Channeling Agent and Drug Release from a Central Core Matrix Tablet

A new oral dosage form for controlled and complete release of drug after a predetermined lag time is described. The system, designed to exploit the relatively constant small intestine transit time, consists of a drug-containing core coated with a polymeric matrix formed by a channeling agent (NaCl, mannitol, and Emdex) and an inert polymer (Eudragit RS100). The lag time was found to be dependent on type and particle size of the channeling substances used. Also, rheological properties of the binary mixtures (channeling substance-polymer) can affect the lag time periods. On the other hand, the release kinetics were found to be influenced significantly by excipient type and particle size. Results obtained from in vitro dissolution testing demonstrated that this device potentially could be used to deliver drugs orally for up to once-a-day dosing at controllable rates.     

Channeling Agent and Drug Release from a Central Core Matrix Tablet

A new oral dosage form for controlled and complete release of drug after a predetermined lag time is described. The system, designed to exploit the relatively constant small intestine transit time, consists of a drug-containing core coated with a polymeric matrix formed by a channeling agent (NaCl, mannitol, and Emdex) and an inert polymer (Eudragit RS100). The lag time was found to be dependent on type and particle size of the channeling substances used. Also, rheological properties of the binary mixtures (channeling substance–polymer) can affect the lag time periods. On the other hand, the release kinetics were found to be influenced significantly by excipient type and particle size. Results obtained from in vitro dissolution testing demonstrated that this device potentially could be used to deliver drugs orally for up to once-a-day dosing at controllable rates.     

A novel three-layered tablet for extended release with various layer formulations and in vitro release profiles

A novel three-layered tablet consisting of a water-soluble mid-layer and two barrier layers with swellable polymers was investigated to develop a preferable once-a-day formulation containing terazosin HCl as a hydrophilic model drug. When the tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. It facilitated the tablet to absorb a lot of water compared with monolithic matrix. Moreover, formation of a lot of pores in the tablet during dissolution could be observed, suggesting significant water absorption in the inner matrix and swollen polymers of the tablet. Barrier layers influenced drug release profiles significantly, potentially due to differences in viscosity after swelling that produce different diffusion coefficients and mechanical strength. The drug in the mid-layer showed the sigmoid type of release pattern because a period of time might be needed to release the drug from the mid-layer through the barrier layers, but the drug in barrier layers showed the typical release pattern of monolithic matrix. As the amount of water-soluble excipient in the mid-layer increased, the degree of swelling also increased, suggesting that its amount in the layer may affect the overall swelling properties of the tablet. It was also shown that more hydrophilic mid-layer caused faster erosion rate, which was related to the results of swelling property. The three-layered tablets showed more consistent release kinetics than the matrix tablets. These results can give good information for the development of sustained drug delivery systems, especially once-a-day administration.     

Sustained-release from Layered Matrix System Comprising Chitosan and Xanthan Gum

ABSTRACT

Sustained-release tablets of propranolol HCl were prepared by direct compression using chitosan and xanthan gum as matrix materials. The effective prolongation of drug release in acidic environment was achieved for matrix containing chitosan together with xanthan gum which prolonged the drug release more extensive than that containing single polymer. Increasing lactose into matrix could adjust the drug release characteristic by enhancing the drug released. Component containing chitosan and xanthan gum at ratio 1:1 and lactose 75% w/w was selected for preparing the layered matrix by tabletting. Increasing the amount of matrix in barrier or in middle layer resulted in prolongation of drug release. From the investigation of drug release from one planar surface, the lag time for drug release through barrier layer was apparently longer as the amount of barrier was enhanced. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first order, Higuchi's and zero order) was performed to study the drug release mechanism. Layering with polymeric matrix could prolong the drug release and could shift the release pattern approach to zero order. The drug release from chitosan-xanthan gum three-layer tablet was pH dependent due to the difference in charge density in different environmental pH. FT-IR and DSC studies exhibited the charge interaction between of NH₃⁺ of chitosan molecule and COO^? of acetate or pyruvate groups of xanthan gum molecule. The SEM images revealed the formation of the loose membranous but porous film that was due to the gel layer formed by the polymer relaxation upon absorption of dissolution medium. The decreased rate of polymer dissolution resulting from the decreased rate of solvent penetration was accompanied by a decrease in drug diffusion due to ionic interaction between chitosan and xanthan gum. This was suggested that the utilization of chitosan and xanthan gum could give rise to layered matrix tablet exhibiting sustained drug release.     

