This study aimed to evaluate glycerol monooleate (GMO) as a carrier to develop viscoelastic and i... more 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 sustainedrelease 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.
Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung c... more Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung cancer therapy, dry powder for inhalation (DPI) offers many advantages compared to other techniques and seems to be a technique that is well-adapted to an anticancer treatment. DPI formulations were developed using the cytotoxic drug temozolomide and a new folate-grafted self-assembling copolymer, a conjugate of three components, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD). F-PEG-HMD was synthesized using carbodiimide-mediated coupling chemistry in three main steps. F-PEG-HMD was characterized by 1H-NMR, mass spectrometry and thermal analysis. F-PEG-HMD presented a critical micellar concentration in water of 4x10-7 M. F-PEG-HMD nanomicelles were characterized by a trimodal particle size distribution with Z-average diameter of 83±1 nm in water. Temozolomide-loaded nanomicelles were prepared by solubilization of F-PEG-HMD in the presence of temozolomide. Temozolomide solubility in water was increased in the presence of F-PEG-HMD (2-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The temozolomide-loaded F-PEG-HMD nanomicelles were characterized by a Z-average diameter of ~50 to ~60 nm, depending on the F-PEG-HMD concentration used. The nanomicelles were then spray-dried to produce dry powders. Temozolomide remained stable during all the formulation steps, confirmed by similar in vitro anticancer properties for the DPI formulations and a raw temozolomide solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD nanomicelles quickly in aqueous media. Moreover, in vitro, the two DPI formulations showed wide pulmonary deposition in the lower respiratory tract where adenocarcinomas are more often found. The present study, therefore, shows that F-PEG-HMD-based dry powders for inhalation could constitute an interesting drug delivery system able to release nanomicelles that are useful in adenocarcinomas that overexpress folate receptors.
Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of pa... more Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect
International Journal of Pharmaceutics, Jul 17, 2001
Poly-N-isopropylacrylamide (PNIPAAm) thermosensibility makes this polymer a very attractive candi... more Poly-N-isopropylacrylamide (PNIPAAm) thermosensibility makes this polymer a very attractive candidate for controlled drug delivery systems. The polymer possesses a lower critical solution temperature (LCST) which was found to be around 32°C in pure water, but which can be affected by the medium composition, i.e. presence of salts or surfactants. The knowledge of the effects of such substances on the LCST is very important while using PNIPAAm as a controlled drug delivery agent. The influence of a number of physiological and non-physiological salts and surfactants has been studied. The results obtained show that the addition of salts provokes an important decrease of the LCST of the polymer (salting out effect). A strong influence of the valence and of the size of the anions of the halide group was found. As to the surfactants, according to their type and concentration, a decrease or an increase of the LCST or even no effect at all were found. The effect of the GI secretions on the PNIPAAm phase separation temperature is also discussed.
European Journal of Lipid Science and Technology, 2014
Pulmonary delivery is becoming the standard route of administration for treating respiratory diso... more Pulmonary delivery is becoming the standard route of administration for treating respiratory disorders such as asthma and chronic obstructive pulmonary disease. It is also gaining interest for non-invasive systemic delivery of peptides and proteins. A limited number of excipients is approved or authorized for the pulmonary tract. This restricts the commercial potential of some formulations. Phospholipids and more particularly 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) are the main components of lung surfactant and are recognized as generally recognized as safe (GRAS) excipients for pulmonary drug delivery by the Food and Drug Administration. Moreover, phospholipids could modulate the physicochemical properties of drug delivery systems and therefore the drug release and/or dissolution. They can potentially modulate the drug pharmacokinetic by enhancing the drug permeability through the lung epithelium using palmitoyl-based phospholipids, and/or by reducing recognition of the drug delivery systems by the alveolar macrophages by including DPPC or polyethyleneglycol (PEG) at their surface. Therefore, this review focuses on the formulations containing phospholipids or PEGylated phospholipids, such as micelles, liposomes, lipid micro-/nanoparticles, large porous particles, solid dispersions, and microparticle suspensions.
