Novel aqueous chitosan-based dispersions as efficient drug delivery systems for topical use. Rheological, textural and release studies.

The use of a novel cross-linked thiolated chitosan (CTS) was investigated as the main component of aqueous dispersions (at 1% and 3% w/v) for topical drug delivery systems. The nonionic theophiline (Th) and the cationic diltiazem(.)HCl (Dt) (at 0.5% w/v concentration) were used as model drugs. All aqueous dispersions behaved as viscoelastic fluids. The CTS 1% dispersions showed predominance of viscous component and low viscosity. However, in the CTS 3% dispersions, both the elastic component and high viscosities prevailed. So, texture parameters improved from CTS 1% to 3% dispersions and CTS 3%-Dt showed greater cohesion and adhesion than CTS 3%-Th, but always below CTS alone. All dispersions showed a Fickian diffusion mechanism. Despite release profiles of both drugs almost fully overlapped at 1% CTS, diffusion coefficients confirmed Dt released faster than Th at 3% CTS. The rheological behavior and the chemical nature of the drugs explained these results.

Invivo absorption behaviour of theophylline from starch-methyl methacrylate matrix tablets in beagle dogs.

This study evaluates in vivo the drug absorption profiles from potato starch-methyl methacrylate matrices(*) using theophylline as a model drug. Healthy beagle dogs under fasting conditions were used for in vivo studies and plasma samples were analyzed by a fluorescence polarization immunoassay analysis (FPIA method). Non-compartmental and compartmental (population approach) analysis was performed to determine the pharmacokinetic parameters. The principle of superposition was applied to predict multiple dose plasma concentrations from experimental single dose data. An in vitro-in vivo correlation (IVIVC) was also assessed. The sustained absorption kinetics of theophylline from these formulations was demonstrated by comparison with two commercially available oral sustained-release theophylline products (Theo-Dur(®) and Theolair(®)). A one-compartment model with first order kinetics without lag-time best describes the absorption/disposition of theophylline from the formulations. Results revealed a theophylline absorption rate in the order FD-HSMMA≥Theo-Dur(®)≥OD-CSMMA>Theolair(®)≥FD-CSMMA. On the basis of simulated plasma theophylline levels, a twice daily dosage (every 12h) with the FD-CSMMA tablets should be recommended. A Level C IVIVC was found between the in vitrot50% and the in vivo AUC/D, although further optimization of the in vitro dissolution test would be needed to adequately correlate with in vivo data.

Synthesis and characterization of a novel chitosan-N-acetyl-homocysteine thiolactone polymer using MES buffer.

We report a new "green" approach to synthesize a novel thiolated chitosan conjugate, chitosan-N-acetyl-homocysteine thiolactone (chitosan-AcHcys) using a "Good's buffers", 2-(N-morpholino)ethanesulfonic acid (MES). After that, the crosslinked Xr-chitosan-AcHcys was obtained only in the presence of air, without other reactants. The chitosan-AcHcys spectrum shows a partial incorporation of the thiolactone onto the polymer backbone. The derivative thermogravimetric analysis confirmed that chitosan-AcHcys is slightly less stable than starting chitosan; however, the peak profile is broadened which is indicative of deeper changes in the thermal degradation process. Also, aqueous dispersions with different concentrations of the crosslinked material (Xr-chitosan-AcHcys) were prepared and rheologically characterized. All aqueous dispersions are viscoelastic fluid with shear-thinning behavior. The viscosity of the dispersions (1-7% of chitosan-AcHcys) increases as a function of polymer concentration. So, we have achieved to disperse a high concentration of thiolated-chitosan derivative in water with different rheological characteristics, which could affect the drug release.

In vitro release testing of matrices based on starch-methyl methacrylate copolymers: effect of tablet crushing force, dissolution medium pH and stirring rate.

