Naima Zerrouk

In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions

The present work extended previous physico-chemical investigations on the effects of solid dispersion on the solubility, the dissolution rate and the pharmacokinetic profile of carbamazepine. Solubility studies showed a linear increase in carbamazepine solubility with the increase of PEG 6000 concentration. There is no marked difference between physical mixtures and solid dispersions for the enhancement of carbamazepine solubility by PEG 6000. Less than 60% of pure carbamazepine was dissolved in 90 min. Physical mixtures (carbamazepine phase III) and solid dispersions (carbamazepine phase II) dissolution rates were higher in comparison of the parent drug. The dissolution of carbamazepine phase III was more pronounced than that evoked by the phase II. The dissolution profiles indicated that the percentage of the drug dissolved was dependent on the proportion of PEG 6000. In solid dispersions there was a remarkable enhancement in the dissolution rates of the drug in the vicinity of the eutectic composition as compared with those of corresponding physical mixtures. Hence, the optimum value for the solid dispersion was 80.5+/-1.7% of carbamazepine having dissolved within the first 10 min compared to 40+/-1% for the corresponding physical mixtures of the same composition. Statistical analysis of pharmacokinetic parameters confirmed that the carbamazepine:PEG 6000 binary systems displayed higher bioavailability of the drug than the pure carbamazepine. The area under the curve (AUC) values highlighted the evidence that only slight differences in the bioavailability of the drug occur between physical mixtures and solid dispersions prepared at the 80:20 and 50:50 drug:carrier compositions. However, the mean normalized plasma concentrations showed that standard error deviations are rather wide intervals for pure drug and physical mixtures in comparison to solid dispersions. One additional interesting point to consider is the disappearance of the multiple peaks on the individual kinetic curves of the 50:50 solid dispersion composition. Furthermore, our investigations have highlighted the interest of solid dispersions prepared at <<near>>-eutectic composition as our preliminary data show that the plasma concentration (C(5h)) of the drug for the 15:85 dispersed sample containing 150 mg of carbamazepine is not significantly different from that obtained for the 50:50 dispersed sample containing 300 mg of the drug.

Development and characterization of naproxen–chitosan solid systems with improved drug dissolution properties

The solubilizing and amorphizing properties toward naproxen (a poorly water-soluble antiinflammatory drug) of chitosan, an emerging pharmaceutical biopolymer, have been investigated. Solid binary systems at different drug/polymer ratios have been prepared according to different techniques (mixing, cogrinding, kneading, coevaporation) using chitosan at low (CS-L(w)) and medium (CS-M(w)) molecular weight, and tested for dissolution properties. Drug-carrier interactions were investigated in both the liquid and solid state, by phase solubility analysis, differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy, and scanning electron microscopy. Drug dissolution parameters improved with increasing the polymer amount in the mixture, reaching the highest values at the 1:9 (w/w) drug/polymer ratio, and CS-L(w) was more efficacious than CS-M(w). Cogrinding was the most effective technique, showing the strongest amorphizing effect toward the drug and enabling an increase of more than ten times its relative dissolution rate. Coground mixtures at 3:7 (w/w) drug/polymer ratio were able to give directly compressed tablets which maintained unchanged the improved drug dissolution properties. Enhancer dissolution properties combined with its direct compression feasibility and antiulcerogenic action make CS-L(w) an optimal carrier for developing fast-release oral solid dosage forms of naproxen.

Microspheres for colonic delivery of ketoprofen-hydroxypropyl-β-cyclodextrin complex

A new multiparticulate system, with the potential for site-specific delivery to the colon, has been developed using ketoprofen as model drug. The system simultaneously exploits cyclodextrin complexation, to improve drug solubility, and vectorization in microspheres (MS) based on Ca-pectinate and chitosan. The effect of complexation with hydroxypropyl-beta-cyclodextrin (HPbetaCyd) and of chitosan presence on drug entrapment efficiency and release properties, as well on the drug permeation rate across Caco-2 cells has been investigated. Solid-state interactions between the components have been investigated by FTIR spectroscopy, differential scanning calorimetry and X-ray powder diffractometry. The morphology of MS was examined by scanning electron microscopy. Release studies revealed a different behaviour for MS containing drug alone or as complex: drug alone was released faster than in the presence of cyclodextrin from MS without chitosan, due to a reservoir effect. The opposite was found for MS containing chitosan, due to a competition effect between polymer and drug for the cyclodextrin. Cytotoxicity tests demonstrated the safety of these formulations. Permeation studies showed an increased permeation of the drug formulated as MS, particularly marked when it was used as complex, thus revealing an enhancing power of both cyclodextrin and chitosan with a synergistic effect in improving drug permeation.