In the course of the development of a new drug delivery concept, four thermosensitive copolymers ... more In the course of the development of a new drug delivery concept, four thermosensitive copolymers of poly(N-isopropylacrylamide) (PNIPAAm), with phase transition temperature slightly higher than 37 • C, were synthesised and used as time-controlled drug delivery agents.
The aim of this study was to evaluate the possible penetration through human skin of organic and ... more The aim of this study was to evaluate the possible penetration through human skin of organic and inorganic filters contained in sunscreen emulsions packaged in aerosol cans, using an in vitro method. Experiments were carried out on two different types of emulsion: W/Si and W/O. This study was conducted using static diffusion cells (Franz cells). The determination of organic UV filters [Methylene Bis Benzotriazolyl Tetramethylbutylphenol (MBBT); Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (BEMT); Diethylamino Hydroxybenzoyl Hexyl Benzoate (DHHB); Ethylhexyl Methoxycinnamate (EMC); and 2-Ethylhexyl Dimethyl PABA (ED-PABA)] was performed by High Performance Liquid Chromatography (HPLC). Therefore, it was important to develop a single analytical method for the quantification of the five organic filters with the aim of facilitating the experiment. The determination of inorganic filters [titanium dioxide (TiO(2)) and zinc oxide (ZnO)] was performed using an emission spectrometric analysis method (ICP-OES). The HPLC and ICP-OES methods were validated. After a penetration test of 24 h duration, the results showed very low penetration only for two of the organic filters (maximum penetration of 1.21 microg cm(-2) h(-1) for EMC and 0.14 microg cm(-2) h(-1) for MBBT) and no penetration for the inorganic filters. Moreover, more than 50% of each sunscreen agent stayed on the surface on the skin. These results are consistent with those in the literature that presents similar experiments. This study showed that the sprayable sunscreen products developed, which contained high concentrations of UV filters, presented a low level of skin penetration.
The feasibility of preparing floating pellets by melt pelletization was investigated. The pellets... more The feasibility of preparing floating pellets by melt pelletization was investigated. The pellets were prepared in a high shear mixer. Formulations were based on a mixture of Compritol ® and Precirol ® as lipidic binders and on sodium bicarbonate as a gas-generating agent. The floating ability of the pellets was evaluated in vitro. Good floating capabilities were obtained for formulations containing the gas-generating agent in both the inner matrix and the outer coating layer of the pellets. As an example, a placebo formulation containing 50% lactose 450 Me, 22% Compritol ® , 15% Precirol ® , 8% sodium bicarbonate and 5% Methocel ® K100 (w/w) in the inner matrix, and 66% Precirol ® and 34% sodium bicarbonate (w/w) as a coating effervescent layer, showed very good floating capabilities. The percentage of floating placebo pellets was around 80% after 1 h and still above 75% for 23 h. Floating pellet formulations with high drug content, based on the use of tetracycline hydrochloride and theophylline were also evaluated. They showed a comparable floating ability to placebo formulations, combined with sustained release properties thanks to the lipophilic character of the binders used.
Pulmonary administration of drugs presents several advantages in the treatment of many diseases. ... more Pulmonary administration of drugs presents several advantages in the treatment of many diseases. Considering local and systemic delivery, drug inhalation enables a rapid and predictable onset of action and induces fewer side effects than other routes of administration. Three main inhalation systems have been developed for the aerosolization of drugs; namely, nebulizers, pressurized metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). The latter are currently the most convenient alternative as they are breath-actuated and do not require the use of any propellants. The deposition site in the respiratory tract and the efficiency of inhaled aerosols are critically influenced by the aerodynamic diameter, size distribution, shape and density of particles. In the case of DPIs, since micronized particles are generally very cohesive and exhibit poor flow properties, drug particles are usually blended with coarse and fine carrier particles. This increases particle aerodynamic behavior and flow properties of the drugs and ensures accurate dosage of active ingredients. At present, particles with controlled properties are obtained by milling, spray drying or supercritical fluid techniques. Several excipients such as sugars, lipids, amino acids, surfactants, polymers and absorption enhancers have been tested for their efficacy in improving drug pulmonary administration. The purpose of this article is to describe various observations that have been made in the field of inhalation product development, especially for the dry powder inhalation formulation, and to review the use of various additives, their effectiveness and their potential toxicity for pulmonary administration.
