Fatal exacerbation of fibrosing alveolitis associated with systemic sclerosis in a patient treated with adalimumab.
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Adalimumab↗
Biomedical subjects
C Caramella
Publications and source records attributed to C Caramella.
Histological evaluation of buccal penetration enhancement properties of chitosan and trimethyl chitosan.
The aim of the present work was to compare the penetration enhancement properties of chitosan hydrochloride (HCS) both as a polymeric solution and as a nanoparticulate system with that of trimethyl chitosan hydrochloride (TMC) on buccal mucosa. The hydrophilic high molecular weight fluorescein isothiocyanate dextran (FD4; 4400 Da) was used as a macromolecule model. The mechanism involved in the HCS (solution and nanoparticles) and TMC solution penetration enhancement was investigated on pig buccal mucosa, characterized by having stratified epithelium and lacking in tight junctions. The permeation/penetration of FD4 and the change in morphology and histology of the mucosa after contact with the polymers were assessed: the experiments were performed ex-vivo by applying the formulations on excised porcine buccal tissue. For the morphology and the histology studies, the epithelial cell layers from freshly excised pig buccal mucosa were analysed with light microscopy by means of routine histopathology analysis (haematoxylin and eosin staining and Toluidine blue staining) and immunohistochemistry reactions. The organization of desmosomal junctions was assessed by means of an immunochemical reaction on desmosomes and transmission electron microscopy. Confocal laser scanning microscopy (CLSM) was used to find evidence of the location of FD4 in the tissue. Furthermore, the increase of the FD4 apparent permeability coefficient was quantified by means of Franz diffusion cells using isolated buccal epithelium to demonstrate the penetration enhancement properties of the polymer systems. Morphological analysis, performed by light microscopy, transmission electron microscopy and CLSM, suggests a similar mechanism of penetration enhancement for both HCS and TMC solutions and for HCS nanoparticles. Such a mechanism probably involves a repackaging of the epithelial cells up to the basal membrane and a partial disarrangement of desmosomes. The cell viability and the nuclear integrity indicated on the semi-thin section stained with Toluidine blue and by CLSM analysis, respectively, suggest that HCS as a polymer solution and a nanoparticulate system, and TMC polymer solution, do not cause cell damage. Trimethyl chitosan and chitosan nanoparticulate systems were able to increase FD4 permeation across buccal epithelium to a greater extent than the chitosan solution.
Administration, Oral↗
Is low-dose methotrexate nephrotoxic? Case report and review of the literature.
Methotrexate (MTX) has become the most commonly prescribed disease-modifying anti-rheumatic drug. However, toxicity is an important drawback of MTX therapy and permanent discontinuation of MTX for adverse effects occurs in 1 patient out of 10. Although high-dose MTX is known to be nephrotoxic, data on low-dose MTX renal effects are scanty. We report an insidious and progressive deterioration of renal function during long-term low-dose MTX in a 59-year-old woman. Kidney biopsy revealed advanced kidney fibrosis with extensive interstitial and glomerular fibrosis, and vascular sclerosis. We suggest that patients on low-dose MTX therapy even alone, should be periodically monitored for creatinine levels.
Antirheumatic Agents↗
Development of oral controlled-release tablet formulations based on diltiazem-carrageenan complex.
Diltiazem HCl and lambda carrageenan react in distilled water to give a slightly soluble interaction product. The aim of this work was to verify the possible employment of lambda carrageenan-diltiazem (DTZ) complex in controlled-release formulations. The influence of complex particle size, compression force, pH of the dissolution medium, and tablet dimensions on drug release has been evaluated. The results confirm the suitability of the DTZ-carrageenan interaction product for controlled-release formulations. Good compaction properties allow tablets to slowly erode, with only the addition of the amount of hydroxypropyl methylcellulose (HPMC) necessary as a binding agent. The use of the finest sieve fraction results in the highest crushing strength values and in the slowest release rate, both in pH 1.2 and in pH 6.8. The force of compression does not affect the drug release for values over 16 kN. The release rate increases when the geometry of the tablet is varied so the surface/ volume ratio of the tablet is increased, suggesting a release mechanism involving surface dissolution/erosion.
Administration, Oral↗
Sequential atomic force microscopy imaging of a spontaneous nanoencapsulation process.
