The Steady-State Comparative Bioavailability of Intramuscular Risperidone ISM and Oral Risperidone: An Open-Label, One-Sequence Study.

INTRODUCTION: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment. METHODS: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized. RESULTS: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40-65% and 38-52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80-1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16-1.34], 1.17 [1.08-1.27], and 1.25 [1.16-1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone. CONCLUSION: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.

In vivo evaluation of two new sustained release formulations elaborated by one-step melt granulation: level A in vitro-in vivo correlation.

The objective of this study was to evaluate in vivo two sustained release formulations elaborated by a one-step melt granulation method using theophylline as model drug. Both formulations presented differences in the in vitro release profile due to the hydrophilic or lipophilic nature of the binder employed (PEG 6000 or glycerol monostearate). The formulations were administered to Beagle dogs, and plasma levels were compared. Both formulations provided a sustained plasma concentration profile after oral administration to dogs. Significant differences (p<0.05) in the plasma concentration-time curves between the two formulations were found, with higher C(max) (6.05+/-2.00 vs. 2.55+/-0.82 microg/mL), higher AUC(0-infinity) (70.24+/-16.10 vs. 33.00+/-8.96 h microg/mL) and delayed T(max) (6.00+/-2.12 vs. 3.17+/-0.98 h) for the formulation containing PEG 6000. Absolute bioavailability of theophylline was 96% and 46% for the formulations containing PEG 6000 and glycerol monostearate, respectively. These results are consistent with those obtained in vitro, with slower release rate of theophylline from tablets elaborated with glycerol monostearate than that obtained with tablets elaborated with PEG 6000. Moreover, the formulation containing PEG 6000 provided a plasma concentration-time profile similar to that obtained with the marketed formulation Theo-Dur. A very good Level A IVIVC was observed between dissolution and absorption profiles of the drug from both test formulations. Our results showed that one-step melt granulation in a high shear mixer allows for an easy modulation of the release profile and, consequently, of the plasma level profile of the drug by selecting the type of binder used.

Preparation of sustained release hydrophilic matrices by melt granulation in a high-shear mixer.

PURPOSE: The objective of this work was to prepare theophylline sustained release matrix tablets based on the combination of hydroxypropyl methylcellulose (HPMC K4M and K100M) and different meltable binders by melt granulation in a high-shear mixer. METHODS: Dissolution profiles of each formulation were compared to those of TheoDur 200 mg tablets and the mean dissolution time (MDT) and similarity factor (f2 factor) were calculated. The matrices swelling behavior was investigated by texture analysis. RESULTS: The results obtained show that the type of excipient influenced the drug release rate. In particular, the dissolution rate was delayed when lipophilic binders were used and only formulations containing Gelucire 50/13 or PEG 6000 with HPMC K4M had a profile similar to the commercial formulation. The release mechanism of theophylline from the formulations was described by Peppas's equation showing a non-Fickian release mechanism. The investigation of matrices swelling behavior showed that the gel layer thickness increased continuously over the time period studied. Moreover, a correlation between gel layer thickness and strength with the percentage released was found. CONCLUSIONS: These results suggest that melt granulation could be an easy and fast method to formulate sustained release tablets.