Intestinal Absorption Site-Guided Development and Evaluation of Oral Disintegrating Controlled Release Tablets of Mirabegron.

The aim was to employ site-dependent absorption of mirabegron (MB) as a guide for fabrication of oral disintegrating controlled release tablet (ODCRT) which undergoes instantaneous release of loading fraction followed by delayed release of the rest of MB. The goal was to release MB in a manner consistent with the chronobiology of overactive bladder (OAB) syndrome. In situ rabbit intestinal permeability of MB was adopted to assess absorption sites. MB was subjected to dry co-grinding with citric acid to develop the fast-dissolving fraction in the mouth. Delayed release fraction was formulated by ethanol-assisted co-processing with increasing proportions of Eudragit polymer (S100) as pH responsive polymer. The developed dry mixtures underwent thermal (DSC) and physical (X-ray diffraction) characterization, in addition to in vitro release behavior. Optimized fast dissolving and delayed release formulations were mixed with tablet excipient before compression in ODCRT which was assessed for release profile using continuous pH variation. MB underwent preferential permeation through ileum and colon. Co-grinding with citric acid provided co-amorphous powder with fast dissolution. Co-amorphization of MB with Eudragit S100 (1:5) showed pH-dependent release to release most of the dose at pH 7.4. The developed ODCRT released 43.5% of MB in the buccal environment and retained MB at acidic pH to start release at pH 7.4. The study successfully fabricated ODCRT guided by site-dependent absorption. The ODCRT instantaneously released loading fraction to support the patient after administration with delayed fraction to sustain the effect.

Cubosomes for Enhancing Intestinal Absorption of Fexofenadine Hydrochloride: In situ and in vivo Investigation.

Purpose: The aim of this work was to probe cubosomes for enhanced intestinal absorption and oral bioavailability of poorly absorbable fexofenadine HCl (FEX-HCl). Materials and Methods: Two cubosomal systems were fabricated utilizing glyceryl mono-oleate, a lyotropic mono lamellar lipid as oil phase and poloxamer407 as stabilizer at weight ratios of 8:2 and 7:3. The morphology of cubosomes was researched using transmission electron microscopy (TEM) and particle size was measured using photon correlation spectroscopy. FEX-HCl release was monitored in vitro. The effect of cubosomal encapsulation on intestinal absorption was assessed using in situ rabbit intestinal perfusion technique. Carrageenan induced rat paw edema model was utilized to monitor in vivo anti-inflammatory effect before and after cubosomal encapsulation. Results: TEM revealed the existence of spherical and polygonal nanostructures arranged in honeycomb organization. Size measurement reflected nanoparticles with reduced size at higher poloxamer concentration. Release studies revealed liberation of FEX-HCl from cubosomes based on Higuchi kinetics model. The intestinal permeability data indicated incomplete absorption of FEX-HCl from simple aqueous solution with P-glycoprotein efflux contributing to this poor intestinal absorption. Incorporation of FEX-HCl in cubosomes enhanced membrane transport parameters. The intestinal absorption did not correlate with drug release suggesting that drug release is not the rate limiting with possible intact cubosomal transport. Cubosomal encapsulation of FEX-HCl significantly enhanced its in vivo anti-inflammatory efficacy compared to the aqueous FEX-HCl dispersion. Conclusion: Cubosomes are promising novel carriers for enhancing intestinal absorption of FEX-HCl. Intact FEX-HCl-cubosomal absorption is possible via trans-lymphatic pathway but this requires further investigations.

Investigation of the effect of verapamil on the regional absorption of sofosbuvir from rabbit intestine in situ.

