Jonathan Goole

Department of Drug Research and Development (DPP)

Therapeutic Chemistry (CPO)

Research activities

His main research interests aim at creating new pharmaceutical forms, improving manufacturing processes and increasing the bioavailability of active molecules.

He is especially interested in: the development of solid dosage forms, including modified-release systems; the formulation of biotherapeutics, including encapsulated systems and implantable dosage forms; the solubility enhancement for poorly-soluble drugs, including the creation of amorphous structures, nanoparticules or solid-dispersions.

More recently, he focused a part of his research on the development of customized dosages forms made by 3D printing techniques especially dedicated to personalized therapies.

Top ten recent articles

Articles dans des revues avec comité de lecture

2023

What Are the Key Anatomical Features for the Success of Nose-to-Brain Delivery? A Study of Powder Deposition in 3D-Printed Nasal Casts

Nose-to-brain delivery is a promising way to improve the treatment of central nervous system disorders, as it allows the bypassing of the blood-brain barrier. However, it is still largely unknown how the anatomy of the nose can influence the treatment outcome. In this work, we used 3D printing to produce nasal replicas based on 11 different CT scans presenting various anatomical features. Then, for each anatomy and using the Design of Experiments methodology, we characterised the amount of a powder deposited in the olfactory region of the replica as a function of multiple parameters (choice of the nostril, device, orientation angle, and the presence or not of a concomitant inspiration flow). We found that, for each anatomy, the maximum amount of powder that can be deposited in the olfactory region is directly proportional to the total area of this region. More precisely, the results show that, whatever the instillation strategy, if the total area of the olfactory region is below 1500 mm2, no more than 25% of an instilled powder can reach this region. On the other hand, if the total area of the olfactory region is above 3000 mm2, the deposition efficiency reaches 50% with the optimal choice of parameters, whatever the other anatomical characteristics of the nasal cavity. Finally, if the relative difference between the areas of the two sides of the internal nasal valve is larger than 20%, it becomes important to carefully choose the side of instillation. This work, by predicting the amount of powder reaching the olfactory region, provides a tool to evaluate the adequacy of nose-to-brain treatment for a given patient. While the conclusions should be confirmed via in vivo studies, it is a first step towards personalised treatment of neurological pathologies.

Eudragit® FS Microparticles Containing Bacteriophages, Prepared by Spray-Drying for Oral Administration

Stability of supported hybrid lipid bilayers on chemically and topographically-modified surfaces

Hybrid lipid bilayers are a particular case of supported lipid bilayers with the two monolayer leaflets composed by different types of molecules. These nanostructures can be produced in a well-controlled array fashion and are suitable for the study of biomembrane-related phenomena via electrochemical or plasmonic sensing. Understanding how the underlying solid surface affects the supported membrane formation and organization is necessary for the potential use of these hybrid platforms in applications for which surfaces are not flat and topographically complex. Here we assess the role of lipid phase, substrate surface energy and topography on the formation and stability of hybrid supported membranes from vesicle precursors using complementary surface sensitive techniques, namely quartz crystal microbalance with dissipation and atomic force microscopy. The stability of hybrid bilayers against thermal and osmotic changes is evaluated and compared to standard supported lipid bilayers formed onto hydrophilic SiO2. Force spectroscopy measurements reveal an overall weaker lateral organization of hybrid membranes as a result of the underlying self-assembled monolayer being not optimally organized. Hybrid bilayers display a decoupled behavior between the two leaflets when vertically compressed at constant speed. On microcontact printed Au surfaces, hybrid bilayers were formed over printed patches, while surprisingly, supported lipid bilayers were observed on non-patterned Au regions suggesting a non-trivial self-assembled monolayer reorganization when in aqueous environment

In vitro Evaluation of Paliperidone Palmitate Loaded Cubosomes Effective for Nasal-to-Brain Delivery

2022

Validation and Sensitivity analysis for a nasal spray deposition computational model

Instillation of a Dry Powder in Nasal Casts: Parameters Influencing the Olfactory Deposition With Uni- and Bi-Directional Devices

Nose-to-brain delivery is a promising way to reach the central nervous system with therapeutic drugs. However, the location of the olfactory region at the top of the nasal cavity complexifies this route of administration. In this study, we used a 3D-printed replica of a nasal cavity (a so-called “nasal cast”) to reproduce in vitro the deposition of a solid powder. We considered two different delivery devices: a unidirectional device generating a classical spray and a bidirectional device that relies on the user expiration. A new artificial mucus also coated the replica. Five parameters were varied to measure their influence on the powder deposition pattern in the olfactory region of the cast: the administration device, the instillation angle and side, the presence of a septum perforation, and the flow rate of possible concomitant inspiration. We found that the unidirectional powder device is more effective in targeting the olfactory zone than the bi-directional device. Also, aiming the spray nozzle directly at the olfactory area is more effective than targeting the center of the nasal valve. Moreover, the choice of the nostril and the presence of a perforation in the septum also significantly influence the olfactory deposition. On the contrary, the inspiratory flow has only a minor effect on the powder outcome. By selecting the more efficient administration device and parameters, 44% of the powder can reach the olfactory region of the nasal cast.

