Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1995-12-08
2001-09-04
Geist, Gary (Department: 1211)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S103000
Reexamination Certificate
active
06284746
ABSTRACT:
The invention relates to the inclusion complexes of Taxol [2aR-[2a&agr;, 4&bgr;;4&agr;&bgr;,6&bgr;,9&agr;(&agr;R*,&bgr;S*),11&agr;-12&agr;,12a&agr;, 12b&agr;]]-&bgr;-(Benzoylamino)-&agr;-hydroxybenzene-propanoic acid 6,12-b-bis (acetyloxy)-12-(benzoyloxy)-2a,3,4,4a, 5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihyroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]-benz-[1,2-b]oxet-9-yl ester or Taxotere (butoxycarbonyl-10-deacetyl-N-debenzoyl taxol) and Taxus extracts (comprising besides taxol other diterpene taxan-derivatives such as cephalomannine, 10-deacetyl-taxol, deacetyl baccatine-III, baccatine-III, cinnamoyl-taxicines, taxusine) formed with a cyclodextin derivative or cyclodextrin-derivative-mixture.
Even though taxol shows a rather promising biological effectivity and significant antitumor activity, it's therapeutical application is associated with a lot of difficulties:
taxans are very slightly soluble in water, for exanple the water solubility of taxol is between 0.55-0.59 &mgr;g/ml at 25° C. (determined at Cyclolab)
taxol is very sensitive to light and the pH, during. its decomposition biologically inactive products are forming.
results given on taxol in pharmacology are challenged of validity because of the cytotoxic solvents used (Cremophor EL) /Denis, J. N: J.Am. Chem. Soc. 110. 5917. 1988 and Fjaellskog M. L. et al.: Lancet, 342-873. 1993 and Webster, L. et al.: J. Natl. Cancer Inst. 85. 1685. 1993.
Numerous processes are known to improve the disadvantageous features mentioned above:
Using solubilizing agents (mixture of Cremophor EL—anhydrous ethanol in the rate of 1:1, Natl. Cancer Institute, PACLITAXEL Documentation);
Forming chemically modified micromicelles using phosphatydil-ethanolamines (Patent of Lipid Specialities, Inc. EP 118 316)
Using mixtures of ethanol-polysorbates as solubility increasing agents (Patent of Rhone-Poulenc Rorer EP 522 936, and Rhone Poulenc Rorer EP 522 937)
Using Liposomal taxol formulations (e.g. Aquilar, R. and Rafaelloff, R. WO 93/18751 and Alkan, M. H. et al.: J. Liposome Research 3. 42. 1993.)
There were some trials to increase the water solubility of taxol by forming synthetic derivatives as well.(e.g. written by Zhao, H. et. al. J.Nat. Prod. 54.6. 1607. 1991., Kingston, D. I. Xang, Y. Y. EP Pat. Appl. EP 537905 and Deutsch, H. M. et al. U.S. Pat. No. 5.157.049)
The biological effectivity of the chemically modified, increased soluble taxol derivatives changes for the worse, mostly the multidrug-resistance shows an upward tendency and the cytotoxicity—just the biological effect—is diminished.
To solve difficulties during the parenteral application of taxol, Taxol-prodrugs with increased water solubility have also been synthetized. (Matthew A. et. al.: J.Med.Chem. 35. 1. 145 1992.).
By microencapsulating of tixol Bartoli et. al. wanted to improve the generally poor stability of it (Bartoli H; et. al.: J.Microencapsulation 7.2. 191. 1990).
There are a lot of difficulties in preparing especially the parenteral pharmaceutical products containing taxol, because the diterpenoid-type, rather lipophilic taxan-derivatives can not be formulated as suitable stable and concentrated solutions even in the presence of large amount of detergents and mixtures of water and organic solvents. /Tarr, B. Pharm. Res. 4.2. 162. 1987.