Direct-compressed matrix tablets were obtained from a variety of potato starch-methyl methacrylate copolymers(1) as sustained-release agents, using anhydrous theophylline as a model drug. The aim of this work was to investigate the influence of the copolymer type, the tablet crushing force and dissolution variables such as the pH of the dissolution medium and the agitation intensity on the in vitro drug release behaviour of such matrices. Commercial sustained-release theophylline products (Theo-Dur(®) 100mg, Theolair(®) 175 mg) were used as standards. Test formulations were compacted into tablets at three different crushing force ranges (70-80, 90-100 and 110-120 N) to examine the effect of this factor on the porous network and drug release kinetics. In vitro release experiments were conducted in a pH-changing medium (1.2-7.5) with basket rotation speeds in the range 25-100 r.p.m. to simulate the physiological conditions of the gastrointestinal tract. The release rate of theophylline was practically not affected by pH in the case of Theo-Dur(®) and HSMMA matrices. In contrast, Theolair(®) and CSMMA tablets demonstrated a biphasic drug release pattern, which appeared to be sensitive to the pH of the dissolution medium. An increase in the crushing force of the copolymer matrices was accompanied by a reduction of the matrix porosity, although the porous network depends markedly on the type of copolymer, having a strong influence on the drug release kinetics. Mathematical modelling of release data shows a Fickian diffusion or anomalous transport mechanism. Based on the similarity factor f2, FD-HSMMA, OD-CSMMA and FD-CSMMA at 90-100 N were selected for agitation studies. In general, all formulations showed an agitation speed-dependent release, with Theo-Dur(®) and FD-CSMMA matrices being the less susceptible to this factor.

Compaction properties, drug release kinetics and fronts movement studies of matrices combining mixtures of swellable and inert polymers. III: effect of polymer substitution type.

Theophylline radial release from cellulose derivatives with different substitution type (HPMC K4M, HPC H, MC A4M) matrix tablets has been modulated by the introduction of a new inert polymeric excipient, at different proportions (75, 50, 25%). The new polymer was hydroxypropylcellulose-methyl methacrylate (HCMMA), which was dried either in a vacuum oven (OD-HCMMA) or freeze-dried (FD-HCMMA). MC A4M and its mixtures presented the best compaction properties results, especially mixed with FD-HCMMA, according to 100% mixtures. Only high levels of HCMMA (75%) in the matrices showed interesting differences to drug release modulation. Also, at this proportion (75:25), the HPC H mixtures presented the highest differences in relation with OD or FD HCMMA respect to the other cellulose polymers. HPMC K4M and HPC H mixtures showed a combination of diffusion and erosion release mechanisms. The last one was nearly negligible in MC A4M mixtures, according with its highest diffusion rate constant values, and the absence of hydroxypropyl substituents. Only HPMC K4M mixtures presented a diffusion front that moves outwards, while HPC H and MC A4M moves inwards. The modulation of theophylline radial release was obtained using a high percentage of HCMMA, and the use of two cellulosic ethers, one of them with just one type of substituent (MC A4M or HPC H) and the other with two types of substituent (HPMC K4M). Another possibility is changing the HCMMA copolymer (OD or FD) in the 75/25 mixture with HPC.

Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: drug release and fronts movement kinetics.

A previous paper deals with the physicochemical and technological characterization of novel graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS). The results obtained suggested the potential application of these copolymers as excipients for compressed non-disintegrating matrix tablets. Therefore, the purpose of the present study was to investigate the mechanism governing drug release from matrix systems prepared with the new copolymers and anhydrous theophylline or diltiazem HCl as model drugs with different solubility. The influence of the carbohydrate nature, drying procedure and initial pore network on drug release kinetics was also evaluated. Drug release experiments were performed from free tablets. Radial drug release and fronts movement kinetics were also analysed, and several mathematical models were employed to ascertain the drug release mechanisms. The drug release markedly depends on the drug solubility and the carbohydrate nature but is practically not affected by the drying process and the initial matrix porosity. A faster drug release is observed for matrices containing diltiazem HCl compared with those containing anhydrous theophylline, in accordance with the higher drug solubility and the higher friability of diltiazem matrices. In fact, although diffusion is the prevailing drug release mechanism for all matrices, the erosion mechanism seems to have some contribution in several formulations containing diltiazem. A reduction in the surface exposed to the dissolution medium (radial release studies) leads to a decrease in the drug release rate, but the release mechanism is not essentially modified. The nearly constant erosion front movement confirms the behaviour of these systems as inert matrices where the drugs are released mainly by diffusion through the porous structure.