Paliperidone palmitate as model of heat-sensitive drug for long-acting 3D printing application

In this work, two technologies were used to prepare long-acting implantable dosage forms in the treatment of schizophrenia. Hot-melt extrusion (HME) as well as fused deposition modelling (FDM) were used concomitantly to create personalized 3D printed implants. Different formulations were prepared using an amorphous PLA as matrix polymer and different solid-state plasticizers. Paliperidone palmitate (PP), a heat sensitive drug prescribed in the treatment of schizophrenia was chosen as model drug. After extrusion, different formulations were characterized using DSC and XRD. Then, an in vitro dissolution test was carried out to discriminate the formulation allowing a sustained drug release of PP. The formulation showing a sustained drug release of the drug was 3D printed as an implantable dosage form. By modulating the infill, the release profile was related to the proper design of tailored dosage form and not solely to the solubility of the drug. Indeed, different release profiles were achieved over 90 days using only one formulation. In addition, a stability test was performed on the 3D printed implants for 3 months. The results showed the stability of the amorphous state of PP, independently of the temperature as well as the integrity of the matrix and the drug.

Interactions of hydrophilic quantum dots with defect-free and defect containing supported lipid membranes

Quantum dots (QDs) are semiconductor nanoparticles with unique optical and electronic properties, whose interest as potential nano-theranostic platforms for imaging and sensing is increasing. The design and use of QDs requires the understanding of cell-nanoparticle interactions at a microscopic and nanoscale level. Model systems such as supported lipid bilayers (SLBs) are useful, less complex platforms mimicking physico-chemical properties of cell membranes. In this work, we investigated the effect of topographical homogeneity of SLBs bearing different surface charge in the adsorption of hydrophilic QDs. Using quartz-crystal microbalance, a label-free surface sensitive technique, we show significant differences in the interactions of QDs onto homogeneous and inhomogeneous SLBs formed following different strategies. Within short time scales, QDs adsorb onto topographically homogeneous, defect-free SLBs is driven by electrostatic interactions, leading to no layer disruption. After prolonged QD exposure, the nanomechanical stability of the SLB decreases suggesting nanoparticle insertion. In the case of inhomogeneous, defect containing layers, QDs target preferentially membrane defects, driven by a subtle interplay of electrostatic and entropic effects, inducing local vesicle rupture and QD insertion at membrane edges.

2021

A Design of Experiment Approach to Optimize Spray-Dried Powders Containing Pseudomonas aeruginosa Podoviridae and Myoviridae Bacteriophages

In the present study, we evaluated the effect of spray-drying formulations and operating parameters of a laboratory-scale spray-dryer on the characteristics of spray-dried powders containing two Pseudomonas aeruginosa bacteriophages exhibiting different morphotypes: a podovirus (LUZ19) and a myovirus (14-1). We optimized the production process for bacteriophage-loaded powders, with an emphasis on long-term storage under ICH (international conference on harmonization) conditions. D-trehalose-/L-isoleucine-containing bacteriophage mixtures were spray-dried from aqueous solutions using a Büchi Mini Spray-dryer B-290 (Flawil, Switzerland). A response surface methodology was used for the optimization of the spray-drying process, with the following as-evaluated parameters: Inlet temperature, spray gas flow rate, and the D-trehalose/L-isoleucine ratio. The dried powders were characterized in terms of yield, residual moisture content, and bacteriophage lytic activity. L-isoleucine has demonstrated a positive impact on the activity of LUZ19, but a negative impact on 14-1. We observed a negligible impact of the inlet temperature and a positive correlation of the spray gas flow rate with bacteriophage activity. After optimization, we were able to obtain dry powder preparations of both bacteriophages, which were stable for a minimum of one year under different ICH storage conditions (up to and including 40 °C and 75% relative humidity).

The importance of pre-formulation studies and of 3D-printed nasal casts in the success of a pharmaceutical product intended for nose-to-brain delivery

Asymmetric Lipid Transfer between Zwitterionic Vesicles by Nanoviscosity Measurements

The interest in nano-sized lipid vesicles in nano-biotechnology relies on their use as mimics for endosomes, exosomes, and nanocarriers for drug delivery. The interactions between nanoscale size lipid vesicles and cell membranes involve spontaneous interbilayer lipid transfer by several mechanisms, such as monomer transfer or hemifusion. Experimental approaches toward monitoring lipid transfer between nanoscale-sized vesicles typically consist of transfer assays by fluorescence microscopy requiring the use of labels or calorimetric measurements, which in turn require a large amount of sample. Here, the capability of a label-free surface-sensitive method, quartz crystal microbalance with dissipation monitoring (QCM-D), was used to monitor lipid transfer kinetics at minimal concentrations and to elucidate how lipid physicochemical properties influence the nature of the transfer mechanism and dictate its dynamics. By studying time-dependent phase transitions obtained from nanoviscosity measurements, the transfer rates (unidirectional or bidirectional) between two vesicle populations consisting of lipids with the same head group and differing alkyl chain length can be estimated. Lipid transfer is asymmetric and unidirectional from shorter-chain lipid donor vesicles to longer-chain lipid acceptor vesicles. The transfer is dramatically reduced when the vesicle populations are incubated at temperatures below the melting of one of the vesicle populations.