Since hydrophilic matrices were proposed for controlled drug delivery, many polymeric excipients have been studied in order to make drug release fit the desired profiles. It has been pointed out that lambda-carrageenan, a sulphated polymer from algae, can suitably control the release rate of basic drugs from hydrophilic matrices with no need for complex technological processes. In this work, we propose a method to monitor morphologically the interaction between lambda-carrageenan and dexchlorpheniramine maleate (D-CPM), in order to find out how the release profiles can be so easily controlled. To this end, solutions of both polymer and drug were prepared at very low concentration. Solutions were mixed and samples were taken every hour over a period of 20 h. The characterization technique employed, atomic force microscopy (AFM), provides a high resolution, allowing to show the three-dimensional morphology of the samples within the nanometric scale. The results demonstrate that lambda-carrageenan is able to nanoencapsulate spontaneously D-CPM molecules, which offers the possibility to easily control the release rate of the drug. This work has moreover demonstrated the suitability of AFM for the specific case of the on-time monitoring of interaction processes that happen in pharmaceutical systems.
Carrageenan↗
Characterization of chitosan hydrochloride--mucin rheological interaction: influence of polymer concentration and polymer:mucin weight ratio.
The aim of the present work was to investigate the influence of polymer concentration and polymer:mucin weight ratio on chitosan--mucin interaction, assessed by means of viscosimetric measurements. Two hydration media, distilled water and 0.1 M HCl, were used. Chitosan solutions were prepared at concentrations greater than the characteristic entanglement concentration and mixed with increasing amounts of porcine gastric mucin. Viscosity measurements were performed on the polymer--mucin mixtures and on polymer and mucin solutions having the same concentrations as in the mixtures. The flow curves were fitted according to a modified form of Cheng--Evans equation in order to obtain the relevant model parameters: low shear viscosity eta(0) and high shear viscosity eta(infinity), indexes of the sample structure at rest and upon high shear, respectively. The formation of chitosan--mucin interaction products was determined on the basis of the changes in eta(0) and eta(infinity) of the mixtures as a function of polymer:mucin weight ratio. Rheological synergism parameter was also calculated. The results obtained suggest that two different types of rheological interaction occur between chitosan and mucin in both media, depending on polymer concentration and polymer:mucin weight ratio: one is characterized by a minimum in viscosity and occurs at higher polymer:mucin weight ratio, the other one produces a positive rheological synergism and is observed in presence of an excess of mucin. Only the last one causes a 'strengthening' of the mucoadhesive interface and it is responsible for the mucoadhesive joint. This hypothesis is confirmed by tensile stress measurements performed on HCS solutions in presence of mucin dispersions at different concentrations.
Animals↗
Factorial analysis of the influence of dissolution medium on drug release from carrageenan-diltiazem complexes.
This research studied the influence of buffer composition, pH, and ionic strength on the release of diltiazem hydrochloride from a complex of the drug with lambda carrageenan. Two viscosity grades of carrageenan were also compared. A factorial analysis was used to evaluate the influence of individual variables and their interactions. Both the complex solubility, measured as the drug concentration in equilibrium with the solid complex, and the drug release rate from constant surface area were considered. The increase of ionic strength significantly increased complex solubility in all the buffer systems. A significant effect of polymer grade on complex solubility was evidenced only in phosphate buffer with a pH of 6.8, indicating lower solubility of the complex when higher polymer molecular weight was involved. In most cases, drug release rate decreased when high polymer grade was involved in the complex. Ionic strength did not always have a significant effect on drug release rate and was quantitatively less important than for solubility. Ionic strength especially affected the drug release profiles. At higher ionic strength drug release was no longer constant, but decreased with time, probably because of lower polymer solubility.
Buffers↗
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.
Calcium Channel Blockers↗
Characterization of chitosan hydrochloride-mucin interaction by means of viscosimetric and turbidimetric measurements.
In the present work the interaction between chitosan hydrochloride (HCS) and two different types of mucin - one obtained from bovine submaxillary glands and the other from porcine stomach - was investigated. Two hydration media were tested: distilled water and 0. 1 M HCl. Intrinsic viscosity, which provides information about polymeric chain conformation, was assessed in both media for HCS and bovine submaxillary mucin. Changes in the specific viscosity of HCS-mucin mixtures were observed as a function of the polymer:mucin weight ratio. The formation of interaction products was indicated by a minimum in the specific viscosity. Such a minimum occurred at different polymer:mucin weight ratios depending on the hydration medium and mucin type. This suggested a different stoichiometry of interaction. Turbidimetric measurements were also effected in order to evidentiate the eventual precipitation of the polymer-mucin interaction products. While in distilled water the precipitation of the interaction product did occur, in acidic medium, although a minimum in specific viscosity was observed, no precipitate was formed. The two techniques employed, viscosimetric and turbidimetric, allowed us to investigate for both mucins the influence of hydration medium on the formation of the HCS-mucin interaction products and to conclude that a slightly acid-neutral pH favours the interaction between HCS and mucins.
