several difficulties:
the solubility of taxanes is rather poor, e.g. taxol dissolves in water at 25° C. by 0.55-0.59 &mgr;g/ml (determined by Cyclolab Kft. Budapest);
taxol is very sensitive to light and pH, during its decomposition biologically inactive products are formed;
the pharmacological results relating to taxol are questionable because the solvents used (Cremophor EL) are themselves cytotoxic [J. N. Denis; J. Am Chem. Soc. 110, 5917 (1988); M. I. Fjaellskog et al: Lancet. 342-873 (1993); and L. Webster et al: J. Natl. Cancel Inst. 85, 1685 (1993)].
Several processes are known for eliminating the disadvantageous features described above:
use of solubilizing agents [1:1 mixture of Cremophor EI and anhydrous ethanol (Natl. Cancer Institute, Paclitaxel Documentation)];
forming of chemically modified micromicelles by using phosphatidylethanolamines (Lipis Specialities, Inc., European patent specification No. 118.316);
use of ethanol polysorbate mixtures for increasing solubility (Rhone-Poulenc Rorer, European patent specifications Nos. 522.936 and 522.937);
use of liposomic taxol formulations [e.g. R. Aquilar and R. Rafaelloff: published patent specification No. WO 93/18751; A. Sharma et al: Pharm. Res. 11, 889-896 (1994); and M. H. Alkan et al: J. Liposome Research 3.42 (1993)]: a Taxol concentration of about 1 mg/ml was obtained in unstable (four days at room temperature) compositions.
Attempts have been made for increasing the water-solubility of taxol also by forming synthetic derivatives [Zhao et al: J. Nat Prod. 54, 6, 1607 (1991); D. I. Kingston and Y. Y. Xang: European patent specification No. 537.905 and H. M. Deutsch et al: U.S. Pat. No. 5,157,0049]. The biological effectiveness of the chemically modified taxol derivatives having increased water-solubility was, however, modified disadvantageously, the multidrug resistance showed generally an increasing tendency while cytotoxicity, i.e. the biological effect, decreased.
To overcome the difficulties connected with the parenteral administration of taxol, taxol prodrugs with increased water-solubility have also been synthetized [A. Matthew et al: J. Med. Chem. 35, 1, 145 (1992)].
Bartoli et al tried to improve the generally weak stability of taxol by its microencapsulation [H. Bartoli et al: J. Microencapsulation, 7, 2, 191, (1991)].
Especially the preparation of liquid taxol-containing pharmaceutical compositions for parenteral administration is difficult as the diterpenoid-type, very lipophilic taxane derivatives cannot be converted into suitable storable solutions in the desired concentration even by using significant amounts of detergents and mixtures containing aqueous-organic solvents [D. Tarr et al: Pharm. Res. 4, 162-165 (1987)]. The taxol composition described contains soybean oil, lecithin, egg-yolk, phosphilipids and glycerol, its taxol-content is, however, only 0.3 mg/ml due to the low solubility. A taxol emulsion with a taxol content of 20 mg/ml has also been developed; this composition contains 50% of triacetine (1,2,3-triacetyl-glycerol) but this triacetine has also been proved toxic (in mouse experiments LD
50
=1.2 mg/ml, a 50% triacetine emulsion).
The registered parenteral taxol compositions are formulated in emulsions in a concentration of 6 mg/ml containing a 1:1 by volume mixture of polyoxyethylated castor oil (Cremophor-EL): alcohol and are diluted to ten-fold volume when administered. The use of these parenteral compositions is accompanied by several disadvantageous side effects such as a heavy allergy due to the Cremophor EL administered intravenously. Further, the taxol formulations prepared in an ethanolic solvent mixture are not clear solutions but are slightly opalescent [L. A. Trissel: Am. J. Hosp. Pharm. 50, 300 (1993)], thus they can precipitate when diluted or administered simultaneously with other medicines.
The only commercially available Taxol composition, i.e. PACLITAXEL (prepared by the firm Bristol-Myers-Squibb), contains 6 mg/ml of Taxol together with 527 mg/ml Cremophor EL and 47% by weight of anhydrous ethanol. Before administration it is to be diluted by 0.9% physiologic sodium chloride solution of 5% dextrose to a concentration of 0.03 mg/ml. The physical and chemical stability of the diluted solution is indicated between 12 and 24 hours. The diluted solution must be filtered through a 0.2&mgr;membrane filter before its administration by infusion as the solution may be opalescent due to the non-ionic surfactants, such as Cremophor EL.
Although the Cremophor EL generally used in Taxol derivatives is well soluble and is a solvent generally used in the preparation of other pharmaceutical compositions, it is not a biologically inert agent. It causes sensitivity reactions accompanied by different vasodilating, air-thirst causing and hypotensive effects. According to literature references [e.g; Pharmacology and Toxicology of Cremophor EL diluent: The Annals of Pharmacotheraphy, 1994 May, Vol. 28, S11-S115; Pharmaceutical Research, Vol. II., No. 6, 889-895; and Vol. II, No. 2, 206-212, (1994)] Cremophor EL is toxic and causes allergic reactions. Its toxic effect has been proved also by our own biological pharmacological tests. The Journal of the National Cancer Institute (Vol. 85, No. 20, Oct. 20, 1993) describes that Cremophor EL is not only toxic but in case of Taxol compounds inhibits the active ingredients to exert their effect in the intracellular field.
A mixed-miceller proliposomal Taxol composition suitable for parenteral administration is described by H. A. Onynksel et al (Pharm. Res. Vol. 11, No. 2, 206-212). Taxol is dissolved in a mixed micelle system containing bile acid salt and phospholipide and the spontaneously formed liposomes are diluted. The solubility of Taxol can be increased only to 0.8 mg/ml even by using various bile acid salts (sodium desoxycholate, sodium cholate, sodium taurocholate, sodium taurodesoxycholate).
According to the authors the large-scale production is connected with plenty of problems and the stability of the composition is limited as Taxol is precipitated upon standing. A slight precipitation is declared in case of a composition containing 0.4 mg/ml of Taxol stored at a temperature of 7 to 24° C. The composition is diluted directly before administration. Mouse tests prove that bile acid salts are less toxic than Cremophor EL.
In patent specification No. WO 94/07484 published recently (Research Corporation Technologies Inc., USA) Taxol-containing solutions and emulsions are disclosed. Taxol is dissolved in alcohol, then in oil and oil-in-water type emulsions containing 0.5-5 mg/ml of Taxol and having a drop size of 2-10 &mgr;m are prepared. These compositions are, however, unsuitable for administration by injection or infusion.
In patent specifications Nos. WO 94/12030 and WO 94/12198 injectable Taxol compositions are disclosed. In order to increase their stability, the pH-value of the Taxol and Cremophor EL containing comp

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