M. E. Pina

Oral Controlled-Release Dosage Forms. I. Cellulose Ether Polymers in Hydrophilic Matrices

AbstractAn appropriately designed controlled-release drug delivery system can be a major advance towarb solving problems concerning the targeting of a drug to a specific organ or tissue and controlling the rate of drug delivery to the target tissue. Hydrophilic matrices are an interesting option when developing an oral controlled-release formulation. The present study focuses on oral controlled-release dosage forms and the application of cellulose ether polymers in hydrophilic matrices. Key Words. Controlled-release matrices; Hydrophilic matrices; Cellulose ether polymers; Hydroxypropylmethylcellulose; HPMC

A dissolução in vitro na previsão da absorção oral de fármacos em formas farmacêuticas de liberação modificada

The aim of the present work focused on the theoretical and practical aspects of the dissolution studies of the modified release pharmaceutical dosage forms. This paper was divided in three parts: the first refers to the classification, therapeutic interest and release of the drug; the second part presents the theory of the dissolution process, the models of drug release, dissolution systems and their validation, specifications and acceptance criteria for the dissolution studies and the factors conditioning the dissolution, release and absorption of the drug; the third part discusses the conditions in which the dissolution studies are performed and the physiological parameters making reference to the dissolution media, to the composition of the gastrointestinal tract lumen and to the hydrodynamic models.

Physical properties of chitosan pellets produced by extrusion-spheronisation: influence of formulation variables

Pellets comprising chitosan, cellulose microcrystalline, povidone, filler excipient and diclofenac sodium as model drug were prepared by extrusion-spheronisation. The effects of chitosan load (zero, 0%, low, 4% and high, 16% levels), type of filler (lactose, tribasic calcium phosphate and beta-cyclodextrin) and composition of the binding liquid (ethanol/water mixtures 20 and 50%) on physical characteristics of pellets were evaluated. A three-factor factorial design was employed in the study. Analysis of variance (ANOVA) indicated that single factors had significant effect on the physical characteristics of the pellets. The type of filler followed by polymer load markedly affected the density. The type of binding liquid had negligible effect on the shape and surface roughness of the pellets. Increase in the chitosan load resulted in pellets of lower porosity values. This could be attributed to the binding capacity of chitosan and povidone leading to more compacted structures. Chitosan load and type of filler had significant influence on the surface roughness. The surface of pellets became rougher as the chitosan load increased, however, there was no significant difference between zero and low contents of chitosan. Pellets prepared using tribasic calcium phosphate showed a smoother surface when compared with formulations including lactose or beta-cyclodextrin. Chitosan was useful to provide pellets of acceptable physical characteristics when employing an alcohol/water mixture 50% (v/v) as binding liquid for the extrusion-spheronisation process.

Role of Cellulose Ether Polymers on Ibuprofen Release from Matrix Tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE20 h), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.

Oral Controlled Release Dosage Forms. II. Glassy Polymers in Hydrophilic Matrices

Part I of this article reported general considerations of oral controlled release dosage forms and the applications of cellulose ether polymers in hydrophilic matrices. Part II of this study describes the advantages and disadvantages of limited swelling hydrophilic matrices, their preparation, mechanism, and parameters affecting drug release from these systems.

Influence of Cellulose Ether Mixtures on Ibuprofen Release: MC25, HPC and HPMC K100M

The influence of cellulose ether derivatives on ibuprofen release from matrix tablets was investigated. Raman spectroscopy and differential scanning calorimetry (DSC) experiments were used, in order to examine the compatibility between the matrix components: both excipients and ibuprofen. While both the DSC and Raman results did not detect any incompatibilities, DSC revealed the existence of some drug:excipient interactions, reflected by variations in the hydration/dehydration processes. Formulations containing mixtures of polymers with both low and high viscosity grades—methylcellulose (MC25) or hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K100M), respectively—were prepared by a direct compression method (using 20, 25, and 30% of either MC25 or HPC). The tablets were evaluated for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, surface area, and volume. Parameters such as the mean dissolution time (MDT) and the dissolution efficiency (DE) were calculated in all cases. The solid formulations presently studied demonstrated a predominantly Fickian diffusion release mechanism.

Influence of Technological Variables on the Release of Theophylline from Hydrophilic Matrix Tablets

This study presents the results of in vitro dissolution of controlled-release theophylline tablets using hydroxypropylmethylcellulose as a rate-retarding polymer. The effects of the proportion of the polymer, the addition of diluents, and the surface area of matrix tablets on the theophylline release rate have been investigated. The results of the dissolution tests show that the drug was gradually released in all cases, and that the tablets had released 80% of their contents after 8 hr. The release rate decreased when the proportion of the polymer increased. The influence of adding diluents and effect of the surface area of matrix tablets were not observed in this study.

Compatibility studies between ibuprofen or ketoprofen with cellulose ether polymer mixtures using thermal analysis.

ABSTRACT Differential scanning calorimetry (DSC) was used to investigate and detect incompatibilities between drugs such as: ibuprofen (IBU) or ketoprofen (KETO) with cellulose ether derivatives, which are frequently applied on controlled release dosage forms. Binary mixtures concerning methylcellulose (MC25) or hydroxypropylcellulose (HPC) with hydroxypropylmethylcellulose (HPMC) K15M or K100M in different ratios were prepared and evaluated by the appearance, shift, or disappearance of peaks and/or variations in the corresponding ΔH values. According to the DSC results, binary mixtures between those polymers were found to be compatible, but their mixture with IBU or KETO, promotes a solid–solid interaction mainly with 1:1:1 (w/w) ratio (drug-excipient). However, when the drug:excipient interactions were detected, they were not found to affect the drug bioavailability. DSC was successfully employed to evaluate the compatibility of the drugs with the selected polymers.

Effect of Polymer Hydration on the Kinetic Release of Drugs: A Study of Ibuprofen and Ketoprofen in HPMC Matrices

Abstract Samples of drug/hydroxypropylmethylcellulose (HPMC) mixtures and matrices (drug/HPMC mixtures plus excipients) were allowed to equilibrate in closed chambers with defined relative humidities (RHs). Their water uptake and drug release were evaluated by differential scanning calorimetry/thermogravimetric analysis and dissolution studies, respectively. Analysis of the thermal behaviors of the drug/HPMC mixtures and of the polymer alone, as functions of RH, leads to the conclusion that most of the hydration water is retained by the polymer, and points to the occurrence of different types of hydration water, from the strongly polymer-bound water molecules at RH values up to 81%, to the almost “free water” for RH values close to 100%. In addition, application of the Korsmeyer model to the dissolution results leads to the conclusion that the rate determining dissolution processes are predominantly of the fickian type.

The influence of diluent on the release of theophylline from hydrophilic matrix tablets.

The role of β-cyclodextrin (β-CD) on the apparent solubility of theophylline was investigated by the solubility method. Binary systems of theophylline and β-CD were prepared using the dry co-grinding method. Their characterization was performed by differential scanning calorimetry (DSC). The dissolution rate of theophylline and theophylline/β-CD and dissolution studies of matrix tablets prepared from mixtures containing theophylline and ground theophylline were carried out. It can be concluded that β-CD is related to an increase in the apparent solubility and dissolution rate of the drug, promoting improvement on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC). This can be attributed to the amorphous state and the increased wettability of the drug.