Swelling and drug release behaviour of xanthan gum matrix tablets

The swelling and drug release behaviour of xanthan gum matrix tablets were studied using three drugs having different properties, i.e., caffeine as a soluble neutral drug, indomethacin as an insoluble acidic drug, and the sodium salt of indomethacin as a soluble acidic drug. Swelling was ascertained by measuring the axial and the radial expansion of matrix tablets following exposure to media of physiological ionic strength. The mean drug dissolution time and swelling rate were calculated from dissolution and swelling experiments, respectively, and were used as responses for comparison under different experimental conditions. The dependence of drug release on the swelling of the polymer matrix and on the type of the drugs added was established. The former is mainly influenced by the ionic strength and buffer concentrations. The latter is affected by the solubility of the drug. The mechanism of matrix swelling follows Case I diffusion, whereas drug release from this polymer matrix conforms to Case II diffusion.     

Compaction, compression and drug release characteristics of xanthan gum pellets of different compositions.

Compaction and compression of xanthan gum (XG) pellets were evaluated and drug release from tablets made of pellets was characterised. Three formulations were prepared by extrusion-spheronisation and included, among other excipients, diclofenac sodium (Dic Na), at 10% (w/w); xanthan gum, at 16% (w/w); and one of three different fillers (lactose monohydrated (LAC), tribasic calcium phosphate (TCP) and beta-cyclodextrin (beta-CD)), at 16% (w/w). Five hundred milligrams of pellets (fraction 1000-1400microm) were compacted in a single punch press at maximum punch pressure of 125MPa using flat-faced punches (diameter of 1.00cm). Physical properties of pellets and tablets were analysed. Dissolution was performed according to the USP paddle method. Pellets showed close compressibility degrees (49.27% LAC; 51.32% TCP; and 50.48% beta-CD) but densified differently (3.57% LAC; 14.84% TCP; 3.26% beta-CD). Permanent deformation and densification were the relevant mechanisms of compression. Fragmentation was regarded as non-existent. The release behaviour of tablets made of pellets comprising LAC or beta-CD was anomalous having diffusional exponent (n) values of 0.706 and 0.625, respectively. Drug diffusion and erosion were competing mechanisms of drug release from those tablets.     

Compaction, compression and drug release properties of diclofenac sodium and ibuprofen pellets comprising xanthan gum as a sustained release agent

Compaction and compression of xanthan gum pellets were evaluated and drug release from tablets made of pellets was characterised. Two types of pellets were prepared by extrusion-spheronisation. Formulations included xanthan gum, at 16% (w/w), diclofenac sodium or ibuprofen, at 10% (w/w), among other excipients. An amount of 500 mg of pellets fraction 1000-1400 microm were compacted in a single punch press at maximum punch pressure of 125 MPa using flat-faced punches (diameter of 1.00 cm). Physical properties of pellets and tablets were analysed. Laser profilometry analysis and scanning electron microscopy of the upper surface and the surface of fracture of tablets revealed that particles remained as coherent individual units after compression process. Pellets were flatted in the same direction of the applied stress evidencing a lost of the original curvature of the spherical unit. Pellets showed close compressibility degrees (49.9% for pellets comprising diclofenac sodium and 48.5% for pellets comprising ibuprofen). Xanthan gum pellets comprising diclofenac sodium experienced a reduction of 65.5% of their original sphericity while those comprising ibuprofen lost 49.6% of the original porosity. Permanent deformation and densification were the relevant mechanisms of compression. Fragmentation was regarded as non-existent. The release of the model drug from both type of tablets revealed different behaviours. Tablets made of pellets comprising ibuprofen released the model drug in a bimodal fashion and the release behaviour was characterised as Case II transport mechanism (release exponent of 0.93). On the other hand, the release behaviour of diclofenac sodium from tablets made of pellets was anomalous (release exponent of 0.70). For the latter case, drug diffusion and erosion were competing mechanisms of drug release.     

Comparative evaluation of rate of hydration and matrix erosion of HEC and HPC and study of drug release from their matrices.