Compaction properties, drug release kinetics and fronts movement studies from matrices combining mixtures of swellable and inert polymers. II. Effect of HPMC with different degrees of methoxy/hydroxypropyl substitution.

The aim of this paper is the modification of the release behaviour of hydrophilic HPMC-based matrices of different substitution degree (E4M, F4M, K4M) by the introduction of a new inert polymeric excipient hydroxypropylcellulose-methyl methacrylate (HCMMA) at different proportions (75:25, 50:50 and 25:75). The product (HCMMA) was dried either in a vacuum oven--OD copolymers--or freeze-dried-FD copolymers. HPMC E4M formulations showed the worst compaction properties. All mixtures presented a percentage of theophylline release between 47% and 32% at 1440 min. The drying methods employed had only influence over the drug release in E4M and K4M formulations, at higher proportions of HCMMA, showing the highest release the mixtures containing OD-HCMMA. Combinations of diffusion and erosion release mechanisms were found to matrix tablets. All mixtures with F4M did not modify relaxation rate constant values of Peppas and Shalin equation (k(r)) respect to F4M 100%. However, all mixtures with K4M showed the highest k(r) values, which decreased when HCMMA proportion decreased. Only K4M mixtures showed a different diffusion front movement than the other mixtures. The modulation of theophylline monoaxial release was obtained using a high percentage of HCMMA, and HPMCs with a substantial difference of hydroxypropyl groups (F4M and K4M or E4M).

Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: physicochemical and technological characterisation.

Nowadays, graft copolymers are being used as an interesting option when developing a direct compression excipient for controlled release matrix tablets. New graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS) were synthesised by free radical polymerization and alternatively dried in a vacuum oven (OD) or freeze-dried (FD). This paper evaluates the performance of these new macromolecules and discusses the effect of the carbohydrate nature and drying process on their physicochemical and technological properties. Grafting of EMA on the carbohydrate backbone was confirmed by IR and NMR spectroscopy, and the grafting yields revealed that graft copolymers present mainly a hydrophobic character. The graft copolymerization also leads to more amorphous materials with larger particle size and lower apparent density and water content than carbohydrates (MS, MHS). All the products show a lack of flow, except MHSEMA derivatives. MSEMA copolymers underwent much plastic flow and less elastic recovery than MHSEMA copolymers. Concerning the effect of drying method, FD derivatives were characterised by higher plastic deformation and less elasticity than OD derivatives. Tablets obtained from graft copolymers showed higher crushing strength and disintegration time than tablets obtained from raw starches. This behaviour suggests that these copolymers could be used as excipients in matrix tablets obtained by direct compression and with a potential use in controlled release.

Drug release behaviour from methyl methacrylate-starch matrix tablets: effect of polymer moisture content.

The aim of this work was to study the effect of the initial moisture content of the polymer on the tabletting and drug release behaviour of controlled release inert matrices elaborated with methyl methacrylate (MMA)-starch copolymers. The copolymers, obtained by free radical polymerisation and dried by two different methods (oven-drying or freeze-drying), were equilibrated at different relative humidities (0%, 25%, 50% and 75% RH) at room temperature. From these copolymers, matrix systems were directly compressed containing either a slightly water-soluble drug (anhydrous theophylline) or a freely water-soluble drug (salbutamol sulphate), and their compaction properties and in vitro dissolution profiles were evaluated. The release profiles were compared following model-independent methods, such as the Qt parameter and the similarity factor f2. Moreover, several kinetic models were employed to evaluate the possible changes in the release mechanism. For anhydrous theophylline, the initial moisture content of the copolymers did not affect the release characteristics from the inert matrices under study, and a typical Fickian diffusion mechanism was observed for the different formulations. However, in case of salbutamol sulphate, the presence of moisture might induce a fast drug dissolution, promoting the weakness of the matrix structure and hence, its partial disintegration. So, an "anomalous" mixed phenomenon of diffusion and erosion was found, influenced by the initial moisture content of the copolymer.

