Gilles Ponchel

Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract

The oral route constitutes the preferred route for drug delivery. However, numerous drugs remain poorly available when administered by this route. In order to circumvent this problem, it has been proposed, successfully for several of them, to associate drugs to polymeric nanoparticulate systems (or small particles in the range of the micrometre in size) because of their propensity to interact with the mucosal surface. The present review focuses on the gastrointestinal bioadhesion of micro- and nanoparticles. Bioadhesion can be obtained by the building of either non-specific interactions with the mucosal surface, which are driven by the physicochemical properties of the particles and the surfaces, or specific interactions when a ligand attached to the particle is used for the recognition and attachment to a specific site at the mucosal surface. The relative merits of those systems are discussed. Their fate in the gastrointestinal tract, including at least three different pathways: (i) bioadhesion, (ii) translocation through the mucosa and (iii) transit and direct faecal elimination, is also presented.

BIOADHESIVE ANALYSIS OF CONTROLLED-RELEASE SYSTEMS. I. FRACTURE AND INTERPENETRATION ANALYSIS IN POLY(ACRYLIC ACID)-CONTAINING SYSTEMS

Abstract Novel bioadhesive controlled release tablets were prepared from poly (acrylic acid) and hydroxypropyl methylcellulose. Their bioadhesive behavior was studied in a modified tensile tester in contact with bovine sublingual mucus, and the force-elongation behavior was measured up to the breakpoint. The work of adhesion was calculated and related to bioadhesive characteristics of the tablets. It was found that the bioadhesive bond strength between these tablets and the bovine mucus was a monotonically increasing function of their poly (acrylic acid) content. The bioadhesive results were analyzed in terms of a new theoretical framework based on the fracture and interpenetration (diffusion) theories of bioadhesion. Important molecular parameters were calculated and new bioadhesive correlations were verified.

Cyclodextrins in targeting. Application to nanoparticles.

For some years cyclodextrins and their hydrophilic derivatives have been described in the literature as solubilizers capable of enhancing the loading capacity of liposomes and microparticles. We present here two new possibilities of using cyclodextrins in the design of colloidal carriers. The first possibility consists in increasing the loading capacity of poly(isobutyl cyanoacrylate) nanospheres prepared by anionic polymerization, by employing hydroxypropyl cyclodextrins. The second possibility consists in the spontaneous formation of either nanocapsules or nanospheres by the nanoprecipitation of amphiphilic cyclodextrin diesters. These two new techniques are very promising because of the great interest presented by nanoparticles for drug administration by the oral or parenteral routes.

Cyclodextrins and carrier systems

This paper describes two new possibilities of using cyclodextrins to increase water solubility and bioavailability of poorly water-soluble drugs intended for targeting delivery by the oral or the parenteral route. They use either amphiphilic cyclodextrin nanoparticles or polymeric nanoparticles containing cyclodextrins. Amphiphilic skirt-shaped cyclodextrins, resulting from the esterification of primary hydroxyl groups by hydrocarbon chains varying from C6 to C14, are capable of forming spontaneously nanoparticles which have been loaded with a series of steroid drugs. The drug in the amphiphilic cyclodextrin nanoparticles is molecularly dispersed and can be released very rapidly. Poly(isobutylcyanoacrylate) nanoparticles can be loaded with natural or hydroxypropyl cyclodextrins. This technique results in a significant increase in the loading capacity of nanoparticles with a series of steroids and in a very rapid release of the drug. Both methods are described as well as their potential interest for water-insoluble drugs.

Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract☆

The oral route is the preferred route for drug delivery. However, numerous drugs remain poorly available when administered by this route. In order to circumvent this problem, it has been proposed, successfully for several of them, to associate drugs with colloidal polymeric particle systems. Orally administered nano- and microparticles can follow at least three different pathways: (i) capture by gut-associated lymphoid tissue; (ii) mucoadhesion; and (iii) direct faecal elimination. The relative importance of these different mechanisms is discussed. Emphasis has been laid on mucoadhesion which has been assessed in vitro and in vivo by using polystyrene and poly(lactic acid) nanoparticles as models. On the one hand, in vitro adsorption and desorption studies have shown that particles could be captured to a considerable extent by the mucous gel layer lining the gastro-intestinal tract through a mucoadhesion mechanism. On the other hand, the in vivo behaviour of the particles in the intestinal lumen has been accurately investigated by means of radiolabelled particles. Direct particle translocation through the intestinal mucosa was not predominant. On the contrary, a significant fraction of the particles was captured by the mucous gel layer while the remainder of the particles underwent unmodified transit. It can be concluded that the therapeutic potential of colloidal drug carriers after oral administration is probably not to deliver the drug directly into the blood flow but to increase bioavailability by protecting the drug from denaturation in the gastro-intestinal lumen, or by increasing the drug concentration for a prolonged period of time directly at the surface of the mucous membrane.

