Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1996-07-09
1998-06-02
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424494, 424488, 424480, 424461, 424470, 424 113, A61K 914
Patent
active
057595801
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT application Ser. No. PCT/EP 95/00489, filed Feb. 10. 1995, which claims priority from U.S. patent application Ser. No. 08/197,988, filed on Feb. 17, 1994.
The present invention relates to pharmaceutical compositions comprising as active ingredient a micronized form of solid nebivolol or a pharmaceutically acceptable acid addition salt thereof and ways of preparing said compositions.
Nebivolol is the generic name of o-3,4-dihydro-2H-1-benzopyran-2-methanol!. The general structure of nebivolol is shown as formula (I). The structure of formula (I) has four stereogenic centers which are each indicated with an asterisk. ##STR2##
Nebivolol is a mixture of equal amounts of 2 enantiomers having respectively the SRRR- and the RSSS-configuration. The SRRR-configuration is referred to as SR.sub.3 -nebivolol (d-nebivolol) and the RSSS-configuration is referred to as RS.sub.3 -nebivolol (l-nebivolol). SR.sub.3 -nebivolol is a potent and selective .beta..sub.1 -adrenergic antagonist both in vitro and in vivo. Nebivolol can be distinguished from other .beta.-adrenergic antagonists because it acutely lowers blood pressure in spontaneously hypertensive rats, decreases total peripheral vascular resistance and augments stroke volume in anaesthetised dogs. These haemodynamic effects are largely attributable to RS.sub.3 -nebivolol. It was also discovered that RS.sub.3 -nebivolol is a potentiator for a series of antihypertensive agents such as atenolol, propanolol, prazosin, hydralazine and, interestingly, also its own enantiomer, i.e. SR.sub.3 -nebivolol. Several clinical trials have also demonstrated the therapeutic potential of nebivolol as a .beta..sub.1 -selective beta-blocker and antihypertensive agent.
EP-0,145,067 generally describes 2,2'-iminobisethanol derivatives useful for the treatment and/or prevention of disorders of the coronary vascular system. EP-0,334,429 describes including nebivolol.
Nebivolol may be prepared according to the procedures described in EP-0,145,067 and more specifically in EP-0,334,429. Nebivolol has basic properties and may be converted into its pharmaceutically acceptable acid addition salt forms by treatment with appropriate acids. Appropriate acids are, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. The acid addition salt that is preferred in this invention is the hydrochloride acid addition salt.
Pharmaceutical compositions according to the present invention are solid or semi-solid pharmaceutical compositions. Interesting solid pharmaceutical compositions are, for instance, powders, pills, capsules, tablets and the like. The term "semi-solid pharmaceutical composition" refers to pharmaceutical compositions substantially consisting of a dispersion of solid active ingredient in a (highly) viscous formulating agent. Interesting semi-solid pharmaceutical compositions are, for instance, suppositories, creams, gels, ointments and the like.
Interesting solid pharmaceutical compition is a single-unit dosage form, i.e. a non-multi-particulate dosage form.
The solid dosage form that is preferred within the present invention is a tablet. The person skilled in the art has to take into account the characteristics of tablets while searching for a composition. Specific characteristics of tablets are shape, disintegration time, and particularly hardness.
Oral administration constitutes the generally preferred route for administration of pharmaceuticals since this route is particularly convenient and acceptable to
Gilis Paul Marie Victor
Jans Eugeen Marie Jozef
Smans Guido Franciscus
Benston, Jr. William E.
Ciambrone Coletti Ellen
Janssen Pharmaceutica N.V.
Page Thurman K.
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