Domperidone nanocrystals with boosted oral bioavailability: fabrication, evaluation and molecular insight into the polymer-domperidone nanocrystal interaction.

The aim of this study was to employ experimental and molecular modelling approaches to use molecular level interactions to rationalise the selection of suitable polymers for use in the production of stable domperidone (DOMP) nanocrystals with enhanced bioavailability. A low-energy antisolvent precipitation method was used for the preparation and screening of polymers for stable nanocrystals of DOMP. Ethyl cellulose was found to be very efficient in producing stable DOMP nanocrystals with particle size of 130 ± 3 nm. Moreover, the combination of hydroxypropyl methylcellulose and polyvinyl alcohol was also shown to be better in producing DOMP nanocrystals with smaller particle size (200 ± 3.5 nm). DOMP nanosuspension stored at 2-8 °C and at room temperature (25 °C) exhibited better stability compared to the samples stored at 40 °C. Crystallinity of the unprocessed and processed DOMP was monitored by differential scanning calorimetry and powder X-ray diffraction. DOMP nanocrystals gave enhanced dissolution rate compared to the unprocessed drug substance. DOMP nanocrystals at a dose of 10 mg/kg in rats showed enhanced bioavailability compared to the raw drug substance and marketed formulation. A significant increase in plasma concentration of 2.6 µg/mL with a significant decrease in time (1 h) to reach maximum plasma concentration was observed for DOMP nanocrystals compared to the raw DOMP. Molecular modelling studies provided underpinning knowledge at the molecular level of the DOMP-polymer nanocrystal interactions and substantiated the experimental studies. This included an understanding of the impact of polymers on the size of nanocrystals and their associated stability characteristics.

Development, optimization and in vivo characterization of domperidone-controlled release hot-melt-extruded films for buccal delivery.

OBJECTIVE: The aim of the present investigation was the development and in vivo characterization of domperidone (DOM) hot-melt extruded (HME) controlled release films by central composite design (CCD) for buccal delivery. METHODS: Concentration of PEO N750 (X1) and HPMC E5 LV (X2) as independent variables and tensile strength (Y1), percent drug release at 6 h (Q6, Y2) and percent drug permeated at 6 h (Y3, P6) as responses. In total, 13 formulations were prepared and studied. HME films were evaluated for drug excipient compatibility, physico-mechanical properties, drug content, in vitro drug release, bioadhesion, swelling and erosion, ex vivo permeation. Furthermore, statistically optimized formulation was subjected for bioavailability studies in healthy human volunteers. RESULTS: Statistically optimized formulation exhibited a tensile strength (3.86 kg/mm(2)), 93.62 ± 2.84% of drug release and 63.36 ± 2.12% of drug permeated in 6 h. HME films demonstrated no drug excipient interaction and excellent content uniformity. Furthermore, optimized formulation exhibited elongation at break (38.6% mm(2)), peak detachment force (1.75 N), work of adhesion (3.21 mJ), swelling index (240.4%) and erosion (8.5%). Bioavailability from the statistically optimized buccal films was 3.2 times higher than the oral dosage form (p < 0.05). The ex vivo-in vivo correlation was found to have biphasic pattern and followed type A correlation. The stability of the optimized formulation was studied and no significant changes were detected in 6 months. CONCLUSION: The results indicate that hot-melt extrusion is a viable technique for the preparation of DOM buccal-adhesive controlled release films with improved bioavailability by CCD.

Exposure to nicotine produces an increase in dopamine D2(High) receptors: a possible mechanism for dopamine hypersensitivity.

Dopamine D2 receptors exist in both low- and high-affinity states (D2(High)), the latter being the functionally relevant state. Cocaine self-administration produces an increase in D2(High), a phenomenon that could explain why cocaine administration results in hypersensitivity to dopamine, even though drug addicts were found to have a decreased number of striatal dopamine D2 receptors. As nicotine acts through the same mesocortical dopaminergic signaling pathways as other stimulant drugs, which are known to increase the levels of D2(High), we hypothesized that nicotine exposure could produce an increase in D2(High) levels. We determined D2(High) levels in rats after nicotine administration (1.5 mg/kg/day; 14 days), in rats voluntarily self-administering nicotine using an intravenous self-administration (IVSA) protocol (mean dose 0.5 mg/kg/day; 14 days), as well as after a prolonged withdrawal. An increase in the levels of D2(High) was found in rats who had nicotine administered at a uniform dose, as well as in rats who self-administered nicotine via IVSA, but these changes appear to normalize over time, as indicated by lower D2(High) levels in rats after a prolonged withdrawal period. We suggest that nicotine-induced elevation in D2(High) levels could be participating in hypersensitivity to dopamine following nicotine exposure.

Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity.

This Letter describes the synthesis and structure-activity-relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of alternative halogenated piperidinyl benzimidazolone privileged structures, in combination with a key (S)-methyl group, novel PLD inhibitors with low nM potency and unprecedented levels of PLD1 isoform selectivity (approximately 1700-fold) over PLD2 were developed.

Optimization of halopemide for phospholipase D2 inhibition.

Halopemide, which was identified by HTS to inhibit phospholipase D2 (PLD2), provided the basis for an exploratory effort to identify potent inhibitors of PLD2 for use as inflammatory mediators. Parallel synthesis and purification were utilized to rapidly identify orally available amide analogs derived from indole 2-carboxylic acids with superior potency versus PLD2.

Design, optimization and evaluation of domperidone coevaporates.

Coevaporates of domperidone were prepared using different polymers by solvent evaporation technique. Ethyl cellulose and hydroxypropyl methylcellulose phthalate were used in preparation of coevaporates. The coevaporates were characterized by X-ray diffraction studies, IR spectrophotometry and differential scanning calorimetry. The dissolution behavior of coevaporates was studied using buffer solution of pH 1.2 for the first 2 h and that of pH 6.8 thereafter up to 12 h. A two-factor, three-level design was used to quantitate the effect of polymers on dissolution profile of domperidone. The drug release rate was found to be dependent on the concentration of polymers in the coevaporates. Dissolution of drug in a pH 6.8 buffer improved with increasing concentration of hydroxypropyl methylcellulose phthalate in coevaporates. Bioavailability studies in human volunteers confirmed that domperidone coevaporates sustained drug release.