Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-05-06
1998-01-27
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514169, 514182, 514777, A61K 31705
Patent
active
057122601
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to pharmaceutical compositions comprising an estramustine derivative and a cyclodextrin. Cyclodextrins (hereinafter CD) are well known cyclic oligosaccharides, made up of D-glucose residues, having a cylindrical cavity shaped structure capable of including various guest molecules. Indeed, one of the most interesting properties of CD is their ability to form inclusion compounds or complexes. This interaction greatly depends on the hydrophobicity of the guest molecule, the steric hindrance between the drug and the CD, and the size of the CD cavity. Anyway, this kind of complexation confers new physicochemical properties to the drugs, and is extensively used in the pharmaceutical field to et al., Drug Dev. Ind. Pharm., 17, 1503 (1991); J. Szejtli, Pharm. Tech. Int., February 1991, 15! and, as a consequence, their dissolution characteristics and bioavailability.
More generally, the drug-CD complexation is used to improve the bioavailability of active molecules presenting a very low water solubility al., STP Pharma, 323 (1985)!. Said inclusion complexes are usually prepared in a liquid medium, and then, upon drying they are obtained in powder form.
Various methods for preparing solid inclusion compounds, such as kneading et al., U.S. Pat. No. 4,603,123, Jul. 29 (1986)! are suitable.
In some cases the formation of the complex in the solid phase is thermodynamically spontaneous and inclusion could be normally achieved by
We have now surprisingly found that the bioavailibility characteristics of certain drugs can be still improved with CD also for molecules with high water solubility, that theoretically do not need any particular formulation approach specifically intended for improving their solubility or their rate of dissolution from a therapeutic dosage form.
The present invention relates to pharmaceutical composition comprising an estramustine derivative and a cyclodextrin.
Estramustine derivatives according to the invention are, for example, the compounds of formula (I): ##STR3## wherein R is ##STR4## in which R.sub.1 is C.sub.1 -C.sub.4 alkyl and n is 0, 1 or 2, and the pharmaceutically acceptable salts thereof.
Particularly preferred estramustine derivatives are the compounds of formula (I) wherein R is ##STR5## i.e. Estramustine-17-phosphate, and its disodium salt, i.e. Estramustine-17-disodium phosphate; or wherein R is ##STR6## i.e. Estramustine-17-L-alaninate, and its methansulfonate salt, i.e. Estramustine-17-L-alaninate methan-sulfonate.
Estramustine-17-phosphate disodium salt (GB patent 1016959) is a drug used in prostatic cancer therapy, most widely in the treatment of patients who can no longer be treated with hormones and patients with a poor prognosis. The drug is used above all by patients in whom the illness has spread through metastatic tumors. Since the size of the tumor is reduced, the pain caused by the cancer is also relieved. Although effective in therapy and absorbable through the gastrointestinal wall, Estramustine-17-phosphate disodium salt has strong limitations in the oral administration due to its interaction with foods and drinks: it is necessary to administer the drug in fasting condition in order to avoid the reprecipitation of the drug that is induced by cations and in Pharmac., 38, 189 (1990)!.
This fact dramatically reduces the bioavailibility of the drug and induces gastrointestinal side effects.
Estramustine-17-L-alaninate (patent application EP351561) has the same therapeutic indications as Estramustine-17-phosphate disodium salt and quite the same trouble of reprecipitation, although induced by anionic species, such as chlorine ions. The present invention generally refers to the use of any CD, natural (.alpha.-CD, .beta.-CD and .gamma.-CD), synthetic or semi-synthetic (as for example hydroxypropyl-.beta.-CD or 5,126,333, Jun. 30 (1992)!. In particular, preferred cyclodextrins are .beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin and .gamma.-cyclodextrin.
What we surprisingly found is that when cyclodextrins are mixed with Estramustine-17-
REFERENCES:
patent: 3299104 (1967-01-01), Fex
patent: 5126333 (1992-06-01), Martini et al.
Cserhati, Tibor. Biomed. Chromat., vol. 8(6): 267-272, (1994).
Cserhati, Tibor. Fresnius J. Anal. Chem., vol. 349(10-11): 751-755, (1994).
Loftsson et al. Int. J. Pharm., vol. 79(2-3): 107-112, (1992).
Cserhati, Tibor. Int. J. Pharm., vol. 108(1): 69-75, (1994).
Buzzi Giovanni
Colombo Giuseppe
Maccari Giuseppe
Martini Alessandro
Muggetti Lorena
Kight John
Lee Howard C.
Pharmacia AB
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