Comparison of the effect of chitosan and polyvinylpyrrolidone on dissolution properties and analgesic effect of naproxen

The solubilizing and absorption enhancer properties towards naproxen of chitosan and polyvinylpyrrolidone (PVP) have been investigated. Solid binary systems prepared at various drug-polymer ratios by mixing, cogrinding or kneading, were characterized by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy, and tested for dissolution behavior. Both carriers improved drug dissolution and their performance depended on the drug-polymer ratio and the system preparation method. Chitosan was more effective than PVP, despite the greater amorphizing power of PVP as revealed by solid state analyses. The 3/7 (w/w) drug-carrier coground systems with chitosan and PVP were the best products enabling, respectively, an improvement of 4.8 and 3.6 times of drug dissolution efficiency. In vivo experiments in mice demonstrated that administration of 45 mg/kg of drug coground with PVP or chitosan resulted, respectively, in a 25 and 60% reduction of acetic acid-induced writhings in comparison to pure drug, which, instead, was statistically ineffective as compared to the control group. Moreover, the 3/7 (w/w) drug-chitosan coground product demonstrated an antiwrithing potency 2.4 times higher than the coground with PVP. Thus, the direct-compression properties and antiulcerogenic activity, combined with the demonstrated solubilizing power and analgesic effect enhancer ability towards the drug, make chitosan particularly suitable for developing a reduced-dose fast-release solid oral dosage form of naproxen.

Comparative study of ibuproxam complexation with amorphous β-cyclodextrin derivatives in solution and in the solid state

The complexing, solubilizing and amorphizing abilities toward ibuproxam (a poorly water-soluble anti-inflammatory agent) of some randomly substituted amorphous beta-cyclodextrin derivatives (i.e. methyl- (MebetaCd), hydroxyethyl- (HEbetaCd), and hydroxypropyl- (HPbetaCd) beta-cyclodextrins) were investigated and compared with those of the parent beta-cyclodextrin. Equimolar drug-cyclodextrin solid systems were prepared by blending, cogrinding, coevaporation, and colyophilization. Drug-carrier interactions were studied in both the liquid and solid state by phase solubility analysis, supported by molecular modelling, differential scanning calorimetry, X-ray powder diffractometry, Fourier transform infrared spectroscopy and scanning electron microscopy. All the betaCd derivatives showed greater solubilizing efficacies toward ibuproxam than the parent one, due to their higher water solubility. On the contrary, a clear reduction of complexing ability was observed, indicative of some steric interferences to drug inclusion due to the presence of substituents, as confirmed by molecular modelling studies. However, this negative effect was not reflected in the dissolution behaviour (evaluated according to the dispersed amount method) of their solid binary systems, probably thanks to the greater amorphizing properties shown (DSC and X-ray analyses) by betaCd derivatives. In fact their dissolution efficiencies were not significantly different (MebetaCd) or only slightly lower (HEbetaCd and HPbetaCd) than those of the corresponding products with beta-cyclodextrin. Colyophilized products were in all cases the most effective, followed by coground and coevaporated systems, whose dissolution efficiencies were over four times higher than the corresponding physical mixtures and about 15 times higher than the pure drug.

Improvement of oxaprozin solubility and permeability by the combined use of cyclodextrin, chitosan, and bile components.

The effect of the combined use of randomly methylated β-cyclodextrin (RAMEB), chitosan (CS), and bile components (dehydrocholic (DHCA) or ursodeoxycholic (UDCA) acids and their sodium salts) on solubility and permeability through Caco-2 cells of oxaprozin (a very poorly water-soluble non-steroidal anti-inflammatory drug) has been investigated. Addition of CS, bile acids, and their sodium salts increased the RAMEB solubilizing power of 4, 2, and 5 times, respectively. Drug-RAMEB-CS co-ground systems showed very higher dissolution rate than corresponding drug-RAMEB systems. Addition of bile components further improved drug dissolution rate. The CS presence enabled a significant increase in drug permeability through Caco-2 cells with respect to drug-RAMEB systems. Moreover, CS and NaDHC showed a synergistic enhancer effect, enabling a 1.4-fold permeability increase in comparison with systems without bile salt. However, unexpectedly, no significant differences were found between physical mixtures and co-ground products, indicating that drug permeation improvement was due to the intrinsic enhancer effect of the carriers and not to drug-carrier interactions brought about by co-grinding, as instead found in dissolution rate studies. The combined use of RAMEB, CS, and NaDHC could be exploited to develop effective oral dosage forms of oxaprozin, with increased drug solubility and permeability, and then improved bioavailability.

