Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-06-15
2001-10-23
Huang, Evelyn Mei (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S240000
Reexamination Certificate
active
06306886
ABSTRACT:
FIELD OF THE INVENTION
The potent platelet glycoprotein IIb/IIIa antagonist, roxifiban, is produced in crystalline form. Crystalline roxifiban exists in two polymorphic forms, designated Form 1 and Form 2. These polymorphic forms are characterized by x-ray powder diffraction and solid-state carbon NMR. Pharmaceutical compositions and methods for the treatment or prevention of diseases mediated by platelet aggregation are described.
BACKGROUND OF THE INVENTION
The present invention relates to crystalline forms of a potent platelet glycoprotein IIb/IIIa antagonist known as roxifiban. Roxifiban is an acetate salt methyl ester prodrug form of a potent platelet glycoprotein IIb/IIIa antagonist. It is a non-peptide isoxazoline compound represented by the following structural formula:
Roxifiban is known by its chemical name, methyl-N
3
-[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N
2
-(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate acetate salt. Roxifiban is encompassed within the description and claims of Patent Cooperation Treaty application number PCT/US94/13155 (International Publication Number WO 95/14683) filed on Nov. 14, 1994, the disclosure of which is incorporated herein by reference. This international patent application claims priority from U.S. Ser. No. 08/157,598, filed Nov. 24 1993, U.S. Ser. No. 08/232,961, filed Apr. 22, 1994 and U.S. Ser. No. 08/337,920, filed Nov. 10, 1994, the disclosure of each of which is incorporated herein by reference. The synthesis of the trifluoroacetic acid salt of the prodrug base of roxifiban is described in Example 314B of PCT/US94/13155.
The active component of roxifiban has been found to inhibit the binding of soluble adhesive proteins, such as fibrinogen, von Willebrand factor, fibronectin and vitronectin, to the platelet glycoprotein IIb/IIIa complex. As a consequence, the compound is capable of inhibiting the activation and aggregation of platelets induced by all known endogenous platelet agonists. roxifiban is, therefore, useful for the treatment or prevention of thromboembolic disorders including thrombosis or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerlosis, stroke, myocardial infarction and unstable angina. Other diseases that involve cell adhesion processes may also be treated by the administration of roxifiban. Such diseases include, for example, rheumatoid arthritis, asthma, allergies, adult respiratory syndrome, organ transplantation rejection, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastatis, diabetic retinopathy, inflammatory conditions and inflammatory bowel disease.
Treatment or prevention of the foregoing disorders is accomplished by administering a therapeutically effective amount of roxifiban to a human or animal subject in need of such treatment or prevention. The compound may be administered enterally or parenterally in solid or liquid dosage forms. In general dosages of from about 0.001 to about 10 mg/kg of body weight per day, preferably from about 0.005 to about 1 mg/kg of body weight per day are employed.
The synthesis of roxifiban and its recovery as a substantially pure crystalline product are described by Zhang et al.,
Tetrahedron Letters,
37(26), 4455-58 (1996); Zhang et al.,
J. Org. Chem.,
62(8), 2469 (1997). Roxifiban has not been known previously to exist in stable crystalline polymorphic forms.
For the manufacture, purification and formulation of roxifiban, the drug advantageously is produced in a crystalline form. Accordingly, a need exists for stable crystalline forms of the drug and reliable and reproducible procedures for their manufacture.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to crystalline roxifiban. A related aspect resides in novel crystalline polymorphs of roxifiban, designated Form 1 and Form 2. The Form 1 polymorph has been characterized and distinguished from the Form 2 polymorph by solid-state carbon NMR and powder X-ray diffraction analysis.
Further aspects of the invention involve pharmaceutical compositions of crystalline roxifiban and its Form 1 and Form 2 polymorphs. The crystalline prodrug products of this invention may be formulated into conventional solid pharmaceutical dosage forms or used for the preparation of liquid dosage forms by combining a therapeutically effective amount of the crystalline prodrug with a pharmaceutically acceptable carrier. In another aspect, the present invention involves a method for inhibiting the binding of a soluble adhesion protein to the platelet glycoprotein IIb/IIIa complex which comprises administering an amount of crystalline roxifiban sufficient to result in the platelet glycoprotein IIb/IIIa being contacted with an effective inhibitory amount of the active drug substance. In particular aspects, the invention involves methods for treating or preventing various thromboembolic disorders and other disorders involving cell adhesion, which comprise administering a therapeutically effective amount of a pharmaceutical composition comprising the novel crystalline forms of roxifiban of this invention.
REFERENCES:
patent: 5849736 (1998-12-01), Wityak
patent: WO9514683 (1995-06-01), None
Zhang et al., Tetrahedon Letters, 1996, 37 (26), 4455-58.
Zhang et al., J. Org. Chem, 1997, 62 (8), 2466-2470.
Kauffman Goss S.
Ma Philip
Maurin Michael Blaise
Meloni David John
Pesti Jaan A.
DuPont Pharmaceuticals Company
Huang Evelyn Mei
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