Investigation of Hypromellose Particle Size Effects on Drug Release from Sustained Release Hydrophilic Matrix Tablets

Selected combinations of six model drugs and four hypromellose (USP 2208) viscosity grades were studied utilizing direct compression and in vitro dissolution testing. Experimental HPMC samples with differing particle size distributions (coarse, fine, narrow, bimodal) were generated by sieving. For some formulations, the impact of HPMC particle size changes was characterized by faster drug release and an apparent shift in drug release mechanism when less than 50% of the HPMC passed through a 230 mesh (63 μm) screen. Within the ranges studied, drug release from other formulations appeared to be unaffected by HPMC particle size changes.     

Codelivery of Anti‐PD‐1 Antibody and Paclitaxel with Matrix Metalloproteinase and pH Dual‐Sensitive Micelles for Enhanced Tumor Chemoimmunotherapy

Immune checkpoint blockade (ICB) is demonstrating great potential in cancer immunotherapy nowadays. Yet, the low response rate to ICB remains an urgent challenge for tumor immunotherapy. A pH and matrix metalloproteinase dual‐sensitive micellar nanocarrier showing spatio‐temporally controlled release of anti‐PD‐1 antibody (aPD‐1) and paclitaxel (PTX) in solid tumors is prepared to realize synergistic cancer chemoimmunotherapy. Antitumor immunity can be activated by PTX‐induced immunogenic cell death (ICD), while aPD‐1 blocks the PD‐1/PD‐L1 axis to suppress the immune escape due to PTX‐induced PD‐L1 up‐regulation, thus resulting in a synergistic antitumor chemoimmunotherapy. Through decoration with a sheddable polyethylene glycol (PEG) shell, the nanodrug may better accumulate in tumors to boost the synergistic antitumor treatment in a mouse melanoma model. The present study demonstrates a potent antitumor chemoimmunotherapy utilizing tumor microenvironment‐sensitive micelles bearing a sheddable PEG layer to mediate site‐specific sequential release of aPD‐1 and PTX.     

Formulation Development and Human In Vitro‐In Vivo Correlation for a Novel,Monolithic Controlled‐Release Matrix System of High Load and Highly Water‐Soluble Drug Niacin

Novel, controlled‐release formulations for high drug load, highly water soluble compound niacin based on polyethylene oxide (PEO) and hydroxypropylmethyl cellulose (HPMC) matrices were developed and investigated. The effect of sodium bicarbonate as a modulator of swelling, erosion, and drug release and its impact on changes in the kinetics of axial swelling and gel strength were evaluated by textural analysis during dissolution study. The drug release rate from PEO‐based matrices was faster and correlated with lower gel strength, greater water uptake, and greater matrix erosion. Slower release rate and greater release duration correlated significantly with greater matrix swelling with negligible matrix erosion for the HPMC‐based matrix system. Inclusion of sodium bicarbonate in the polymeric matrix salted out the macromolecules and increased gel strength and gel viscosity, especially in the vicinity of the swelling fronts. An in vivo study in human subjects after administration of the formulations and a commercial product exhibited similar plasma concentrations. For the formulation of interest, the mean drug fraction absorbed by the body was calculated by the Wagner‐Nelson technique, and a level A “in vitro‐in vivo correlation” was observed between the percent released in vitro and percent absorbed in vivo. The developed formulations appear to be robust and easy to manufacture with maximum flexibility with respect to drug dose, polymeric carriers, duration, and kinetics of drug release.