Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1994-06-01
1995-10-24
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
514326, 514327, 424 129, A61K 31445
Patent
active
054608295
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel pharmaceutical form based on 1,4-substituted piperidine derivatives.
DESCRIPTION OF THE INVENTION
The pharmaceutical compounds which are the subject of the formulation described in the present invention are described in European Patent Application EP 134,124, which is included in the present Application by incorporation by reference.
These compounds, and even more specifically the following compound, for which the internationally recognized name is ebastime or 4-diphenylmethoxy-1-[3-(4-tert-butylbenzoyl)propyl]piperidine of formula: ##STR1## display, when they are formulated in solid form, a very mediocre bioavailability. This insufficient bioavailability is in part linked to a poor water solubility. It is thus difficult, from the crude starting material described in the abovementioned patent, to place it in a solid form which may be used by man, and which displays a correct bioavailability and, consequently, a correct biological activity. The compound of formula (I), in the form of a salt, and more particularly in the form of the lactate, has an optimum solubility, at pH 2, which is equal to 0.8 mg/ml; the compound of formula (I) in basic non-salified form has an even lower water solubility.
These compounds have an antihistamine H.sub.1 activity and are useful for treating respiratory, allergic or cardiovascular diseases. Thus, they relax vascular and bronchial smooth muscles in vitro and in vivo.
They also inhibit the constricting effect of adrenaline and of potassium ions, both in the intestine and in the trachea. Thus, they block the bronchoconstriction induced by histamine aerosols at doses as low as 1 mg/kg.
These compounds are active via the parenteral route as well as the oral route. During their oral administration, the active principle of formula (I), due to its low solubility in water, requires a very long dissolution time in the aqueous medium of the stomach, which may result in a loss of the active principle, which remains undissolved and is thus not absorbable, during emptying of the gastric system, and may thus result in the use of an overdose, which is always dangerous in the medical field. Thus, in the abovementioned patent application, that is to say European Patent Application EP 134,124, when tablets are prepared, according to Example 9 which is the only example to describe a tablet form, dissolution of the active principle in an acidic medium is extremely slow.
The present invention has sought to develop a new solid administration form for the compounds of formula (II) below, in which the active principle displays an improved solubility and thus an improved bioavailability.
The present invention relates to a new solid form based on compounds corresponding to the following formula (II): ##STR2## in which: R.sub.1 represents a thienyl group, a phenyl group optionally substituted with a halogen, an alkoxy group containing 1 to 6 carbon atoms or an alkyl group containing i to 6 carbon atoms, containing 1 to 6 carbon atoms or an alkyl group containing 1 to 6 carbon atoms, containing 1 to 6 carbon atoms, an alkyl group containing 1 to 6 carbon atoms, an alkylthio group containing 1 to 6 carbon atoms, a cycloalkyl group containing 5 or 6 carbon atoms or a group of formula: ##STR3## where R4 and R5 represent, independently of each other, a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, R6 represents a cycloalkyl group containing 3 to 6 carbon atoms or a hydroxymethyl or carboxyl group or an alkoxycarbonyl group containing 2 to 7 carbon atoms, characterized in that the active principle of formula (II) is micronized.
This form has the advantage of displaying an initial rate of dissolution which is approximately 40% higher than the pharmaceutical form obtained from a non-micronized compound of formula (II).
According to a form which is further improved in terms of dissolution of the compounds of formula (II), in addition to the micronization, a hydrophilization of the product is carried out, which enables it to a
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Bobee Jean-Marc
Conrath Guillaume
Gousset Gabriel
Ponsot Michel
Veillard Michel
Raymond Richard L.
Rhone-Poulenc Rorer S.A.
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