Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-07-31
2000-09-26
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548491, A61K 31405, C07D20912
Patent
active
06124340&
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE97/01097 filed Jun. 18, 1997.
TECHNICAL FIELD
This invention relates to a novel form of the HMG-CoA reductase inhibitor fluvastatin, more specifically to a highly crystalline form of fluvastatin sodium, referred to as fluvastatin sodium form B. The invention also relates to processes for production of fluvastatin sodium form B, to pharmaceutical compositions comprising fluvastatin sodium form B, and to the use of fluvastatin sodium form B in medical treatment
BACKGROUND ART
Fluvastatin, of which the full chemical name is R*, S*-(E)-(.+-.)-7-[3-(4-fluorophenyl)-1-(1-methyl-ethyl)-1H-indol-2-yl]-3,5- dihydroxy-6-heptenoic acid, as well as its sodium salt, are disclosed in EP-A-0 114 027. Fluvastatin is an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is a key enzyme in the regulation of cholesterol biosynthesis. Fluvastatin can be used pharmaceutically particularly as a hypercholesterolemic, hyperlipoproteinemic and antiatherosclerotic agent Fluvastatin sodium recovered by lyophilization is disclosed in U.S. Pat. No. 4,739,073.
In EP-A-0 547 000 it is disclosed that fluvastatin sodium is extremely susceptible to degradation at pH below about 8. The suggested solution is to provide compositions comprising the drug substance and an alkaline medium, which is capable of by imparting a pH of at least 8 to an aqueous solution or dispersion of the composition. ##STR1##
It is pointed out in EP-A-547 000 that, in addition to the pH sensitivity, the heat and light sensitivity, as well as the hygroscopicity, of fluvastatin sodium impose particular requirements on the manufacture and storage of pharmaceutical dosage forms of fluvastatin sodium. It is known in the art that lower hygroscopicity will lead to improved chemical stability and longer shelf life of chemical compounds.
Consequently, there is a need for new forms of fluvastatin sodium having improved chemical stability, making possible the preparation of pharmaceutical formulations of fluvastatin sodium with less need for stabilizing agents and with prolonged shelf life, and with the possibility of being provided in less sophisticated packages.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: FT-IR absorbance spectra of fluvastatin sodium (A) form A and (B) form B. Abscissa scale: 4000-450 cm.sup.-1. Ordinate scale: Absorbance maximum 0.66 at 1577 cm.sup.-1 for spectrum A, 1.11 at 1587 cm.sup.-1 for spectrum B.
FIG. 2: FT-IR absorbance spectra of fluvastatin sodium (A) form A and (B) form B. Abscissa scale: 1800-450 cm.sup.-1. Ordinate scale: Absorbance maximum 0.66 at 1577 cm.sup.-1 for spectrum A, 1.11 at 1587 cm.sup.-1 for spectrum B.
FIG. 3: X-ray powder diffractogram of fluvastatin sodium form A.
FIG. 4: X-ray powder diffractogram of fluvastatin sodium form B.
FIG. 5: Water sorption/desorption profiles: (a) fluvastatin sodium form A; (b) fluvastatin sodium form B.
DISCLOSURE OF THE INVENTION
We have found that lyophilization of fluvastatin sodium yields a mixture of a crystalline form and amorphous material. The crystalline form comprised in this mixture is referred to as fluvastatin sodium form A. It has surprisingly been shown that fluvastatin sodium can crystallize in a new crystalline form, hereinafter referred to as fluvastatin sodium form B.
Fluvastatin sodium form B is a novel form of polymorphic fluvastatin sodium which has several advantageous properties compared with previously known forms of fluvastatin sodium: fluvastatin sodium;
It is predicted that these advantageous properties will lead to improved chemical stability and longer shelf life both for the pure substance and for pharmaceutical dosage forms containing fluvastatin sodium form B. Consequently, there will be less need for the addition of stabilizing agents in pharmaceutical dosage forms and fewer demands on packages, in particular on the water permeability and light transmission. Packages can thus be made of materials that are less complicated and more environmental friendly, for instance blister packs can be made
REFERENCES:
patent: 4739073 (1988-04-01), Kathawala
Astra Aktiebolag
McKane Joseph K.
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