Showing papers by "Gordon L. Amidon published in 1993"

Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: a mathematical model.

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.

Multi-stage drug delivery system

Abstract: A drug delivery system includes a first capsule half having an inner chamber for containing a drug therein. A plug is disposed in a passageway of the capsule half for plugging the opening thereof. The plug is releasable from the passageway opening upon the application of pressure from within the inner chamber. A pump mechanism causes an increase in pressure within the inner chamber and forces the plug out of the passageway to release the drug from the inner chamber and out of the passageway thereby providing a second pulse of drug release at a predetermined time after initial ingestion of the capsule. The invention further provides a method of manufacturing the drug delivery system and method by which the drug delivery system provides the drug to the body.

An Investigation into the Mechanical and Transport Properties of Aqueous Latex Films: A New Hypothesis for the Film-Forming Mechanism of Aqueous Dispersion System

Abstract: The effects of plasticizer, physical aging, and film-forming temperature on the mechanical and transport properties of films formed from aqueous dispersions of ethylcellulose latex were investigated. The water vapor permeability of latex films was found to decrease with diethyl phthalate to a minimum value and then to increase with diethyl phthalate at higher concentrations. Because of the decrease in free volume and the further coalescence of particles of latex polymer films in the physical aging range, the creep compliance of latex films decreased with physical aging time. Within 60 to 100 degrees C, the film-forming temperature was found to have no effect on the mechanical and transport properties of Aquacoat films. However, since many pinholes formed in the latex films when the film-forming temperature was above 100 degrees C, the water vapor permeability of latex films was higher than that of latex films formed between 60 and 100 degrees C. The formation of films from aqueous latex dispersions is suggested to proceed gradually from the top to the bottom of the latex dispersion in this study.

Peptide Carrier-Mediated Transport in Intestinal Brush Border Membrane Vesicles of Rats and Rabbits: Cephradine Uptake and Inhibition

Abstract: The uptake kinetics of cephradine, an amino-beta-lactam antibiotic, were studied in rat and rabbit intestinal brush border membrane vesicles preparations using both the Ca2+ and the Mg2+ methods of preparation, in the presence of an inward proton gradient. The Ca2+ method demonstrated greater uptake of cephradine in intestinal brush border vesicles prepared from both rat and rabbit and was used for these studies. The transport was observed to be of Michaelis-Menten carrier-mediated type with a passive transport component. The kinetic parameters obtained were as follows: for rat and rabbit, respectively, Km, 1.6 and 1.9 mM; Jmax', 1.7 and 20.7 nmol/mg/min; Pc' (= Jmax'/Km), 1.1 and 10.9 microL/mg/min; and Pm', 0.4 and 0.8 microL/mg/min. The kinetic parameters for the rat vesicles are consistent with those from our previous perfusion study using a conversion factor of 0.71 cm2/mg protein. The rabbit vesicles exhibited a similar Michaelis constant and a 10-fold larger maximal transport velocity, suggesting a quantitative advantage for the study of carrier-mediated transport in the rabbit compared to rat vesicles from the intestine. Cephradine uptake was inhibited by phenylpropionylproline, a proline derivative, and enalapril, an ACE inhibitor, which do not have an alpha-amino group, as well as dipeptides, tripeptides, and amino-beta-lactam antibiotics in both rat and rabbit vesicles. These results support the suggestion that they share the same peptide carrier pathway for oral absorption and that the vesicles may be a useful tool in developing orally effective peptide-type drugs.

Mass balance approaches for estimating the intestinal absorption and metabolism of peptides and analogues: theoretical development and applications.

