Bioequivalence study of stressed and nonstressed hard gelatin capsules using amoxicillin as a drug marker and gamma scintigraphy to confirm time and GI location of in vivo capsule rupture.

PURPOSE: Evaluate if crosslinked hard gelatin capsules (HGCs) having different in vitro dissolution profiles changed in vivo release times or altered bioavailability of a drug marker; assess if a two-tier dissolution test (with and without enzyme) predicted in vivo performance. METHODS: Two classifications of stressed HGCs were artificially produced by exposure to formaldehyde (HCHO). HGCs were categorized as, a) pass/pass (p/p) which met in vitro dissolution criterion (75% drug dissolution at 45 min), b) moderately crosslinked fail/pass (f/p) which failed dissolution criterion in the absence of enzymes and passed in the presence of enzymes, and c) severely crosslinked fail/fail (f/f) which failed in vitro standards with or without enzymes. A six-way, single dose bioequivalence study (n = 10) administered the three HGCs under the fasted and fed condition. In vivo capsule rupture and GI transit were monitored via gamma scintigraphy, and blood samples were collected through six hours. RESULTS: Each crosslinked HGC was bioequivalent to the control p/p capsule when using AUC(0-infinity) and Cmax for comparison. Mean in vivo disintegration of the p/p capsule was 7 +/- 5 min for the fasted condition and 11 +/- 7 min for the fed condition. In vivo rupture for the f/p capsule was 22 +/- 12 min and 23 +/- 11 min for the fasted and fed studies, respectively, while the f/f HGC ruptured at 31 +/- 15 min and 71 +/- 19 min under the fasted and fed condition, respectively. Onset of amoxicillin absorption was dependent on in vivo HGC rupture and subsequent entry of the released radioactive marker into the small intestine. Consequently, fasted Tmax values were significantly later for the f/p HGC (1.62 +/- 0.53 hr) and f/f HGC (1.85 +/- 0.58 hr) as compared to the p/p HGC (1.17 +/- 0.30 hr). Fed Tmax values were statistically different only for the f/f capsule (2.55 +/- 0.44 hr) where Tmax values for the p/p and f/p HGCs under the fed condition were 1.50 +/- 0.47 hr and 1.60 +/- 0.46 hr, respectively. CONCLUSIONS: A two-tier dissolution procedure that retested a crosslinked hard gelatin capsule with addition of gastric or intestinal enzymes provided an adequate in vitro indicator of the formulation's in vivo performance. The observed delays in the onset of amoxicillin absorption and Tmax for the severely crosslinked f/f HGC was attributed to delayed in vivo capsule rupture, however, this delay did not adversely change AUC(0-infinity) nor Cmax.

Novel vaginal controlled-delivery systems incorporating coprecipitates of nonoxynol-9.

The purpose of this study was to formulate Nonoxynol-9 (N-9) into a solid coprecipitate form which can be used in preparing pharmaceutically attractive and nonirritating vaginal controlled-release delivery systems (DDSs) such as gelatin capsules (HGC) and tablets. N-9 was coprecipitated with polyvinylpyrrolidone (PVP) with or without iodine to produce solid powders which were incorporated into either (a) bilayer tablet DDSs which possess a fast- (outer) and slow- (inner core) releasing compartment, and (b) HGC DDSs (named Triad HGC) composed of fast- (outer), intermediate- (granules), and slow- (pellets) releasing compartments. The rates of release of iodine and/or [14C]N-9 from the two DDSs were studied in vitro in phosphate buffer at pH 5.0, in human seminal plasma and in vivo after intravaginal administration in rabbits. In all of the above-described release studies, the DDSs were shown to release their N-9 or iodine content rapidly, reaching spermicidal levels within 3 min. This was further substantiated by experiments in which the DDSs were introduced in whole human semen containing live spermatozoa. Complete spermicidal kill was obtained in less than 1 min and in less than 3 min from the bilayer tablet and the Triad HGC, respectively. Furthermore, the release of N-9 from the two DDSs was shown to continue for at least 4 hr in buffers (pH 5.0), human seminal fluid, and after intravaginal administration in rabbits. The resulting powder from the coprecipitation of N-9 and PVP (K-30) can be appropriately formulated into a controlled-released HGC or bilayer tablet to produce vaginal controlled-release DDSs which are nonirritating and have the potential to become effective spermicidal products.

Increased 252Cf therapeutic advantage for an advanced murine lymphoma (LSA) growing in vivo.

The relative biological effectiveness (RBE) was determined for 252Cf irradiation of the murine LSA lymphoma growing in vivo. Irradiation was performed on Days 1-3, i.e. on the young and rapidly growing tumour, on Day 5, i.e. the early stationary phase, or on Day 7, i.e. the advanced tumour. Mice inoculated with 10(5) cells would die on about Day 9 with disseminated tumour if untreated. Irradiation with acute 60Co or low-dose-rate 252Cf total-body irradiation increased the mean survival time (MST). For 252Cf the MST increased linearly with dose, the effectiveness being independent of the day of irradiation. For 60Co, the MST increased linearly with dose for the tumours irradiated on Days 1-3 but two-component curves were noted after irradiation on Days 5-7. Tumour response showed an increasing photon-resistant component which gave no increase in MST with dose. The RBE was approximately 4 for the early tumours but was greater than 5 for the advanced and more photon-resistant tumours. 252Cf was effective for the treatment of early or advanced stages but was especially effective against the advanced, more radioresistant tumours.