Odile Chambin

Colonic drug delivery: influence of cross-linking agent on pectin beads properties and role of the shell capsule type.

ABSTRACT For colonic delivery, pectin beads obtained by ionotropic gelation method have been already reported as an interesting approach. This study investigated the influence of the cross-linking agent (calcium or zinc) and the type of shell capsule used (classical or enteric capsules) on pectin beads properties and on their performance to target the colon (in vitro dissolution studies with subsequent pH change to mimic overall gastro-intestinal tract). Zinc pectinate beads seemed to be relatively similar to calciums ones in morphological point, except on the surface aspect. When beads were introduced in classical hard capsules, ketoprofen release was not significantly different between CPG and ZPG beads, and it was too premature and too quick due to a chemical erosion of the pectinate matrix (acid + basic attacks). However, zinc pectinate beads showed slower ketoprofen release compared with calcium pectinate beads when enteric hard capsules were used. This interesting finding could be due to the strength of the network formed during the process between the zinc cations and the LM-pectin following the “egg-box” model. This network was stronger and induced a reduction of swelling and hydration when contact with dissolution medium, then subsequently a decrease of drug release. Thus, the zinc pectinate beads could protect sufficiently drug entrapped from the upper gastro-intestinal conditions and drug release will be controlled by pectin degradation with colonic microflora. Finally, these zinc pectinate beads in enteric hard capsules are promising as a carrier for specific colonic delivery of drugs after oral administration.

Zinc-pectinate beads as an in vivo self-assembling system for pulsatile drug delivery

Zinc-pectinate beads are interesting drug carriers for oral delivery. In order to investigate their in vitro and in vivo release behaviour, ionotropic gelation was used to entrap theophylline into calcium- or zinc-pectinate beads. Beads were investigated in vitro for their particle properties, especially the release kinetic in different media, and their in vivo pharmacokinetic parameters were tested in rats. Particle size varied between 1.8 and 2.8mm and encapsulation rates between 27 and 30% for Ca- and Zn-pectinate beads, respectively. While Ca-pectinate beads revealed a relative fast disintegration, drug release profiles from Zn-pectinate beads were very much release medium-dependent. Especially, in the presence of phosphate ions, the release from Zn-pectinate beads was blocked at 20% and 40% of the total drug load when tested in phosphate buffer or simulated colonic medium. In vivo Zn-pectinate beads (t(max): 12.0 ± 0.1h) led to a significant lag time for the theophylline absorption compared to Ca-pectinate (t(max): 6.0 ± 2.8h) or free theophylline (t(max): 2.5 ± 2.1h). This delayed release was attributed to the formation of a zinc phosphate coating in vitro and in vivo inducing the retention of theophylline release. Zn-pectinate beads exhibit interesting properties due to its potential as pulsatile delivery system induced by the in situ formation of Zn phosphate, while Ca-pectinate was found to be of limited suitability for controlled release of theophylline.

Structure of calcium and zinc pectinate films investigated by FTIR spectroscopy.

Calcium and zinc pectinate gels were prepared using a method which allowed calcium or zinc to diffuse from the cross-linking solution through a dialysis membrane to form a gel with amidated low-methoxyl pectin. The gel thus obtained was then dried, and the film structure was studied using FTIR spectroscopy as a function of the cation content (0%, 5%, 10%, and 15% w/v). Important consideration was given to the three functional groups (amide, carboxyl ester, and carboxylate groups) present in the pectin. When the zinc content was increased, the three wavenumber values corresponding to these three functional groups did not change significantly, while for calcium pectinate, the three wavenumber values were shifted profoundly when the amount of calcium ions changed. These results confirm that calcium ions could form stable interactions with carboxylate groups as described by the eggbox model [Grant, G.T.; Morris, E.R.; Rees, D.A.; Smith, P.J.C.; Tho, D. FEBS Lett.1973, 32, 195-198] while the lower coordination number of zinc does not permit a structured gel to develop.

Silica-coated calcium pectinate beads for colonic drug delivery

The aim of this work is to develop novel organic-inorganic hybrid beads for colonic drug delivery. For this purpose, calcium pectinate beads with theophylline are prepared by a cross-linking reaction between amidated low-methoxyl pectin and calcium ions. The beads are then covered with silica, starting from tetraethyoxysilane (TEOS), by a sol-gel process. The influence of TEOS concentration (0.25, 0.50, 0.75 and 1.00 M) during the process is studied in order to modulate the thickness of the silica layer around the pectinate beads and thus to control the drug release. The interactions between the silica coating and the organic beads are weak according to the physicochemical characterizations. A good correlation between physicochemical and in-vitro dissolution tests is observed. At concentrations of TEOS beyond 0.25 M, the silica layer is thick enough to act as a barrier to water uptake and to reduce the swelling ratio of the beads. The drug release is also delayed. Silica-coated pectinate beads are promising candidates for sustained drug delivery systems.

Influence of low methoxyl pectin gel textures and in vitro release of rutin from calcium pectinate beads

This study described the preparation and characterization of low methoxyl pectin (LMP) gels and beads for controlled release applications. The rheological characterization of the various formulations was proposed. Then the mechanical and morphological characterizations of beads were determined. Finally, the controlled release studies taking rutin as a model drug was evaluated. The results showed that Youngs modulus values of non-amidated LMP gels decrease when adding up to 15% sorbitol. Calcium pectinate beads loaded with rutin are about 600 μm, oblong shaped with dense matrix. Beads containing sodium bicarbonate showed about 80% lower rutin encapsulation efficiency by increasing the pH of the cross-linking solution. The rutin loaded in non-amidated pectinate beads containing 15% sorbitol showed the best release efficiency and swelling behavior. Therefore, the gel texture affects the release rate of the active compounds encapsulated in calcium pectinate beads and can be used as a parameter to modulate drug release.

