Preparation and evaluation of caffeine bioadhesive emulgels for cosmetic applications based on formulation design using QbD tools.

OBJECTIVE: The aim of the present study was to evaluate the influence of the incorporation of caffeine as a model active ingredient on the quality attributes of a bioadhesive emulgel formulation previously optimized by Quality by Design (QbD) tools. Emulgels are emerging topical drug delivery systems for cosmetic or pharmaceutical uses, which combine the advantages of both emulsions and gels. METHODS: In this work, the observed and predicted values for spreadability, phase separation by centrifugation and detachment forces performed by texturometer were compared with those of the control and active-containing emulgel formulations. In addition, rheological properties, release of caffeine and comparative in vitro/ex vivo bioadhesion properties were evaluated using human skin. RESULTS: The flow curves of emulgel formulations showed the typical pseudoplastic and no thixotropic flow with yield stress. The incorporation of active ingredient did not produce significant changes. All emulgels were uniformly spread and no significant differences in spreadability values between control and caffeine containing formulations and neither respect to those predicted values from experimental design optimization were found. Emulgel formulations showed appropriate detachment forces values and no significant differences between caffeine loading and control emulgel formulations were observed. CONCLUSION: Caffeine was successfully vehiculized in this optimized bioadhesive emulgel formulation, which showed high robustness regarding the process variability. There were no significant changes in the critical quality attributes after the incorporation of the active ingredient and a promising stability was observed for at least one year. Results suggested that the optimized emulgel is an interesting topical biodhesive delivery system for cosmetic applications, including agents for skin conditioning, not present in gels formulations.

OBJECTIF: la présente étude visait à évaluer l'influence de l'incorporation de la caféine comme une substance active modèle dans les attributs de qualité d'une préparation d'émulgel bioadhésif préalablement optimisée grâce à des outils QbD (Quality by Design, Qualité par la conception). Les émulgels sont des systèmes d'administration de médicaments topiques émergents destinés à des usages cosmétiques ou pharmaceutiques, qui associent les avantages des émulsions et des gels. MÉTHODES: dans cet étude, les valeurs observées et prédites en matière d'étalement, de séparation des phases par centrifugation et de forces de détachement par texturomètre ont été comparées à celles des préparations de contrôle et d'émulgel contenant des actifs. En outre, les propriétés rhéologiques, la libération de caféine et la comparaison des propriétés de bioadhérence in vitro / ex vivo ont été évaluées sur la peau humaine. RÉSULTATS: les courbes de débit des préparations d'émulgel révèlent un flux pseudoplastique typique et non thixotropique avec charge d'écoulement. L'incorporation de la substance active n'a pas produit de changements importants. Tous les émulgels ont été uniformément étalés et aucune différence significative dans les valeurs d'étalement entre les préparations de contrôle et celles contenant de la caféine n'a été observée. Aucune différence concernant les valeurs prédites dans l'optimisation de la conception expérimentale n'a été observée. Les préparations d'émulgel ont montré des valeurs de forces de détachement appropriées et aucune différence significative n'a été observée entre les préparations d'émulgel à base de caféine et les préparations de contrôle. CONCLUSION: la caféine a été administrée avec succès dans cette préparation optimisée d'émulgel bioadhésif, qui a affiché une grande résistance en ce qui concerne la variabilité du procédé. Il n'y a pas eu de changement significatif dans les attributs de qualité critiques après l'incorporation de la substance active et une stabilité prometteuse a été observée pendant au moins un an. Les résultats ont suggéré que l'émulgel optimisé est un système d'administration de bioadhérence topique intéressant pour les applications cosmétiques, y compris les agents de revitalisation de la peau qui ne se trouvent pas dans les préparations de gels.

Urinary excretion of ciprofloxacin after administration of extended release tablets in healthy volunteers. Swellable drug-polyelectrolyte matrix versus bilayer tablets.

