Slow Release Component Research Articles

Development and characterization of bimodal chrono modulated drug delivery of methylphenidate hydrochloride

The study's goal was to develop chrono modulated pulsatile tablets of methylphenidate hydrochloride with an extended-release pattern in the morning and an immediate burst release in the afternoon for exaggerated symptoms of attention deficit hyperactivity disorder match the circadian rhythm of disease, where high levels of l-3, 4-dihydroxyphenylalanine (DOPA) are observed in the afternoon, necessitating higher drug concentrations. The core tablets were made with Kollidon CL-SF as a super disintegrant at 4% and 8% concentrations, with microcrystalline cellulose PH 102 (Pharma grade) and Ludipress as diluents.The core tablets were then compress coated with a slow-release component blend containing different grades of hydroxypropyl methylcellulose (HPMC) at various concentrations of HPMC E50, HPMC E15M, or HPMC E4M, as well as 4% Ethocel. Among all formulations, the F10 formulation containing HPMC E50 at 70% showed the best drug release, with 60% of the dose released slowly over 4 h, followed by an immediate burst of the remaining 40% at the 5th hour. The effect of different diluents on in vitro drug release kinetics and in vitro dissolution studies were performed for all formulations, and A1 formulation containing Cellactose-80 as a diluent showed the best results, with results matching the circadian variations in the disease condition.

Population pharmacokinetics of immediate-release and modified-release paracetamol and its major metabolites in a supratherapeutic dosing study

Objectives Overdose with paracetamol modified-release (MR) formulation, a bilayer tablet containing 69% slow-release component, has been increasing since its introduction to the market. However, little evidence exists for the management of MR paracetamol overdose. We aimed to develop a population pharmacokinetic (PK) model for immediate-release (IR) and MR paracetamol and its major metabolism, and quantitatively understand the formulation difference in toxicity assessment based on the nomogram line. Methods Data from a cross-over study design in nine healthy volunteers administered a single supratherapeutic oral dose (80 mg/kg) of either IR and MR paracetamol were available from a published study. Plasma concentrations for paracetamol and its metabolites glucuronide (APAPG) and sulfate conjugate (APAPS) for both formulations were measured and analysed with population pharmacokinetic (PK) method using NONMEM. Toxicity in both formulations was assessed by comparing the simulated paracetamol concentrations under different paracetamol dose levels with the 150 mg/L nomograms. The difference in the assessment was compared between the two formulations. Results Paracetamol concentrations for the IR formulation were described with a two-compartment model with first-order input and a lag time. The delayed time-course of MR paracetamol concentrations was best captured by a parallel absorption model in which the slow-release component was a serial zero-order then the first-order process. The formation of APAPG was linear, while APAPS concentrations were best fitted by a Michaelis-Menten process. The relative bioavailability of MR paracetamol compared to IR () was estimated as 0.81. The simulated probability of making different toxicity assessments based on nomogram line was increased with dose levels and was as high as 14.6% after 22 g IR or MR paracetamol ingested. Conclusions A joint parent-metabolite model to describe time-course profiles of both IR and MR paracetamol and its metabolites APAPG and APAPS concentrations was developed. Simulations from the model showed that toxicity assessment based on the 150 mg/L nomograms is not suitable in MR paracetamol overdoses.

A Sequential Vesicle Pool Model with a Single Release Sensor and a Ca2+-Dependent Priming Catalyst Effectively Explains Ca2+-Dependent Properties of Neurosecretion

Neurotransmitter release depends on the fusion of secretory vesicles with the plasma membrane and the release of their contents. The final fusion step displays higher-order Ca2+ dependence, but also upstream steps depend on Ca2+. After deletion of the Ca2+ sensor for fast release – synaptotagmin-1 – slower Ca2+-dependent release components persist. These findings have provoked working models involving parallel releasable vesicle pools (Parallel Pool Models, PPM) driven by alternative Ca2+ sensors for release, but no slow release sensor acting on a parallel vesicle pool has been identified. We here propose a Sequential Pool Model (SPM), assuming a novel Ca2+-dependent action: a Ca2+-dependent catalyst that accelerates both forward and reverse priming reactions. While both models account for fast fusion from the Readily-Releasable Pool (RRP) under control of synaptotagmin-1, the origins of slow release differ. In the SPM the slow release component is attributed to the Ca2+-dependent refilling of the RRP from a Non-Releasable upstream Pool (NRP), whereas the PPM attributes slow release to a separate slowly-releasable vesicle pool. Using numerical integration we compared model predictions to data from mouse chromaffin cells. Like the PPM, the SPM explains biphasic release, Ca2+-dependence and pool sizes in mouse chromaffin cells. In addition, the SPM accounts for the rapid recovery of the fast component after strong stimulation, where the PPM fails. The SPM also predicts the simultaneous changes in release rate and amplitude seen when mutating the SNARE-complex. Finally, it can account for the loss of fast- and the persistence of slow release in the synaptotagmin-1 knockout by assuming that the RRP is depleted, leading to slow and Ca2+-dependent fusion from the NRP. We conclude that the elusive ‘alternative Ca2+ sensor’ for slow release might be the upstream priming catalyst, and that a sequential model effectively explains Ca2+-dependent properties of secretion without assuming parallel pools or sensors.

