Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Patent
1993-05-10
1995-02-21
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
424476, 424468, A61K 948
Patent
active
053913779
DESCRIPTION:
BRIEF SUMMARY
This invention relates to pharmaceutical formulations. In particular, the invention relates to a formulation for lipophilic drugs which may enhance the bioavailability of such drugs.
Many lipophilic pharmaceuticals, such as cardiovascular drugs, are subject to an extensive yet variable "first-pass" metabolism. This occurs because orally administered drugs absorbed from the gastrointestinal tract are transported in the hepatic portal blood supply directly to the liver. Since the liver is the major site of drug metabolism, and lipophilic drugs are more prone to rapid metabolism, a major portion of an absorbed lipophilic drug may be prevented from reaching the systemic circulation. Classes of drugs to which this consideration particularly applies involve lipophilic beta-blocking agents and calcium channel blocking agents. However, other classes of lipophilic drugs suffer high hepatic first-pass metabolism.
In the case of conventional dosage forms of drugs susceptible to the first-pass metabolism, the variability in hepatic first-pass metabolism between individuals or in the same individual at different times leads to an unpredictability in therapeutic response to a given drug dose. Determinants of the extent of hepatic first-pass metabolism include: enzymes present in the liver; hepatic drug metabolism in the elderly; and children.
Lipophilic cardiovascular drugs, in particular beta-blocking agents and calcium channel blockers, are among those absorbed from the gastrointestinal tract into the hepatic portal blood system by a passive first order process. This absorption has been found to be virtually complete, but the drugs have been found to be subjected to variable and extensive metabolism before reaching the systemic circulation. The metabolism may be in the gastrointestinal lumen, the intestinal wall, or in the liver, but generally the liver is assumed to be the major site of this metabolism due to the virtually complete appearance of the drug in the hepatic portal vein. This metabolism of the drug during its first passage through the liver is called the "first-pass effect", as discussed above.
The first-pass effect has been reported frequently for lipophilic bases (e.g. propranolol) and esters of lipophilic acids (e.g. acetyl salicylic acid), but is uncommon for lipophilic acids (e.g. salicylic acid). Because of the extensive extraction or metabolism of the drug by the liver, these drugs exhibit bioavailabilities of less than 50%, together with a large variability in this parameter of a more than two-fold range.
Unpredictable hepatic drug extraction causes wide inter and intra subject variation in steady-state plasma drug concentrations in patients during chronic treatment, and hence it contributes to an unreliable dose response for a given drug. It is also apparent that drugs which undergo extensive first-pass metabolism may produce different plasma metabolite concentration versus time profiles after oral and parenteral administration.
It is generally found with lipophilic cardiovascular drugs that there is saturation of the metabolic pathways in the liver with increasing concentrations of drug in the hepatic portal blood supply. This saturation effect, which commonly occurs at the physiological concentrations encountered with normal dosing, is called the Michaelis-Menten effect and the drug is said to exhibit Michaelis-Menten kinetics.
When the drug concentrations in the hepatic portal vein are sufficiently low so as not to cause saturation of the metabolic pathways, or when the drug concentrations are so high as to cause total saturation of the metabolic pathways, then the pharmacokinetics are found to be linear. This means that the amount of drug entering the systemic circulation is proportional to the dosage. In the case of saturation of the metabolic pathways, a threshold dose is required to saturate the metabolic pathways before linearity is apparent.
When Michaelis-Menten kinetics are in effect, then the pharmacokinetics are non-linear, as increasing the dose increases the degree of saturation of
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Benston, Jr. William E.
Cortecs Limited
Page Thurman K.
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