Development of mAb-loaded 3D-printed (FDM) implantable devices based on PLGA

Development of mAb-loaded 3D-printed (FDM) implantable devices based on PLGA

The main objective of this work was to explore the feasibility to print monoclonal antibody (mAb)-loaded implantable systems using fused-deposition modelling (FDM) to build complex dosage form designs. Indeed, to our knowledge, this work is the first investigation of mAb-loaded devices using FDM. To make this possible, different steps were developed and optimized. A mAb solution was stabilized using trehalose (TRE), sucrose (SUC), hydroxypropyl-β-cyclodextrin (HP-β-CD), sorbitol or inulin (INU) in order to be spray dried (SD). Printable filaments were then made of poly(lactide-co-glycolide) (PLGA) and mAb powder (15% w/w) using hot melt extrusion (HME). The FDM process was optimized to print these filaments without altering the mAb stability. TRE was selected and associated to L-leucine (LEU) to increase the mAb stability. The stability was then evaluated considering high and low molecular weight species levels. The mAb-based devices were well-stabilized with the selected excipients during both the HME and the FDM processes. The 3D-printed devices showed sustained-release profiles with a low burst effect. The mAb-binding capacity was preserved up to 70% following the whole fabrication process. These promising results demonstrate that FDM could be used to produce mAb-loaded devices with good stability, affinity and sustained-release profiles of the mAb.

2020

Correlation between adhesion strength and phase behaviour in solid-supported lipid membranes

Fundamental understanding of vesicle adhesion in the size range ≤ 200 nm is of major importance when addressing biologically relevant processes involving the presence of small vesicles like exosomes or endosomes. Using quartz crystal microbalance with dissipation monitoring, we investigate the correlation between vesicle deformation and eventual membrane rupture on surfaces with different adhesion levels, as well as their respective thermotropic phase transitions. In particular, phase transitions of solid-supported membranes on Au resemble the cooperative behaviour of lipid membrane transitions in bulk. In contrast, solid-supported membranes on SiO2 exhibit broadened ‘double-peak' transitions, rendering a ‘decoupling' effect during melting due to stronger interactions with SiO2. This paper provides a comprehensive view of the correlation between size, geometry and phase transitions observed in the layer of adsorbed lipid vesicles/membranes. It paves the way to explore structural changes on more complex biointerfaces by acoustic-based sensors.

A consensus research agenda for optimising nasal drug delivery

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors.

2019

Development and evaluation of budesonide-based modified-release liquid oral dosage forms

Modified-release oral drug delivery dosage forms are widely used in the pharmaceutical field to overcome all the potential issues imposed by the physiological variabilities of the gastrointestinal tract as well as to maintain drug concentrations within the therapeutic window. In the market, they are available only as solid dosage forms such as capsules or tablets. The development of a liquid oral dosage form with modified-release properties has been keenly awaited. This form could increase the compliance of patients with a swallowing impairment (i.e. paediatric, older or critically ill patients) and, consequently, the efficacy of the therapeutic treatment. In this study, budesonide was used as a model drug to develop a modified-release liquid oral dosage form (i.e. colonic-release, sustained-release). For this purpose, multi-layered particles were obtained, starting from small microcrystalline cellulose neutral cores (Cellets® with a mean diameter lower than 500 μm), in a lab-scale fluid-bed coater. Poly(meth)acrylate polymers commonly available under the trade name of Eudragit®, such as S100, RS PO, RL100 and E100, were used to get defined drug release profiles. They were also used to guarantee the stability of the reconstituted liquid syrup during 2 weeks of storage at room temperature.

Development of PLGA microparticles with high immunoglobulin G-loaded levels and sustained-release properties obtained by spray-drying a water-in-oil emulsion

In this study, the possibility of producing highly antibody-loaded microparticles with sustained-release properties was evaluated. Polyclonal immunoglobulin G (IgG) was used as a model of antibody and its encapsulation into poly(lactide-co-glycolide) acid (PLGA) microparticles was performed by spray-drying a water-in-oil (w/o) emulsion. It was demonstrated that the use of the Resomer® RG505 PLGA allowed an IgG loading of 20% w/w with an encapsulation efficiency higher than 85%. The produced microparticles were characterized by a mean diameter lower than 10 µm. The burst effect was shown to reach a maximal value of 40%. IgG stability after encapsulation was also assessed. The use of this single PLGA provided a lag time of 3 months which dramatically slowed down the release rate after the initial release of the encapsulated IgG. Using blends of PLGA characterized by different inherent viscosities allowed decreasing the lag time and modulating the dissolution profile of the IgG from the spray-dried microparticles. Therefore, spray-drying a water-in-oil emulsion appeared to be a promising strategy to produce highly antibody-loaded microparticles characterized by sustained-release properties.

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods

Nasal delivery offers many benefits over other conventional routes of delivery (e.g. oral or intravenous administration). Benefits include, among others, a fast onset of action, non-invasiveness and direct access to the central nervous system. The nasal cavity is not only limited to local application (e.g. rhinosinusitis) but can also provide direct access to other sites in the body (e.g. the central nervous system or systemic circulation). However, both the anatomy and the physiology of the nose impose their own limitations, such as a small volume for delivery or rapid mucociliary clearance. To meet nasal-specific criteria, the formulator has to complete a plethora of tests, in vitro and ex vivo, to assess the efficacy and tolerance of a new drug-delivery system. Moreover, depending on the desired therapeutic effect, the delivery of the drug should target a specific pathway that could potentially be achieved through a modified release of this drug. Therefore, this review focuses on specific techniques that should be performed when a nasal formulation is developed. The review covers both the tests recommended by regulatory agencies (e.g. the Food and Drug Administration) and other complementary experiments frequently performed in the field.

