Towards controlling the crystallisation behaviour of fenofibrate melt: triggers of crystallisation and polymorphic transformation

Fenofibrate (FEN) is a dyslipidemia treatment agent which is poorly soluble in water. FEN has tendency to form polymorphs and its crystallisation behaviour is difficult to predict. The nucleation process can be initiated by mechanical disruption such as ball milling or surface scratching which may result in different crystallisation behaviour to that observed in the unperturbed system. This study has obtained insights into the controllability of FEN crystallisation by means of regulating the exposed surface and growth temperatures during its crystallisation. The availability of an open top surface (OTS) during the crystallisation of the FEN melt resulted in a mixture containing FEN form I and IIa (I ≫ IIa) at room temperature, and in the range 40 to 70 °C. Covering the surface led to significant increases in the yield of form IIa at room temperature and at 40 and 50 °C. These temperatures also yielded the highest amount of form IIa in the OTS samples whilst crystallisation at 70 °C led to only FEN form I crystals regardless of the availability of the free surface. The metastable FEN form IIa transforms to the stable form I under the influence of a mechanical stress. Additionally, the introduction of OTS before the completion of crystallisation of form IIa led to a ‘switch’ of from IIa growth to form I. This study demonstrates that the polymorph selection of FEN can be obtained by the manipulation of the crystallisation conditions

Sublingual Priming with a HIV gp41-Based Subunit Vaccine Elicits Mucosal Antibodies and Persistent B Memory Responses in Non-Human Primates

Persistent B cell responses in mucosal tissues are crucial to control infection against sexually transmitted pathogens like human immunodeficiency virus 1 (HIV-1). The genital tract is a major site of infection by HIV. Sublingual (SL) immunization in mice was previously shown to generate HIV-specific B cell immunity that disseminates to the genital tract. We report here the immunogenicity in female cynomolgus macaques of a SL vaccine based on a modified gp41 polypeptide coupled to the cholera toxin B subunit designed to expose hidden epitopes and to improve mucosal retention. Combined SL/intramuscular (IM) immunization with such mucoadhesive gp41-based vaccine elicited mucosal HIV-specific IgG and IgA antibodies more efficiently than IM immunization alone. This strategy increased the number and duration of gp41-specific IgA secreting cells. Importantly, combined immunization improved the generation of functional antibodies 3 months after vaccination as detected in HIV-neutralizing assays. Therefore, SL immunization represents a promising vaccine strategy to block HIV-1 transmission.These studies were supported by Institut National de la Santé et de la Recherche Médicale (INSERM, France) by Centre National de Recherche Scientifique (CNRS, France), by the Agence Nationale de Recherche sur le SIDA (France), the SIDACTION (France), by the Euroneut-41 European Consortium (FP7 program), by the National Research Agency (ANR) through the “Investments for the Future” LABEX SIGNALIFE (ANR-11-LABX-0028-01) and the “Investments for the future” under Grant ANR-11-INBS-0008 funding the Infectious Disease Models and Innovative Therapies (IDMIT, Fontenay-aux-Roses, France) infrastructure and ANR-10-EQPX-02-01 funding the FlowCyTech facility

Improved dissolution behavior of lipophilic drugs by solid dispersions : a matter of composition

Solid dispersions can be used to improve the dissolution behavior of poorly water-soluble drugs and thereby their bioavailability after oral administration. Solid dispersions are generally composed of drugs incorporated in hydrophilic carriers. In this thesis, the effects of the type and molecular weight of the hydrophilic carrier, the drug load and the presence of additives on the dissolution behavior and stability of tablets prepared from solid dispersions were investigated. It was found that when the drug load was high and/or when the carrier dissolved fast, the dissolution rate of the drug was slow. This phenomenon was attributed to uncontrolled crystallization of the drug in the near vicinity of the dissolving tablet due to a high supersaturation. Higher drug loads could be applied without the occurrence of recrystallization of the drug when carriers were used that interacted with the drugs. This could be ascribed to an increased solubility of the drug in the near vicinity of the dissolving tablet due to a high local concentration of the carrier. Furthermore, it was found that the incorporation of a superdisintegrant in the solid dispersion tablets can also prevent recrystallization of the drug. In this case, the tablet disintegrated so fast that supersaturation of the drug in the near vicinity of the dissolving tablet was prevented. To demonstrate the potential of this platform technology, it was applied to a range of different drugs such as diazepam, fenofibrate, ritonavir, efavirenz and tacrolimus. Finally, a number of the solid dispersion tablets that showed excellent dissolution behavior also showed an excellent storage stability.

Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets by incorporation of superdisintegrants

In this study, it was shown that the incorporation of superdisintegrants in solid dispersion tablets containing a high drug load can strongly enhance the dissolution rate of the highly lipophilic drug fenofibrate. In addition, the dissolution rate was more increased when the superdisintegrant was incorporated in the drug containing solid dispersions than when it was physically mixed with the solid dispersions. The dissolution rate enhancement strongly depended on the type of superdisintegrants and increased in the order Polyplasdone®XL-10 <Polyplasdone®XL ≪ Ac-Di-Sol®≈ Primojel®. The dissolution behavior also depended on the type of hydrophilic carriers. Solid dispersion tablets based on inulin 4 kDa, polyethylene glycol 20 K and polyvinylpyrrolidone K30 showed a much faster dissolution than those based on mannitol and hydroxypropyl-β-cyclodextrin. Finally, inulin 4 kDa-based solid dispersion tablets showed excellent storage stability, while polyethylene glycol 20 K-and polyvinylpyrrolidone K30-based solid dispersion tablets did not. © 2009 Elsevier B.V. All rights reserved

Improved dissolution behavior of lipophilic drugs by solid dispersions:the production process as starting point for formulation considerations

Introduction: Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several methods have been developed to prepare solid dispersions. To obtain a product with the desired attributes, both the formulation and production processes should be considered. Areas covered: The most currently used methods to produce solid dispersions, such as the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation, are reviewed in this paper. In addition, the physicochemical characteristics of the obtained solid dispersions are discussed. Expert opinion: Solid dispersions can be successfully prepared by simple fusion, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation. Hot melt extrusion, spray drying and freeze drying are processes that can be applied for large scale production. The simple fusion method is not very suitable for large scale production, but is particularly suitable for screening formulations. The most recent method to produce sold dispersions is supercritical fluid precipitation. The process conditions of this method need extensive investigation, in particular in relationship with the selection of the type of carrier and/or solvent. Both processes and formulation aspects strongly affect the characteristics of solid dispersion products. Furthermore, application of crystalline solid dispersions is gaining increasing interest because they are thermodynamically more stable than amorphous solid dispersions

Effect of drug-carrier interaction on the dissolution behavior of solid dispersion tablets

The objective of this study was to compare the dissolution behavior of tablets prepared from solid dispersions with and without drug-carrier interactions. Diazepam and nifedipine were used as model drugs. Two types of carriers were used; polyvinylpyrrolidone (PVP K12, K30 and K60) and saccharides (inulin 1.8kDa, 4kDa and 6.5kDa). Solid dispersions with various drug loads were prepared by lyophilization. It was found that the drug solubility in aqueous PVP solutions was significantly increased indicating the presence of drug-carrier interaction while the drug solubility was not affected by the saccharides indicating absence of drug-carrier interaction. X-ray powder diffraction and modulated differential scanning calorimetry revealed that all solid dispersions were fully amorphous. Dissolution behavior of solid dispersion tablets based on either the PVPs or saccharides was governed by both dissolution of the carrier and drug load. It was shown that a fast drug dissolution of solid dispersions with a high drug load could be obtained with carrier that showed interaction with the drug. © 2010 Informa Healthcare USA, Inc

Surface-active derivative of inulin (Inutec® SP1) is a superior carrier for solid dispersions with a high drug load

The aim of this study was to compare the applicability of inulin, its surface-active derivative (Inutec® SP1), and polyvinylpyrrolidone (PVP) as carriers in high drug load solid dispersions (SDs) for improving the dissolution rate of a range of lipophilic drugs (diazepam, fenofibrate, ritonavir, and efavirenz). The SDs were prepared by spray freeze-drying. Scanning electron microscopy showed that the obtained samples were highly porous spherical particles. Modulated differential scanning calorimetry showed that the drugs incorporated in these carriers were fully or partially amorphous. The solubility of the drugs in solutions of the different carriers was increased in an order: inulin 2.3kDa <PVP K30≪ Inutec® SP1. The dissolution behavior of SD tablets was evaluated. Inutec® SP1-based SD tablets showed the best performance followed by PVP- and inulin-based SD tablets. The superior dissolution behavior of the drugs from Inutec® SP1-based SDs could be ascribed to its surface-active nature. In addition, Inutec® SP1-based SD tablets gave good physical stability at 20°C/45% relative humidity (RH) and 40°C/75% RH for 3 months. © 2011 Wiley-Liss, Inc