Modification of Gelatin Beadlets for Zero-Order Sustained Release

A three-phase suspension process was used for the preparation of gelatin beadlets containing succinylsulfathiazole. When the beadlets were hardened with 10% formalin at 5°C for varying periods of time up to 24 hr, the 6-hr hardening time gave the slowest release rate. Drug release rate from gelatin beadlets was slower in simulated gastric fluid (SGF) than in simulated intestinal fluid (SIF) but the sustained effect was too limited to be useful for most applications. When the hardened gelatin beadlets were coated with cellulose acetate butyrate (CAB) by an emulsion–solvent evaporation method, a more pronounced sustained effect and a nearly zero-order release were found in SIF. The effects of the amount of gelatin used, the amount of CAB employed, and the length of hardening time on drug release were investigated. The treatment of gelatin beadlets with formalin reduced the swelling action of gelatin in aqueous medium. A nonzero-order drug release rate was observed when the gelatin swelled sufficiently to rupture the CAB coating. The drug release rate can be adjusted by using different ratios of hardened gelatin beadlets and CAB coating in which the gelatin enhances the release rate and the CAB serves as a barrier.     

Choline increases endogenous GABA release in rat hippocampus by a mechanism sensitive to hemicholinium-3

Summary The effects of choline (Ch) on the spontaneous release of endogenous 7-aminobutyric acid (GABA) and of ³H-GABA were studied in superfused rat hippocampal synaptosomes. Choline enhanced in a concentration-dependent way the release of endogenous GABA but did not affect that of the radioactive aminoacid. The effect of Ch was not antagonized by atropine or mecamylamine; moreover, it was not mimicked by acetylcholine, oxotremorine or carbachol. The Ch-induced GABA release was counteracted by hemicholinium-3. Thus the release of endogenously synthesized GABA (but not that of the aminoacid taken up) may be regulated by Ch through a mechanism involving penetration into the releasing terminal through a Ch uptake system. Send offprint requests to M. Raiteri     

Effect of perchlorate on calcium release in skinned fibres stimulated by ionic substitution and caffeine

We have determined the effects of the perchlorate ion on the contracture of skinned (sarcolemma removed) skeletal muscle fibres, stimulated either by ionic substitution or caffeine. Calcium release was monitored in single cells by measuring the peak height of tension transients. Perchlorate significantly sensitizes fibres to activation by ionic substitution, a manipulation that is thought to trigger calcium release via the normal physiological pathway. Adding 0.8 mM perchlorate to the solutions shifted the curve relating the magnitude of ionic substitution to the level of activation leftward, such that smaller stimuli were needed to produce a contracture of a given height. Perchlorate could also trigger a contracture directly. Exposing fibres to 1.0 mM perchlorate caused contractures averaging 60% of bracketing controls. In contrast to contractures stimulated by ionic substitution, those triggered by caffeine were unaffected by perchlorate. Since caffeine is thought to act directly on the sarcoplasmic reticulum to cause calcium release, these results suggest that perchlorate enhances activation in skinned fibres by interacting with transverse tubular membranes.     

In Vitro Release Profile of Mitomycin C from Albumin Microspheres: Extrapolation from Macrospheres to Microspheres

To analyze the in vitro release profiles of mitomycin C from albumin microspheres prepared by chemical denaturation in a multiparticulate system, a method to calculate the total cumulative amount of mitomycin C released from a batch of microspheres was developed. Mitomycin C-loaded albumin macrospheres (diameter in mm range) were prepared, and the in vitro release kinetics of mitomycin C from individual macrospheres were determined. Then the relationship between the kinetic parameters and the physical parameters (e.g., diameter, weight) was investigated under the assumption that macrospheres and microspheres behave identically. Further, the size distribution of microspheres was measured, and the total cumulative amount of mitomycin C released from albumin microspheres was calculated. The release profiles of mitomycin C from individual macrospheres fitted first-order release kinetics better than spherical matrix kinetics. The calculated initial mitomycin C contents and first-order release rate constants for individual macrospheres were correlated with the weight and reciprocal of surface area of the macrospheres, respectively. The observed in vitro release profile for the microspheres agreed with the calculated values. These results suggest that this method is valid for calculating drug release from albumin microspheres.     

苯妥英钠缓释片溶出度的研究

本文研究了苯妥英钠缓释片的处方、制备工艺。溶出度达到USP ⅩⅪ版苯妥英钠缓释胶囊在水中的溶出要求。即在30min溶出标示量的15～35%,60min溶出标示量的30～70%,120min溶出不低于标示量的75%。在2h内溶出曲线呈现一级线性关系。     

Short- and long-term fluoride release from glass ionomer based liners

Abstract— The aim of the study was to measure the fluoride release from glass ionomer based liners/bases after storing the specimens for 24 h and for 6 months in running water. The fluoride release was greater in the beginning than after half a year. From most liner materials the initial and the long-term release was greater than from the glass ionomer filling material studied for comparison. From two liners the release was minimal, just at the detection limit.     