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.

The impact of whey protein preheating on the properties of emulsion gel bead

Thermal treatment effect (70 or 80 °C for 5 or 30 min) was evaluated on functional properties of whey protein isolate (WPI) dispersions used for the development of novel vitamin A delivery systems based on emulsion gel beads. This process combines an (O/W) emulsion diluted by a polysaccharide solution and a cold-set gelation induced by salt addition. Pre-heated WPI had a significant impact on the denaturation degree and on the surface hydrophobicity, respectively studied by differential scanning calorimetry and fluorescence. Stronger heating conditions (i.e. duration or temperature) induced complete denaturation, an increase of surface hydrophobicity and of viscosity. Under these conditions, the final emulsion showed a decrease particle size and an enhancement of stability. The resulting beads offered better vitamin A yield and stability during storage. These delivery systems bring a good protection of vitamin A to pH changes and control the release of this lipophilic component.

Binding of Divalent Cations to Polygalacturonate: A Mechanism Driven by the Hydration Water.

We have investigated the interactions between polygalacturonate (polyGal) and four divalent cations (M(2+) = Ba(2+), Ca(2+), Mg(2+), Zn(2+)) that differ in size and affinity for water. Our results evidence that M(2+)-polyGal interactions are intimately linked to the affinity of M(2+) for water. Mg(2+) interacts so strongly with water that it remains weakly bound to polyGal (polycondensation) by sharing water molecules from its first coordination shell with the carboxylate groups of polyGal. In contrast, the other cations form transient ionic pairs with polyGal by releasing preferentially one water molecule (for Zn(2+)) or two (for Ca(2+) and Ba(2+)), which corresponds to monodentate and bidentate binding modes with carboxylates, respectively. The mechanism for the binding of these three divalent cations to polyGal can be described by two steps: (i) monocomplexation and formation of point-like cross-links between polyGal chains (at low M(2+)/Gal molar ratios, R) and (ii) dimerization (at higher R). The threshold molar ratio, R*, between these two steps depends on the nature of divalent cations and is lower for calcium ions (R* < 0.1) than for zinc and barium ions (R* > 0.3). This difference may be explained by the intermediate affinity of Ca(2+) for water with respect to those of Zn(2+) and Ba(2+), which may induce the formation of cross-links of intermediate flexibility. By comparison, the lower and higher flexibilities of the cross-links formed by Zn(2+) and Ba(2+), respectively, may shift the formation of dimers to higher molar ratios (R*).

Physico-chemical state influences in vitro release profile of curcumin from pectin beads.

Curcumin is a polyphenolic compound with diverse effects interesting to develop health benefit products but its formulation in functional foods or in food supplement is hampered by its poor water solubility and susceptibility to alkaline conditions, light, oxidation and heat. Encapsulation of curcumin could be a mean to overcome these difficulties. In this paper, curcumin was encapsulated by ionotropic gelation method in low methoxyl pectin beads associated with different surfactants: Solutol(®), Transcutol(®) and sodium caseinate. After encapsulation, physico-chemical properties of encapsulated curcumin such as its solubility, physical state, tautomeric forms and encapsulation efficiency as well as encapsulation yield were characterized. In vitro dissolution of curcumin from beads displayed different kinetic profiles according to bead composition due to different matrix network. As Solutol(®) was a good solvent for curcumin, the drug was present into amorphous form in these beads inducing a rapid release of curcumin in the simulated digestive fluids. In contrast, drug release was slower from sodium caseinate beads since curcumin was not totally dissolved during the manufacturing process. Moreover, the FLIM studies showed that a part of curcumin was encapsulated in caseinate micelles and that 34% of this drug was in keto form which may delay the curcumin release. The Transcutol beads showed also a slow drug release because of the low curcumin solubility and the high density of the matrix.

Influence of drug polarity upon the solid-state structure and release properties of self-emulsifying drug delivery systems in relation with water affinity

To overcome low oral bioavailability of poorly water-soluble drugs, self-emulsifying drug delivery systems (SEDDS) have been noted as a promising strategy. However, incorporation of drugs into SEDDS composed of Gelucire44/14 could induce interactions not yet well understood. The aim of this study was to investigate the influence of drug polarity upon the solid-state structure of SEDDS formulation, particularly in terms of wettability, thermal behaviour and microscopic aspects and their effect upon the release properties of the SEDDS. Model drugs were naproxen and sodium naproxen (10% w/w), two drugs with similar chemical structure but different water solubilities. Both drugs had an effect on the structure and behaviour of SEDDS: sodium naproxen mainly increased surface wettability while naproxen modified its thermal behaviour. Moreover, influence of Gelucire44/14 as self-emulsifying matrix was very marked for naproxen with a huge increase of naproxen release, the less water-soluble drug in condition where the solubility was the limiting parameter (at pH 1.2). Study of SEDDS structure and its physico-chemical properties using different techniques brought novel findings about the behaviour of SEDDS with different kinds of drugs (various water solubilities) and could be linked to their performances during in vitro dissolution.