International Journal of Pharmaceutics, Jul 8, 2002
The purpose of this work is to develop a new delivery concept making a thermosensitive polymer ba... more The purpose of this work is to develop a new delivery concept making a thermosensitive polymer based on poly(N-isopropylacrylamide) (PNIPAAm) useful as a time-controlled drug release device, without any temperature changes of the dissolution medium. It was previously found that some salts induce a decrease of the polymer lower critical solution temperature (LCST). Use is here made of that property to show that salt concentration variations can be used as a substitute for temperature changes to make the polymer coating of compression-coated tablets soluble or insoluble, consequently creating a possible new concept of drug delivery control from delivery systems containing thermoresponsive polymers. The obtained results show the influence of the type and amount of salts incorporated into compression-coated tablets on the release lag time of a model drug.
European Journal of Pharmaceutics and Biopharmaceutics, 2006
The present study relates to compositions of solid lipidic microparticles (SLmP), composed of bio... more The present study relates to compositions of solid lipidic microparticles (SLmP), composed of biocompatible phospholipids and cholesterol, and their use as carriers or as fillers delivering drugs directly to the lungs via a dry powder inhaler (DPI). SLmP were obtained by spray-drying and were formulated as lipidic matrices entrapping budesonide or as physical blends (drug carrier). They were developed in
The purpose of the study was to examine the suitability of the Spraytec ® laser diffraction techn... more The purpose of the study was to examine the suitability of the Spraytec ® laser diffraction technique for measuring the size distribution of aerosol particles generated from dry powder inhalators. A range of formulations with different dispersion properties were produced by spray-drying. The percentage of particles below 5.0 m of these formulations was measured by laser diffraction (Mastersizer ® 2000 and Spraytec ® ) and inertial impaction (MsLI and NGI) using various inhaler devices and at different flow rates between 30 and 100 l/min. Linear relationships and correlations (R 2 > 0.9) existed between the results obtained from, on one hand, the Mastersizer ® 2000 and the Spraytec ® , and, on the other hand, the MsLI and the Spraytec ® regardless of flow rates and inhaler devices. The Spraytec ® could be a reliable technique for the development, evaluation and quality control of dry powder aerosol formulations.
The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble ac... more The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, d-␣tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f 2 < 50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 ± 3 ng/ml to 46 ± 2 ng/ml). However, the fine particle fraction dropped from 47 ± 2% to 37.2 ± 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ.
This work relates to the development and the in vitro evaluation of sustained-release minitablets... more 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.
Invasive pulmonary aspergillosis (IPA) presents high incidence and high mortality in immunocompro... more Invasive pulmonary aspergillosis (IPA) presents high incidence and high mortality in immunocompromised patients. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole are becoming the first-or second-line therapy, respectively.
Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytost... more Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytostatic and/or cytotoxic effects in six human and mouse cancer cell lines. The in vitro growth inhibitory effects of these bastadins were similar in cancer cell lines sensitive to pro-apoptotic stimuli versus cancer cell lines displaying various levels of resistance to pro-apoptotic stimuli. While about ten times less toxic than the natural cyclic bastadins, the synthetically derived 5,5'-dibromohemibastadin-1 (DBHB) displayed not only in vitro growth inhibitory activity in cancer cells but also anti-angiogenic properties. At a concentration of one tenth of its in vitro growth inhibitory concentration, DBHB displayed actual antimigratory effects in mouse B16F10 melanoma cells without any sign of cytotoxicity and/or growth inhibition. The serum concentration used in the cell culture media markedly influenced the DBHB-induced antimigratory effects in the B16F10 melanoma cell population. W...
