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Journal ArticleDOI

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.

AbstractA 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.

Topics: Dissolution testing (66%), Biopharmaceutics Classification System (61%), Drug (51%), In vivo (51%), Bioavailability (50%)

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Journal ArticleDOI
TL;DR: Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions, as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.
Abstract: Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

2,602 citations


Journal ArticleDOI
TL;DR: Of specific interest is the use of cyclodextrin-containing polymers to provide unique capabilities for the delivery of nucleic acids.
Abstract: Cyclodextrins are cyclic oligomers of glucose that can form water-soluble inclusion complexes with small molecules and portions of large compounds. These biocompatible, cyclic oligosaccharides do not elicit immune responses and have low toxicities in animals and humans. Cyclodextrins are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current cyclodextrin-based therapeutics are described and possible future applications discussed. Cyclodextrin-containing polymers are reviewed and their use in drug delivery presented. Of specific interest is the use of cyclodextrin-containing polymers to provide unique capabilities for the delivery of nucleic acids.

1,526 citations


Journal ArticleDOI
TL;DR: This review is intended to give a general background to the use of cyclodextrin as solubilizers as well as highlight kinetic and thermodynamic tools and parameters useful in the study of drug Solubilization bycyclodextrins.
Abstract: Cyclodextrins are useful functional excipients that have enjoyed widespread attention and use. The basis for this popularity from a pharmaceutical standpoint, is the ability of these materials to interact with poorly water-soluble drugs and drug candidates resulting in an increase in their apparent water solubility. The mechanism for this solubilization is rooted in the ability of cyclodextrin to form non-covalent dynamic inclusion complexes in solution. Other solubilizing attribute may include the ability to form non-inclusion based complexes, the formation of aggregates and related domains and the ability of cyclodextrins to form and stabilize supersaturated drug solutions. The increase in solubility also can increase dissolution rate and thus improve the oral bioavailability of BCS Class II and IV materials. A number of cyclodextrin-based products have reached the market based on their ability to camouflage undesirable physicochemical properties. This review is intended to give a general background to the use of cyclodextrin as solubilizers as well as highlight kinetic and thermodynamic tools and parameters useful in the study of drug solubilization by cyclodextrins.

1,518 citations


Journal ArticleDOI
TL;DR: It is concluded that Caco-2 monolayers can be used to identify drugs with potential absorption problems, and possibly also to select drugs with optimal passive absorption characteristics from series of pharmacologically active molecules generated in drug discovery programs.
Abstract: This review examines the use of Caco-2 monolayers in the prediction of intestinal drug absorption. First, the different routes of drug transport in Caco-2 monolayers are compared with those seen in vivo. Second, the prediction of drug absorption in vivo from transport experiments in cell monolayers is discussed for different classes of drugs. Finally, the use of Caco-2 monolayers as a reference model in physico-chemical and theoretical predictions of drug absorption is discussed. We conclude that Caco-2 monolayers can be used to identify drugs with potential absorption problems, and possibly also to select drugs with optimal passive absorption characteristics from series of pharmacologically active molecules generated in drug discovery programs.

1,316 citations


Journal ArticleDOI
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.
Abstract: Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

1,226 citations


Cites background from "A Theoretical Basis for a Biopharma..."

  • ...F a is largely controlled by the physicochemical parameters of the parent or prodrug, that is, its gastrointestinal permeability, solubility, dissolution rate and dose numbe...

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References
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Book
25 May 1984
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.

5,085 citations


Journal ArticleDOI
01 Aug 1986-Gut
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.

823 citations


Journal ArticleDOI
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.

284 citations


Journal ArticleDOI
Abstract: 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. This method was used to estimate the particle size distribution of drug contained in 3 capsule formulations which differed only in the extent of milling of drug used to make the capsules. These distributions served to demonstrate the effect of milling on dissolution rate and were used to simulate their effect on the amount of drug absorbed orally.

273 citations


Journal ArticleDOI
TL;DR: It was shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment and the low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption.
Abstract: Recently a new in vivo approach in man, using a regional intestinal perfusion technique, has been developed. The perfusion tube consists of a multichannel tube with two inflatable balloons, which are placed 10 cm apart. The tube is introduced orally and the time required for insertion and positioning of the tube is approximately 1 hr. In the present study eight healthy subjects were perfused in the proximal jejunum on three separate occasions. The first two perfusion experiments used the same flow rate, 3 ml/min, and the third experiment used 6 ml/min. Phenazone (antipyrine) was chosen as the model drug. The recovery of PEG 4000 in the outlet intestinal perfusate was complete in experiments 1 and 2, but slightly lower (90%) when the higher flow rate was used. The mean (+/- SD) fraction of phenazone absorbed calculated from perfusion data was 51 +/- 12% (3 ml/min), 64 +/- 19% (3 ml/min), and 42 +/- 27% (6 ml/min) for the three experiments, respectively. The mean fraction absorbed estimated by deconvolution of the plasma data was 47 +/- 16%, 51 +/- 19%, and 38 +/- 26%, respectively. The effective permeability of phenazone was 5.3 +/- 2.5, 11 +/- 6.8, and 11 +/- 12 (x 10(4) cm/sec, respectively. We have shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment. The low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

229 citations