Estimation of the release profiles of multi-unit dose tablets of theophylline from the release profiles of their components

Purpose: The objective of this study is to investigate whether the drug release profile of a multi-unit dose form consisting of fast and slow release components can be predicted from the release profiles of their components by simple summation. Method: The fast release component consisted of conventional granules of theophylline made by wet massing the drug powder with starch mucilage (20%w/v). The slow release component consisted of matrix granules of the drug made by triturating the drug powder with melted carnuba wax (i.e. melt granulation). Each type of granules was compressed to tablets of weight 100, 150 or 200mg. To form the multi-unit dosage tablets of drug content 300mg each, the conventional and matrix granules were mixed in the ratio 1:2, 1:1 and 2:1, and compressed. The tablets were subjected to dissolution test and from the experimental release curve the prompt release (m p) in the first 1h, the maximum release (m �) and the time to attain it (t �) were obtained. Result: For a given composition of the multi-unit dose tablets, the theoretical release curve was obtained by summation of the release from each component at the different time intervals. The m p values of the theoretically estimated release curves were generally higher,

Synaptotagmin-1 and -7 are functionally overlapping Ca 2+ sensors for exocytosis in adrenal chromaffin cells

Synaptotagmin-1, the canonical isoform of the synaptotagmin family, is a Ca(2+) sensor for fast synchronous neurotransmitter release in forebrain neurons and chromaffin cells. Even though deletion of synaptotagmin-1 abolishes fast exocytosis in chromaffin cells, it reduces overall secretion by only 20% because of the persistence of slow exocytosis. Therefore, another Ca(2+) sensor dominates release in these cells. Synaptotagmin-7 has a higher Ca(2+) affinity and slower binding kinetics than synaptotagmin-1, matching the proposed properties for the second, slower Ca(2+) sensor. Here, we examined Ca(2+)-triggered exocytosis in chromaffin cells from KO mice lacking synaptotagmin-7, and from knockin mice containing normal levels of a mutant synaptotagmin-7 whose C(2)B domain does not bind Ca(2+). In both types of mutant chromaffin cells, Ca(2+)-triggered exocytosis was decreased dramatically. Moreover, in chromaffin cells lacking both synaptotagmin-1 and -7, only a very slow release component, accounting for approximately 30% of WT exocytosis, persisted. These data establish synaptotagmin-7 as a major Ca(2+) sensor for exocytosis in chromaffin cells, which, together with synaptotagmin-1, mediates almost all of the Ca(2+) triggering of exocytosis in these cells, a surprising result, considering the lack of a role of synaptotagmin-7 in synaptic vesicle exocytosis.

Slow kinetics of InsP 3-induced Ca 2+release: differences between uni- and bi-directional 45Ca 2+ fluxes

The effects of a long-lasting stimulation with inositol 1,4,5-trisphosphate (InsP 3) have been studied in monolayers of permeabilized A7r5 cells. When measured under unidirectional 45Ca 2+ efflux conditions, i.e. in the presence of 2 μM thapsigargin, an initial fast release was observed which then progressively slowed down into a slow phase which persisted for up to 20 min. When measured under bidirectional 45Ca 2+ flux conditions with functional Ca 2+ pumps, a transient phase of re-uptake occurred between the initial fast and the subsequent slow release phase. These kinetics are compatible with intrinsic inactivation of the InsP 3 receptor. However, this inactivation did not prevent the slow release component. The slow component was not due to the accumulation of an InsP 3 metabolite nor to a GTP-dependent translocation of Ca 2+ between stores. The slow release phase was more pronounced when the Ca 2+ pumps were active than when they were inhibited. This observation is compatible with other findings indicating that the InsP 3 receptor is controlled by luminal Ca 2+. The decreasing effectiveness of a 20 min lasting InsP 3 challenge in mobilizing Ca 2+ from less filled stores is most likely due to a progressive depletion of the store and cannot be considered as an experimental artifact caused by a preferential emptying of InsP 3-sensitive Ca 2+ stores. We conclude that the InsP 3 receptor can intrinsically inactivate but that this inactivation is unable to prevent the slow release, which is especially pronounced when Ca 2+ pumps are active.

