Pediatric suppositories of sulpiride solid dispersion for treatment of Tourette syndrome: in vitro and in vivo investigations.

Pharmaceutical development was adopted in the current study to propose a pediatric rectal formulation of sulpiride as a substitute to the available oral or parenteral formulations in the management of Tourette syndrome (TS). The goal was to formulate a product that is easy to use, stable, and highly bioavailable and to achieve a rapid clinical efficacy. Towards this aim, sulpiride solid dispersion (SD) with tartaric acid at a weight ratio of 1:0.25 was incorporated into different suppository bases, namely witepsol W25, witepsol H15, witepsol E75, suppocire NA, suppocire A, glycerogelatin, and polyethylene glycols. The formulae were evaluated in vitro using different pharmacotechnical methods such as visual, melting, weight and content uniformities, drug release, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and X-ray diffraction (XRD) analyses. In vivo bioavailability was also assessed in rabbits to compare the bioavailability of either raw sulpiride-incorporated or its SD-incorporated witepsol H15-based suppositories to its oral suspension (reference). Sulpiride SD-incorporated witepsol H15 formulation showed acceptable in vitro characteristics with a bioavailability of 117% relative to oral dosing, which excel that in humans (27% after dosing of oral product). In addition, the proposed formula not only passed the 6-month stability study but also proposed a promising scale-up approach. Hence, it showed a great potential for pediatric product development to manage TS in rural areas.

Prolongation of residence time of liposome by surface-modification with mixture of hydrophilic polymers.

The objective of this study is to evaluate the biodistribution characteristics of liposomes surface-modified with the mixture of polyethylene glycol (PEG) and polyvinyl alcohol (PVA) as a drug carrier for passive targeting of drugs. The liposomes (egg phosphatidylcholine:cholesterol=55:40, molar ratio) modified with both PEG and PVA (4:1 molar ratio) (PEG4%/PVA1% liposome) provided the largest AUC, which could be attributed to the smallest hepatic clearance of the liposomes. The liver perfusion studies clearly indicated that lower hepatic disposition of PEG4%/PVA1% liposome was ascribed to the decrease in its hepatic uptake via receptor-mediated endocytosis. Furthermore, the amounts of whole serum proteins and of opsonins such as complement C3 and immunoglobulin G adsorbed on PEG4%/PVA1% liposome were significantly smaller than those on the liposome solely modified with PEG (PEG5% liposome). On the other hand, several proteins were adsorbed at larger amount on PEG4%/PVA1% liposome than PEG5% liposome, and the protein identification by LC-MS/MS suggested that some of those proteins including albumin might function as dysopsonins. The decrease in the adsorbed amount of several opsonins and the increase in the adsorbed dysopsonins would be responsible for its lower affinity to the liver and long residence in the systemic circulation of PEG4%/PVA1% liposome.

In-vivo disposition characteristics of PEG niosome and its interaction with serum proteins.

Three different nonionic surfactants (Brij 72, Span 20 and Tween 60) were used to prepare various naked and PEG niosomes. In-vivo study demonstrated that PEGylation dramatically increased the AUC and decreased the affinity to the liver of Brij 72 and Span 20 niosomes in rats. Liver perfusion experiments suggested that the hepatic uptake of naked Brij 72 and Span 20 niosomes could mainly be ascribed to the receptor-mediated uptake, while PEGylation of these niosomes could diminish the receptor-mediated hepatic disposition. Evaluation of serum proteins associated with niosomes revealed that PEGylation of these niosomes significantly reduced the association of serum proteins with them, including typical opsonins such as IgG and C3. On the other hand, in the case of Tween 60 niosomes, naked Tween 60 niosome showed large AUC and its PEGylation did not show any additional effect on the in-vivo pharmacokinetics. Furthermore, PEGylation of Tween 60 niosome did not significantly affect the hepatic disposition or the association of serum proteins with Tween 60 niosome. These results demonstrated that niosomes would exhibit distinct in-vivo disposition characteristics depending on the physicochemical properties of surfactants used and that PEGylation of niosomes with adequate compositions would be a powerful tool to improve their in-vivo behavior.