Endotoxemia affects citrulline, arginine and glutamine bioavailability

Eur J Clin Invest 2012; 42 (3): 282–289

Influence of cross-linking agent type and chitosan content on the performance of pectinate-chitosan beads aimed for colon-specific drug delivery.

Pectinate-chitosan-beads aimed for colon theophylline delivery have been developed. The effect of zinc or calcium ions as cross-linking agent, and of chitosan concentration on the properties and colon-targeting performance of beads was investigated. Beads were characterized for morphology, entrapment efficiency and mucoadhesion properties. Zn-pectinate-chitosan beads formed a stronger gel network than the Ca-containing ones, enabling a greater entrapment efficiency, which further increased with chitosan content, probably due to polyelectrolyte complexes formation. Transport studies across Caco-2 cells evidenced a significant (p > 0.05) drug permeation increase from all beads with respect to drug alone, attributable to the enhancer and/or mucoadhesion properties of the polymers, and Ca-pectinate-chitosan beads were more effective than the Zn-containing ones. Beads formulated as enteric-coated tablets demonstrated good colon-targeting properties, and no differences were observed in drug-release profiles from Zn- or Ca-pectinate-chitosan beads. Therefore, Ca-pectinate-chitosan beads emerged as the choice formulation, joining colon-targeting specificity with better permeation enhancer power.

Copper(II)–l-glutamine complexation study in solid state and in aqueous solution

Abstract Among copper transport alterations in humans, Menkes disease is due to a lethal genetic disorder. The current treatment is the administration of physiological Cu(II)– l -histidine complex. However, this therapy is only effective in some cases and when started early in life. In order to distribute copper in all the biological compartments for Menkes disease patients, the administration of other Cu(II) amino acids complexes has been considered. Several ternary Cu(II)–amino acids complexes were detected in human serum playing an important role in the copper pathway, in particular l -histidine–Cu(II)– l -glutamine. Before the biopharmaceutical studies of l -histidine–Cu(II)– l -glutamine complex, a physicochemical characterisation of binary Cu(II)– l -glutamine complex must be conducted. Indeed, the identification of Cu(II)– l -glutamine species has not been clearly determined at physiological pH in the past. In the present work, the stoichiometry, formation constants and distribution of the various Cu(II)– l -glutamine species have been determined by polarography and UV–Vis spectroscopy in a large pH range. [Cu(II)(Gln) 2 ] complex is the major component at physiological pH and its formation constant is equal to 10 12.5 l 2 mol −2 . For the first time, the structure of [Cu(II)(Gln) 2 ] has been determined in the solid state and in solution. Given the small size of the obtained crystals, it has been necessary to use an X-ray synchrotron source to collect the diffraction data. X-ray crystal structure showed a 4-2 distorted octahedral geometry. In the basal plane Cu–O and Cu–N distances ranged from 1.93 to 1.98 A. Two additional oxygen atoms at 2.70 and 2.86 A complete a severely distorted octahedron. EXAFS and EPR results have shown that the structure of [Cu(II)(Gln) 2 ] is preserved at physiological pH in aqueous solution.

Effect of Chitosan-Coated Alginate Microspheres on the Permeability of Caco-2 Cell Monolayers

ABSTRACT Alginate microspheres were prepared by emulsification/internal gelation and coated with chitosan. The ability of chitosan-coated alginate microspheres to increase the paracellular transport across Caco-2 cell monolayers was evaluated in comparison to uncoated microspheres and chitosan solutions. Transport studies were performed by using a permeability marker, Lucifer Yellow (LY), and by measuring the transepithelial electric resistance (TEER) variations. Furthermore, the occurrence of cytotoxic effects was assessed by evaluating neutral red uptake in viable cells and lactate dehydrogenase (LDH) release from damaged cells. A 3-fold increase on LY permeability was obtained for coated microspheres when compared to chitosan solutions. TEER variations were in agreement with permeability results. Chitosan solutions exhibited a dose-dependent toxicity, but coated microspheres did not decrease the viability of cells. Chitosan-coated alginate microspheres have potential to be used as carriers of poorly absorbable hydrophilic drugs to the intestinal epithelia and possibly increase their oral bioavailability.