Abstract: A theoretical analysis for estimating the extent of intestinal peptide and peptide analogue absorption was developed on the basis of a mass balance approach that incorporates convection, permeability, and reaction. The macroscopic mass balance analysis (MMBA) was extended to include chemical and enzymatic degradation. A microscopic mass balance analysis, a numerical approach, was also developed and the results compared to the MMBA. The mass balance equations for the fraction of a drug absorbed and reacted in the tube were derived from the general steady state mass balance in a tube: [formula: see text] where M is mass, z is the length of the tube, R is the tube radius, Pw is the intestinal wall permeability, kr is the reaction rate constant, C is the concentration of drug in the volume element over which the mass balance is taken, VL is the volume of the tube, and vz is the axial velocity of drug. The theory was first applied to the oral absorption of two tripeptide analogues, cefaclor (CCL) and cefatrizine (CZN), which degrade and dimerize in the intestine. Simulations using the mass balance equations, the experimental absorption parameters, and the literature stability rate constants yielded a mean estimated extent of CCL (250-mg dose) and CZN (1000-mg dose) absorption of 89 and 51%, respectively, which was similar to the mean extent of absorption reported in humans (90 and 50%). It was proposed previously that 15% of the CCL dose spontaneously degraded systematically; however, our simulations suggest that significant CCL degradation occurs (8 to 17%) presystemically in the intestinal lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Viscoelasticity of anionic polymers and their mucociliary transport on the frog palate

Abstract: The influence of formulation variables on the rheology of polyanionic formulations and the relationships between viscoelastic properties and mucociliary transport rate were investigated. Polymeric samples were oscillated from 0.001 to 5 Hz using either a "cone and plate” or a "coaxial cylinder” measuring system. The mucociliary transport rates of polymeric samples were determined and compared movement of charcoal powder on the frog palate. For the linear polymeric solutions, sodium carboxymethylcellulose and sodium alginate, the elastic modulus (G′) increased with increasing amplitudes during frequency scan. However, the G′ or viscous modulus (G″) of partially cross-linked polyacrylic acid (cPAA) samples did not change significantly under oscillation. Both G′ and G″ of cPAA samples were significantly influenced by the amount of salt present in the formulation. The rheology of 2% (w/w) cPAA in 90:10 (w/w) propylene glycol:alcohol changed from a viscous fluid to a coarse suspension after neutralization. The pH increased gradually when the nonaqueous formulation reacted with water and the maximum dynamic moduli were obtained after incorporating 20% (w/w) water in the formulation. A negative correlation was found between the G′ of linear polyanionic samples and the relative transport rate. However, the lowest mucociliary transport rate was observed when the loss tangent (G″/G′) was around 0.4–0.5.

Determinants of the Modulated Release of Antiarrhythmic Drugs by Iontophoresis through Polymer Membranes

Abstract: For the purpose of preventing progressive ventricular arrhythmias, iontophoretic delivery of several antiarrhythmic drugs (classes I-IV) and a model cationic drug, (*)-phenylpropanolamine (PPA), through polymer membranes was investigated. Rate-limiting membranes were prepared by mixing simple cation-exchange resin into silicone rubber matrices. Transport of the drug cations was evaluated at 37 "C as a function of drug size and external salt concentration by using diffusion cells, a constant current source, a digital multimeter, and Ag/AgCl electrodes. Release of the antiarrhythmic agents d-sotalol and lidocaine through the above membranes was modulated over 2.5- and 6-fold ranges as a function of input current at doses and response times that were consistent with prior investigations of therapeutic epicardial drug delivery in dogs. The application of a negative current (opposing the movement of drug) reduced the delivery rate of PPA relative to the zero-current rate, and a 13-fold range of release rates was observed for this species over the entire current interval (-20 to +80pA). The reduced drug conductance (TD), ameasure of the relative membrane permeability for the drug to Na+, was found to decrease with increasing molecular mass with a particularly sharp decline between (*)-acebutolol (MM = 327 amu, and ~ABL = 0.011 * 0.002) and (*I- verapamil (MM = 456 amu, and yvp~ = O.OOO6 * 0.0002). Increasing external salt concentration from 0.01 M NaCl to Stirensen buffer pH 7.3, increased membrane conductance (KN~+ = 1.04 * 0.08 to 12 i 1 kW) but only marginally reduced membrane water content and membrane permselectivity for Na+. The release of lidocaine was controlled at clinically relevant doses (0.8 to 5.0 mg/h) and response times (-30-60 min) under rigorous conditions (0.15 M LDN hydrochloride into Stirensen buffer, pH 7.3). Hence, iontophoresis through these membranes may be a valuable approach for the development of clinically useful modulated epicardial release implants.