Colin R. Gardner

Controlled Gastric Emptying. 1. Effects of Physical Properties on Gastric Residence Times of Nondisintegrating Geometric Shapes in Beagle Dogs

The importance of three physical parameters (size, shape, and flexibility) on gastric retention in fasting dogs was examined to assess the feasibility of designing a dosage form to achieve a consistent and predictable residence in the stomach. Test shapes were molded from Silastic elastomer or made from extruded polyethylene or polyethylene blends and included 15% barium sulfate for X-ray visualization. Beagle dogs were dosed with test shapes administered in gelatin capsules. Gastric retention was monitored by X ray over a 24-hr period. Six shapes (ring, tetrahedron, cloverleaf, disk, string, and pellet) were screened in vivo for their gastric retention potential. The tetrahedrons (each leg 2 cm in length) exhibited 91–100% retention at 24 hr. The rings (3.6-cm diameter) provided 100% retention at 24 hr. Rings and tetrahedrons of varying flexural moduli were prepared by blending low-density polyethylene and ethylene: vinyl acetate copolymer. A positive correlation existed between flexural modulus and gastric retention. The results indicate that it is feasible to design a platform for a dosage form that can be administered to beagle dogs in capsule form and be retained for 24 hr.

Potential and limitations of drug targeting: An overview

Potential and limitations of current efforts in drug targeting are discussed in terms of the criterion that targeting strategies must ultimately be gauged by their success in producing selectivity of pharmacological response thereby reducing or eliminating side effects which are not mechanism-related. A wide variety of approaches are considered, including: local drug administration, differential metabolism, carriers and vehicles, macromolecular recognition, site-specific activation and molecular specificity. Each approach is briefly assessed for its potential to be developed as a realistic candidate for human health care.

In Vitro Drug Absorption Models. II. Salicylate, Cefoxitin, α-Methyldopa and Theophylline Uptake in Cells and Rings: Correlation with In Vivo Bioavailability.

Isolated mucosal cells and everted intestinal rings have been examined as potential in vitro models for intestinal drug absorption. The uptake of salicylate, cefoxitin, α-methyldopa and theophylline was characterized on the basis of time, concentration and temperature dependence and compared to in vivo drug absorption. Theophylline was well absorbed in all systems. Biochemical studies supported a passive transport mechanism, although a significant temperature dependence was observed. Salicylate, cefoxitin and α-methyldopa demonstrated time- and concentration-dependent absorption. The uptake of α-methyldopa was temperature-dependent in both the isolated cell and ring studies. With all drugs, cellular uptake exhibited greater variability than drug accumulation in rings. A comparison of in vitro and in vivo absorption demonstrated a good correlation between the data from in vivo studies and intestinal rings. Cellular drug uptake did not completely mimic that observed in vivo. On the basis of technical aspects of preparation, reproducibility of results, and correlation with in vivo drug bioavailability, everted intestinal rings were judged to be the best in vitro model for intestinal drug absorption.

Controlled Gastric Emptying. II. In Vitro Erosion and Gastric Residence Times of an Erodible Device in Beagle Dogs

An erodible gastric retention device fabricated from various polymeric blends was examined in vitro for its dissolution properties and in vivo in fasting dogs for assessment of its gastric retention potential. Dissolution studies were conducted with extruded rods of polymer blends to assess their potential as candidates for the erodible component of a gastrically retained device. Based on results from dissolution studies, rods of poly(ortho ester)/polyethylene blends (POE/PE) (45% erosion at pH 1.5 and 24 hr) were used to fabricate arms for tetrahedron-shaped devices. Corners for the tetrahedral device were fabricated from Silastic 382 loaded with 15% barium sulfate for X-ray visualization. Beagle dogs were dosed with tetrahedron-shaped test devices administered in gelatin capsules and gastric retention monitored by X ray over a 24-hr period. A comparison of in vitro erosion rates and in vivo performance of various polymer blends indicated a definite trend for increased gastric retention of devices made from the more slowly eroding blends. The results indicate that the blending of erodible and nonerodible polymers is a valid approach for obtaining materials that will provide the necessary structural properties to achieve gastric retention yet lose integrity within a desired time.

Gastrointestinal Barrier to Oral Drug Delivery

During the last ten to twenty years there have been major changes in the drug discovery process. As a result of a greater understanding of the pathology and biochemical defects responsible for disease processes the drug industry has moved from large scale screening operations to much more rational approaches to drug design in which active molecules are synthesized and tested on the basis of in vitro measurements of interactions with specific receptors or enzymes. While this process is very efficient in defining and refining structures active at the desired target site, it leaves problems of drug delivery largely unexplored until active lead compounds are tested in whole animal models. Questions of rate and extent of absorption, degree of pre-systemic metabolism and optimal delivery pattern are critical to the success of a therapeutic agent and deserve important attention in the development of new drug entities.