Simple Approach for a Self-Healable and Stiff Polymer Network from Iminoboronate-Based Boroxine Chemistry

Despite offering robust mechanical properties, polymer networks suffer from a lack of recyclability, reshaping, and healability. Designing stiff and remendable polymer networks that can repair under mild conditions remains a challenge to extend their field of applications. Herein, we describe a simple approach to design a nonisocyanate-based polyurethane network featuring multiresponsiveness (to humidity and temperature) and outstanding healing properties, as obtained by combining iminoboronate and boroxine chemistry. In spite of the presence of abundant dynamic bonds, the network has a high stiffness (Young's modulus of 551 MPa) and tensile strength (11 MPa). C?N iminoboronate and B-O boroxine exchange reactions at high temperature enable efficient network recycling over multiple cycles without compromising its properties. Owing to these features, 3D objects could be designed and printed. The present approach provides excellent sustainable and high-performance substitution to conventional polyurethane networks requiring the use of toxic isocyanates.

2018

Chitosan-coated liposome dry-powder formulations loaded with ghrelin for nose-to-brain delivery

The nose-to-brain delivery of ghrelin loaded in liposomes is a promising approach for the management of cachexia. It could limit the plasmatic degradation of ghrelin and provide direct access to the brain, where ghrelin's specific receptors are located. Anionic liposomes coated with chitosan in either a liquid or a dry-powder formulation were compared. The powder formulation showed stronger adhesion to mucins (89 ± 4% vs 61 ± 4%), higher ghrelin entrapment efficiency (64 ± 2% vs 55 ± 4%), higher enzymatic protection against trypsin (26 ± 2% vs 20 ± 3%) and lower ghrelin storage degradation at 25 °C (2.67 ± 1.1% vs 95.64 ± 0.85% after 4 weeks). The powder formulation was also placed in unit-dose system devices that were able to generate an appropriate aerosol characterized by a Dv50 of 38 ± 6 µm, a limited percentage of particles smaller than 10 µm of 4 ± 1% and a reproducible mass delivery (CV: 1.49%). In addition, the device was able to deposit a large amount of powder (52.04% w/w) in the olfactory zone of a 3D-printed nasal cast. The evaluated combination of the powder formulation and the device could provide a promising treatment for cachexia.

2017

Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia

The aim of the present study was to develop a ghrelin-containing formulation based on liposomes coated with chitosan intended for nose-brain delivery for the treatment of cachexia. Among the three types of liposomes developed, anionic liposomes provided the best results in terms of encapsulation efficiency (56%) and enzymatic protection against trypsin (20.6% vs 0% for ghrelin alone) and carboxylesterase (81.6% vs 17.2% for ghrelin alone). Ghrelin presented both electrostatic and hydrophobic interactions with the anionic lipid bilayer, as demonstrated by isothermal titration calorimetry. Then, anionic liposomes were coated with N-(2-hydroxy)propyl-3-trimethyl ammonium chitosan chloride. The coating involved a size increment from 146.9±2.7 to 194±6.1 nm, for uncoated and coated liposomes, respectively. The ζ-potential was similarly increased from -0.3±1.2 mV to 6±0.4 mV before and after coating, respectively. Chitosan provided mucoadhesion, with an increase in mucin adsorption of 22.9%. Enhancement of permeation through the Calu3 epithelial monolayer was also observed with 10.8% of ghrelin recovered in the basal compartment in comparison to 0% for ghrelin alone. Finally, aerosols generated from two nasal devices (VP3 and SP270) intended for aqueous dispersion were characterized with either coated or uncoated liposomes. Contrarily to the SP270 device, VP3 device showed minor changes between coated and uncoated liposome aerosols, as shown by their median volume diameters of 38.4±5.76 and 37.6±5.74 µm, respectively. Overall, the results obtained in this study show that the developed formulation delivered by the VP3 device can be considered as a potential candidate for nose-brain delivery of ghrelin.

Triple-stimuli responsive polymers with fine tuneable magnetic responses

The formation of multi-stimuli responsive polymers exhibiting magnetic, pH and light sensitivity is reported. After quaternization of tertiary amines along poly(2-(N,N-dimethylamino) ethyl methacrylate) (PDMAEMA) with varied alkyl and benzyl halides, a series of tetrahalogenoferrate(iii) salts were obtained by anion metathesis, conferring tailored and high magnetic responses. Experimental and theoretical Raman analyses allowed one to distinguish between the different magnetic anions present in the materials. This strategy was then implemented to the formation of multi-responsive compounds, by using random copolymers that incorporate various amounts of DMAEMA (∼40, 65 and 80%) and diazobenzene units. Partial or total quaternization of the dimethylamino end groups (10, 50 and 100%) followed by magnetic anion exchange afforded the magnetic-responsive copolymers, as evidenced by their magnetic susceptibility. Free ternary amino groups and diazobenzene moieties further brought pH and light sensitivity, giving rise to triple-stimuli responsive materials. This simple and rapid procedure offers the opportunity to fine tune the magnetic properties of remotely controlled smart devices.

Controlled Functionalization of Gold Nanoparticles with Mixtures of Calix[4]arenes Revealed by Infrared Spectroscopy

Labile ligands such as thiols and carboxylates are commonly used to functionalize AuNPs, though little control over the composition is possible when mixtures of ligands are used. It was shown recently that robustly functionalized AuNPs can be obtained through the reductive grafting of calix[4]arenes bearing diazonium groups on the large rim. Here, we report a calix[4]arene-tetradiazonium decorated by four oligo(ethylene glycol) chains on the small rim, which upon grafting gave AuNPs with excellent stability thanks to the C-Au bonds. Mixtures of this calixarene and one with four carboxylate groups were grafted on AuNPs. The resulting particles were analyzed by infrared spectroscopy, which revealed that the composition of the ligand shell clearly reflected the ratio of calixarenes that was present in solution. This strategy opens the way to robustly protected AuNPs with well-defined numbers of functional or postfunctionalizable groups.