Animals↗
Characterisation of particle properties and compaction behaviour of hydroxypropyl methylcellulose with different degrees of methoxy/hydroxypropyl substitution.
The particle characteristics and compaction behaviour of hydroxypropyl methylcellulose (HPMC) powders from two different suppliers were studied regarding effects of methoxy/hydroxypropyl substitution. Samples included Methocel K4M (low substitution ratio), E4M (medium) and F4M (high) and the corresponding substitution ratios from Metolose: 90 SH 4000, 60 SH 4000, and 65 SH 4000. Characterisation of the particle properties and compaction behaviour of the pure polymers suggested that reported differences in drug release behaviour of Methocel E4M compared with the other two powders may be related to the lower powder surface area, differing particle morphology and lower fragmentation propensity during compaction. In addition, compacts of Methocel E4M were weaker when tested in both axial and radial directions and had different porosity and elastic recovery properties. There were no differences between the polymers in degree of disorder, as evaluated by solid-state nuclear magnetic resonance spectroscopy. The different behaviour of Methocel E4M could, however, be related to the overall higher total degree of substitution of this polymer and in particular the high content of methoxy groups compared to the other polymers. The methoxy substituent is hydrophobic and may, when present in sufficiently high concentrations, change the particulate and mechanical properties of the powder, thus potentially affecting the compactability. The high content of methoxy groups might also decrease the development of inter- and intraparticulate hydrogen bonds during compaction, and suppress the actions of the hydrophilic hydroxypropyl groups, both of which could affect drug release.
Compressive Strength↗
Model-based interpretation of creep profiles for the assessment of polymer-mucin interaction.
PURPOSE: This paper presents a new rheological approach, based on a stationary viscoelastic test (creep test), to describe the interaction between a mucoadhesive polymer and mucin. METHODS: An automated model builder tool is used to identify accurate compliance models from experimental data. This approach is applied to study the interaction of gastric porcine mucin with three viscosity grades of a mucoadhesive polymer, sodium carboxymethylcellulose. RESULTS: By comparing the compliance models of polymer solutions and their mixtures with mucin, prepared at different concentrations and concentration ratios, we observed an increase in the order of the model of the mixtures at the lowest polymer concentration for all the three viscosity grades; this effect is more pronounced for the low viscosity grade. On the other hand, an increase in mucin concentration does not result in a further increase in model order, but rather in a decrease in retarded compliance and an increase in newtonian viscosity. CONCLUSIONS: We interpret the model order as the number of different interactions between polymer and mucin, and the parameter values as a measure of their strength. The results indicate the suitability of the approach for a deep characterization of the interactions involved in mucoadhesion.
Adhesiveness↗
A modified Franz diffusion cell for simultaneous assessment of drug release and washability of mucoadhesive gels.
A modified Franz cell is proposed to simultaneously measure the amount of drug diffused from semisolid preparations into the receptor chamber and the amount washed away by a tangential buffer stream. Four gels containing acyclovir as model drug and based on hydrophilic polymers (sodium carboxymethylcellulose, methylvinyl ether/maleic anhydride copolymer, methacrylic acid/methacrylic acid methylester copolymer, and polyacrylic acid) were tested. The drug release profiles to the receptor chamber of a standard Franz cell apparatus were obtained and compared to the profiles obtained with the modified apparatus at two buffer stream rates (1.0 and 0.3 ml/min). Some significant differences were observed between the wash-away profiles obtained with the two buffer stream rates. At both flux rates the amount of drug washed away was quite high, and in turn, the drug release profiles to the receptor chamber were lower with respect to those obtained with the standard Franz cell test. The importance of this phenomenon was not the same for all of the polymers: the polyacrylic acid sample, because of the presence of slight crosslinking, was less sensitive to wash away. For all of the other samples, when 1.0 ml/min tangential stream was used, the amount of drug released to the receptor chamber was significantly lower with respect to the standard method. With 0.3 ml/min buffer stream, some significant reduction in release amounts could be observed for the methacrylic acid/methacrylic acid methylester copolymer sample only, which was also the most erodible sample. The method proposed appears suitable to differentiate the examined samples for sensitivity to the washing effect.
Acyclovir↗
Drug release and washability of mucoadhesive gels based on sodium carboxymethylcellulose and polyacrylic acid.