Hydrophilic polymers, in contact with the dissolution medium, may swell and make a continuous gel layer, erode or undergo combination of the two. The swelling action of these polymers is controlled by the rate of their hydration in the dissolution medium. The extent of polymer swelling, relative mobilities of dissolution medium and drug, and matrix erosion dictate the kinetics as well as mechanism of drug release from the polymeric matrices. The objective of the present investigations was to study the rate of hydration and the rate of matrix erosion of two hydrophilic, non-ionic cellulose ethers, i.e., hydroxyethylcellulose (HEC) and hydroxypropylcellulose (HPC), and to compare the kinetics and mechanism of drug release from their matrices. Chlorpheniramine maleate was used as the model drug. Matrix tablets containing chlorpheniramine maleate, HEC or HPC and dicalcium phosphate were compressed at 156 MPa pressure. The rate of hydration of the polymer, rate of erosion of the matrices and in vitro drug release studies were carried out in phosphate buffer (pH 7.4). The hydration studies of the two polymers demonstrated that due to relatively larger water uptake, the degree of swelling of HEC matrices was considerably higher as compared to the HPC matrices. Also, HEC matrices exhibited relatively higher erosion as compared to HPC matrices. The drug release from HEC matrices occurred by non-Fickian transport, i.e., combination of drug diffusion and polymer swelling, while drug release from HPC matrices was controlled primarily by diffusion through pores and channels in the structure. The t(50%), time to reach 50% drug release, for HEC matrices was 4.8 h and that for HPC matrices was 6.5 h which indicates that a higher polymer level was needed in the case of HEC matrices to sustain the drug release for up to 12 h of dissolution as compared to HPC matrices due to relatively higher hydrophilicity of HEC.     

Properties of sustained release hot-melt extruded tablets containing chitosan and xanthan gum

The aim of this study was to investigate the influence of pH, buffer species and ionic strength on the release mechanism of chlorpheniramine maleate (CPM) from matrix tablets containing chitosan and xanthan gum prepared by a hot-melt extrusion process. Drug release from hot-melt extruded (HME) tablets containing either chitosan or xanthan gum was pH and buffer species dependent and the release mechanisms were controlled by the solubility and ionic properties of the polymers. All directly compressed (DC) tablets prepared in this study also exhibited pH and buffer species dependent release. In contrast, the HME tablets containing both chitosan and xanthan gum exhibited pH and buffer species independent sustained release. When placed in 0.1N HCl, the HME tablets formed a hydrogel that functioned to retard drug release in subsequent pH 6.8 and 7.4 phosphate buffers even when media contained high ionic strength, whereas tablets without chitosan did not form a hydrogel to retard drug release in 0.1N HCl. The HME tablets containing both chitosan and xanthan gum showed no significant change in drug release rate when stored at 40 °C for 1 month, 40 °C and 75% relative humidity (40 °C/75% RH) for 1 month, and 60 °C for 15 days.     

Gamma-scintigraphic study of the gastrointestinal transit and in vivo dissolution of a controlled release diclofenac sodium formulation in xanthan gum matrices

A xanthan gum matrix controlled release tablet formulation containing diclofenac sodium was evaluated in vitro and was found to release the drug at a uniform rate. The gastrointestinal transit behaviour of the formulation as determined by gamma scintigraphy, using healthy male volunteers under fasted and fed conditions, indicated that gastric emptying was delayed with food intake. In contrast, the small intestinal transit remained practically unchanged under both food statuses. Therefore, the delay in caecal arrival observed in the fed state can be attributed to the delay in gastric emptying. Rate of diclofenac sodium absorption was generally higher in the fed state compared to the fasted state, however the total amount absorbed under both food statuses remained practically the same. The rate of in vivo dissolution of the drug in the fed state was faster compared to that in the fasted state. Thus, at the time of caecal arrival, in vivo dissolution was complete in the fed state, unlike in the fasted state, where almost 60% of the drug was delivered to the colon.     

Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly water-soluble drug nimodipine

Modified gum karaya (MGK), a recently developed excipient was evaluated as carrier for dissolution enhancement of poorly soluble drug, nimodipine (NM). The advantages of MGK over the parent gum karaya (GK) were illustrated by differences in the in vitro dissolution profiles of respective solid mixtures prepared by co-grinding technique. The influence of process variable, such as polysaccharide concentration and method of preparation of solid mixture on dissolution rate was studied. Solubility studies were also performed to explain the differences in dissolution rate. Solid mixtures were characterized by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD) and scanning electron microscopy (SEM). The dissolution rate of NM was increased as the MGK concentration increased and optimum ratio was found to be 1:9 w/w ratio (NM:MGK). It is found that method of preparation of solid mixtures was significantly effected the dissolution rate of NM from solid mixtures. The order of method of preparation in according to their Dissolution Efficiency is physical mixture < co-grinding mixture < swollen carrier mixture < kneading mixture (water as kneading agent) < kneading mixture (70% v/v ethanol as kneading agent) < solid dispersion. Though, the solid mixtures prepared by other methods like solid dispersion, swollen carrier mixture and kneading technique gave faster release, co-grinding mixture prepared in 1:9 w/w ratio (NM:MGK) was found to exhibit a significant improvement in dissolution rate without requiring addition of organic solvents or high temperatures for its preparation and the process is less cumbersome. Hence, co-grinding technique appears to be more easier and the most convenient method from a practical point of view.     

Konjac glucomannan/xanthan gum enzyme sensitive binary mixtures for colonic drug delivery

The polysaccharide konjac glucomannan (KGM) is degraded in the colon but not the small intestine, which makes it potentially useful as an excipient for colonic drug delivery. With xanthan gum (XG) KGM forms thermoreversible gels with hitherto unexplored biodegradation properties. In this work, rheological measurements of KGM and KGM/XG systems incubated with and without Aspergillus niger beta-mannanase (used to mimic colonic enzymes) showed that KGM was degraded by the enzyme even when interacting with XG. Tablets with KGM/XG/sucrose matrices that varied in accordance with a simplex design and bore diltiazem as a typical highly soluble drug load were prepared by wet granulation, and in most cases were found to possess satisfactory mechanical strength and exhibit slow, nearly zero-order drug release. Drug release from these tablets remained zero-order, but was accelerated (presumably due to degradation of KGM), in the presence of A. niger beta-mannanase at concentrations equivalent to human colonic conditions. However, marked differences between Japanese and American varieties of KGM as regards degree of acetylation and particle size led to significant differences in swelling rate and drug release between formulations prepared with one and the other KGM: whereas a formulation with Japanese KGM released its entire drug load within 24h in the presence of beta-mannanase, only 60% release was achieved under the same conditions by the corresponding formulation with American KGM, suggesting that with this KGM it will be necessary to optimize technological variables such as compression pressure in order to achieve suitable porosity, swelling rate, and drug release. To sum up, the results of this study suggest that sustained release of water-soluble drugs in the colon from orally administered tablets may be achieved using simple, inexpensive formulations based on combinations of KGM and XG that take the variability of KGM characteristics into account.     

Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms and optimal performance

The majority of oral drug delivery systems (DDS) are matrix-based. Swellable matrices are monolithic systems prepared by compression of a powdered mixture of a hydrophilic polymer and a drug. Their success is linked to the established tabletting technology of manufacturing. Swellable matrix DDS must be differentiated from true swelling-controlled delivery systems. This review focuses on hydrophilic swellable matrix tablets as controlled DDS. Gel-layer behaviour, front movement and release are described to show the dependence of the release kinetics on the swelling behaviour of the system. In vivo behaviour of matrix systems is also considered.     