2016

Development and evaluation of insulin-loaded cationic solid lipid nanoparticles for oral delivery

Cationic solid lipid nanoparticles (cSLN) loaded with insulin for oral delivery were prepared by the so-called water-in-oil-in-water double emulsion technique. The lipid matrix was composed of glyceryl palmitostearate and 1,2-dioleoyl-3-trimethylammonium-propane as a cationic lipid. Depending on the formulation, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] was incorporated to decrease the adsorption of insulin onto the surface of the nanoparticles. This aimed to achieve a positive zeta potential to obtain bioadhesion properties. The cSLN were characterized by a Z-average lower than 300 nm and by a zeta potential higher than 33 mV. The loading efficiency was ranged between 30% and 42%. It was shown that all the nanoparticles developed were able to fix solubilized mucin, which was used to evaluate bioadhesion properties. The cSLN also allowed the encapsulated insulin to be protected from the enzymatic activity of both pepsin and trypsin. The dissolution profiles of the insulin from the cSLN were characterized by a biphasic release. There was an initial burst release in the first 30 min, followed by a sustained release of the peptide. Moreover, compared to free insulin in solution, the cSLN developed significantly increased the passage of the encapsulated insulin through a monolayer of co-cultured Caco-2/HT29 cells. This went from 1.16 ± 0.27% to 2.89 ± 0.39% after 4 h, for the free insulin and the cSLN respectively.

3D printing in pharmaceutics: A new tool for designing customized drug delivery systems

Three-dimensional printing includes a wide variety of manufacturing techniques, which are all based on digitally-controlled depositing of materials (layer-by-layer) to create freeform geometries. Therefore, three-dimensional printing processes are commonly associated with freeform fabrication techniques. For years, these methods were extensively used in the field of biomanufacturing (especially for bone and tissue engineering) to produce sophisticated and tailor-made scaffolds from patient scans. This paper aims to review the processes that can be used in pharmaceutics, including the parameters to be controlled. In practice, it not straightforward for a formulator to be aware of the various technical advances made in this field, which is gaining more and more interest. Thus, a particular aim of this review is to give an overview on the pragmatic tools, which can be used for designing customized drug delivery systems using 3D printing.

2015

Amino Acid Induced Fractal Aggregation of Gold Nanoparticles: Why and How

Gold colloids are the object of many studies as they are reported to have potential biological sensing, imaging and drug de-livery applications. In the presence of certain amino acids the aggregation of the gold nanoparticles into linear structures is observed, as highlighted by the appearance of a second plasmon band in the UV-Vis spectra of the colloid. The mechanism behind this phenomenon is still under debate. In order to help elucidate this issue, the interaction between gold colloids and different amino acids, modified amino acids and molecules mimicking their side-chain was monitored by UV-Vis absorp-tion, DLS and TEM. The results show that phenomenon can be rationalized in terms of the Diffusion Limited Colloid Ag-gregation (DLCA) model which gives rise to the fractal aggregation colloids. The global charge of the compound, which in-fluences the ionic strength of the solution, and the ease with which the compound can interact with the GNPs and affect their surface potential, are, the two parameters which control the DLCA regime. Calculations based on the Derjaguin, Lan-dau, Verwey and Overbeek (DLVO) theory confirm all the experimental observations.

Development and evaluation in vitro and in vivo of injectable hydrolipidic gels with sustained-release properties for the management of articular pathologies such as osteoarthritis

Abstract This study aimed to evaluate glycerol monooleate (GMO) as a carrier to develop viscoelastic and injectable sustained-release drug delivery systems. The potential pro- and antioxidant activity of the developed hydrolipidic gels were evaluated by measuring the production of ROS by polymorphonuclear leukocytes (PMNs). In addition, the biocompatibility and effectiveness of two selected gel candidates were evaluated in vivo by evaluating the benefit of a single intraarticular injection of these new treatments in a model of osteoarthritis in rabbits. The in vitro study demonstrated that the carrier F1 did not have a pro-oxidative effect and even protected PMNs against natural auto-activation, regardless of the incorporation of either clonidine chlorhydrate or betamethasone dipropionate. The in vivo study demonstrated that F1 and F1-BDP induced a loss of cartilage quality in comparison to the control and reference groups but that the lesions of cartilage observed were generally mild, with not much full-depth erosion. Moreover, no exacerbating inflammation was observed when considering the synovial membranes and the PGE2 and CRP levels. These results seemed to demonstrate that the sustained-release formulation based on GMO could be well-tolerated after intraarticular injection. Moreover, it could have the potential to prevent inflammatory conditions while sustaining drug activity locally over weeks.

Development and evaluation of chitosan and chitosan derivative nanoparticles containing insulin for oral administration

Chitosan and chitosan derivative-based nanoparticles loaded with insulin were prepared by self-assembly, via electrostatic interactions between the negatively charged drug and the positively charged polymers. In the investigated chitosan derivatives, the amine groups were substituted to different extents (33, 52 or 99%) by 2-hydroxypropyl-3-trimethyl ammonium groups, rendering the polymers permanently positively charged, irrespective of the pH. This is an important property for this type of advanced drug delivery system, since the pH value changes throughout the gastrointestinal tract and electrostatic interactions are of crucial importance for the stability of the nanoparticles. Permanent positive charges are also in favor of mucoadhesion. In contrast, the electric charges of chitosan molecules depend on the pH of the surrounding medium. Since the solubility of the chitosan derivatives increased due to the introduction of quaternary ammonium groups, sodium tripolyphosphate (TPP) was added to the systems to create supplementary cross-links and stabilize the nanoparticles. The presence of TPP influenced both the dissolution of the polymer matrix as well as the resulting release kinetics. The underlying drug release mechanisms were found to be more complex than simple diffusion under constant conditions, likely involving also ionic interactions and matrix dissolution. The most promising formulation was based on a chitosan derivative with 33% substitution degree and characterized by a Z-average of 142 ± 10 nm, a zeta potential of 29 ± 1 mV, an encapsulation efficacy of 52 ± 3% and, most importantly, the release of insulin was sustained for more than 210 min.

