Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
2000-07-11
2001-12-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S415000, C424S486000, C424S488000, C424S464000
Reexamination Certificate
active
06333361
ABSTRACT:
This application is the national phase of international application PCT/GB98/03371 filed Nov. 10, 1998 which designated the U.S.
The present invention relates to a pharmaceutical composition and more particularly to a pharmaceutical composition comprising 4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulfonylbenzamide (zafirlukast) or a pharmaceutically acceptable salt thereof and a gelling agent.
It is desirable in the treatment of a number of diseases, both therapeutically and prophylactically, to provide the active pharmaceutical ingredient in a form that provides a modified release profile. Such modified release profiles may, in certain circumstances, include controlled release, extended release or sustained release profiles. The modified release formulation provides an alternative dosage form and/or regime which adds to the physician's armoury. Preferably the modified release provides a generally uniform and constant rate of release over an extended period of time which achieves a stable and desired blood (plasma) level of the active ingredient preferably without the need for frequent administration of the medicament.
Accordingly, a need exists for modified release pharmaceutical compositions of medicaments such as, 4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulfonylbenzamide or a pharmaceutically acceptable salt thereof, which provide alternative release profiles and in particular alternative release profiles which achieve more constant blood (plasma) levels throughout the day.
U.S. Pat. No. 4,859,692 discloses formulations which comprise a leukotriene antagonist and croscarmellose sodium (Example 128(i)) or polyvinylpyrrolidone (Example 128 (ii)). U.S. Pat. No. 5,294,636 discloses a formulation which comprises form X of N-[4-[5-(cyclopentyloxycarbonyl)-amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide, polyvinylpyrrolidone and croscarmellose sodium (Example 4). U.S. Pat. No. 5,319,097 discloses formulations which comprise form A of N-[4-[5-(cyclopentyloxycarbonyl)-amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide, croscarmellose sodium and/or polyvinylpyrrolidone (Examples 3, 5 and comparison Example 3). While it is noted that croscarmellose sodium and polyvinylpyrrolidone can, under certain circumstances, act as gelling agents, the above-described formulations would not provide for formulations with modified release properties as the croscarmellose sodium and polyvinylpyrrolidone are not taught as being present in sufficient enough quantities.
According to the present invention there is provided a modified release pharmaceutical composition comprising a gelling agent, preferably hydroxypropyl methylcellulose, and 4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulfonylbenzamide, or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutical composition comprises a hydrophilic matrix comprising a gelling agent, preferably hydroxypropyl methylcellulose, and 4-(5-cyclopentyloxy-carbonylamino-1-methylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulfonylbenzamide, or a pharmaceutically acceptable salt thereof, optionally together with one or more pharmaceutically acceptable excipients.
The term gelling agent as used herein means any substance, particularly a hydrophilic substance, which forms a gel when in contact with water and thus includes such substances as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl ethylcellulose, methylcellulose, ethylcellulose, carboxyethylcellulose, carboxymethyl hydroxyethylcellulose, carbomer, sodium carboxymethylcellulose, polyvinylpyrrolidone, or mixtures thereof. The gelling agent is preferably hydroxypropyl methylcellulose.
The gelling agent, for example hydroxypropyl methylcellulose, is preferably present in an amount which is sufficient to provide a matrix. This matrix formulation is believed to provide a modified release profile. The gelling agent is conveniently present in about 5 to 50% (by weight), more conveniently about 5 to 45%, most conveniently about 5 to 40%, preferably about 9 to 40%, more preferably about 14 to 40%, most preferably about 20 to 40% and in particular about 25 to 40%.
The hydroxypropyl methylcellulose may contain more than one grade of polymer and is commercially available under several trademarks, e.g. METHOCEL® E, F, J and K from the Dow Chemical Company, U.S.A. and METOLOSE™ SH from Shin-Etsu, Ltd., Japan. The various grades available under a given trademark represent differences in methoxy and hydroxypropoxy content as well as in viscosity. The methoxy content ranges from 16.5 to 30% by weight, the hydroxypropoxy content ranges from 4 to 32% by weight and the viscosities of a 2% aqueous solution at 20° C. range from 3 cps to 100,000 cps. For example, the hydroxypropyl methylcellulose preferably comprises (a) a polymer with a viscosity of about 40 to 60 cps (in particular about 50 cps), a methoxy content of about 28 to 30% by weight and a hydroxypropoxy content of from about 7 to less than 9% by weight; or (b) a polymer with a viscosity of about 3,500 to 5,600 cps (in particular about 4,000 cps), a methoxy content of about 28 to 30% by weight and a hydroxypropoxy content of about 7 to 12% by weight; or (c) a polymer with a viscosity of about 80 to 120 cps (in particular about 100 cps), a methoxy content of about 19 to 24% by weight and a hydroxypropoxy content of from about 7 to less than 9% by weight; or (d) a polymer with a viscosity of about 3500 to 5600 cps (in particular about 4,000 cps), a methoxy content of about 19 to 24% by weight and a hydroxypropoxy content of about 7 to 12% by weight, or mixtures thereof. More preferably, the hydroxypropyl methylcellulose is selected from the group consisting of (a)-(d) or mixtures thereof as described above and in particular from the group consisting of (a), (c) and (d) or mixtures thereof as described above, with the proviso that if the pharmaceutical composition contains a hydroxypropyl methylcellulose described under (d) above the total amount of hydroxypropyl methylcellulose present in the pharmaceutical composition must be greater than 25.8% by weight.
The compound, 4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulfonylbenzamide (see Formula I below), its various physical forms and its pharmaceutically acceptable salts exhibit useful leukotriene antagonist activity. Thus, they antagonize the actions of one or more of
the arachidonic acid metabolites known as leukotrienes, for example, C
4
, D
4
, and/or E
4
, which are known to be powerful spasmogens (particularly in the lung), to increase vascular permeability and have been implicated in the pathogenesis of asthma and inflammation (see J. L. Marx,
Science,
1982, 215 1380-1383) as well as endotoxic shock (see J. A. Cook, et al.,
J. Pharmacol. Exp. Ther.,
1985, 235, 470) and traumatic shock (see C. Denzlinger et al.,
Science,
1985. 230, 330). The compounds are thus useful in the treatment of diseases in which leukotrienes are implicated and in which antagonism of their action is desired. Such diseases include for example, allergic pulmonary disorders such as asthma, hay fever and allergic rhinitis and certain inflammatory diseases such as bronchitis, ectopic and atopic eczema, and psoriasis as well as vasospastic cardiovascular disease and endotoxic and traumatic shock conditions. The compounds are particularly useful in the treatment of asthma.
The preparation, physical properties and beneficial pharmacological properties of 4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-yl-methyl)-3-methoxy-N-o-tolylsulfonylbenzamide, its various physical forms and its pharmaceutically acceptable salts are described in European Patents EP 199,543, 490,649 and 490,648 as well as in corresponding U.S. Pat. Nos. 4,859,692, 5,294,636 and 5,319,097, the entire contents of which are herein incorporated by referen
Corvari Susan Jane
Main Karen Beth
Parikh Bharvnish Vinod
Fubara Blessing
Page Thurman K.
Pillsbury & Winthrop LLP
Zeneca Limited
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