André Jules Moes

Effect of some physiological and non-physiological compounds on the phase transition temperature of thermoresponsive polymers intended for oral controlled-drug delivery

Poly-N-isopropylacrylamide (PNIPAAm) thermosensibility makes this polymer a very attractive candidate for controlled drug delivery systems. The polymer possesses a lower critical solution temperature (LCST) which was found to be around 32 degrees C in pure water, but which can be affected by the medium composition, i.e. presence of salts or surfactants. The knowledge of the effects of such substances on the LCST is very important while using PNIPAAm as a controlled drug delivery agent. The influence of a number of physiological and non-physiological salts and surfactants has been studied. The results obtained show that the addition of salts provokes an important decrease of the LCST of the polymer (salting out effect). A strong influence of the valence and of the size of the anions of the halide group was found. As to the surfactants, according to their type and concentration, a decrease or an increase of the LCST or even no effect at all were found. The effect of the GI secretions on the PNIPAAm phase separation temperature is also discussed.

Studies of pectin HM/Eudragit® RL/Eudragit® NE film-coating formulations intended for colonic drug delivery

Theophylline pellets were coated with Eudragit NE30D aqueous dispersions, containing various pectin HM/Eudragit RL30D ionic complexes, using an Uni-Glatt fluidized-bed apparatus. Dissolution studies were then carried out on the coated pellets at pH 6.0, in absence and in presence of commercial pectinolytic enzymes. The theophylline release from the coated pellets, after an initial latency phase, occurred linearly as a function of time. The theophylline release rate was dependent on the pectin HM content of the complexes incorporated in the coatings. The lowest theophylline release from the coated pellets was obtained when the pectin HM content of the complexes was 20.0% w/w (related to Eudragit RL), i.e. when the complexation between pectin HM and Eudragit RL is optimal. The theophylline release from the coated pellets was slower in presence of the pectinolytic enzymes when the pectin content of complexes is higher than 20% w/w. On the other hand, the effect of the enzymes induced an increase of the theophylline release when the pectin HM content of the coatings ranged between 10.0 and 15.0% w/w (related to Eudragit RL).

Evaluation of a new controlled-drug delivery concept based on the use of thermoresponsive polymers.

The purpose of this work is to develop a new delivery concept making a thermosensitive polymer based on poly(N-isopropylacrylamide) (PNIPAAm) useful as a time-controlled drug release device, without any temperature changes of the dissolution medium. It was previously found that some salts induce a decrease of the polymer lower critical solution temperature (LCST). Use is here made of that property to show that salt concentration variations can be used as a substitute for temperature changes to make the polymer coating of compression-coated tablets soluble or insoluble, consequently creating a possible new concept of drug delivery control from delivery systems containing thermoresponsive polymers. The obtained results show the influence of the type and amount of salts incorporated into compression-coated tablets on the release lag time of a model drug.

Leaching of pectin from mixed pectin/insoluble polymer films intended for colonic drug delivery

Investigations intended to combine pectin HM or calcium pectinates with commercially available aqueous polymer dispersions for colon-specific drug delivery have been conducted on isolated films. The mixed films were prepared from Aquacoat® ECD 30, Surelease® clear, Eudragit® RS30D or Eudragit® NE30D containing 5, 10 or 15% w/w (related to insoluble polymer content) of pectin HM or 10% w/w of calcium pectinates. The kinetics of pectin leaching from the mixed films, incubated in 0.05 M acetate–phosphate buffer (pH 4.5, 37°C) in the absence of pectinolytic enzymes, showed that pectin HM or calcium pectinates were quickly released from the different films except from the mixed pectin/Eudragit® RS films. Moreover, in these cases, the leaching of pectin from Eudragit® RS films containing up to 10% w/w (related to Eudragit® RS polymer content) of pectin HM or pectin LM, was significantly faster in the presence of enzymes than in absence. These results indicate that the associations of pectin HM or LM and Eudragit RS are likely to give more suitable coating materials for colon-specific drug delivery than the other combinations.