2014

Ciprofloxacin monoolein water gels as implants for the treatment of chronic osteomyelitis: In vitro characterization

This work investigated the possibility of using the biodegradable gentamicin-monoolein-water gels as models, in order to obtain a similar sustained release of ciprofloxacin hydrochloride. Four gels containing antibiotics were prepared and were examined with regard to their physicochemical properties and in vitro drug release characteristics. Ciprofloxacin, unlike gentamicin, which was dissolved in the matrix, was in dispersed form. However, despite its insolubility, microscopic observation, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction showed that the developed gel was in the cubic liquid crystalline structure and have maintained their ability to progressively release ciprofloxacin. ciprofloxacin-monoolein-water (5:80:15% w/w), which released in vitro approximately 85% of ciprofloxacin after 16 days could possibly be considered as an alternative to a gentamicin-monoolein-water gel for the treatment of chronic osteomyelitis.

Stability study of full-length antibody (anti-TNF alpha) loaded PLGA microspheres

Antibodies (Abs) require the development of stable formulations and specific delivery strategies given their susceptibility to a variety of physical and chemical degradation pathways. In this study, the encapsulation of an antibody into polylactide-co-glycolide (PLGA) based microspheres was explored to obtain a controlled-release of the incorporated drug. In order to avoid stability issues, a solid-in-oil-in-water (s/o/w) method was preferred. The solid phase was made of anti-TNF alpha monoclonal antibody (MAb) spray-dried microparticles, and the PLGA microspheres were produced using two different polymers (i.e., Resomer® RG505 and Resomer® RG755S). The stability of the MAb incorporated into the microspheres was investigated under three conditions (5 ± 3 °C, 25 ± 2°C/60% RH and 40 ± 2°C/75% RH) for 12 weeks. During this stability study, it was demonstrated that the MAb loaded PLGA microspheres were stable when stored at 5 ± 3°C and that the Resomer® RG755S, composed of 75% (w/w) lactic acid as PLGA, was preferred to preserve the stability of the system. Storage at temperatures higher than 5°C led to antibody stability issues such as aggregation, fragmentation and loss of activity. The release profiles were also altered. Physical ageing of the system associated with changes in the glass transition temperature and enthalpy of relaxation was noticed during the storage of the MAb loaded PLGA microspheres. © 2014 Elsevier B.V.

2013

Encapsulation of immunoglobulin G by solid-in-oil-in-water: Effect of process parameters on microsphere properties.

Antibodies (Abs) are prone to a variety of physical and chemical degradation pathways, which require the development of stable formulations and specific delivery strategies. In this study, injectable biodegradable and biocompatible polymeric particles were employed for controlled-release dosage forms and the encapsulation of antibodies into polylactide-co-glycolide (PLGA) based microspheres was explored. In order to avoid stability issues which are commonly described when water-in-oil (w/o) emulsion is used, a solid-in-oil-in-water (s/o/w) method was developed and optimized. The solid phase was made of IgG microparticles and the s/o/w process was evaluated as an encapsulation method using a model Ab molecule (polyclonal bovine immunoglobulin G (IgG)). The methylene chloride (MC) commonly used for an encapsulation process was replaced by ethyl acetate (EtAc), which was considered as a more suitable organic solvent in terms of both environmental and human safety. The effects of several processes and formulation factors were evaluated on IgG:PLGA microsphere properties such as: particle size distribution, drug loading, IgG stability, and encapsulation efficiency (EE%). Several formulations and processing parameters were also statistically identified as critical to get reproducible process (e.g. the PLGA concentration, the volume of the external phase, the emulsification rate, and the quantity of IgG microparticles). The optimized encapsulation method has shown a drug loading of up to 6% (w/w) and an encapsulation efficiency of up to 60% (w/w) while preserving the integrity of the encapsulated antibody. The produced microspheres were characterized by a d(0.9) lower than 110μm and showed burst effect lower than 50% (w/w).

Characterization and optimization of GMO-based gels with long term release for intraarticular administration.

Osteoarthritis is characterized by slow degenerative processes in the articular cartilage within synovial joints. It could be interesting to develop a sustained-release formulation that could be effective on both pain/inflammation and restoration of mechanical integrity of the joint. Recently, an injectable system based on glycerol monooleate (GMO), containing clonidine as a model hydrophilic analgesic/anti-inflammatory drug and hyaluronic acid as a viscoelastic scaffold, showed promising potential as a biodegradable and biocompatible preparation to sustain the drug activity. However, drug release from the system is relatively fast (complete within 1 week) and the underlying drug release mechanisms not fully understood. The aims of this study were: (i) to significantly improve this type of local controlled drug delivery system by further sustaining clonidine release, and (ii) to elucidate the underlying mass transport mechanisms. The addition of FDA-approved inactive ingredients such as sodium oleate or purified soybean oil was found to be highly effective. The release rate could be substantially reduced (e.g., 50% release after 10 days), due to the increased hydrophobicity of the systems, resulting in slower and reduced water uptake and reduced drug mobility. Interestingly, Fick's second law of diffusion could be used to quantitatively describe drug release.