Insights into the swelling process and drug release mechanisms from cross-linked pectin/high amylose starch matrices

Cross-linked pectin/high amylose mixtures were evaluated as a new excipient for matrix tablets formulations, since the mixing of polymers and cross-linking reaction represent rational tools to reach materials with modulated and specific properties that meet specific therapeutic needs. Objective: In this work the influence of polymer ratio and cross-linking process on the swelling and the mechanism driving the drug release from swellable matrix tablets prepared with this excipient was investigated. Methods: Cross-linked samples were characterized by their micromeritic properties (size and shape, density, angle of repose and flow rate) and liquid uptake ability. Matrix tablets were evaluated according their physical properties and the drug release rates and mechanisms were also investigated. Results: Cross-linked samples demonstrated size homogeneity and irregular shape, with liquid uptake ability insensible to pH. Cross-linking process of samples allowed the control of drug release rates and the drug release mechanism was influenced by both polymer ratio and cross-linking process. The drug release of samples with minor proportion of pectin was driven by an anomalous transport and the increase of the pectin proportion contributed to the erosion of the matrix. Conclusion: The cross-linked mixtures of high amylose and pectin showed a suitable excipient for slowing the drug release rates.     

Novel biodegradable blend matrices for controlled drug release

Phosphorylcholine-functionalized poly-epsilon-caprolactone (PC-PCL) is a new biodegradable polymer with good biocompatibility. In this study modulation of the controlled release of Ibuprofen (IB), a model drug, from poly-epsilon-caprolactone (PCL) by direct blending with PC-PCL is investigated. The influence of several factors such as the content of PC-PCL in the blend, drug loading and the molecular weight of PCL matrix upon the IB release is recognized. The release mechanism is discussed in terms of degradation/erosion profiles and hydrophilicity of the blend matrices. The IB release rate increased with the PC-PCL content because PC-PCL increased the hydrophilicity and biodegradability of the blends. Simultaneously, that release rate decreased with increase in the molecular weight of PCL in the blend. The drug loading in the blend also affected the release property of the matrix. Analysis of the release profiles following the power law indicated that the IB release was governed mainly by diffusion kinetics.     

Modeling of drug release from bioerodible polymer matrices

Models for drug release from bioerodible polymer matrices are proposed in this article. We consider that drug is released continually by diffusion that is influenced by polymer chain degradation, and polymer matrix erosion starts and enhances the drug release at a certain time. The models give excellent reproduction of drug release profiles within the whole release period, and the parameters can be correlated to various factors such as γ-irradiation dose, copolymer composition, and initial drug loading, this correlation indicates that the new models can be used to predict the effects of various factors on drug release profiles based on limited experimental data.     

Parametric simulation of drug release from hydrogel-based matrices

Objectives In this work a model recently proposed to describe the drug release from hydrogel‐based matrices was applied to describe the fractional drug release from matrices based on hydroxypropylmethylcellulose (HPMC) and diclofenac. Methods The model, firstly proposed to describe the behaviour of systems based on HPMC and theophylline and a single set of preparation variables, is based on mass balances and transport phenomena evaluation and it was solved by an FEM‐based numerical code. The experimental data on the HPMC–diclofenac matrices, taken from literature, have been obtained by varying the drug loading ratio, the compression force, the powder size of both the drug and the polymer. Key findings A good agreement between experimental data and model predictions, as calculated in the present work, was obtained without the use of any adjustable parameters. Conclusions The predictive nature of the model has been confirmed, even changing the drug molecule and other preparative parameters.     

黄原胶和槐豆胶提高维生素C稳定性研究

目的:研究黄原胶和槐豆胶对维生素C稳定性的作用.方法:比较加入黄原胶和槐豆胶前后维生素C在水中含量的变化规律,进行稳定性的研究.结果:黄原胶能显著提高维生素C的稳定性,黄原胶和槐豆胶混合使用具有更好的效果.结论:黄原胶和槐豆胶的配比使用有利于维生素C的稳定,可作为添加剂运用于食品和药品的生产,提高维生素C的稳定性.     

