Dominique Duchêne

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.

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.

Inclusion complexes of tretinoin with cyclodextrins

Abstract Complexes of tretinoin with β-cyclodextrin, hydroxypropyl β-cyclodextrin and dimethyl β-cyclodextrin were prepared by dissolving the products in suitable organo-aqueous solvents under nitrogen and sheltered from light and then stirred for 8 days. The solvents were then evaporated, the free tretinoin eliminated and the complexes dried. Characterization of the products was carried out by electron scanning microscopy, differential scanning calorimetry, IR spectrophotometry, X-ray analysis and 1H-NMR study, which confirmed the existence of an inclusion compound but with weak affinity between tretinoin and the different cyclodextrins. Tretinoin solubility was dramatically enhanced by inclusion, especially in dimethyl β-cyclodextrin. However, in every case, the dissolved products dissociated more or less rapidly leading to reprecipitation of free tretinoin.

Bioadhesive analysis of controlled-release systems. III. Bioadhesive and release behavior of metronidazole-containing poly(acrylic acid)-hydroxypropyl methylcellulose systems

Abstract Bioadhesive controlled release systems for the delivery of metronidazole were prepared by compression of hydroxypropyl methylcellulose with poly(acrylic acid), which served as the bioactive adhesive compound. The release behavior of systems containing 50 wt% metronidazole and various amounts of the two polymers was found to be non-Fickian. The bioadhesive strength of the bond formed between surface-preswollen systems and the sublingual bovine mucus was determined by novel tensile experiments and it was found to be dependent on the poly( acrylic acid) content.

Direct Formation of Nanospheres from Amphiphilic β-Cyclodextrin Inclusion Complexes

AbstractPurpose. The aim of this work was to develop and characterize a highly loaded nanoparticulate system based on amphiphilic β-cyclodextrins (CDs) to facilitate the parenteral administration of poorly soluble antifungal model drugs bifonazole and clotrimazole. Methods. Inclusion complexes were characterized with spectroscopic techniques. Particle size distribution of nanospheres were determined by photon correlation spectroscopy (PCS). Nanospheres were assessed for hemolytic activity. Entrapped and released drug quantities were determined and minimum inhibitory concentration (MIC) values of drugs, amphiphilic β-CDs, and drug loaded nanospheres were evaluated. Results. 1:1 inclusion complexes of model drugs with amphiphilic β-CDs gave nanospheres <300 nm (polydispersity index < 0.15) by nanoprecipitation technique without using surfactants. By direct preparation from preformed inclusion complexes, loading was increased 2- to 8-fold depending on CD type and loading technique. Conventionally loaded CD nanospheres displayed immediate release whereas preloaded and highly loaded nanospheres liberated model drugs over a period of 1 h reducing the initial burst effect. MIC values of bifonazole and clotrimazole were lowered significantly when associated to amphiphilic β-CD nanospheres. Conclusion. Amphiphilic β-CDs form nonsurfactant, highly loaded nanospheres with lower hemolytic activity than that of natural CDs directly from inclusion complexes. They enhanced solubility and subsequently therapeutic efficacy of the model drugs.

Bioadhesion of solid oral dosage forms, why and how?☆

This review focuses on two kinds of bioadhesive solid oral dosage form: tablets for buccal administration, and nanoparticles for intestinal and more specifically colonic administration. For each of these dosage forms, the advantages of the form for drug delivery are presented as well as a short explanation of its bioadhesion mechanism and the bioadhesion evaluation methods. For bioadhesive tablets examples are given concerning the influence of tablet characteristics and of the surrounding medium on bioadhesion. For nanoparticles, examples are given concerning the influence of the nanoparticle surface charges and of the presence of lectins on their intestinal bioadhesion at various pH.

An original method for studying in vitro the enzymatic degradation of cross-linked starch microspheres.

A reproducible technique based on microvolume measurements has been described which can be used for the assessment of the enzymatic degradation of small samples of microspheres (typically 104 to 105 micrometer3). As a model, the degradation pattern of epichlorohydrin cross-linked starch microspheres by alpha-amylase has been studied in the range of 5 to 100 IU/l by this technique. On the one hand, analysis of the decrease in volume of the microspheres by a cubic root law suggested that the degradation profiles were dependent on the initial size distribution of the microspheres. On the other hand, no internal rupture of the microspheres was detected from size distribution data, suggesting that enzymatic degradation of starch microspheres is surface-controlled.

Development of a new colloidal drug carrier from chemically-modified cyclodextrins: Nanospheres and influence of physicochemical and technological factors on particle size

Abstract A new nanosphere carrier system has been obtained from amphiphilic β-cyclodextrin (fatty acid chains varying from 2 to 14 carbons grafted at the O 2 and O 3 positions of β-cyclodextrin). The nanospheres, with a mean diameter varying between 90 and 150 nm, are prepared by progressive dispersion of an organic solution of modified β-cyclodextrin in an aqueous phase with or without surfactant. Various physicochemical parameters have been studied: the effect of the chain length of acyl groups (βCD with 6, 12 and 14 fatty acid carbons), and type of surfactant on the size and physicochemical properties and stability of the nanospheres. A preliminary investigation of water-soluble and insoluble drug entrapment by nanospheres was carried out.

Indomethacin and cyclodextrin complexes

Abstract Different complexes of indomethacin and both β-cyclodextrin (βCD) and hydroxypropyl jS-cyclodextrin (HPβCD) were prepared using different methods: kneading, spray-drying and neutralization followed by freeze-drying. The complexes obtained were studied in the solid phase by differential scanning calorimetry (DSC), thermomicroscopy (TM), and infrared spectroscopy (IR), and in the liquid phase by 1 H-NMR. The results showed that the nature of the end products depends on the method of preparation. The neutralization technique led to a true inclusion of sodium indomethacin in the cyclodextrin cavity, while the nature of the spray-dried product, indomethacin (acid form)/cyclodextrin, was not well defined. The kneading method did not lead to a real inclusion. In any case, the complexes obtained may be of great value as rapidly dissolving forms of indomethacin in water.

Preparation and characterization of lectin-latex conjugates for specific bioadhesion

This paper reports on the preparation and characterization of certain bioadhesive model drug deliver systems formed by a carrier (e.g. modified nanoparticles of polystyrene) and a ligand (e.g. tomato lectin, asparagus pea lectin, Mycoplasma gallisepticum lectin or albumin). Three different manufacturing methods (carbodiimide and glutaraldehyde coupling and physical adsorption) were studied. The activity of the lectin-latex conjugates and albumin-latex conjugate (control) were tested with gastric pig mucin. The manufacturing method had an insignificant effect on the activity, but all lectin-latex conjugates interacted two or three times more with mucin than with the control.