Hydrophilic Matrix Systems Research Articles

Evaluation of xanthan and highly substituted galactomannan from M. scabrella as a sustained release matrix

A highly substituted galactomannan (G) from Mimosa scabrella Bentham (Man:Gal 1.1:1), isolated from the seeds of a Brazilian leguminous tree and xanthan (X), an exopolysaccharide secreted by Xanthomonas campestris (Keltrol), were evaluated as a hydrophilic matrix system (XG) for controlled release (CR) of diclofenac sodium (DS) in tablets and capsules. The performance of XG (2:1) matrices containing 50 mg (A) or 100 mg (B) of DS was compared with a commercial CR product of DS. The drug release studies were carried out using a dissolution apparatus (paddle method) with gradual increase of pH values, from pH 1.4, to pH 4.0 (after1 h) and to pH 6.8 (after 2 h). The results suggested the potential of XG systems as release retarding materials, which released 78.6 and 35.1% of drug after 24 h for capsules (A) and tablets (A), respectively. Drug release decreased with the increase of amount of drug and it is dependent of dosage form. Analysis of release data indicate a rather zero-order drug release with the erosion mechanism playing a dominant role.

Evaluation of new polysaccharides networks for extended-release purposes: mesquite seed gum (MSG), xanthan gum and chitosan

The aim of this work was to design new hydrophilic matrix (HM) systems by cross-linking Mesquite Seed Gum (MSG), a galactomannan that occurs in the endosperm layer of the seeds of a Brazilian tree,Prosopis juliflora DC, with two well-known polysaccharides with the ability of retarding drug release, chitosan and xanthan gum. This had in mind the idea of using these new compounds in the preparation of extended-release dosage oral forms. The first part of this study was dedicated to the evaluation of MSG in terms of its functionality as a hydrophilic matrix (HM) system for extended-release purposes. Next, we started the study of water uptake profile of all polymers of interest (MSG, Xanthan Gum and Chitosan), in the following media: water, SGF and SIF. Following, we searched for the best cross-linking agent between Glutharaldehyde (GA) and Hexamethylenediisocyanate (HMDI), which turned out to be the GA. Next step we begun to prepare new hydrophilic matrices of MSG_Chitosan and MSG_Xanthan Gum, with different ratios, 1:1, 1:2 and 2:1. Finally, after deciding which new HM system presented best results, by using statistics tools, we investigated the mechanism controlling the rate release of the model drug, from tablets made with this new matrix. As a final result we concluded that the best combination of polysaccharides was achieved with MSG and Xanthan Gum, with mass ratio of 1:2, using glutharaldehyde aqueous solution as cross-linking agent. It presented a prevalent zero order kinetics, which is a very important feature when thinking about an extended-release oral dosage.

Controlled release formulation of tramadol hydrochloride using hydrophilic and hydrophobic matrix system

The effect of concentration of hydrophilic (hydroxypropyl methylcellulose [HPMC]) and hydrophobic polymers (hydrogenated castor oil [HCO], ethylcellulose) on the release rate of tramadol was studied. Hydrophilic matrix tablets were prepared by wet granulation technique, while hydrophobic (wax) matrix tablets were prepared by melt granulation technique and in vitro dissolution studies were performed using United States Pharmacopeia (USP) apparatus type II. Hydrophobic matrix tablets resulted in sustained in vitro drug release (>20 hours) as compared with hydrophilic matrix tablets (<14 hours). The presence of ethylcellulose in either of the matrix systems prolonged the release rate of the drug. Tablets prepared by combination of hydrophilic and hydrophobic polymers failed to prolong the drug release beyond 12 hours. The effect of ethylcellulose coating (Surelease) and the presence of lactose and HPMC in the coating composition on the drug release was also investigated. Hydrophobic matrix tablets prepared using HCO were found to be best suited for modulating the delivery of the highly water-soluble drug, tramadol hydrochloride.

Influence of Physiological Variables on the In Vitro Drug-Release Behavior of a Polysaccharide Matrix Controlled-Release System

Hydrophilic matrix systems are popular and versatile controlled release systems. Amongst polysaccharide derivatives used to produce such systems, there are a range of cellulose ethers, e.g., hydrox...

