Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-08
2002-01-01
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S396000
Reexamination Certificate
active
06335331
ABSTRACT:
The present invention relates to new pseudopolymorphic crystalline forms of 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, to processes for their preparation and to pharmaceutical compositions containing them.
2-[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid, also known and hereinafter referred to as efletirizine (INN: International Non-proprietary Name), is the compound of the following formula:
Efletirizine is encompassed within general formula I of European patent No. 58146 in the name of the applicant, which relates to substituted benzhydrylpiperazine derivatives.
Like 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid, also known and hereinafter referred to as cetirizine (INN), efletirizine has been found to possess excellent antihistaminic properties. It belongs to the pharmacological class of second generation histamine H
1
-receptor antagonists and shows in vitro high affinity and selectivity for H
1
-receptors. Like cetirizine, it is useful as an antiallergic, antihistaminic, bronchodilator and antispasmodic agent. Recent clinical studies have shown the utility of efletirizine when administered in the form of a nasal spray for the treatment of allergic rhinitis and rhino-conjunctivitis (J. F. Dessanges et al., Allergy and Clin. Immunol. News (1994), Suppl. n°2, abstract 1864; C. De Vos et al., Allergy and Clin. Immunol. News (1994), Suppl. n°2, abstract 428).
Another recent clinical pharmacology study (to be published) has shown that efletirizine gives unexpectedly good results in the treatment of urticaria, atopic dermatitis and prurit.
Due to increasing therapeutic interest for efletirizine, we have set out to prepare pharmaceutical compositions containing efletirizine.
Efletirizine is an amorphous solid. However, it is highly desirable to dispose of a product with reproducible characteristics, which always performs in the same way during formulation, in particular in order to comply with regulatory requirements. For these reasons, we attempted to prepare crystalline forms of efletirizine. Although efletirizine has been studied for its therapeutic utility, no attention has yet been given to such crystalline forms.
The present invention derives from the unexpected discovery of two pseudopolymorphic crystalline forms of efletirizine dihydrochloride, namely anhydrous efletirizine dihydrochloride and efletirizine dihydrochloride monohydrate. For the sake of identification, anhydrous efletirizine dihydrochloride will be hereinafter designated as “Form A” and efletirizine dihydrochloride monohydrate will be hereinafter designated as “Form B”.
According to another embodiment, the present invention provides for the preparation of these new pseudopolymorphic forms, and further provides processes for the conversion of Form A into Form B and of Form B into Form A.
The present invention also derives from the discovery that these two new pseudopolymorphic forms have different properties. In particular, we have discovered that solid pharmaceutical compositions comprising Form A of efletirizine dihydrochloride exhibit better storage stability over time than solid pharmaceutical compositions comprising Form B. This better storage stability appears to be due to better compatibility with the solid carriers and diluents commonly used in such solid pharmaceutical compositions.
Accordingly, the present invention also relates to pharmaceutical compositions comprising Form A or Form B in association with suitable pharmaceutical excipients, carriers or diluents therefor, preferably to solid pharmaceutical compositions comprising Form A.
As to the preparation processes of these pseudopolymorphic forms of efletirizine dihydrochloride, Form B may be obtained by hydrolysis in an aqueous medium of 2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide in the presence of hydrochloric acid, at a temperature comprised between 40° C. and the reflux temperature of the reaction mixture. Form B can then be recrystallised in aqueous acid or in a mixture of solvents containing water and hydrochloric acid.
Form B can then be transformed into Form A by heating up to reflux in a solvent, such as acetone or methylethylketone. Optionally, Form A can be converted back into Form B by recrystallisation in aqueous hydrochloric acid.
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Berwaer Monique
Bodson Guy
Deleers Michel
Dogimont Charles
Fanara Domenico
Bernhardt Emily
UCB S.A.
Wenderoth , Lind & Ponack, L.L.P.
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