Combined hydroxypropyl-β-cyclodextrin and poly(anhydride) nanoparticles improve the oral permeability of paclitaxel

The aim of this work was to study the effect of the combination between 2-hydroxypropyl-beta-cyclodextrin (HPCD) and bioadhesive nanoparticles on the encapsulation and intestinal permeability of paclitaxel (PTX). In this context, a solid inclusion complex between PTX and HPCD was prepared by an evaporation method. Then, the complex was incorporated in poly(anhydride) nanoparticles by a solvent displacement method. The resulting nanoparticles, PTX-HPCD NP, displayed a size of about 300 nm and a drug loading of about 170 microg/mg (500-fold higher than in the absence of HPCD). The effect of these nanoparticles on the permeability of intestinal epithelium was investigated using the Ussing chamber technique. The apparent permeability (P(app)) of PTX was found to be 12-fold higher when formulated as PTX-HPCD NP than when formulated as Taxol (control). Furthermore, when interaction between nanoparticles and the mucosa was avoided, the permeability of PTX significantly decreased. In summary, the association between PTX-HPCD and poly(anhydride) nanoparticles would induce a positive effect over the intestinal permeability of paclitaxel, being the bioadhesion a mandatory condition in this phenomena.

Particle uptake by Peyer’s patches: a pathway for drug and vaccine delivery

Particle uptake by Peyer’s patches offers the possibility of tailoring vaccines that can be delivered orally. However, particle uptake by the follicle-associated epithelium in the gastrointestinal tract depends on several different factors that are the physicochemical properties of the particles, the physiopathological state of the animal, the analytical method used to evaluate the uptake and finally the experimental model. These parameters do not allow a clear idea about the optimal conditions to target the Peyer’s patches. The goal of this review is to clarify the role of each factor in this uptake.

Novel core(polyester)-shell(polysaccharide) nanoparticles: protein loading and surface modification with lectins

This study describes new lectin-decorated or protein-loaded nanoparticles with a hydrophobic poly(epsilon-caprolactone) (PCL) core and a hydrophilic dextran (Dex) corona. In this view, a family of block Dex-PCLn copolymers was first synthesized, consisting of a Dex backbone to which n preformed PCL blocks were grafted. The ability of these new copolymers to form nanoparticles was evaluated in comparison with a series of PCL homopolymers of various molecular weights (2000, 10,000 and 40,000 g/mole). Two different nanoparticle preparation methods have been developed and tested for their efficacy to incorporate proteins. For this, three proteins were used: a model protein, bovine serum albumin (BSA), a lectin from leaves of Bauhinia monandra (BmoLL) and Lens culinaris (LC) lectin. All these proteins were successfully incorporated in nanoparticles with a mean diameter around 200 nm. Lectins could also be adsorbed onto the surface of Dex-PCLn nanoparticles. Surface-bound BmoLL conserved its hemagglutinating activity, suggesting the possible application of this type of surface-modified nanoparticles for targeted oral administration. Caco-2 cellular viability was higher than 70% when put in contact with Dex-PCLn nanoparticles, even at concentrations as high as 660 microg/ml.

Gliadin Nanoparticles as Carriers for the Oral Administration of Lipophilic Drugs. Relationships Between Bioadhesion and Pharmacokinetics

AbstractPurpose. The aim of this work was to evaluate the bioadhesive properties of non-hardened gliadin nanoparticles (NPs) and cross-linked gliadin nanoparticles (CL-NP) in the carbazole pharmacokinetic parameters obtained after the oral administration of these carriers. Methods. A deconvolution model was used to estimate the carbazole absorption when loaded in the different gliadin nanoparticles. In addition, the elimination rates of both adhered and non-adhered nanoparticulate fractions within the stomach were estimated. Results. Nanoparticles dramatically increased the carbazole oral bioavailability up to 49% and provided sustained release properties related to a decrease of the carbazole plasma elimination rate. The carbazole release rates from nanoparticles (NP and CL-NP), calculated by deconvolution, were found to be of the same order as the elimination rates of the adhered fractions of nanoparticles in the stomach mucosa. In addition, good correlation was found between the carbazole plasmatic levels, during the period of time in which the absorption process prevails, and the amount of adhered carriers to the stomach mucosa. Conclusion. Gliadin nanoparticles significantly increased the carbazole bioavailability, providing sustained plasma concentrations of this lipophilic molecule. These pharmacokinetic modifications were directly related to the bioadhesive capacity of these carriers with the stomach mucosa.

DESIGN ASPECTS OF POLY(ALKYLCYANOACRYLATE) NANOPARTICLES FOR DRUG DELIVERY

Poly(alkylcyanoacrylate) (PACA) nanoparticles were first developed 25 years ago taking advantage of the in vivo degradation potential of the polymer and of its good acceptance by living tissues. Since then, various PACA nanoparticles were designed including nanospheres, oil-containing and water-containing nanocapsules. This made possible the in vivo delivery of many types of drugs including those presenting serious challenging delivery problems. PACA nanoparticles were proven to improve treatments of severe diseases like cancer, infections and metabolic disease. For instance, they can transport drugs accross barriers allowing delivery of therapeutic doses in difficult tissues to reach including in the brain or in multidrug resistant cells. This review gives an update on the more recent developments and achievements on design aspects of PACA nanoparticles as delivery systems for various drugs to be administered in vivo by different routes of administration.