Polymer particle erosion controlling drug release. I. Factors influencing drug release and characterization of the release mechanism

The present study deals with controlled drug delivery from hydrocolloid tablets by polymer particle erosion. The influence of excipients and formulation factors on the dissolution behaviour of the methyl hydroxyethyl cellulose (MHEC)-tablets is investigated. Linear drug release with low susceptibility to hydrodynamic stress is obtained. The use of drugs with higher solubility leads to a slight acceleration of the release due to the contribution of diffusion to the release process. Higher drug loading and consequently lower polymer content expedites dissolution as well as changes in the tablets' geometry resulting in enlarged release surfaces. Furthermore, alterations of the composition of the dissolution medium affect drug release. However, neither viscosity grade nor the particle size of the polymer or compaction pressure has a marked impact on the dissolution. Investigations to clarify the mechanism of polymer particle erosion include erosion studies and the comparison of different batches of MHEC, of products from different manufacturers and of fibrous trial products. There is evidence that the insoluble fibres within the water soluble MHEC are responsible for the occurrence of polymer particle erosion by disturbing swelling and formation of a thick coherent gel layer and thus, causing erosion of the hydrocolloid tablet with synchronous drug release.     

Controlled release of cephalexin through gellan gum beads: effect of formulation parameters on entrapment efficiency, size, and drug release.

Gellan gum beads containing cephalexin were prepared by extruding the dispersion of cephalexin and gellan gum into a solution containing a mixture of calcium and zinc ions (counterions). Beads were prepared by changing experimental variables such as pH of the counterion solution and amount of cephalexin loading in order to optimize process variables on the final % drug entrapment efficiency, release rates, size, and morphology of the beads. Absence of chemical interactions between drug, anionic polymer, and counterions after production of beads was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry was used to understand the crystalline nature of the drug after its successful entrapment. These data indicated the amorphous dispersion of cephalexin in the polymer matrix. Beads were spherical in shape, with the average bead size ranging from 925 to 1183 microm as measured by the laser light scattering technique. Cephalexin entrapment of up to 69.24% was achieved. In vitro release studies were performed in 0.1 N HCl or pH 7.4 phosphate buffer and the release of cephalexin was achieved up to 6 h. Dynamic swelling studies were performed in 0.1 N HCl or pH 7.4 phosphate buffer. Diffusion coefficients were calculated for spherical geometry. The release data have been fitted to an empirical relation to estimate the transport parameters. Mathematical modeling studies were performed for spherical geometry by solving Fick's equation to compute concentration profiles. These results were correlated with the release profiles.     

Effects of the method of preparation on the compression, mechanical, and release properties of khaya gum matrices

A study has been made of the compression properties of khaya gum matrices and the effects of drug concentration and method of preparation of the material on the compression, mechanical and the drug release characteristics of the matrices. Khaya gum matrix tablets were prepared by direct compression and wet granulation methods. The compression properties of the formulations were assessed using the equations of Heckel and Kawakita. The mechanical properties of the tablets were evaluated using crushing strength and friability of the tablets, whereas the release properties of the tablets were evaluated by using the disintegration and dissolution times. The results obtained show that khaya gum deformed mainly by plastic deformation. The compression properties of the formulations were affected by the concentration of the drug and the method of preparation of the materials for compression. Tablets prepared by wet granulation showed faster onset and higher amount of plastic deformation during compression than those prepared by direct compression. Tablets containing dicalcium phosphate showed higher mechanical strength and disintegration and dissolution times. Wet granulation also increased the mechanical strength of the tablet without significantly affecting the drug release characteristics from the matrix tablets. Thus, the wet granulation method could be useful in the preparation of khaya gum matrix tablet with acceptable mechanical properties and drug release properties.     

Compressed biodegradable matrices of spray-dried PLGA microspheres for the modified release of ketoprofen

A spray-drying technique was used to prepare poly(lactide-co-glycolide) (PLGA) drug loaded microspheres. Ketoprofen was chosen as a model NSAID drug. The microspheres were characterized in terms of morphology, drug content and release behaviour. The spray-dried particles were subject to a direct compression process for the preparation of biodegradable matrix tablets. The spray-dried powders were found to have good compaction properties. Tablets were also prepared from a mixture of microspheres and microcrystalline cellulose, mannitol and hydroxypropylmethylcellulose or sodium alginate. The release of ketoprofen in phosphate buffer (pH 7.4) was significantly sustained, indicating the suitability of using tabletted spray-dried PLGA microspheres for controlled drug delivery. The results show that spray-dried PLGA particles have promising properties as direct compression and release controlling excipients in matrix tablets for oral administration.