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Research Interests: Chemistry, Kinetics, Medicine, Pharmaceutics, Vancomycin, and 15 morePolymer, Differential scanning calorimetry, Drug Delivery Systems, Cyclodextrin, Gels, Anti-Bacterial Agents, Implant, Ciprofloxacin, Bone Substitutes, Durapatite, Drug Stability, Ciprofloxacin Hydrochloride, Sepharose, Pharmacology and pharmaceutical sciences, and Agarose
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The aim of this work was to better understand the importance of the type of experimental setup used to monitor antibiotic release from functionalized hydroxyapatite implants. Microporous hydroxyapatite discs were prepared by sintering and... more
The aim of this work was to better understand the importance of the type of experimental setup used to monitor antibiotic release from functionalized hydroxyapatite implants. Microporous hydroxyapatite discs were prepared by sintering and subsequently functionalized with hydroxypropyl-β-cyclodextrin (HPβCD) polymer crosslinked with butanetetracarboxylic acid. On one hand, polymerization was performed within the implant after its impregnation with the monomers (CD-HA-M implant). On the other hand, a pre-synthesized HPβCD polymer was loaded and fixed onto the HA discs (CD-HA-P implant). Both types of implants were soaked with ciprofloxacin hydrochloride or vancomycin hydrochloride solution and dried at 37°C. The DSC study highlighted that the cyclodextrin polymer could interfere with both drugs, due to the carboxylic groups carried by the crosslinks. Drug release was measured into phosphate buffered saline pH 7.4 in agitated vials, or into agarose gels to more realistically mimic in v...
Research Interests: Chemistry, Kinetics, Medicine, Pharmaceutics, Vancomycin, and 15 morePolymer, Differential scanning calorimetry, Drug Delivery Systems, Cyclodextrin, Gels, Anti-Bacterial Agents, Implant, Ciprofloxacin, Bone Substitutes, Durapatite, Drug Stability, Ciprofloxacin Hydrochloride, Sepharose, Pharmacology and pharmaceutical sciences, and Agarose
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The first proof of concept in vivo for a new type of microbiota-sensitive film coatings allowing for colon targeting is presented. The efficacy of these polysaccharide barriers to optimize drug release for the treatment of inflammation is... more
The first proof of concept in vivo for a new type of microbiota-sensitive film coatings allowing for colon targeting is presented. The efficacy of these polysaccharide barriers to optimize drug release for the treatment of inflammation is demonstrated in an experimental colitis model with Wister rats. 5-Aminosalicylic acid (5-ASA) pellets were prepared by extrusion-spheronization and coated with Nutriose:ethylcellulose (EC) 1:4 or peas starch:ethylcellulose 1:2 blends. The pellets were mixed with standard chow, and the daily drug dose was 150mg/kg. For reasons of comparison, also commercially available Pentasa pellets and placebo pellets were studied. At day 3 after the beginning of the treatment, colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS). Animals were sacrificed on day 6. Macroscopic and histological evaluations of colitis were performed blindly. In addition, inflammatory markers were evaluated using ELISA and real-time PCR. Rats receiving TNBS and placebo pellets developed a severe colitis in the distal half of the colon. 5-ASA administered in the form of Pentasa pellets reduced macroscopic inflammation by only 5%. In contrast, the colon lesions were much less severe upon treatment with Nutriose:EC- and peas starch:EC-coated pellets: The macroscopic score was reduced by 25 and 24%, respectively. Decreases of 37 and 38% of the histological lesions confirmed the efficacy of these new colon targeting systems. Also, inflammatory markers (MPO, IL-1β mRNA, TNF mRNA) were significantly decreased in rats receiving Nutriose:EC- and peas starch:EC-coated pellets compared to Pentasa pellets. Furthermore, real-time PCR analysis indicated increased activation of the target receptor PPAR-γ and the HMGCS2 gene in rats upon administration of 5-ASA loaded Nutriose:EC- and peas starch:EC pellets compared to the commercial product. Also, HPLC-MS/MS analysis of plasma samples demonstrated that the level of the main metabolite of the drug (N-acetyl-5-ASA) was much lower upon administration of Nutriose:EC or peas starch:EC coated pellets compared to Pentasa pellets, indicating that undesired premature drug release in the upper gastrointestinal tract was more effectively hindered. In addition to the rat study, in vivo imaging of transgenic mice expressing the luciferase gene evidenced much more pronounced PPAR-γ activation upon 5-ASA administration in the form of Nutriose:EC-coated pellets versus Pentasa pellets. All these results clearly demonstrate the superiority of these microbiota-sensitive polysaccharide-based film coatings for colon targeting in vivo.