This paper builds on a previous paper in which new ciprofloxacin extended-release tablets were developed based on a ciprofloxacin-based swellable drug polyelectrolyte matrix (SDPM-CIP). The matrix contains a molecular dispersion of ciprofloxacin ionically bonded to the acidic groups of carbomer, forming the polyelectrolyte-drug complex CB-CIP. This formulation showed that the release profile of the ciprofloxacin bilayer tablets currently commercialised can be achieved with a simpler strategy. Thus, since ciprofloxacin urine concentrations are associated with the clinical cure of urinary tract infections, the goal of this work was to compare the urinary excretion of SDPM-CIP tablets with those of the CIPRO XR® bilayer tablets. A batch of SDPM-CIP tablets was manufactured by the wet granulation method and the CB-CIP ionic complex was obtained in situ. Fasted healthy volunteers received a single oral dose of 500 mg ciprofloxacin of either formulation in a randomised crossover study. Urinary concentrations were assessed by HPLC at intervals up to 36 h. Pharmacokinetic parameters (rate of urinary excretion, maximum urine excretion rate, tmax, area under the curve, amount and percentage of the ciprofloxacin dose excreted in urine) showed no statistical differences between both formulations at any of the time intervals of collection. The processing conditions to obtain SDPM-CIP tablets are easy to scale up since they involve technology currently employed in the pharmaceutical industry and the process is less challenging to implement. In addition, SDPM-CIP tablets met pharmacopoeial quality specifications.

The improvement of aqueous chemical stability of a model basic drug by ion pairing with acid groups of polyelectrolytes.

Carbomer (C) and procaine (P) were selected respectively as models of polyelectrolyte (PE) and basic drug (B) of low stability in aqueous solution. The purpose of this investigation was to test if a (C-P) aqueous system provides a microenvironment in which P is less exposed to hydroxyl ion catalyzed degradation, its main degradation pathway over a wide pH range. It was determined that in (C-P) a high fraction of P was present in the form of ion pairs [RCOO-PH+] with the carboxylate groups of C. The [RCOO-PH+] fraction was above 97% for compositions containing higher than 50 mol% of P. The chemical stability of C-P was assayed at two selected pHs (7.5 and 8.5) in comparison with conventional reference solutions (RS) without C. Procaine in (C-P) was 4.2 and 6.2 times more stable than in its respective RS at the two conditions assayed. The stabilizing factor was calculated as the ratio of the rate constants k(obs)(RS)/k(obs)(C-P).Since C-B systems exhibit negative electrokinetic potential that attracts positive ions such as (H+) and repels negative ones such as (OH(-)), the stabilizing effect would be associated with the higher acidity of (C-P) environment, in which PH+ molecules attached to the PE should also have lower kinetic energy than those in the bulk medium.

Equilibrium properties and mechanism of kinetic release of metoclopramide from carbomer hydrogels.

Equilibrium properties and kinetics of metoclopramide release of carbomer-metoclopramide (C-M) hydrogels are reported. A set of (C-M)(X) (x=moles percent of M=50, 75, 100) that covers a pH range between 6.49 and 8.40 was used. Hydrogels exhibited a high negative electrokinetic potential (zeta). Concentrations of ion pair [R-COO(-)MH(+)] and free species [M] and [MH(+)] were determined by the selective extraction of M with 1,2-dichloroethane (DCE) together with pH measurements. The system (C-M) is characterized by a high proportion of drug present in the form of ion pairs and a negative zeta potential that attracts MH(+) and H(+) and repeals OH(-), providing a microenvironment of higher acidity than the bulk medium. Delivery rates of M were measured in a Franz type bi-compartmental device using water and NaCl 0.9% solution as receptor media. (C-M) hydrogels behave as a reservoir that releases the drug at a slow rate to water; the rate increases 14 times as water is replaced by NaCl solution. The pH effect on delivery rate suggests that, under the main conditions assayed, the rate of dissociation of R-COO(-)MH(+) together with the low change of pH in the polyelectrolyte environment are the factors that control releasing rates.