Spray freeze-drying - the process of choice for low water soluble drugs?

Most of the novel highly potent drugs, developed on the basis of modern molecular medicine, taking into account cell surface recognition techniques, show poor water solubility. A chemical modification of the drug substance enhancing the solubility often decreases the pharmacological activity. Thus, as an alternative an increase of the solubility can be obtained by the reduction of the size of the drug particles. Unfortunately, it is often difficult to obtain micro or nanosized drug particles by classical or more advanced crystallization using supercritical gases or by milling techniques. In addition, nanosized particles are often not physically stable and need to be stabilized in an appropriate matrix. Thus, it may be of interest to manufacture directly nanosized drug particles stabilized in an inert hydrophilic matrix, i.e. nanostructured and nanocomposite systems. Solid solutions and solid dispersions represent nanostructured and nanocomposite systems. In this context, the use of the vacuum-fluidized-bed technique for the spray-drying of a low water soluble drug cosolubilized with a hydrophilic excipient in a polar organic solvent is discussed. In order to avoid the use of organic solvents, a special spray-freeze-drying technique working at atmospheric pressure is presented. This process is very suitable for temperature and otherwise sensitive drugs such as pharmaproteins.

Quantitative NMR imaging study of the mechanism of drug release from swelling hydroxypropylmethylcellulose tablets

NMR imaging has been used to study the release behavior of two model drugs, triflupromazine–HCl and 5-fluorouracil, from swelling hydroxypropylmethylcellulose (HPMC) tablets. Preliminary experiments were performed on equilibrium mixtures of drug, polymer and water to determine how properties such as NMR relaxation parameters and self-diffusion were affected by the drug and polymer concentrations. The tablet swelling was restricted to one dimension and distributions of the water and model drugs were obtained by 1H and 19F imaging, respectively. The HPMC distribution at each time in the swelling process was determined indirectly from its effect on the relaxation parameters of the water and the drugs. In the one-dimensional swelling tablet, distributions of drug and polymer were compared to determine what factors influenced the release of drug from the swelling tablet. The distributions for triflupromazine–HCl and HPMC paralleled each other and the drug was only released at the eroding edge of the tablet where the HPMC concentration dropped below 10%. In contrast, 5-fluorouracil was released much more rapidly from the tablet and appeared to escape by diffusion from regions as high as 30% HPMC. An empirical measure of the rate of tablet edge movement can be obtained from plots of the edge position as a function of the square root of time. For HPMC, the rate of tablet expansion was determined in this way to be (2.4±0.8)×10 −6 cm 2 s −1. The self-diffusion of triflupromazine–HCl in equilibrated mixtures of similar composition to the eroding tablet edge is ∼3×10 −6 cm 2 s −1 while the self-diffusion coefficient of 5-fluorouracil remained higher than this value until the HPMC concentration reached about 30%. This comparison of ‘diffusion’ properties may be useful in predicting the mechanism of drug release from other swelling hydrophilic matrix systems.

Characterization of a diltiazem-lambda carrageenan complex

In the present paper the interaction between lambda carrageenan, a natural sulphated polysaccharide, and diltiazem HCl, a Ca channel blocking agent, was studied. Dialysis equilibria were performed to quantify the binding capacity of lambda carrageenan for diltiazem. The relevance of the interaction to hydrophilic matrix systems was confirmed: a relationship was found between the binding capacity and the release profiles of matrix tablets containing a fixed amount of drug and different percentages of lambda carrageenan. Dialysis equilibria in buffered media showed that the interaction is quite insensitive to the pH of the medium (in the range 1.8–6.8), while it is reduced by increasing ionic strength; this behaviour is in line with the importance of ionic bonds in diltiazem-carrageenan interaction. On the basis of the calculated binding capacity, the complex was prepared, dried and milled. A preliminary characterization of the diltiazem-carrageenan complex in the solid state was effected by means of X-ray and DSC analysis. The amount of drug going into solution from the complex was not significantly affected by the pH of the medium (in the range 1.8–6.8), while it was increased by increasing ionic strength.