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A β-cyclodextrin (β-CD) polymer obtained by crosslinking β-CD with citric acid in its water-insoluble (PCD-I) and soluble (PCD-S) forms was used as a multifunctional direct compression excipient for tablet designing. PCD-I powder was... more
A β-cyclodextrin (β-CD) polymer obtained by crosslinking β-CD with citric acid in its water-insoluble (PCD-I) and soluble (PCD-S) forms was used as a multifunctional direct compression excipient for tablet designing. PCD-I powder was obtained after grinding the solid fraction through a 200μm grid. PCD-S powder was recovered after lyophilization or spray drying of the PCD-S aqueous solutions, eventually followed by a wet granulation step. Both PCD-I and PCD-S powders were characterized, separately and mixed in variable ratios, based on dynamic water vapor sorption, SEM, particle size distribution, tapped density, compressibility, and flowability. PCD-I and spray dried and lyophilized/wet granulated PCD-S, as well as the mixture PCD-I/PCD-S=90/10, presented optimal free flowing characteristics. Then, PCD-I or PCD-S powders - separately or mixed in variable ratios - were used for tablets preparation by direct compression without adding any other excipient (e.g. binder, lubricant, disintegrant etc). As PCD-I decreased, tablets resistance to crushing and disintegration time increased from 15s to 15min (against 30min for β-CD), showing the improved disintegrant functionality of PCD-I, that rapidly swelled once in contact with water. Finally, PCD was force-fed to Sprague-Dawley rats (2g/kg) which were then observed during 14days for any clinical signs of toxicity.
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Coma, vegetative state (VS) and minimally conscious state (MCS) are disastrous outcomes following severe traumatic brain injury. Due to the extent of the resultant neurological deficits including hemisphere damage, loss of cellular... more
Coma, vegetative state (VS) and minimally conscious state (MCS) are disastrous outcomes following severe traumatic brain injury. Due to the extent of the resultant neurological deficits including hemisphere damage, loss of cellular integrity, altered and abnormal movements such as flexor and extensor patterns, and alterations in cranial nerve function, it can become difficult for the interprofessional team to identify when a patient is emerging from their coma. The Glasgow Coma Scale (GCS), commonly used to assess patients with traumatic brain injury (TBI) is not comprehensive or sensitive enough to provide concrete evidence that a patient is emerging from VS to an MCS. The purpose of this paper is to present a case study of a patient who has emerged from a persistent VS to promote a deeper understanding of what is involved when working with this clientele. Challenges in assessment of cognitive functioning, the development of successful communication through the use of technology an...
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The aim of this work is to characterize the aerosols obtained by jet nebulization with cyclodextrin solutions and to study the influence of operating conditions on nebulization efficiency. Two cyclodextrins, an hydroxypropyl cyclodextrin... more
The aim of this work is to characterize the aerosols obtained by jet nebulization with cyclodextrin solutions and to study the influence of operating conditions on nebulization efficiency. Two cyclodextrins, an hydroxypropyl cyclodextrin (Kleptose HP) and a polydisperse methyl beta cyclodextrin (Crysmeb), were tested with 14 nebulizers that differ geometrically. We first determined the physicochemical properties of density, viscosity, and surface tension for the cyclodextrin solutions. Nebulization efficiency was evaluated by measuring droplet size, nebulization rate, quantity of solution nebulized, and nebulization time. We studied the influence of the technological parameters of pressure and nebulizer type and the influence of the formulation on performance efficiency. The use of different nebulizers and different pressure conditions results in variable efficiency. Regardless of the type of nebulizer, an increase in pressure decreases droplet size and increases nebulization rate. The influence of the nebulizer design is considerable. The aqueous cyclodextrin solutions studied can generate aerosols in particle size ranges suitable for pulmonary deposition. Large quantities of aerosol can be nebulized in acceptable nebulization times. The cyclodextrin concentration does not modify nebulization efficiency in the range tested.
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Extrusion-spheronisation technology is an agglomeration process that makes it possible to obtain spheroids. The aim of this work was to obtain 400microm spheroids that could be sprinkled on food to improve patient observance in particular... more
Extrusion-spheronisation technology is an agglomeration process that makes it possible to obtain spheroids. The aim of this work was to obtain 400microm spheroids that could be sprinkled on food to improve patient observance in particular with children and old people. A methodology to select wet masses for extrusion-spheronisation through a 400microm orifice was developed. First, it was nesessary to define the parameters that make it possible to appreciate the qualities that the wet mass and the extrudates have to possess and their method of evaluation: plasticity, cohesiveness, brittleness of the mass and the extrudates, appearance of extrudates. A feasibility assay made on the drum extruder was then performed. After proving the feasibility of 400microm spheroids of Gelucire 50/02 we considered the association of a drug with it.