PURPOSE: Sofosbuvir, a nucleotide antiviral drug, is a Biopharmaceutics Classification System (BCS) class III prodrug suffering from limited intestinal absorption due to its high hydrophilicity and low intestinal permeability. This research aims to investigate the luminal stability of Sofosbuvir, the influence of anatomical site on its intestinal absorption and the effects of verapamil on such absorption. METHOD: The study utilized in situ rabbit intestinal perfusion technique to examine absorption of Sofosbuvir from duodenum, jejunum, ileum and ascending colon. This was conducted both with and without verapamil. RESULTS: The luminal stability study showed that Sofosbuvir was subjected to premature degradation with varying fractions degraded from the different intestinal segments. The in situ perfusion data showed incomplete absorption of Sofosbuvir from small and large intestinal segments. The recorded values of the absorptive clearance per unit length (Pe.A/L) of Sofosbuvir were 0.026, 0.0075, 0.0026, & 0.054 ml/min.cm for duodenum, jejunum, ileum, and ascending colon, respectively. The Pe.A/L values were ordered as colon > duodenum > jejunum > ileum. This is the opposite rank of P-gp content in the different intestinal segments. The recorded values of the length required for complete Sofosbuvir absorption (L95%) were 29.58, 128.47, 949.2 and, 13.63 cm for duodenum, jejunum, ileum, and ascending colon, respectively. Co-perfusion with verapamil significantly increased Pe.A/L and reduced the L95% of Sofosbuvir from both jejunum and ileum (P-value < 0.05). CONCLUSION: The results indicated that the absorptive clearance of Sofosbuvir was site dependent and associated with the content of P-glycoprotein, in addition to the expected drug interactions that can occur in polymedicated hepatitis C virus (HCV) infected patients.

Influence of piperine and omeprazole on the regional absorption of Daclatasvir from rabbit intestine.

The study assessed the site dependent intestinal absorption of Daclatasvir and investigated the effects of piperine and omeprazole on such absorption utilizing in situ rabbit intestinal perfusion technique. The intestinal absorption of Daclatasvir was assessed in four segments: duodenum, jejunum, ileum, and colon. The effect of co-perfusion with omeprazole was monitored through the tested anatomical sites. The effect of piperine, a P-glycoprotein (P-gp) inhibitor on Daclatasvir absorption from jejunum and ileum was tested. The results showed that Daclatasvir was incompletely absorbed from the rabbit small and large intestine. The absorptive clearance per unit length (PeA/L) was site dependent and was ranked as colon > duodenum > jejunum > ileum. This rank is the opposite of the rank of P-gp intestinal content suggesting possible influence for P-gp. Co-perfusion with omeprazole increased PeA/L and this was evidenced also with reduced the L95% of Daclatasvir from both small and large intestinal segments. Significant enhancement in Daclatasvir absorption through jejunum and ileum was shown in presence of piperine. Daclatasvir showed site dependent intestinal absorption in a manner suggesting its affection by P-gp efflux. This effect was inhibited by piperine. Co-administration of Daclatasvir with omeprazole can enhance intestinal absorption a phenomenon which requires extension to human pharmacokinetic investigation.

Regional difference in intestinal drug absorption as a measure for the potential effect of P-glycoprotein efflux transporters.

OBJECTIVES: The aim of this research was to assess regional difference in the intestinal absorption of ranitidine HCl as an indicator for the potential effect of P-glycoprotein (P-gp) efflux transporters. METHODS: In situ rabbit intestinal perfusion was used to investigate absorption of ranitidine HCl, a substrate for P-gp efflux from duodenum, jejunum, ileum and colon. This was conducted both in the presence and absence of piperine as P-gp inhibitor. KEY FINDINGS: Ranitidine HCl was incompletely absorbed from rabbit intestine. The length normalized absorptive clearance (PeA/L) of ranitidine HCl was ranked as colon > duodenum > jejunum > ileum. This is the reverse order of the magnitude of P-gp expression. Coperfusion of piperine with ranitidine HCl significantly increased the PeA/L of ranitidine HCl from jejunum and ileum with no significant change on the absorption from duodenum and colon. This was confirmed by significant reduction in the length required for complete ranitidine HCl absorption from jejunum and ileum in presence piperine. CONCLUSIONS: The results indicate that P-gp transporters play a major role in determining regional difference in intestinal absorption of ranitidine HCl. Thus, the regional absorption of drugs may be taken as an indirect indication for the role of P-gp in intestinal absorption.