Compaction properties, drug release kinetics and fronts movement studies from matrices combining mixtures of swellable and inert polymers: effect of HPMC of different viscosity grades.

The aim of this paper is the modification of the release behaviour of hydrophilic HPMC-based matrices of different viscosity grade by the introduction of a new inert polymeric excipient hydroxypropylcellulose-methyl methacrylate (HCMMA). The drug released could be control by both mechanisms, the swelling rate from the hydrophilic matrices, and the porosity, tortuosity and water uptake capacity from inert matrices. The effects of drying methods, presence or absence of viscosity (HCMMA in relation with HPMC), proportion of two polymers and different viscosity grade of HPMC were studied. It was observed that the mixtures with FD-HCMMA needed less pressure, presented higher plasticity and their tablets were easier to obtain compared with OD-HCMMA mixtures. Only FD-HCMMA:K100M mixtures did not show any differences in the percentage of theophylline released when FD-HCMMA proportion changed (f2>95). All mixtures show double release mechanism, diffusion and erosion from the gel layer, but with higher contribution of the relaxation factor than on HPMC tablets. For the different mixtures HCMMA-HPMC, it is possible to see fronts movement profiles similar to swellable matrices. The results demonstrate that the use of high viscosity differences of HPMC or 50% HCMMA or above was required to produce modifications on theophylline monoaxial release modulation.

Influence of moisture content on the mechanical properties of methyl methacrylate-starch copolymers.

The water vapour sorption-desorption behaviour of graft copolymers (hydroxypropylstarch-methyl methacrylate -HSMMA- and carboxymethylstarch-methyl methacrylate -CSMMA-) synthetised by free-radical polymerisation and alternatively dried by oven (OD) or freeze-drying (FD) techniques was investigated in a previous paper. The aim of the present study was to analyse the influence of the amount and distribution of water molecules on the flow and compaction characteristics of this family of methyl methacrylate-starch copolymers. Products were stored at constant temperature (25 degrees C) and different relative humidity conditions (RH). Flow properties of the powdered materials were evaluated using glass and stainless-steel funnels and the densification behaviour was studied in detail by means of Heckel treatment and compression parameters. Results revealed that the storage at 25-50% RH was the optimum condition relating flowability for HSMMA and OD-CSMMA copolymers. At higher RH values, the flow characteristics worsened, due to an increment in cohesive forces. Compaction experiments showed that the 25-50% RH range improved also the compression performance of the copolymers, due to increasing powder compressibility and reduced compact relaxation. Under these circumstances, absorbed water might act as plasticiser and adsorbed water as lubricant.

Water sorption-desorption behaviour of methyl methacrylate-starch copolymers: effect of hydrophobic graft and drying method.

A new family of graft copolymers combining hydrophilic and hydrophobic components have recently been proposed as direct compression excipients. Copolymers were synthetised by free radical copolymerisation of starch derivatives with methyl methacrylate (MMA) and were alternatively dried by oven or freeze-drying techniques. The aim of this study was to investigate the water vapour sorption-desorption behaviour of these copolymers, focusing on the influence of variables such as the hydrophobic component and the drying process. Moisture sorption and desorption isotherms were measured at 25 degrees C and analysed according to GAB and Young-Nelson equations, which distinguish between different physical forms of moisture distribution. The Young-Nelson model gave the best fit to the experimental data. The results obtained showed that the presence of the acrylic component modified not only the total hygroscopicity of the copolymers, as compared with the original starch derivatives, but also the water distribution in the solid, which might have an important role in the effect of moisture content on copolymer characteristics. The main water-sorption mechanism seemed to be absorption into the copolymer particles structure, in agreement with their starching nature. In terms of water sorption-desorption characteristics, no marked differences were found between the two drying methods used.

Drug release kinetics and fronts movement studies from methyl methacrylate (MMA) copolymer matrix tablets: effect of copolymer type and matrix porosity.

