PEGylated Tween 80-functionalized chitosan-lipidic nano-vesicular hybrids for heightening nose-to-brain delivery and bioavailability of metoclopramide.

A PEGylated Tween 80-functionalized chitosan-lipidic (PEG-T-Chito-Lip) nano-vesicular hybrid was developed for intranasal administration as an alternative delivery route to help improve the poor oral bioavailability of BCS class-III model/antiemetic (metoclopramide hydrochloride; MTC). The influence of varying levels of chitosan, cholesterol, PEG 600, and Tween 80 on the stability/release parameters of the formulated nanovesicles was optimized using Draper-Lin Design. Two optimized formulations (Opti-Max and Opti-Min) with both maximized and minimized MTC-release goals, were predicted, characterized, and proved their vesicular outline via light/electron microscopy, along with the mutual prompt/extended in-vitro release patterns. The dual-optimized MTC-loaded PEG-T-Chito-Lip nanovesicles were loaded in intranasal in-situ gel (ISG) and further underwent in-vivo pharmacokinetics/nose-to-brain delivery valuation on Sprague-Dawley rats. The absorption profiles in plasma (plasma-AUC0-∞) of the intranasal dual-optimized MTC-loaded nano-vesicular ISG formulation in pretreated rats were 2.95-fold and 1.64-fold more than rats pretreated with orally administered MTC and intranasally administered raw MTC-loaded ISG formulation, respectively. Interestingly, the brain-AUC0-∞ of the intranasal dual-optimized MTC-loaded ISG was 10 and 3 times more than brain-AUC0-∞ of the MTC-oral tablet and the intranasal raw MTC-loaded ISG, respectively. It was also revealed that the intranasal dual-optimized ISG significantly had the lowest liver-AUC0-∞ (862.19 ng.g-1.h-1) versus the MTC-oral tablet (5732.17 ng.g-1.h-1) and the intranasal raw MTC-loaded ISG (1799.69 ng.g-1.h-1). The brain/blood ratio profile for the intranasal dual-optimized ISG was significantly enhanced over all other MTC formulations (P < 0.05). Moreover, the 198.55% drug targeting efficiency, 75.26% nose-to-brain direct transport percentage, and 4.06 drug targeting index of the dual-optimized formulation were significantly higher than those of the raw MTC-loaded ISG formulation. The performance of the dual-optimized PEG-T-Chito-Lip nano-vesicular hybrids for intranasal administration evidenced MTC-improved bioavailability, circumvented hepatic metabolism, and enhanced brain targetability, with increased potentiality in heightening the convenience and compliance for patients.

Rapidly disintegrating tablets containing taste masked metoclopramide hydrochloride prepared by extrusion-precipitation method.

The purpose of this study was to mask the intensely bitter taste of metoclopramide HCl and to formulate a rapid disintegrating tablet (RDT) of the taste-masked drug. Taste masking was done by complexing metoclopramide HCl with aminoalkyl methacrylate copolymer (Eudragit EPO) in different ratio by the extrusion-precipitation method. Drug-polymer complexes (DPCs) were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.8, taste evaluation in oral cavity and molecular property. The complex having drug-polymer ratio of 1 : 2 shows significant taste masking, confirmed by drug release in SSF and in-vivo taste evaluation; therefore, it was selected for further study. Taste evaluation of DPCs in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value (0.5) within 10 s, whereas, metoclopramide HCl was rated intensely bitter with a score of +3 for 10 s. Tablets were evaluated for various parameters like tensile strength, wetting time, water absorption ratio, in-vitro disintegration time, and disintegration in oral cavity. The effect of diluents, lubricants and sweetening agent (Xylisorb) on the disintegration time was also evaluated. Tablets of batch F3 containing mannitol and microcrystalline cellulose in the ratio 1 : 1 and 8% w/w crosspovidone showed faster disintegration (within 20 s) than the marketed formulation (180 s). Good correlation between in vitro disintegration behavior and in the oral cavity was recognized. Tablets of batch F3 also revealed rapid drug release (t(90), 90 s) in SGF compared with marketed formulation (t(90), 600 s).

[Bromopride: pharmacokinetics in dogs (author's transl)]. / Bromoprid: Pharmakokinetik beim Hund.

The pharmacokinetics of bromopride were studied in dogs following a single oral or i.v. administration. The calculation of the pharmacokinetic parameters was based on an open two-compartment model after i.v. injection and on an open one-compartment model when the drug was given by mouth. Serum elimination half-life following i.v. injection was shown to exceed that after oral ingestion. Bromopride was rapidly transformed into the monodeethyl metabolite accounting for the largest fraction at 4 h after administration.

[Bromopride: metabolism and urinary elimination in dogs (author's transl)]. / Bromoprid: metabolismus und renale Ausscheidung beim Hund.

The elimination of bromopride and its metabolites was studied in dogs. The drug was given by mouth in a single dose of 15 mg/kg or 45 mg/kg and assessed by thin-layer or gas chromatography. Bromopride and its metabolites are excreted mainly within the first 8 h after ingestion. Nine metabolites, above all the N-monodeethyl derivative, were encountered, while 10% of the drug was eliminated as such.

Activated charcoal and syrup of ipecac in prevention of cimetidine and pindolol absorption in man after administration of metoclopramide as an antiemetic agent.

The effects of activated charcoal and ipecac syrup by mouth on cimetidine and pindolol absorption were studied in seven subjects, who had ingested 20 mg metoclopramide 1 h earlier, and compared with the adsorption capacity of charcoal in vitro. Activated charcoal, 50 g, given 5 min after 400 mg cimetidine + 10 mg pindolol, reduced their absorption by 99% or more, based on AUC0-48h and the 48-h urinary excretion of the drugs. Syrup of ipecac caused emesis on each occasion. On the average, ipecac reduced the absorption of cimetidine and pindolol by 75% and 60%, respectively. Based on studies in vitro it seems probable that the adsorbing capacity of charcoal for cimetidine but not for pindolol will be saturated if 50 g charcoal is given after an overdose of about 100 fold the therapeutic dose. Because the use of ipecac allowed an absorption of the drugs at least 30 fold that allowed by charcoal, the immediate administration of activated charcoal, without preceding lavage or emesis, should be considered in such poisonings where the adsorption capacity of high charcoal doses will not be saturated.