Nowadays the officially registered (for example at the National Institutes of Health and the National Cancer Institute) parenteral taxol-forms are formulated as 6 mg/ml concentrated emulsions in polyoxyethylated castor oil (Cremphor EL) and ethanol at the ratio of 1:1, and on application these emulsions have to be diluted tenfold. Application of these parenteral products is associated with numerous unpleasant side-effects among others the most important is the serious allergic by-effect caused in consequence of the parenterally hardly tolerable Cremophor EL. Moreover the taxol-formulations produced in Cremophor EL—ethanol solvent are not clear solutions but slightly opaline (Trissel, L. A.: Am.J. Hosp. Pharm. 50.300.1993) and at diluting or applying them together with some other pharmaceuticals there is a possibility of the formation of precipitation.
In a conference in Japan it was reported that glycosyl- and maltosyl-&bgr;-cyclodextrins used together with ethanol and ethylacetate increased the solubility of taxol up to 20-110 &mgr;g/ml (Mikuni, K. et. al.: 1993.)
According to our present invention, improved aqueous solubility of Taxol and taxan-derivatives can be reached by using suitable cyclodextrins and/or cyclodextrin derivatives and/or mixtures thereof without forming any chemical bonds between taxol and cyclodextrins.
The inclusion complexes of the present invention can be prepared by
a.) reacting Taxol or Taxotere or a Taxus extract in an aqueous medium with a cyclodextrin derivative and isolating the complex from the mixture by means known per se.
b.) reacting Taxol or Taxotere or a Taxus extract with a cyclodextrin derivative in a solid form.
c.) high energy milling of Taxol or Taxotere or a Taxus extract with a cyclodextrin derivative.
The complex can be isolated from the mixture by filtration, centrifugation, lyophilization, spay-drying, or vacuum drying.
The high energy milling of Taxol or Taxotere or Taxus extract with a cyclodextrin derivative can be performed as described or referred to in the published Hungarian Patent Application No. T/52366.
As cyclodextrin derivatives preferably
heptakis-
2,6-0
-dimethyl-&bgr;-cyclodextrin
randomly methylated-&bgr;-cyclodextrin
succinyl-methyl-&bgr;-cyclodextrin
2-hydroxy propyl-&bgr;-cyclodextin
soluble anionic-&bgr;-cyclodextrin (CDPSI)
&bgr;-cyclodextrin
&ggr;-cyclodextrin can be used.
Some of the inclusion complexes of the present invention have improved aqueous solubility and stability such as the inclusion complex of Taxol or Taxotere or a Taxus extract formed with
heptakis-
2,6-0
-dimethyl-&bgr;-cyclodextrin
randomly methylated-&bgr;-cyclodextrin
succinyl-methyl-&bgr;-cyclodextrin so they can be used as active ingredients in pharmaceutical compositions.
The pharmaceutical compositions of the invention containing as active ingredient an effective amount of the inclusion complex of Taxol or Taxotere or a Taxus extract formed with a cyclodextrin derivative, preferably heptakis-
2,6-0
-dimethyl-&bgr;-cyclodextin, randomly methylated-&bgr;-cyclodextrin, succinyl-methyl-&bgr;-cyclodextrin and customary pharmaceutical filling, diluting and further auxiliary materials can be prepared in a manner known per se.
Other inclusion complexes of the present invention do not or do not significantly improve the aqueous solubility, such as the inclusion complex of Taxol or Taxotere or a Taxus extract formed with
2-hydroxy propyl-&bgr;-cyclodextrin
soluble aninonic-&bgr;-cyclodextrin polymer (CDPSI), average molecular weight 6000-8000 daltons.
&bgr;-cyclodextrin
&ggr;-cyclodextrin but they can be used e.g. to extract taxol from the ferment of taxol producing cells.
REFERENCES:
patent: 5059699 (1991-10-01), Kingston et al.
patent: 5278324 (1994-01-01), Kingston et al.
patent: 5298496 (1994-03-01), Vikmon et al.
patent: 5439686 (1995-08-01), Desai et al.
patent: 0 639 380 A1 (1995-02-01), None
patent: 0371431B1 (1995-06-01), None
patent: T052366T (1990-07-01), None
Internal Medicine, 4th Edition, Editor-in-Chief Jay Stein, Chapters 71-72, pp. 699-715.*
Sigma Chemical Company, (1994), p. 962.
Szejtli Jozsef
Szente Lajos
Vikmon Andrasne
Birch & Stewart Kolasch & Birch, LLP
Chinoin Ltd.
Geist Gary
White Everett
LandOfFree
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