Several methyl methacrylate (MMA) copolymers have recently been proposed as an alternative for the formulation of controlled-release matrix tablets. Copolymers were synthesised by free radical copolymerisation of methyl methacrylate with starch or cellulose derivatives and were alternatively dried by oven or freeze-drying techniques. Both the chemical composition and the drying technique were demonstrated to have a considerable influence on the physical properties of the copolymers. The present investigation was focused on the elucidation of the drug release mechanism from MMA copolymer matrices, using anhydrous theophylline as model drug. Drug release experiments were performed from free tablets. Radial drug release and fronts movement were also evaluated using special devices consisting of two Plexiglass discs joined by means of four stainless steel screws. Mathematical analysis of release data was performed using Higuchi, Korsmeyer and Peppas equations and fronts movement was investigated using a colorimetric technique. The drug release rate and the relative positions of the fronts were studied as functions of the type of copolymer and the initial porosity of the tablets. Drug release was controlled mainly by diffusion and the release rate was found to be affected by the drying method and related to the area exposed to the dissolution medium. Three distinct fronts (water uptake, complete wetting, erosion) were observed during the release process and the dynamics of fronts movement confirmed the diffusional mechanism.

The influence of carbohydrate nature and drying methods on the compaction properties and pore structure of new methyl methacrylate copolymers.

Methyl methacrylate (MMA) copolymers have recently been proposed as an alternative in controlled-release matrix tablets. The aims of this study were to assess the potential value of these copolymers as direct compression excipients and to investigate relationships between the physical and structural properties of the polymers and the compression behaviour of the powders and the microstructural properties of the tablets. Copolymers were synthesised by free radical copolymerisation of MMA with starch or cellulose derivatives and were alternatively dried by oven or freeze-drying techniques. Thus, the present study focuses on the influence of the carbohydrate nature and the drying process on the mechanical and compaction properties of MMA copolymers. Particle size, shape and surface texture of the copolymers have been studied in detail and Heckel treatment has been chosen for discriminating the densification behaviour of powdered materials. Total pore volume and pore size distribution of MMA copolymer tablets were investigated with mercury porosimetry. Oven drying gave less porous particles with more homogenous surfaces than those freeze-dried. Differences in morphology between the MMA copolymers were demonstrated by increasing apparent particle densities, smaller flow rates and higher binding capacities for freeze-dried products. The porousness and mean pore radius of the tablets obtained from freeze-dried copolymers were higher than those of tablets obtained from oven-dried ones.

Fronts movement as a useful tool for hydrophilic matrix release mechanism elucidation.

The purpose of this study was to modify the fronts movement method proposed by Colombo et al. in order to apply it to uncoloured drugs and hydrophilic non-swellable matrices. Matrix tablets were prepared using theophylline as a model drug and sodium carboxymethylcellulose (NaCMC) or a new graft copolymer, hydroxypropylcellulose methylmethacrylate dried by lyophilization (HCMMAL), as polymer carriers. Drug release experiments were performed from the whole tablets. Radial drug release and fronts movement were also evaluated using special devices consisting of two Plexiglass(R) discs joined by means of four stainless steel screws. Release kinetics were determined by means of Higuchi, Korsmeyer and Peppas equations and were related to the fronts movement data. The analysis of drug release and fronts movement kinetics revealed a different release mechanism for both matrices. Drug release from NaCMC matrices was mostly controlled by relaxation, whereas drug diffusion through the porous network regulated drug release from HCMMAL matrices. A reduction in the surface exposed to the dissolution medium led to a decrease in the drug release rate, but the release mechanism was not essentially modified. Fronts movement was shown as a useful tool for matrix release mechanism elucidation. A new denomination for the different fronts observed in HCMMAL matrices was proposed.

Determination of the glass transition temperatures of some new methyl methacrylate copolymers using modulated temperature differential scanning calorimetry (MTDSC).