Pharmacokinetics of Multiparticulate Sustained-Release Diltiazem Preparations in Dogs

The in vivo performance of multiparticulate sustained-release diltiazem preparations [HER-SR(A,B,C)] coated with water-insoluble polymer (ethylcellulose), to control the in vitro dissolution rate, was evaluated in dogs. With a decrease in dissolution rate, HER-SR maintained sustained-release characteristics, although the bioavailability decreased slightly. The bioavailability of HER-SR(A,B,C) was comparable with that of a conventional diltiazem tablet (HER). Plasma diltiazem concentrations for the HER-SR preparations were analyzed with a two-fraction absorption model and the pharmacokinetic characteristics were discussed. From the results, it was considered that HER-SR(B) preparation had desirable pharmacokinetic characteristics as sustained-release diltiazem preparations. The absorption site of the slow-release component of HER-SR(B) in the gastrointestinal tract was examined. Almost all of the component had reached the colon within 5 h of administration, the diltiazem content remaining in the component being approximately 60% of the initial amount. Thus, it was shown that the HER-SR(B) preparation had particular absorption characteristics that resulted in the colon being the part of the gastrointestinal tract most receptive to its release. In vivo release profiles of diltiazem from the HER-SR(B) preparation were calculated by the Wagner-Nelson method, and in vitro and in vivo release profiles of HER-SR(B) were further analyzed with a two-fraction release equation. A close correlation of in vitro and in vivo release profiles of HER-SR(B) was found.

Pharmacokinetics of an oral sustained-release diltiazem preparation.

The pharmacokinetics of a new oral sustained-release diltiazem preparation (HER-SR, QD) was investigated in dogs and humans. The mean plasma diltiazem concentration in dogs after oral administration of HER-SR showed a prolonged plasma concentration and a double peak. The bioavailability of HER-SR compared with that of a conventional diltiazem preparation (HER) in dogs was approximately 80%, a value that is relatively close to that of humans. The plasma diltiazem concentrations with a double peak in dogs were analyzed using multifraction absorption models. The HER-SR preparation was apparently divided into two fractions (14.3 and 85.7 mg) in the gastrointestinal tract, each fraction was absorbed at rate constants of 4.560 and 0.152 h-1, respectively, and the lag time of the slow-release component was 8.3 h. The plasma diltiazem concentration data in humans after repetitive oral administration of HER-SR were also analyzed using multifraction absorption models. The initial amount of the fast- and slow-release components were 14.8 and 85.2 mg, respectively. The absorption rate constants were 0.730 h-1 for the fast-release component and 0.060 h-1 for the slow-release component. The lag time of absorption for the slow-release component was 6.0 h. The pharmacokinetic parameters were close to those obtained in dogs except for Ka1 and Vd/F. The results confirm that HER-SR had desirable pharmacokinetic characteristics as judged from the simulated plasma diltiazem concentration and the peak-to-trough fluctuation (fluctuation parameters) calculated using the simulated plasma diltiazem concentration. In addition, population pharmacokinetics of HER-SR after repetitive oral administration was examined in humans.

Effects of reduced coronary flow on thallium-201 accumulation and release in an in vitro rat heart preparation

To study the relation between myocardial thallium-201 (TI-201) uptake, TI-201 release, and reduced coronary flow, isolated Langendorff rat hearts (n = 8) were perfused for 3 hours at constant flows ranging from physiologic (12 ml/min) to severely ischemic (1.5 ml/min); thallium activity was monitored with a scintillation probe. Each heart was perfused for 1 hour with thallium buffer, followed by 2 hours with thallium-free buffer at the same flow rate. Accumulation curves for all 4 flows were monoexponential. However, release curves during the 2 hours of washout with thallium-free buffer demonstrated a biexponential configuration. The early fast release component decreased with reductions in coronary flow, and the later slow release component did not vary significantly with flow. These data show that thallium clearance has at least 2 components: a rapid (possibly extracellular) component related to coronary flow and a slow (possibly intracellular) component independent of coronary flow. These findings should be useful in providing a better understanding of thallium redistribution observed clinically.