This study aimed to evaluate glycerol monooleate (GMO) as a carrier to develop viscoelastic and i... more 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 sustainedrelease 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.
Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung c... more Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung cancer therapy, dry powder for inhalation (DPI) offers many advantages compared to other techniques and seems to be a technique that is well-adapted to an anticancer treatment. DPI formulations were developed using the cytotoxic drug temozolomide and a new folate-grafted self-assembling copolymer, a conjugate of three components, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD). F-PEG-HMD was synthesized using carbodiimide-mediated coupling chemistry in three main steps. F-PEG-HMD was characterized by 1H-NMR, mass spectrometry and thermal analysis. F-PEG-HMD presented a critical micellar concentration in water of 4x10-7 M. F-PEG-HMD nanomicelles were characterized by a trimodal particle size distribution with Z-average diameter of 83±1 nm in water. Temozolomide-loaded nanomicelles were prepared by solubilization of F-PEG-HMD in the presence of temozolomide. Temozolomide solubility in water was increased in the presence of F-PEG-HMD (2-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The temozolomide-loaded F-PEG-HMD nanomicelles were characterized by a Z-average diameter of ~50 to ~60 nm, depending on the F-PEG-HMD concentration used. The nanomicelles were then spray-dried to produce dry powders. Temozolomide remained stable during all the formulation steps, confirmed by similar in vitro anticancer properties for the DPI formulations and a raw temozolomide solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD nanomicelles quickly in aqueous media. Moreover, in vitro, the two DPI formulations showed wide pulmonary deposition in the lower respiratory tract where adenocarcinomas are more often found. The present study, therefore, shows that F-PEG-HMD-based dry powders for inhalation could constitute an interesting drug delivery system able to release nanomicelles that are useful in adenocarcinomas that overexpress folate receptors.
Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of pa... more Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect
International Journal of Pharmaceutics, Jul 17, 2001
Poly-N-isopropylacrylamide (PNIPAAm) thermosensibility makes this polymer a very attractive candi... more Poly-N-isopropylacrylamide (PNIPAAm) thermosensibility makes this polymer a very attractive candidate for controlled drug delivery systems. The polymer possesses a lower critical solution temperature (LCST) which was found to be around 32°C in pure water, but which can be affected by the medium composition, i.e. presence of salts or surfactants. The knowledge of the effects of such substances on the LCST is very important while using PNIPAAm as a controlled drug delivery agent. The influence of a number of physiological and non-physiological salts and surfactants has been studied. The results obtained show that the addition of salts provokes an important decrease of the LCST of the polymer (salting out effect). A strong influence of the valence and of the size of the anions of the halide group was found. As to the surfactants, according to their type and concentration, a decrease or an increase of the LCST or even no effect at all were found. The effect of the GI secretions on the PNIPAAm phase separation temperature is also discussed.
European Journal of Lipid Science and Technology, 2014
Pulmonary delivery is becoming the standard route of administration for treating respiratory diso... more Pulmonary delivery is becoming the standard route of administration for treating respiratory disorders such as asthma and chronic obstructive pulmonary disease. It is also gaining interest for non-invasive systemic delivery of peptides and proteins. A limited number of excipients is approved or authorized for the pulmonary tract. This restricts the commercial potential of some formulations. Phospholipids and more particularly 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) are the main components of lung surfactant and are recognized as generally recognized as safe (GRAS) excipients for pulmonary drug delivery by the Food and Drug Administration. Moreover, phospholipids could modulate the physicochemical properties of drug delivery systems and therefore the drug release and/or dissolution. They can potentially modulate the drug pharmacokinetic by enhancing the drug permeability through the lung epithelium using palmitoyl-based phospholipids, and/or by reducing recognition of the drug delivery systems by the alveolar macrophages by including DPPC or polyethyleneglycol (PEG) at their surface. Therefore, this review focuses on the formulations containing phospholipids or PEGylated phospholipids, such as micelles, liposomes, lipid micro-/nanoparticles, large porous particles, solid dispersions, and microparticle suspensions.