Evaluation of the degradation of clonidine-loaded PLGA microspheres

Synthesis and plasma pharmacokinetics in CD-1 mice of a 18β-glycyrrhetinic acid derivative displaying anti-cancer activity

Objectives The plasma pharmacokinetic profile in CD-1 mice of a novel 18β-glycyrrhetinic acid (GA) derivative, which displays in vitro anti-cancer activity, was assessed. Methods This study involved an original one-step synthesis of N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)- glycyrrhetinamide, (2) a compound that displays marked anti-proteasome and anti-kinase activity. The bioselectivity profile of 2 on human normal NHDF fibroblasts vs human U373 glioblastoma cells was assessed. Maximal tolerated dose (MTD) profiling of 2 was carried out in CD1 mice, and its serum pharmacokinetics were profiled using an acute intravenous administration of 40 mg/kg body weight. Key findings Compound 2 displayed IC50 in vitro growth inhibitory concentrations of 29 and 8 μm on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of ∼4. The intravenous pharmacokinetic parameters revealed that 2 was rapidly distributed (t1/2dist of ∼3 min) but slowly eliminated (t1/2elim = ∼77 min). Conclusions This study describes an original and reliable nanoemulsion of a GA derivative with both anti-proteasome and anti-kinase properties and that should be further tested in vivo using various human xenograft or murine syngeneic tumour models with both single and chronic intravenous administration. © 2012. Royal Pharmaceutical Society.

2012

New sustained-release intraarticular gel formulations based on monolein for local treatment of arthritic diseases.

Inflammatory osteoarthritis (OA) is characterized by painful and destructive inflammatory flares of a single joint, mainly in the back, the knees, the wrists or the hips. Monoarthritis is generally treated by intraarticular (IA) injections of corticosteroids or hyaluronic acid (HA). However, due to their toxicity, the chronic use of corticosteroids should be avoided. The aim of this work was to develop a new slow-release formulation for a parenteral route of administration (e.g., IA). The development's strategy was based on the use of amphiphilic ingredients such as glyceryl monooleate (GMO), which is able to generate viscous crystalline phase structures upon contact with an aqueous fluid (e.g., synovial fluid) to sustain the drug activity over weeks. Clonidine (CLO) was suggested as a small and hydrophilic model drug and HA as a hydrophilic viscoelastic scaffold. Thermal analyses showed that the stability of GMO, HA, and CLO in mixtures with a ratio of 1:1 (wt/wt) was not affected in comparison with the raw materials. In order to obtain a formulation presenting suitable syringeability and containing GMO, CLO, and HA, two elements were found to be essential: a minimum of about 15% (wt/wt) water content and the use of co-solvents such as ethanol (ET) and propylene glycol (PG), approved by the FDA for parenteral use. Several developed gels presented pseudoplastic flow behavior. Moreover, the best composition provided an in vitro release of CLO for about 1 week that was similar to a cubic reference formulation, described by many authors as presenting poor syringeability but the best sustained-release capacity.

In vitro and in vivo evaluation of a dry powder endotracheal insufflator device for use in dose-dependent preclinical studies in mice.

The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M®) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering. The emitted fraction varied in vivo compared to the in vitro condition. Fluorescent particle distribution in the lungs was uniform and reached the alveolar spaces, as visualized by fluorescent microscopy. In terms of drug recovery in lung tissue, a minimum administered powder mass (in this case ∼1mg) was necessary to recover at least 30% of the emitted dose in the lung and to obtain reproducible pulmonary concentrations. To reduce the dose administered in the lung, it was preferable to dilute the active ingredient within the carrier instead of reducing the dry powder mass inserted in the sampling chamber. Dry powder insufflators are devices usable in dose-dependent preclinical trials but have critical parameters to efficiently deliver reproducible doses depending on the type of formulation.

Development and evaluation of sustained-release clonidine-loaded PLGA microparticles.

This work describes the encapsulation of a small, hydrophilic molecule (clonidine) into a PLGA matrix to provide sustained release over more than one month after intra-articular administration. The microparticles were prepared using a double emulsion (w(1)/o/w(2)) method followed by evaporation of the organic solvent. To optimize the efficiency of encapsulation and the mean size of the microparticles, which was targeted around 30μm, the following parameters were modulated: the viscosity and the volume of the organic phase, the molecular weight of the polymer, the volume of the internal and external aqueous phases, the drug loading, the concentration of surfactant, and the stirring parameters. Blends of polymers characterized by different molecular weights (34000-96000Da) as well as copolymers of PLGA-PEG were used to enhance the entrapment of the drug. The pH of the aqueous phases was adjusted to obtain suitable encapsulation efficiency. Characterization was made of the physico-chemical properties of the microparticles, such as their crystallinity (DSC and PXRD) and microstructure (SEM). When performing in vitro dissolution studies, controlled release for up to approximately 30days was achieved with several of the formulations developed. Diffusion was found to be the dominant drug release mechanism at early time points.

2010

The effects of excipients on transporter mediated absorption.

