A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability
01 Mar 1995-Pharmaceutical Research (Kluwer Academic Publishers-Plenum Publishers)-Vol. 12, Iss: 3, pp 413-420
TL;DR: A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption.
Abstract: A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in
vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no
in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.
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University of California, San Francisco1, Food and Drug Administration2, University of North Carolina at Chapel Hill3, Merck & Co.4, Abbott Laboratories5, Eli Lilly and Company6, Novartis7, German Cancer Research Center8, University of Western Ontario9, Pfizer10, University of Helsinki11, GlaxoSmithKline12, University of Tokyo13, University of Maryland, Baltimore14, Genentech15, University of Arizona16
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TL;DR: The most common functional groups that are amenable to prodrug design are described, and examples of prodrugs that are either launched or are undergoing human trials are highlighted.
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References
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Book•
25 May 1984TL;DR: An overview of diffusion and separation processes brings unsurpassed, engaging clarity to this complex topic as mentioned in this paper, which is a key part of the undergraduate chemical engineering curriculum and at the core of understanding chemical purification and reaction engineering.
Abstract: This overview of diffusion and separation processes brings unsurpassed, engaging clarity to this complex topic. Diffusion is a key part of the undergraduate chemical engineering curriculum and at the core of understanding chemical purification and reaction engineering. This spontaneous mixing process is also central to our daily lives, with importance in phenomena as diverse as the dispersal of pollutants to digestion in the small intestine. For students, Diffusion goes from the basics of mass transfer and diffusion itself, with strong support through worked examples and a range of student questions. It also takes the reader right through to the cutting edge of our understanding, and the new examples in this third edition will appeal to professional scientists and engineers. Retaining the trademark enthusiastic style, the broad coverage now extends to biology and medicine.
5,195 citations
TL;DR: The gastrointestinal transit of pharmaceutical dosage forms has been measured in 201 studies in normal subjects using gamma scintigraphy and has implications for the design of dosage forms for the sustained release of drugs in specific positions in the gastrointestinal tract.
Abstract: The gastrointestinal transit of pharmaceutical dosage forms has been measured in 201 studies in normal subjects using gamma scintigraphy. Solutions, small pellets, and single units (matrix tablets and osmotic pumps) were administered with different amounts of food in the stomach, ranging from fasted state to heavy breakfast. Gastric emptying was affected by the nature of the dosage form and the presence of food in the stomach. Solutions and pellets were emptied even when the stomach was in the digestive mode, while single units were retained for long periods of time, depending on the size of the meal. In contrast, measured intestinal transit times were independent of the dosage form and fed state. The small intestinal transit time of about three hours (mean +/- 1 h SEM) has implications for the design of dosage forms for the sustained release of drugs in specific positions in the gastrointestinal tract.
859 citations
TL;DR: In this article, a computer method has been devised to describe the theoretical dissolution rate of a polydisperse powder under non-sink conditions based on its percent weight particle size distribution.
304 citations
TL;DR: The correlation between fraction dose absorbed in humans and Pw* determined from steady-state perfused rat intestinal segments gives an excellent correlation, indicating that Pw*, is one of the key variables controlling oral drug absorption and that the correlation may be useful for estimating oral drugabsorption in humans regardless of the mechanism of absorption.
Abstract: Based on a simple tube model for drug absorption, the key parameters controlling drug absorption are shown to be the dimensionless effective permeability, P
eff
*, and the Graetz number, Gz, when metabolism or solubility/dissolution is not rate controlling. Estimating the Graetz number in humans and assuming that P
aq
* is not rate controlling gives the following equation for fraction dose absorbed: F = 1− e
−2
P*w. The correlation between fraction dose absorbed in humans and P
w
* determined from steady-state perfused rat intestinal segments gives an excellent correlation. It is of particular significance that the correlation includes drugs that are absorbed by passive and carrier-mediated processes. This indicates that P
w
* is one of the key variables controlling oral drug absorption and that the correlation may be useful for estimating oral drug absorption in humans regardless of the mechanism of absorption.
291 citations
TL;DR: It is shown that the extent of drug absorption is expected to be highly variable when Dn and Do are approximately one, and a microscopic mass balance approach has been developed to predict the fraction dose absorbed of suspensions of poorly soluble compounds.
Abstract: A microscopic mass balance approach has been developed to predict the fraction dose absorbed of suspensions of poorly soluble compounds. The mathematical model includes four fundamental dimensionless parameters to estimate the fraction dose absorbed: initial saturation (Is), absorption number (An), dose number (Do), and dissolution number (Dn). The fraction dose absorbed (F) increases with increasing Is, An, and Dn and with decreasing Do. At higher Dn and lower Do, the fraction dose absorbed reaches the maximal F, which depends only on An. The dissolution number limit on F can appear at both lower Do and lower Dn. Likewise, at higher Do and Dn, the fraction dose absorbed reaches a Do limit. Initial saturation makes a significant difference in F at lower Do and Dn. It is shown that the extent of drug absorption is expected to be highly variable when Dn and Do are approximately one. Furthermore, by calculating these dimensionless groups for a given compound, a formulation scientist can estimate not only the extent of drug absorption but also the effect, if any, of particle size reduction on the extent of drug absorption.
242 citations