In the course of the development of a new drug delivery concept, four thermosensitive copolymers ... more In the course of the development of a new drug delivery concept, four thermosensitive copolymers of poly(N-isopropylacrylamide) (PNIPAAm), with phase transition temperature slightly higher than 37 • C, were synthesised and used as time-controlled drug delivery agents.
The aim of this study was to evaluate the possible penetration through human skin of organic and ... more The aim of this study was to evaluate the possible penetration through human skin of organic and inorganic filters contained in sunscreen emulsions packaged in aerosol cans, using an in vitro method. Experiments were carried out on two different types of emulsion: W/Si and W/O. This study was conducted using static diffusion cells (Franz cells). The determination of organic UV filters [Methylene Bis Benzotriazolyl Tetramethylbutylphenol (MBBT); Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine (BEMT); Diethylamino Hydroxybenzoyl Hexyl Benzoate (DHHB); Ethylhexyl Methoxycinnamate (EMC); and 2-Ethylhexyl Dimethyl PABA (ED-PABA)] was performed by High Performance Liquid Chromatography (HPLC). Therefore, it was important to develop a single analytical method for the quantification of the five organic filters with the aim of facilitating the experiment. The determination of inorganic filters [titanium dioxide (TiO(2)) and zinc oxide (ZnO)] was performed using an emission spectrometric analysis method (ICP-OES). The HPLC and ICP-OES methods were validated. After a penetration test of 24 h duration, the results showed very low penetration only for two of the organic filters (maximum penetration of 1.21 microg cm(-2) h(-1) for EMC and 0.14 microg cm(-2) h(-1) for MBBT) and no penetration for the inorganic filters. Moreover, more than 50% of each sunscreen agent stayed on the surface on the skin. These results are consistent with those in the literature that presents similar experiments. This study showed that the sprayable sunscreen products developed, which contained high concentrations of UV filters, presented a low level of skin penetration.
The feasibility of preparing floating pellets by melt pelletization was investigated. The pellets... more The feasibility of preparing floating pellets by melt pelletization was investigated. The pellets were prepared in a high shear mixer. Formulations were based on a mixture of Compritol ® and Precirol ® as lipidic binders and on sodium bicarbonate as a gas-generating agent. The floating ability of the pellets was evaluated in vitro. Good floating capabilities were obtained for formulations containing the gas-generating agent in both the inner matrix and the outer coating layer of the pellets. As an example, a placebo formulation containing 50% lactose 450 Me, 22% Compritol ® , 15% Precirol ® , 8% sodium bicarbonate and 5% Methocel ® K100 (w/w) in the inner matrix, and 66% Precirol ® and 34% sodium bicarbonate (w/w) as a coating effervescent layer, showed very good floating capabilities. The percentage of floating placebo pellets was around 80% after 1 h and still above 75% for 23 h. Floating pellet formulations with high drug content, based on the use of tetracycline hydrochloride and theophylline were also evaluated. They showed a comparable floating ability to placebo formulations, combined with sustained release properties thanks to the lipophilic character of the binders used.
Pulmonary administration of drugs presents several advantages in the treatment of many diseases. ... more Pulmonary administration of drugs presents several advantages in the treatment of many diseases. Considering local and systemic delivery, drug inhalation enables a rapid and predictable onset of action and induces fewer side effects than other routes of administration. Three main inhalation systems have been developed for the aerosolization of drugs; namely, nebulizers, pressurized metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). The latter are currently the most convenient alternative as they are breath-actuated and do not require the use of any propellants. The deposition site in the respiratory tract and the efficiency of inhaled aerosols are critically influenced by the aerodynamic diameter, size distribution, shape and density of particles. In the case of DPIs, since micronized particles are generally very cohesive and exhibit poor flow properties, drug particles are usually blended with coarse and fine carrier particles. This increases particle aerodynamic behavior and flow properties of the drugs and ensures accurate dosage of active ingredients. At present, particles with controlled properties are obtained by milling, spray drying or supercritical fluid techniques. Several excipients such as sugars, lipids, amino acids, surfactants, polymers and absorption enhancers have been tested for their efficacy in improving drug pulmonary administration. The purpose of this article is to describe various observations that have been made in the field of inhalation product development, especially for the dry powder inhalation formulation, and to review the use of various additives, their effectiveness and their potential toxicity for pulmonary administration.