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Novel orally disintegrating system based on multiparticulate form was developed, offering an alternative to encounter major issues in the design of dosage form for pediatric patients, i.e., the difficulty in swallowing large solid dosage... more
Novel orally disintegrating system based on multiparticulate form was developed, offering an alternative to encounter major issues in the design of dosage form for pediatric patients, i.e., the difficulty in swallowing large solid dosage form (tablet or capsule), and the requirement to cover a broad range of doses for different age groups. Microcrystalline cellulose-based pellets containing acetaminophen were prepared via extrusion/spheronization followed by freeze-drying. The in vitro disintegration behavior of these pellets was quantitatively measured with a texture analyzer. Mercury intrusion and gas adsorption techniques, scanning electron microscopy of pellet surface and cross-section were performed in order to characterize their internal porous structure. Pellets characteristics such as size distribution, sphericity, friability and drug release were also determined. The developing process was able to produce pellets containing high drug loading (25, 50 and up to 75%, w/w) with good sphericity (aspect ratio ∼1) and low friability. The pellets exhibited an instantaneous disintegration upon contact with water, which was indicated by two parameters: the disintegration onset was approximating to 0, and the disintegration time less than 5s. The fast disintegration behavior is correlated with the pellet internal structure characterized by a capillary network with pore diameter varying from 0.1 to 10μm. Such a structure not only ensured a rapid disintegration but it also offers to freeze-dried pellets adequate mechanical properties in comparison with conventional freeze-dried forms. Due to pellet disintegration, fast dissolution of acetaminophen was achieved, i.e., more than 90% of drug released within 15min. This novel multiparticulate system offers novel age-appropriate dosage form for pediatric population owing to their facility of administration (fast disintegration) and dosing flexibility (divided and reduced-size solid form).
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Limited information on the effect of the drug concentration on the performance of powders for inhalation is currently published. The aim of this work was to study the influence of drug concentration on the adhesion between drug and... more
Limited information on the effect of the drug concentration on the performance of powders for inhalation is currently published. The aim of this work was to study the influence of drug concentration on the adhesion between drug and carrier and on the drug detachment from the carrier. The study was done with formoterol fumarate and fluticasone propionate blended with lactose Lactohale 200. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. Adhesion characteristics were evaluated by submitting the mixtures to a sieving action by air depression with an Alpine air-jet sieve. Aerodynamic evaluation of fine particle dose and emitted dose was obtained using a Twin Stage Impinger (TSI). Drug concentration of powder blends used in dry powder inhalers influenced adhesion, content uniformity and in vitro deposition of the drug. For the higher concentration ...
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Dry powder formulations are often composed of fine drug particles and coarser carrier particles, typically alpha-lactose monohydrate. However, the performance of a powder formulation may be highly dependent on the lactose quality and... more
Dry powder formulations are often composed of fine drug particles and coarser carrier particles, typically alpha-lactose monohydrate. However, the performance of a powder formulation may be highly dependent on the lactose quality and source. This study investigated the characteristics of lactose that influence the drug-to-carrier interaction and the performance of lactose-based dry powder inhaler formulations. The selected lactoses differed in the preparation processes and the content of fine lactose particles. Efficiency testing was done using fluticasone propionate and terbutaline sulphate as model drugs. Inverse gas chromatography was used to determine the surface heterogeneity distribution of different energy sites of the lactose and to understand the mechanism by which the fine carrier particles can improve the performance of dry powder inhalers. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and consideri...
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The principle of an ultrasonic nebuliser is based on the vibrations of a piezo-electric crystal driven by an alternating electrical field. These periodical vibrations are characterised by their frequency, their amplitude and their... more
The principle of an ultrasonic nebuliser is based on the vibrations of a piezo-electric crystal driven by an alternating electrical field. These periodical vibrations are characterised by their frequency, their amplitude and their intensity which corresponds to the energy transmitted per surface unit. When the vibration intensity is sufficient, cavitation appears and generates droplets. Ventilation enables an airflow to cross the nebuliser and to expulse the aerosol droplets. For a given nebuliser, the vibration frequency of the piezo-electric crystal is fixed and is often in the range of 1-2.5 MHz. In most cases, an adjustment in vibration intensity is possible by modifying vibration amplitude. The ventilation level is adjustable. The influence of these two parameters on the efficiency of ultrasonic nebulisation is studied. The study was carried out with a protein solution that had to be administered into the lungs. The solution used presented a viscosity of 1.25 mPa and a surface ...