A comparative pharmacokinetic and pharmacodynamic study of conventional and sustained-release preparations of acebutolol in healthy volunteers

Pharmacokinetics and the degree of beta-blockade of sustained release (SR) acebutolol (500 mg/day) and conventional acebutolol (200 mg tid) were examined after the first oral dose and after 10 days of treatment in ten healthy volunteers. After the first dose, acebutolol Cmax did not significantly differ between the two formulations; however, on day 10 acebutolol Cmax was significantly higher after SR formulation. Cmax of diacetolol, the major metabolite, did not differ between SR and conventional acebutolol neither on day 1 nor on day 10. The dose-corrected relative bio-availability of acebutolol was not different from 100% on day 1 and day 10; however the dose-corrected diacetolol AUC, SR/conventional ratio, was significantly lower than 100% on days 1 and 10. Both acebutolol preparations exerted a significant reduction in exercise tachycardia over 24 h on day 1 and day 10; however, conventional acebutolol exhibited a greater reduction 24 h after the first dose. Exercise-induced increase in systolic blood pressure was similarly inhibited by both treatments except for 24 h after the first dose when systolic blood pressure was significantly higher with SR than with conventional acebutolol. The percent reduction in heart rate during exercise was linearly correlated with log acebutolol plasma concentrations for each treatment regimen. These results suggest that beta-blockade exerted by SR acebutolol in healthy volunteers is equivalent to that of conventional acebutolol.     

In vivo voltammetric studies on release mechanisms for cocaine with γ-butyrolactone

The effect of cocaine (20 mg/kg SC) on presynaptic mechanisms of release for dopamine (DA) and for serotonin (5-HT) was studied in nucleus accumbens of unrestrained rats (Rattus norvegicus). The studies were done by assaying synaptic concentrations of DA and 5-HT in the presence of the neuronal impulse flow inhibitor, γ-butyrolactone (γ-BL). The results were compared with cocaine effects on accumbens DA and 5-HT in the freely moving rat, without γ-BL treatment. A neurochemical time course profile showed that the cocaine-induced increase in accumbens synaptic concentrations of DA was significantly blocked (p<0.0001) after DA impulse flow was significantly inhibited (p<0.0038) by γ-BL (35.8%). The neurochemical time course profile concurrently showed that the cocaine-induced decrease in accumbens synaptic concentrations of 5-HT was significantly blocked (p<0.0004) after impulse flow was significantly inhibited (p<0.025) by γ-BL (50.6%). The findings show that cocaine's effects on synaptic concentrations for DA and for HT in accumbens are dependent on neuronal impulse flow. The findings indicate that presynaptic releasing mechanisms, which may be different for DA vis-à-vis 5-HT, play a role in the mechanism of action of cocaine.     

Enhancement of glutamate release in the rat striatum following electrical stimulation of the nigrothalamic pathway

The release of unlabelled amino acids and newly synthesized [3H]dopamine was estimated in the striatum of halothane-anaesthetized rats superfused using a push-pull cannula. Electrical stimulation of the substantia nigra pars reticulata (SNR), enhanced the release of glutamate (maximal effect +51%) in the ipsilateral striatum. The outflow of [3H]dopamine, aspartate, serine and glutamine was unchanged. Seven-12 days after electrolytic lesion of the ipsilateral ventromedial nucleus of the thalamus SNR, stimulation no longer increased the striatal release of glutamate. It is suggested that electrical stimulation of the SNR enhances the striatal release of glutamate, presumably originating from corticostriatal fibres, by activating a nigrothalamocortical polysynaptic pathway.     

The action of oxygen and oxygen at high pressure on inhibitory transmission

The effect of 100% oxygen at ambient pressure, 100% oxygen at 1.7 Atmospheres Absolute (ATA), 100% oxygen at 5.1 ATA, helium at 1.7 ATA and helium at 5.1 ATA on inhibitory synaptic transmission was studied using the lobster walking leg neuromuscular preparation. Exposure to 100% oxygen at ambient pressure, at 1.7 ATA or at 5.1 ATA produced a decrease in inhibitory transmission manifest as a fall in inhibitory synaptic conductance (Ginh). The largest decrease in Ginh was seen in 100% oxygen at ambient pressure, while a progressively smaller decrease was seen in 100% oxygen at 1.7 ATA and 5.1 ATA, respectively. Also associated with 100% oxygen at ambient pressure was the disappearance of inhibitory junction potentials. Pressurization with helium produced a fall in Ginh at 5.1 ATA but no change or a slight increase at 1.7 ATA. The action of either 100% oxygen at ambient and at 1.7 or 5.1 ATA or helium at 1.7 or 5.1 ATA was shown to be on presynaptic parameters since the percent decrease in Ro induced by exogenous application of gamma-aminobutyric acid (GABA), the inhibitory transmitter, was the same in either 100% oxygen at ambient pressure, 100% oxygen or helium at 1.7 ATA and 5.1 ATA. The similarity in action of oxygen to the action of isoniazid, a known glutamic acid decarboxylase (the enzyme that catalyzes the production of GABA) inhibitor in the same preparation suggests that one possible site of oxygen action is on GABA production.