International Journal of Pharmaceutics, Jul 8, 2002
The purpose of this work is to develop a new delivery concept making a thermosensitive polymer ba... more The purpose of this work is to develop a new delivery concept making a thermosensitive polymer based on poly(N-isopropylacrylamide) (PNIPAAm) useful as a time-controlled drug release device, without any temperature changes of the dissolution medium. It was previously found that some salts induce a decrease of the polymer lower critical solution temperature (LCST). Use is here made of that property to show that salt concentration variations can be used as a substitute for temperature changes to make the polymer coating of compression-coated tablets soluble or insoluble, consequently creating a possible new concept of drug delivery control from delivery systems containing thermoresponsive polymers. The obtained results show the influence of the type and amount of salts incorporated into compression-coated tablets on the release lag time of a model drug.
European Journal of Pharmaceutics and Biopharmaceutics, 2006
The present study relates to compositions of solid lipidic microparticles (SLmP), composed of bio... more The present study relates to compositions of solid lipidic microparticles (SLmP), composed of biocompatible phospholipids and cholesterol, and their use as carriers or as fillers delivering drugs directly to the lungs via a dry powder inhaler (DPI). SLmP were obtained by spray-drying and were formulated as lipidic matrices entrapping budesonide or as physical blends (drug carrier). They were developed in
The purpose of the study was to examine the suitability of the Spraytec ® laser diffraction techn... more The purpose of the study was to examine the suitability of the Spraytec ® laser diffraction technique for measuring the size distribution of aerosol particles generated from dry powder inhalators. A range of formulations with different dispersion properties were produced by spray-drying. The percentage of particles below 5.0 m of these formulations was measured by laser diffraction (Mastersizer ® 2000 and Spraytec ® ) and inertial impaction (MsLI and NGI) using various inhaler devices and at different flow rates between 30 and 100 l/min. Linear relationships and correlations (R 2 > 0.9) existed between the results obtained from, on one hand, the Mastersizer ® 2000 and the Spraytec ® , and, on the other hand, the MsLI and the Spraytec ® regardless of flow rates and inhaler devices. The Spraytec ® could be a reliable technique for the development, evaluation and quality control of dry powder aerosol formulations.
The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble ac... more The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, d-␣tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f 2 < 50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 ± 3 ng/ml to 46 ± 2 ng/ml). However, the fine particle fraction dropped from 47 ± 2% to 37.2 ± 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ.
This work relates to the development and the in vitro evaluation of sustained-release minitablets... more 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.
Invasive pulmonary aspergillosis (IPA) presents high incidence and high mortality in immunocompro... more Invasive pulmonary aspergillosis (IPA) presents high incidence and high mortality in immunocompromised patients. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole are becoming the first-or second-line therapy, respectively.
Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytost... more Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytostatic and/or cytotoxic effects in six human and mouse cancer cell lines. The in vitro growth inhibitory effects of these bastadins were similar in cancer cell lines sensitive to pro-apoptotic stimuli versus cancer cell lines displaying various levels of resistance to pro-apoptotic stimuli. While about ten times less toxic than the natural cyclic bastadins, the synthetically derived 5,5'-dibromohemibastadin-1 (DBHB) displayed not only in vitro growth inhibitory activity in cancer cells but also anti-angiogenic properties. At a concentration of one tenth of its in vitro growth inhibitory concentration, DBHB displayed actual antimigratory effects in mouse B16F10 melanoma cells without any sign of cytotoxicity and/or growth inhibition. The serum concentration used in the cell culture media markedly influenced the DBHB-induced antimigratory effects in the B16F10 melanoma cell population. W...
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Papers by Karim Amighi