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ABSTRACT
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The aim of this work was to study the impact of the process on drug particle size. We chose ibuprofen, practically insoluble in water, as granulometry greatly influences its dissolution rate. We developed an original method using a laser... more
The aim of this work was to study the impact of the process on drug particle size. We chose ibuprofen, practically insoluble in water, as granulometry greatly influences its dissolution rate. We developed an original method using a laser granulometer to assess the size of ibuprofen within a blend before and after granulation and then compression. Wet granulation was performed with a Lodige and a Diosna granulator. The granules were then compressed. The evolution of ibuprofen particle size after these operations was checked. Two grades of ibuprofen differing in size were studied: ibuprofen 25 and ibuprofen 50. After the wet granulation of ibuprofen 50 with a Lodige or a Diosna granulator, a decrease in size was observed. This could be caused by shocks occurring in the granulator. On the other hand, after compression of the granules, ibuprofen particle size increased and was greater than that measured before granulation. Compression could induce some fragmentation of ibuprofen associated with the plastic deformation and then, under pressure, a closeness of the fragments or deformed particles which could bind or associate with one another because the melting point of ibuprofen is not very high. In the case of ibuprofen 25, the same phenomena were observed after compression. But, after granulation, particle size was not modified. There was little breaking of ibuprofen particles in the granulator because they are much smaller than those of ibuprofen 50. This work shows the impact of the process on drug particle size when producing tablets. The method developed made it possible to differentiate and measure the size of ibuprofen particles in a blend.
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The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the feasibility of using different... more
The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the feasibility of using different cyclodextrins (CDs) to elaborate pharmaceutical formulations for the inhalation route and tested the short-term toxicity of such formulations administered by inhalation to C57BL/6 mice. We have shown that HP-h-CD, g-CD, as well as RAMEB aqueous solutions can undergo aerosolization and that the resulting droplet-size ranges are compatible with pulmonary deposition. In vivo, we have demonstrated that short-term exposure to inhaled HP-h-CD, g-CD and RAMEB solutions are non-toxic after assessing bronchoalveolar lavage (BAL), lung and kidney histology, bronchial responsiveness to methacholine and blood urea. The only change noted is a slight increase in lymphocyte count in the BAL after HP-h-CD and g-CD inhalation. We conclude that CDs are useful in significantly enhancing the solubility of apolar drugs with a view to inhalation therapy although an increase in lymphocyte counts in the BAL after CDs inhalations needs further investigations.
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Research Interests: Pharmaceutical Technology, Magnetic Resonance Spectroscopy, Pharmaceutical Chemistry, Aerosols, Humans, and 13 moreViscosity, Drug Delivery Systems, Lung, High Pressure Liquid Chromatography, Particle Size, Surface Tension, Surface Properties, Operant Conditioning, Cyclodextrins, Aqueous Solution, Drug Compounding, Physicochemical Properties, and Droplet Size
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Antisticking power varies according to the talc considered. Besides its chemical properties, it is necessary to assess its physical properties related to functionality. It is difficult to define the physical properties of talc implicated... more
Antisticking power varies according to the talc considered. Besides its chemical properties, it is necessary to assess its physical properties related to functionality. It is difficult to define the physical properties of talc implicated in its antisticking power. In this work, different talcs were characterised and their performance in reducing sticking in tablet manufacturing was evaluated. The following parameters were studied: apparent density, morphogranulometry, roughness, and the specific surface through the adsorption-desorption of argon. Next, the relationship between the characteristics of talcs and their antisticking power was considered. Talc before and after delamination-which is a way to obtain talcs with different physical characteristics-was compared. Antisticking power appeared to be dependent on the basal dimensions of talc, and on the ratio value of the external specific surface measured by diffractometry to the total specific surface by the BET method. Models to express the effect of textural factors of talc particles on antisticking power were defined.
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The objective of this work was to develop a galenic form of activated charcoal appropriate for the needs of clinical toxicology. To preserve the adsorption capacity of charcoal, we developed an extemporaneous preparation of activated... more
The objective of this work was to develop a galenic form of activated charcoal appropriate for the needs of clinical toxicology. To preserve the adsorption capacity of charcoal, we developed an extemporaneous preparation of activated charcoal intended for clinical toxicology. To improve the wettability of activated charcoal, we used densification by wet granulation. The presence of a viscosity agent is necessary to ensure the homogeneity of the suspension and its adhesiveness on gastric mucous membrane. Five formulations with different viscosity agents were prepared, and their adsorption capacity, wettability, viscosity, and adhesiveness were studied.