Performance of multilayered particles: influence of a thin cushioning layer.

Nowadays, oral dosage forms with controlled release kinetics have known an increasing interest. The polymer coating of drug-loaded particles is one of the most common methods used for controlling drug delivery. Such multilayered particles could be either filled into capsules or compressed into tablets for their oral administration. However, many studies have noticed that coating films are damaged during the compression process, leading to significant changes in drug release profiles. The aims of this study were to investigate the effects of a thin cushioning layer [made of HydroxyPropylMethyl Cellulose (HPMC)] applied on coated theophylline particles upon particle characteristics, tablet properties, and then upon their dissolution performance. If no significant effect was shown with particles, this thin HPMC layer played an important role in the tablets. Tablet cohesiveness was decreased due to HPMC cushioning properties and moreover, the theophylline release rate was increased, as HPMC is a water-soluble polymer creating channels in polymer film for dissolution medium. Therefore, a cushioning layer helped to protect polymer coats from fracture during compression but could also affect drug release and so, both effects must be checked in such a drug delivery system.

Influence of cryogenic grinding on properties of a self-emulsifying formulation.

Recently, self-emulsifying drug delivery systems (SEDDS) have been developed as a method to deliver lipophilic drugs. Gelucire 44/14 is an excipient, from the lauroyl macrogolglycerides family, producing a fine oil-in-water emulsion when introduced into an aqueous phase under gentle agitation as SEDDS, improving thereby solubility of poorly water-soluble drugs and their bioavailability. The aims of this study were to process Gelucire 44/14 into a powder by cryogenic grinding to produce solid oral dosage forms and to investigate influence of this process on different properties of a formulation made of Gelucire 44/14 and ketoprofen (90/10). Cryogenic grinding produced Gelucire 44/14 in a powder form and this process did not change its physical properties, emulsification capacities and dissolution performances of the formulation tested. However, interactions took place between ketoprofen and Gelucire 44/14 with a decrease of the melting peak and a reduction of the droplet size of the formed emulsion. The influence of drug-Gelucire 44/14 interactions must be investigated case by case in any formulations.

Effects of different cellulose derivatives on drug release mechanism studied at a preformulation stage.

As a matter of fact, in vitro dissolution is well known to be the method of choice for the pharmaceutical industry to develop effective medicines. However, many experiments must be performed all along a new product life and they represent an overcharge of work for researchers. The purpose of this paper was to assess the relevance of new parameters obtained during preformulation stage by Nuclear Magnetic Resonance (NMR) experiments to better understand drug release mechanism. This study was carried out with three cellulose derivatives currently used as carrier matrices (Microcrystalline cellulose (MCC), Hydroxypropylmethyl cellulose (HPMC) and Ethyl cellulose (EC)). Granules and tablets were produced with these three excipients (60% w/w) and theophylline as drug model (40%). On the one hand, in vitro dissolution studies were performed with the rotating paddle method displaying the different release behaviour of these three matrices (immediate release for MCC, steady release for HPMC and sustained release for EC). On the other hand, the evolution of the T2m spin-spin relaxation time in NMR experiments during granules hydration was recorded. NMR findings shore up dissolution data, both depending on interactions between the matrix and water. NMR spectroscopy appears to be a valuable tool for obtaining, at an earlier stage of drug development, more information about drug release mechanism.

Dry adsorbed emulsion: 2. Dissolution behaviour of an intricate formulation.

The behaviour of a pharmaceutical form, called dry adsorbed emulsion (DAE), containing a sparingly soluble drug (i.e. theophylline) was studied for dissolution drug release kinetic, in relation with DAE structure characterisation. In vitro dissolution testings were performed under different experimental conditions (medium at pH 1.2 and 7.4, medium with or without surfactant addition, different particle sizes, discrete or densified particles). Discrete DAE particles showed an extended release, in comparison with the native drug powder, depending on both drug solubility in the medium and particle size. The relevance of dissolution data was not improved by surfactant addition (0.1% sodium lauryl sulfate: SLS). After an initial release due to theophylline of the DAE superficial layer, the dissolution followed the Higuchi model. This suggested that DAE behaved as an inert matrix, which controlled drug release by diffusion through the hydrophobic part of the DAE. Densified DAE particles showed a slower dissolution rate than discrete DAE particles, because of their weak wettability and their poor disintegrant properties due to the particulate rearrangement under pressure. Lastly in a technological point of view, DAE could be considered as a potential drug delivery system in capsules or tablets to better control bioavailability of drugs.

Dry adsorbed emulsion: 1. Characterization of an intricate physicochemical structure.

A recent solid pharmaceutical form called "Dry Adsorbed Emulsion" (DAE) was characterized in morphological and structural fields. A DAE is an intricate system initiated by a water-in-oil emulsion including the active drug (i.e., theophylline). Each emulsion phase is adsorbed on pulverulent adsorbents with a suitable polarity (silica) to obtain a free-flowing powder with nonporous particles of size from 125 to 710 microm, with small specific surface area and a spherical shape. Different methods, such as scanning electron microscopy combined with chemical microanalysis, dying tests, and electron spin resonance studies, allow the formulator to follow the behavior of DAE aqueous and oily phases during the manufacturing process and then to set up a structural model for DAE particles. These DAE particles appear to be made up of a random pack of hydrophilic and hydrophobic particles, containing a liquid phase adsorbed on silica by weak bonds.

Preformulation: effect of moisture content on microcrystalline cellulose (Avicel PH-302) and its consequences on packing performances.

This study evaluates the influence of moisture content on the packing performances of a new grade of microcrystalline cellulose (MCC) (Avicel PH-302) either by classical method or by an unconventional compression technique (constant volume reduction of powder bed). An increase in moisture content decreases the apparent density of the powder bed, resulting from interparticulate friction enhancement. This modification of apparent density seems to be the main effect caused by the presence of humidity, which explains the variations of compression properties, like an increase of powder plasticity generally observed in the experimental conditions.

[Methodologic study of the stability of intravenous nutritive emulsions]. / Méthodologie d'étude de la stabilité des émulsions nutritives intraveineuses.

Stability studies are one of the main steps of emulsion development, since emulsions are thermodynamically unstable systems. This is even more critical for drugs, and especially for nutritive parenteral emulsions considering the large volumes which are infused to patients. Physico-chemical stability of emulsions can be estimated, either under real storage conditions, or using accelerated testing that are of great interest in formulation. After a literature review of stability testing applied to emulsions, we give an example of procedure which is especially useful for intravenous nutritive emulsions.