Method for increasing bioavailability of oral pharmaceutical compositions
First Claim
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1. A method of formulating an oral pharmaceutical composition, which method comprises:
- admixing a pharmaceutical compound, a pharmaceutical carrier, and a bioenhancer comprising an inhibitor of P-glycoprotein-mediated membrane transport or an inhibitor of a cytochrome P450 3A enzyme in normal gut tissue, said bioenhancer being active only in the gut when administered orally and being present in sufficient amount to provide bioavailability of said pharmaceutical compound in the presence of said bioenhancer greater than the bioavailability of said pharmaceutical compound in the absence of said bioenhancer when said pharmaceutical composition is administered orally to a mammal, and further wherein whether a bioenhancer is active only in the gut is determined by measuring change in bioavailability of said pharmaceutical compound when orally coadministered to said mammal with said bioenhancer, measuring change in integrated systemic concentration of said pharmaceutical compound when said pharmaceutical compound is intravenously administered and said bioenhancer is orally coadministered, and determining that said change in said bioavailability when said pharmaceutical compound is orally administered is a statistically significant increase and said change in said integrated systemic concentration when said pharmaceutical compound is intravenously administered is not statistically significant.
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Abstract
A method for increasing bioavailability of an orally administered hydrophobic pharmaceutical compound, which comprises orally administering the pharmaceutical compound to a mammal in need of treatment with the compound concurrently with a bioenhancer comprising an inhibitor of a cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein-mediated membrane transport, the bioenhancer being present in sufficient amount to provide bioavailability of the compound in the presence of the bioenhancer greater than the bioavailability of the compound in the absence of the bioenhancer.
107 Citations
26 Claims
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1. A method of formulating an oral pharmaceutical composition, which method comprises:
admixing a pharmaceutical compound, a pharmaceutical carrier, and a bioenhancer comprising an inhibitor of P-glycoprotein-mediated membrane transport or an inhibitor of a cytochrome P450 3A enzyme in normal gut tissue, said bioenhancer being active only in the gut when administered orally and being present in sufficient amount to provide bioavailability of said pharmaceutical compound in the presence of said bioenhancer greater than the bioavailability of said pharmaceutical compound in the absence of said bioenhancer when said pharmaceutical composition is administered orally to a mammal, and further wherein whether a bioenhancer is active only in the gut is determined by measuring change in bioavailability of said pharmaceutical compound when orally coadministered to said mammal with said bioenhancer, measuring change in integrated systemic concentration of said pharmaceutical compound when said pharmaceutical compound is intravenously administered and said bioenhancer is orally coadministered, and determining that said change in said bioavailability when said pharmaceutical compound is orally administered is a statistically significant increase and said change in said integrated systemic concentration when said pharmaceutical compound is intravenously administered is not statistically significant. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 17, 18, 19, 20, 21, 22)
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13. A method of increasing bioavailability of the active compound in a first oral pharmaceutical composition, which method comprises:
reformulating said first composition to provide a reformulated composition by admixing said active compound with a bioenhancer comprising an inhibitor of cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein-mediated membrane transport in normal gut tissue, said bioenhancer being active only in the gut when administered orally and being present in sufficient amount to provide bioavailability of said active compound when administered in said reformulated composition greater than said bioavailability of said active compound when administered in said first pharmaceutical composition, and further wherein whether a bioenhancer is active only in the gut is determined by measuring change in bioavailability of said active compound when orally coadministered to said mammal with said bioenhancer, measuring change in integrated systemic concentration of said active compound when said active compound is intravenously administered and said bioenhancer is orally coadministered, and determining that said change in said bioavailability when said active compound is orally administered is a statistically significant increase and said change in said integrated systemic concentration when said active compound is intravenously administered is not statistically significant. - View Dependent Claims (14, 15, 16, 23, 24, 25, 26)
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