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. 2013:2013:569470.
doi: 10.1155/2013/569470. Epub 2013 Aug 20.

A novel multilayered multidisk oral tablet for chronotherapeutic drug delivery

Zaheeda Khan  1 , Yahya E Choonara, Pradeep Kumar, Lisa C du Toit, Valence M K Ndesendo, Viness Pillay
Affiliations

A novel multilayered multidisk oral tablet for chronotherapeutic drug delivery

Zaheeda Khan et al. Biomed Res Int. 2013.

Abstract

A Multilayered Multidisk Tablet (MLMDT) comprising two drug-loaded disks enveloped by three drug-free barrier layers was developed for use in chronotherapeutic disorders, employing two model drugs, theophylline and diltiazem HCl. The MLMDT was designed to achieve two pulses of drug release separated by a lag phase. The polymer disk comprised hydroxyethylcellulose (HEC) and ethylcellulose (EC) granulated using an aqueous dispersion of EC. The polymeric barrier layers constituted a combination of pectin/Avicel (PBL) (1st barrier layer) and hydroxypropylmethylcellulose (HPMC) (HBL1 and HBL2) as the 2nd and 3rd barrier layers, respectively. Sodium bicarbonate was incorporated into the diltiazem-containing formulation for delayed drug release. Erosion and swelling studies confirmed the manner in which the drug was released with theophylline formulations exhibiting a maximum swelling of 97% and diltiazem containing formulations with a maximum swelling of 119%. FTIR spectra displayed no interactions between drugs and polymers. Molecular mechanics simulations were undertaken to predict the possible orientation of the polymer morphologies most likely affecting the MLMDT performance. The MLMDT provided two pulses of drug release, separated by a lag phase, and additionally it displayed desirable friability, hardness, and uniformity of mass indicating a stable formulation that may be a desirable candidate for chronotherapeutic drug delivery.

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Figures

Figure 1
Figure 1
Schematic of the Multilayered Multidisk Tablet (MLMDT) consisting of two drug disks surrounded by barrier layers (PBL1, HBL1, and HBL2).
Figure 2
Figure 2
Schematic model depicting a representative ideal drug release profile from the MLMDT.
Figure 3
Figure 3
Schematic representing a Multilayer Perceptron (MLP) with two hidden layers.
Figure 4
Figure 4
A typical bar chart portraying the ANN-derived sensitivity of HEC, EC, and sodium bicarbonate on k 3.
Figure 5
Figure 5
(a) Profiles showing the effect of EC and HEC on k 3; (b) profile showing the influence of sodium bicarbonate on k 3.
Figure 6
Figure 6
Drug release profiles of optimized (a) THP and (b) DTZ-loaded MLMDT formulations.
Figure 7
Figure 7
Drug release profiles of THP-loaded MLMDTs in pH 1.2 (2 hrs) and pH 6.8 (3 hours onwards).
Figure 8
Figure 8
Drug release profiles of DTZ-loaded MLMDTs in pH 1.2.
Figure 9
Figure 9
Correlation of swelling and erosion profiles of (a) THP-loaded and (b) DTZ-loaded MLMDTs.
Figure 10
Figure 10
Digital images depicting (a) swollen THP-loaded MLMDTs and (b) swollen DTZ-loaded MLMDTs at (A) 2, (B) 4, (C) 6, (D) 8, (E) 10, (F) 12, and (G) 24 hours, respectively.
Figure 11
Figure 11
The MLMDT tablet showing the difference between the top and bottom layers of the device as based on the different polymers employed in the layers.
Figure 12
Figure 12
Typical force-displacement profiles for (a) THP-loaded MLMDTs in pH 1.2 and 6.8 and (b) DTZ-loaded MLMDTs in pH 1.2.
Figure 13
Figure 13
FTIR spectra depicting (a) pure THP and compressed THP MLMDT and (b) pure DTZ and compressed DTZ-loaded MLMDT.
Figure 14
Figure 14
SEM image illustrating morphology of the pectin/Avicel (PBL) and HPMC (HBL1) layers (magnification 355x).
Figure 15
Figure 15
Energy minimized geometrically constrained models of the following. (a) Ethylcellulose and hydroxyethylcellulose before complexation; (b) EC-HEC complex derived from MM computations. The atoms in close interaction proximity are emphasized by space filling model (dots) where the yellow dots depict atoms involved in H-bonding. Color codes for elements are carbon (cyan), nitrogen (blue), oxygen (red), and hydrogen (white). (c) Avicel (cellulose) and pectin before complexation; (d) PEC-AVC complex derived from MM computations. The atoms in close interaction proximity are emphasized by space filling model (dots) where the yellow dots depict atoms involved in H-bonding. Color codes for elements are carbon (cyan), nitrogen (blue), oxygen (red), and hydrogen (white).
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