Design of sustained-release matrix systems for a highly water-soluble compound, ABT-089

ABT-089 is a potent cholinergic channel modulator under investigation for treatment of cognitive disorders. It is a highly water soluble compound with a short elimination half-life of 1.7 h in dogs. Hydrophilic and hydrophobic matrix systems were designed to investigate the feasibility of prolonged oral delivery of ABT-089 and to explore the preliminary in vitro and in vivo correlations. The sustained-release single and layered matrix tablets were prepared by compression. In vitro release testing using a USP apparatus II was performed for formulation screening. The release rates were modulated by varying concentrations of different types of rate controlling materials and by restricting surface area available for drug release. The transport mechanism of the compound from different types of systems typically followed Fickian diffusion. Based on the in vitro release characteristics, two types of prototype matrix systems were evaluated in beagle dogs. Both formulations provided prolonged plasma levels of ABT-089 above the minimum effective concentration for over 22 h with reduced fluctuation of plasma levels. In vivo drug release from the tablet matrix estimated by deconvolution correlated well with drug release in vitro. In conclusion, prolonged oral delivery of highly soluble ABT-089 was achieved using diffusion controlled matrix systems. The hydrophobic matrix was found to be more effective than hydrophilic matrix in extending the release of the compound. Linear relationships between in vitro and in vivo drug release indicated by the initial results for both types of systems can provide useful information for further formulation development.

Sustained-release hydrophilic matrix tablets of zileuton: formulation and in vitro/in vivo studies

Zileuton is a new active 5-lipoxygenase inhibitor which has been shown to be clinically effective in the treatment of asthma. It is a racemic mixture of S- and R-enantiomers. In the present study, hydrophilic polymer matrix tablets were used for oral controlled delivery of zileuton. The prototype formulations with drug loading of 50–60% were prepared and tested in vitro using USP apparatus I, II and III. In vivo absorption of three formulations with differing release rates was evaluated using crossover designs in beagle dogs. Plasma concentrations of the two enantiomers of zileuton were analyzed by a chiral HPLC method. The results indicated that the release of zileuton from the matrix tablets followed apparent zero-order kinetics when tested using USP apparatus I and II. Prolonged absorption of zileuton was achieved using the hydrophilic matrix system. In vivo drug release estimated by deconvolution based on the data of both S- and R-enantiomers was correlated with in vitro release. Linear relationships between in vitro and in vivo release were obtained with more rapid in vivo release than in vitro.

Formulation Development of Sustained-Release Hydrophilic Matrix Tablets of Zileuton

ABSTRACTThe purpose of this paper was to develop a hydrophilic matrix system for extended oral delivery of zileuton, and study the effects of certain formulation, processing, and dissolution variables on in vitro drug release. Tablet formulations with 60–70% drug and varying release rates were prepared by wet granulation using low and medium viscosity grades of hydroxypropylmethocellulose. In vitro drug release was evaluated using USP apparatus I. The in vitro drug release from all formulations followed zero-order kinetics and was independent of compression force. In general, the release rate decreased with increasing drug load and higher polymer concentration or viscosity. High-shear granulation also resulted in lower release rate. Accelerated release was observed with increased agitation as well as in the dissolution media with higher surfactant concentration and/or ionic strength. No stereoselective release from the matrix system was observed. The hydrophilic matrix system effectively controlled the in vitro release of zileuton. Matrix tablets with desired release rates can be prepared by adjusting various formulation and processing parameters. The matrix system also has the advantage of simple processing and relatively low cost.

Vaginal absorption of oestradiol and progesterone

The vaginal absorption of micronized oestradiol/progesterone from a hydrophilic matrix system was investigated before and after 10 days of treatment in 7 post-menopausal women with an average age of 56.1 yr. Oestradiol and progesterone levels were measured on days 1 and 11 before administration and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h afterwards by radioimmunoassay. Peak values were seen 6–12 h after administration. This finding differs from those of other investigations. Sex hormone binding globulin (SHBG) and androgen concentrations were unchanged after 10 days of treatment.