Study of some important factors involved in azo derivative reduction by Clostridium perfringens

In order to design azo polymers having potential for use as colonic coating materials, the most important factors able to affect the bacterial degradation of azo derivatives were evaluated by a reliable method, using Clostridium perfringens ATCC 3626 as colonic bacteria. The azo degradation was followed by recording the decrease of the absorbance of azo dye solutions in phosphate buffer salt (PBS), pH 7.2, containing Clostridium perfringens, vs time. The results obtained show that the degradation of azo substrates is linear (zero order), faster in basic media and when a redox mediator, such as riboflavin or benzylviologen, is introduced in the incubation medium. Moreover, the substrate redox potential was shown not to affect significantly the degradation rates. However, when several azo dyes are introduced simultaneously into the incubation medium, the microbial azo reduction occurs sequentially as a function of the substrate redox potential, the substrate having the smallest negative redox potential being degraded first. Finally, when Eudragit® RL/RS films containing an azo dye (amaranth) are incubated with Clostridium perfringens or NADPH, the time required to bleach the films decreases dramatically when the percentage of Eudragit® RL in the films increases, as a result of the increase of the film permeability.

Influence of Melting and Rheological Properties of Fatty Binders on the Melt Granulation Process in a High-Shear Mixer

The preparation of granules by melt granulation was investigated using a laboratory-scale high-shear mixer (Pellmix PL 1/8) and binary mixtures containing lactose and different lipidic binders, namely, Compritol 888, Cutina HR, or Precirol ATO5. During the process, the product temperature and the impeller motor power consumption were monitored. On the other hand, the melting behavior (thermal analysis) and the rheological properties (controlled stress capillary rheometer) of the different lipophilic binders were also determined. The granule formation was shown to be quite effective at product temperatures even below the melting point of the lipidic binder, that is, when the binder is sufficiently softened to be deformed by the very high shearing forces developed in the high-shear mixer. On the other hand, the performance of lipidic binders during the melt granulation process was shown to be closely dependent on their melting and rheological properties. The granule growth rate was shown to be higher when the binder melting range is narrow and the influence of temperature on the viscosity of the unmelted product is high.

Surfactant induced drug delivery based on the use of thermosensitive polymers.

A novel approach of controlled drug delivery using thermosensitive polymers is developed in this paper. The drug release occurs at physiological temperature, at which the polymer is normally not soluble, and no medium temperature changes are required to bring about the delivery. For this purpose benefit is taken from the specific binding properties of some anionic surfactants and poly(N-isopropylacrylamide) (PNIPAAm) in order to modify the dissolution properties of PNIPAAm and of a copolymer with N-vinyl-acetamide (NVA), and so to induce the release of a drug contained in compression coated tablets. The influence of surfactant type and amount on the drug release rates and lag times from tablets coated with PNIPAAm or with the copolymer are discussed. It was found that the lag time is influenced by the surfactant species and amount. When use is made of a copolymer as coating agent, it is possible to bring about the release of the drug by incorporating only a very small amount (as low as 2%) of sodium dodecyl sulfate (SDS) in the coating.

The topical antiinflammatory effect of chloroform extract from Khaya senegalensis stem barks

The croton oil‐induced mice ear oedema test was used to study the topical antiinflammatory effects of petroleum ether and chloroform extracts of Khaya senegalensis stem barks. It was found that these fractions exhibited dose‐dependent inhibitory effects. The chloroform extract activity was closely related to that of indomethacin used as standard, was more active than the petroleum ether extract and played a pivotal role in the topical antiinflammatory effect of Khaya senegalensis stem barks.

Synthesis and enzymatic degradation of epichlorohydrin cross-linked pectins.

Abstract The water solubility of pectin was successfully decreased by cross-linking with increasing amounts of epichlorohydrin in the reaction media. The initial molar ratios of epichlorohydrin/ galacturonic acid monomer in the reaction mixtures were 0, 0.37, 0.56, 0.74, 1.00, 1.47, and 2.44. The resulting epichlorohydrin cross-linked pectins were thus referred to as C-LP0, C-LP37, C-LP56, C-LP75, C-LP100, C-LP150, and C-LP250, respectively. Methoxylation degrees ranged from 60.5 ± 0.9% to 68.0 ± 0.6%, and the effective cross-linking degrees, determined by quantification of the hydroxyl anions consumed during the reaction, were 0, 17.8, 26.0, 38.3, 46.5, 53.5, and 58.7%, respectively. After incubating the different cross-linked pectins (0.5% w/v) in 25 mL of 0.05 M acetate–phosphate buffer (pH 4.5), containing 50 µL of Pectinex® Ultra SP-L (pectinolytic enzymes), between 60 and 80% of the pectin osidic bounds were broken in less than 1 hr. Moreover, increasing the cross-linking degree only resulted in a weak slowing on the enzymatic degradation velocity.