Traditionally most pharmaceutical excipients used for peroral dosage forms have been considered to be inert, although they have been known to play an important role in governing the release of the active pharmaceutical ingredient (API) required for the desired therapeutic effect. Of considerable interest is the emerging data demonstrating that many of these "inert" excipients may produce subtle changes that could directly or indirectly alter the activity of membrane-spanning proteins such as transporters. In this way, excipients could be altering the overall ADMET properties of an incorporated drug thereby affecting its intended therapeutic efficacy and/or enhancing adverse side effects. Therefore, given this recent evidence, it seems necessary to review what has been reported in the literature on interactions of excipients with human physiological entities, particularly transporters. As of today, safety/toxicity evaluations are typically based on the appearance of gross morphological changes rather than the effects on a cellular level, the ability of excipients in modifying the pharmacological activity of an active drug could lead to toxicity evaluation in routine for each additive used in oral formulations. Further knowledge on this subject will enable formulators to make more rational decisions in dosage form design and will help answer the question of whether certain excipients should be considered active pharmaceutical components of formulations.

2009

Levodopa delivery systems for the treatment of Parkinson's disease: an overview.

This review describes the different drug delivery systems containing levodopa that are used in the treatment of Parkinson's disease. Their composition, process of preparation, advantages, disadvantages and limitations are discussed as well as the major objective in the management of Parkinson's disease according to the pathology of the disease.

2008

Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa.

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.

Evaluation and floating enhancement of levodopa sustained release floating minitablets coated with insoluble acrylic polymer

In vitro evaluation of two concepts of sustained release floating minitablets according to the model drug used

New levodopa sustained-release floating minitablets coated with insoluble acrylic polymer

The aim of this study was to develop a new coated multiple-unit sustained-release floating system that is able to float over an extended period of time. Levodopa was used as a model drug. The system consisted of a 3 mm drug-containing gas-generating core, prepared by melt granulation and subsequent compression, and coated with a flexible polymeric membrane. Eudragit® RL30D and ATEC were used as a film former and a plasticizer, respectively. The coating level was fixed at 20% (w/w). The floating lag time decreased as the proportion of effervescent agents increased. The optimized coated floating minitablets could float within 20 min and remained buoyant for more than 13 h. In addition, a sustained release of levodopa for more than 20 h was observed. © 2007 Elsevier B.V. All rights reserved.

Pharmacoscintigraphic and pharmacokinetic evaluation of tobramycin DPI formulations in cystic fibrosis patients

Tobramycin dry powder formulations were evaluated by gamma scintigraphy and pharmacokinetic methods. In an open single-dose, three-treatment, three-period, cross-over study, nine cystic fibrosis patients received both the two test products and the reference product Tobi® (nebulizer solution) in order to assess lung deposition and systemic comparative bioavailability of the two investigational inhaled products versus the marketed inhaled comparator product. The percentage of dose (mean ± SD) in the whole lung was 53.0 ± 10.0% for the tobramycin Form 1, 34.1 ± 12.4% for the tobramycin Form 2 and 7.6 ± 2.7% for the comparator product Tobi®. Lung deposition expressed as a percentage of the nominal dose was thus estimated to be 7.0 and 4.5 times higher for the Tobra Form 1 and Tobra Form 2 than for the Tobi®, respectively. Furthermore, the systemic bioavailability (adjusted to correspond to the same drug dose as that of the comparator product deposited in the lung) was found to be 1.6 times higher for the comparator product Tobi® than for the two DPI formulations. The principal advantages of the DPI formulations include reduced systemic availability and thus, side effects, and higher dose levels of the drug at the site of drug action. © 2007 Elsevier B.V. All rights reserved.

2007

Development and evaluation of new multiple-unit levodopa sustained-release floating dosage forms

This work relates to the development and the in vitro evaluation of sustained-release minitablets (MT), prepared by melt granulation and subsequent compression, which are designed to float over an extended period of time. Levodopa was used as a model drug. The importance of the composition and manufacturing parameters of the MT on their floating and dissolution properties was then examined. The investigation showed that MT composition and MT diameter had the greatest influence on drug release, which was sustained for more than 8 h. By using the same formulation, the best floating properties were obtained with 3 mm MT prepared at low compression forces ranging between 50 and 100 N. Their resultant-weight (RW) values were always higher than those obtained with a marketed HBS dosage form within 13 h. When they were filled into gelatin capsules, no sticking was observed. By evaluating the dissolution profiles of levodopa at different pH values, it was found that dissolution profiles depend more on the prolonged-release ability of Methocel® K15M than on the pH-dependent solubility of levodopa. Finally, the robustness of the floating MT was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests. © 2006 Elsevier B.V. All rights reserved.

2006

In vitro and in vivo evaluation of floating riboflavin pellets developed using the melt pelletization process

Floating pellets were prepared using the melt pelletization process in a Mi-Pro® high shear mixer (Pro-C-epT, Belgium). Formulations were based on a mixture of Compritol® and Precirol® as meltable binders and on the use of sodium bicarbonate and tartaric acid as gas-generating agents. Good floating abilities were obtained by using the gas-generating agents in both the inner matrix and the outer coating layer of the pellets. In vitro evaluation of floating capability was performed both by using the resultant weight apparatus and by counting floating pellets at the surface of beakers containing 0.1N HCl solution, in vivo evaluation of floating pellets capabilities was also performed. Riboflavin-containing floating pellets (FRF) were administered orally to nine healthy volunteers versus non-floating pellets (NFRF). Volunteers were divided in two groups, fasted group (n = 4) 729 kcal and fed group (n = 5) 1634 kcal as the total calorie intake on the testing day. An increase of urinary excretion of riboflavin was observed when the volunteers were dosed with the floating pellets, especially after feeding. As riboflavin has a narrow window of absorption in the upper part of small intestine, this phenomenon could be attributable to the gastric retention of floating pellets. © 2006 Elsevier B.V. All rights reserved.

In vitro and in vivo evaluation in healthy human volunteers of floating riboflavin minitablets