|Title:||Pharmaceutical combination composition and associated method|
|Abstract:||A novel combination pharmaceutical composition is described, together with a method for making the same, wherein the pharmaceutically active ingredients are separately milled and then formed into separate granules, and only thereafter blended together to form the combination composition. The method for achieving this novel combination composition is also described. In particular, a novel combination composition of triamterene and hydrochlorothiazide having improved bioavialability and novel effectiveness to prevent or eliminate hypokalemic side effects is also described.|
|Inventor(s):||Blume; Cheryl D. (Morgantown, WV), Bonner; Paul H. (Morgantown, WV)|
|Assignee:||Mylan Pharmaceuticals Inc. (Morgantown, WV)|
|Filing Date:||Feb 17, 1984|
|Claims:||1. A method for enhancing the bioavailability of pharmaceutical combination compositions in solid unit dosage form and composed of at least two solid pharmaceutically-active ingredients of respectively different hydrophilic characteristics, at least one of which is sparingly soluble in physiological fluids, which method consists essentially in |
(1) separately providing each of said active ingredients in finely divided particulate solid form;
(2) separately mixing each of said finely divided active ingredients with respective non-toxic pharmaceutically-acceptable inert carrier materials, in finely-divided particulate form,
of the class including wicking agents, surfactants, lubricants, disintegrants and at least one agent functionally capable of aiding in compacting operations
(3) separately compacting said respective active ingredients with said respective carrier materials to form separate compactions thereof
(4) thereafter separately comminuting said separate compactions to form respectively separate granules of said respective active ingredients
each of such respective granules being composed of a large number of said respective individual finely divided active ingredient particles admixed with said finely divided particulate carrier materials
(5) thereafter mechanically blending said respective granules together in desired optimum pharmaceutically effective proportions to form a granularly heterogeneous blended combination and whereby said respective active ingredients particles are substantially retained within said respective granules
whereafter said thus-blended composition is formulated into unit dosage entities.
2. A method according to claim 1 wherein said unit dosage entities are in capsule form containing said thus-blended composition.
3. A method according to claim 1 wherein said unit dosage entity is a solid tablet, containing in addition to said thus-blended composition a lubricant ingredient blended therewith to aid in the processing of the granules.
4. A method according to claim 3 wherein said tablet further contains a coloring additive.
5. A method according to claim 1 wherein said finely-divided active ingredients will be such that at least 95% thereof will pass through a 100 mesh screen.
6. A method according to claim 1 wherein said granules have a size range from not more than 5% larger than 2 mm to not more than 20% being smaller than 0.075 mm.
7. A pharmaceutical combination composition having at least first and second pharmaceutically-active ingredients,
at least one of which ingredients is sparingly soluble in an aqueous physiological fluid, and which ingredients are of respectively different hydrophobic or hydrophilic characteristics,
and composed of a granularly heterogeneous but substantially homogeneous blend of said ingredients
said respective first and second ingredients being present in finely divided particulate form and having been first separately compacted and then separately comminuted into respectively separate granules, whereby
one set of said respective granules contains substantially only said first active ingredient in admixture with a first set of non-toxic pharmaceutically-acceptable inert carrier materials of the class including
wicking agents, disintegrants, surfactants,
lubricants and compacting aids, and
a second set of respective granules contains said second active ingredient in separate admixture with a second set of non-toxic pharmaceutically-acceptable inert carrier materials of the class including
wicking agents, disintegrants, surfactants, lubricants and compacting aids,
said respective first and second sets of carrier materials being respectively compatible with said first and second active ingredients and functionally capable of aiding disintegration of said repective granules and dissolution of said respective ingredient particles upon exposure of said granules to said physiological fluid,
whereby said composition exhibits enhanced bioavailability of at least one of said ingredients, relative to the bioavailability thereof in a combination of homogenous granules containing both of said respective finely divided ingredient particles in intimate admixture with each other.
8. A composition according to claim 7 formulated in a capsule unit dosage.
9. A composition according to claim 7 formulated as a tablet, and containing a lubricant blended with said respective first and second sets of granules in said tablet.
10. A composition according to claim 7 wherein said finely-divided particulate form has a size range such that at least 95% will pass through a 100 mesh screen.
11. A composition according to claim 7 wherein said granules have a size range such that not more than 5% is larger than 2 mm, to not more than 20% being larger than 0.075 mm.