This study investigated the relationship of the washability of gels based on two mucoadhesive polymers (sodium carboxymethylcellulose [NaCMC] and polyacrylic acid [PAA]) and their mixtures to their physical properties such as consistency and hydration/dissolution. The mucoadhesive properties of the two polymers and the effect of mucus-polymer interaction on gel washability at the mucoadhesive interface were also investigated using mixtures of PAA and NaCMC gels with increasing mucin amounts. Release and wash-away properties of the gels were assessed by means of a simultaneous release and wash-away test, whereas the consistency and hydration/dissolution properties of the gels were investigated by rheological analysis (viscosity and dynamic viscoelastic tests) and liquid uptake measurements, respectively. The results showed that PAA was characterized by lower release and wash-away properties than those of NaCMC. Mixing of two gels at different ratios allowed modulation of the release and wash-away properties. A relationship between washability and hydration/dissolution properties was found. Gel consistency by itself did not always provide a complete explanation of the wash-away process. The two polymers investigated showed different rheological interaction properties with mucin. Depending on the extent of such interaction, gel-mucin mixture had hydration/dissolution and washability properties that were quite different with respect to the initial gel.
Acrylic Resins↗
On the employment of lambda carrageenan in a matrix system. III. Optimization of a lambda carrageenan-HPMC hydrophilic matrix.
The lambda carrageenan/HPMC ratio in matrix tablets has been optimized in order to obtain pH-independent release profiles of chlorpheniramine maleate, a freely soluble drug. Release profiles in acidic (pH1.2) and neutral (pH 6.8) media were fitted according to the Weibull and the power law models. Model independent parameters(t50% and the percentage of drug released after 2 h) were also calculated. The Weibull parameters were found suitable to describe the dependence of the release profiles on matrix composition. Preparation and testing of the optimized formulation showed linear and pH-independent release profiles lasting about 24 h, in good accordance with the values predicted by the optimization procedure.
Carrageenan↗
Dissolution enhancement of an insoluble drug by physical mixture with a superdisintegrant: optimization with a simplex lattice design.
The aim of the present work was to optimize a tablet formulation containing a physical mixture of a practically insoluble drug (prednisone) with a superdisintegrant (croscarmellose sodium) and two filler-binders characterized by differing water solubility (dicalcium phosphate dihydrate and anhydrous beta-lactose). Crushing strength, disintegration, and dissolution were measured for 10 formulations distributed over a factor space according to a simplex lattice design for a special cubic model. Multiple linear regression analysis was used to assess the best fit for each variable. The model predicted that increasing the amount of disintegrant to a critical amount (50%) would result in reduced disintegration time for dicalcium phosphate/beta-lactose ratios > 0.3, no changes in disintegration time for ratios < 0.3, and for all ratios an improvement in dissolution at 10 min. Crushing strength values of dicalcium phosphate increased with increasing disintegration concentration but not for beta-lactose tablets. The physical mixture of a practically insoluble drug with a superdisintegrant was confirmed as a valid approach to the improvement of dissolution, even in presence of other components. The solubility of the filler-binders influenced the minimum amount of disintegrant needed; when a soluble diluent was used, the amount of disintegrant required was reduced.
Anti-Inflammatory Agents↗
Influence of mucin type on polymer-mucin rheological interactions.
There are numerous in vitro methods with which to investigate the mucoadhesive properties of polymers. One recent method is based on the measurement of rheological interactions between polymer and mucin, which implies the use of mucins isolated from the mucous tissue. The extraction and purification of glycoprotein fraction, which is responsible for rheological interaction, can modify the native structure of mucin or spoil it with exogenous substances. Therefore the particulars of the mucin employed (origin, purification grade, the effect of further treatments such as freezing or freeze-drying) are likely to be critical for the interaction. The aim of this work was to compare some commercial mucins of differing origin and grade of purification for their rheological interaction with well-known mucoadhesive polymers (polyacrylic acid and sodium carboxymethylcellulose). For polyacrylic acid, which is sensitive to ions, we found rheological interaction to be strongly influenced by mucin type. The removal of ions, with dialysis, improved the interaction. For sodium carboxymethylcellulose, which is less sensitive to ions, rheological interaction proved to be less dependent on mucin type and improved upon glycoprotein solubilization.
Acrylic Resins↗
[Bioadhesives: rationale, state of the art and therapeutic potential].
Pharmaceutical research is going on the way to formulate drugs in dosage forms and delivery systems able to improve their biopharmaceutical properties. For some routes of administration, among them the transmucosal ones, such improvements may be reached by increasing the time and the nature of the contact between mucosal tissues and drug dosage forms via chemical or physical bioadhesive links. Biopharmaceutical AFI Study Group efforts were oriented in analyzing the actual state of the art in the field of bioadhesive drug delivery. Rationals of use of drug dosage forms with bioadhesive properties, analytical method of control of bioadhesion (both in vitro and in vivo) and therapeutical potentialities are the matter of this review.
Animals↗
[Biopharmaceutics and pharmacokinetics. 6. Metabolism].
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Animals↗