Post-marketing drug surveillance--concepts, insights and applications.

At the present drug approval process consists of preclinical animal testing, followed by three phases of clinical testing. Phase I is usually conducted on non-patient volunteers; phase II involves administration of the drug to a small number of selected patients; and phase III is the final premarketing test of the drug's safety and efficacy. These trials have major limitations, such as restricted patient populations, limited duration of patient exposure, and limited patient numbers. Considerable information remains unknown after the end of phase III testing, including: less common adverse effects; delayed adverse effects; efficacy and toxicity in types of patient usually excluded from premarketing testing, e.g. children, pregnant women and old people; efficacy and toxicity in patients with other illnesses and/or ingesting other drugs; efficacy and toxicity relative to other drugs used for the same purpose; efficacy and toxicity when used for indications other than those initially tested; the toxic effects of a massive overdose; physicians' prescribing habits, etc. The attempt to obtain this information after marketing is postmarketing drug surveillance.

Characteristics of hydrogel as disintegrant in solid dose technology.

A comparison between a hydrogel and the disintegrants Ac-di-sol, Avicel, maize starch and Primojel has been made using theophylline as the test drug in direct compression tableting. Results indicate that the disintegrant action of the hydrogel is comparable with that of the other disintegrants used, with no adverse effect on the dissolution of theophylline from these tablets as observed by thermal analysis study. The hydrogel's physicomechanical performance in direct compression processing appears to have no undesirable effect on the physical properties of tablets. Scanning electron micrographs of freeze-etched samples of hydrogel demonstrated its internal structure. These results strongly suggest that hydrogels have great potential as efficient disintegrants in solid dosage formulations.

Dissolution of theophylline from film-coated slow release mini-tablets in various dissolution media.

The dissolution of an experimental formulation of film-coated slow release theophylline mini-tablets has been investigated using the USP paddle apparatus in test media at pH 1.2 (hydrochloric acid), pH 5.4 and 7.4 (phosphate buffers) at 37 degrees C. Monitoring of in-vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in less than 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in-vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasize the usefulness of an animal model for assessment of in-vivo drug release and subsequent absorption, during the development of modified release dosage forms.

Irritation associated with tear-replacement ophthalmic drops. A pharmaceutical and subjective investigation.

Artificial tears, commonly prescribed for correction of the dry-eye syndrome, are formulated with suitably preserved aqueous polymeric solutions to promote corneal wetting without causing such side-effects as burning, itching, blurred vision and scratchiness. Four of the most commonly used commercial tear-replacement solutions were investigated after complaints of irritation by some users. The solutions were tested for tonicity, viscosity and pH and found to be in the tolerable range (tonicity equivalent to 0.5-1.5% m/v sodium chloride, viscosity 1-15 centipoise and pH 4-9). A double-blind cross-over study was conducted on 16 subjects and the degree of discomfort (non-irritant, irritant, and highly irritant) was determined subjectively. Results indicated that 3 of the tear solutions were acceptable. However, over 50% of the subjects reported irritation from the solution comprising polyvinyl alcohol 1.4% m/v preserved with 0.5% m/v chlorobutanol. To identify the cause of irritation, two extemporaneously prepared controls containing polyvinyl alcohol 1.4% m/v, with and without chlorobutanol 0.5% m/v as preservative, were also included in the study. The irritant response was found to be caused by the presence of chlorobutanol in the formulation. An attempt is made to identify and explain formulation properties likely to elicit adverse responses.

Influence of gamma radiation on the gel rigidity index and binding capability of gelatin.

Changes in the rigidity indices of gelatin gel before and after gamma irradiation were characterized by dynamic mechanical testing, and the significance of these changes on the strength of granules was evaluated. Results illustrate the difficulty of obtaining reproducible values for gels containing less than 20% gelatin. However, rigidity indices for gels with a gelatin content of 20% and higher are consistent and may provide a useful controlling factor for preparation of gelatins of more precise specifications. The data indicate that rigidity degradation kinetics of several concentrations of gelatin gel at different radiation doses are complex, showing both increasing and decreasing rates. These findings strongly suggest that doses of less than 2.0 Mrad of gamma radiation should be used in order to obtain gelatins of acceptable quality for pharmaceutical applications. The crushing strength of granules of lactose powder granulated with irradiated gelatin reveals that the binding capability of such gelatin is significantly reduced. The results obtained for various size fractions and granule hardnesses containing different binder concentrations also suggest that particle size influences the granule strength to a lesser extent than does binder concentration and its consistency.

Inimical effects of compaction speed on microorganisms in powder systems with dissimilar compaction mechanisms.

Tablets were prepared from powders that were consolidated by plastic deformation and fragmentation mechanisms. Cells of Staphylococcus aureus and spores of Bacillus subtilis were incorporated in the tablets by compaction at various pressures and compression speeds. The extent of inactivation of organisms was dependent on the compression behavior of the powders, on the speed of compaction, and on the degree of densification of compacts. Scanning electron micrographs of fractured compacts revealed that particle rearrangement, fragmentation, and deformation significantly influence the "survivor". The "pressure-survivor plots" showed a linear relationship with greater inactivation in brittle material, while the extent in inactivation was reduced, and followed a nonlinear pattern in those powders exhibiting plastic deformation.