PURPOSE: The purpose of this study was to determine the glass transition temperatures of new graft copolymers using Modulated Temperature Differential Scanning Calorimetry (MTDSC), and to assess the differences between starch and cellulosic derivatives of methyl methacrylate and between two different drying methods used in their preparation. METHODS: Graft copolymers of methyl methacrylate were synthesized and dried by oven or freeze-drying. Surface area measurements and different thermal analysis techniques (Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA) and MTDSC) were used to characterize these copolymers. Results. DSC was not sensitive enough to identify the T(g)s of the copolymers, however they were clearly identifiable by MTDSC. T(g) values obtained may depend on the method of preparation that also altered their physical characteristics e.g. specific surface area. Cellulose derivatives showed lower T(g)s than starch derivatives. The results also depended on the drying method used, thus, freeze dried products had slightly lower T(g)s than oven dried products. CONCLUSIONS: MTDSC represents a useful thermal technique that allows the identification of glass transitions in these new copolymers with higher sensitivity and resolution than conventional DSC, separating the transition from overlapping phenomena such as decomposition or dehydration. The Tg of this new class of copolymers appeared to be dependent on polymer composition and drying method used.

Effect of compression speed and pressure on the physical characteristics of maltodextrin tablets.

The present paper studies the effect of applied pressure (0-300 MPa) and compression speed (8 and 40 cycles/min) on the physical characteristics of four varieties of maltodextrins for direct compression. The materials were tableted by using a single-punch tablet machine. On the basis of the mechanical properties it seems to be reasonable to propose a limit in the plastic deformation and consequently bonding between particles. This limit could be approximately 90 MPa, and it was almost independent of the variety compressed. Disintegration behavior and, most probably, release properties are related with this limit; i.e., mechanical parameters and disintegration time increased as applied pressure was increased up to this limit. Above this limit, no differences of note were found. The different movement of particle layers in the single-sided eccentric profile led to the computation of differences between upper and lower tablet hardness surfaces, which were indicative of a consolidation mechanism. The differences obtained were indicative of the plastic deforming nature of maltodextrins.

Effect of Explotab on the tabletability of a poorly soluble drug.

The efficiency of a superdisintegrant (Explotab) in a direct-compression formulation containing a poorly water soluble drug (albumin tanate) at high dosage was investigated. An experimental design with two variables, applied pressure and concentration of Explotab, enabled its effects on the tableting and the mechanical properties of the final tablets to be determined. Differential scanning calorimetry was performed to study the interactions between drug and excipients. No incompatibility was found between drug-excipient mixtures prepared in the proportion 1:1 and in the corresponding formulation at room temperature and after 3 weeks at 50 degrees C. The concentration of Explotab has a positive effect on flow properties. Also, the effect of applied pressure and disintegrant content was found to be significant on all compressional parameters. At low applied pressures, the breaking strength was independent on Explotab concentration. However, at higher applied pressures, the maximum densification obtained with 10% Explotab produced a limited breaking strength lower than that at 0% concentration. The response surface shows a certain level of Explotab, around 7%, at which the disintegration time was the shortest. At this level, the surface response was independent of the applied pressure. In our study, the experimental design was a valuable tool used to establish the optimum manufacturing conditions.

Comparative study of flow parameters of excipients for direct compression excipients determined using a ring shear.

In a previous research it has been attempted to define the selective criteria for excipients used in direct compression by measuring their flow rate and their flow regularity. The control of flowability of Avicel PH 101 and Cellutab has now been realized using a ring shear cell. A comparison of results obtained shows a different behavior in both excipients. In this way, we obtained higher values of cohesion and friction coefficients for Avicel PH 101 than for Cellutab, and values of flow factor that indicate good flow for Avicel PH 101 and excellent flow for Cellutab.

[The effect of two lubricants (magnesium stearate and pruv) in the formation of tablets of four anti-ulcer agents/ by means of direct compression]. / Influence de deux lubrifiants (stéarate de magnésium et pruv) dans l'élaboration de comprimés de quatre anti-ulcéreux au moyen de la compression directe.

In this research we study the influence of two lubricants-Magnesium Stearate and Pruv--on the tablets elaboration of Cimetidine, Ranitidine, Famotidine and Pirenzepine by direct compression. The presence of 0.5% of lubricants improved the flow of all the formulations, but especially the Famotidine's formulation. The formulations with Magnesium Stearate had the worst results in tests of friability and tensile strength. All tablets with drugs and Pruv had high data in indentation hardness. The tablets of Cimetidine, Famotidine and Pirenzepine with Magnesium Stearate had less time of disintegration.