Development and evaluation of a 3D printing protocol to produce zolpidem-containing printlets, as compounding preparation, by the pressurized-assisted microsyringes technique.

Insomnia is a chronic disorder with a mean prevalence ranged from 6% to 15% worldwide. The usual pharmacologic treatment for insomnia has been benzodiazepines and barbiturates. More recently, z-drugs were introduced in the therapeutic arsenal to maximize benefits and minimize treatment damage. Zolpidem tartrate, whose primary indication is for sleep initiation problems, is conventionally used at a recommended dose of 5 mg for women as well as elderly patients (<65 years-old) and 10 mg for non-elderly men. However, it was demonstrated that the dose of zolpidem should be adjusted according to the gender, age, condition of the patient and the presence of polypharmacy to decrease the occurrence of adverse events. Faced with the therapeutic limitations inherent to marketed products, magistral preparations offer medical and legal alternatives to mass treatment. The use of a semi-automatic technique, with standardized protocol, such as 3D printing should be advantageously implemented as an alternative to standard compounding procedures. In this work, the pressure-assisted microsyringes method was selected as it allows the tridimensional printing, and so the customization of the dose, by easily extruding a viscous semi-liquid material, called "slurry", through a syringe at room temperature. It has been demonstrated that this methodology allows obtaining printlets that responded to the zolpidem-containing tablets monograph of the US pharmacopoeia Edition 42. The compounding preparations proposed in this work therefore have the same criteria of requirements as a commercial form.

Hospital preparations of ethanol-free furosemide oral solutions: Formulation and stability study.

Furosemide is a diuretic frequently used in the therapeutic management of edema associated with cardiac, renal, and hepatic failure and hypertension. However, there are a very low number of pharmaceutical dosage forms containing furosemide that are suitable for children under 6- years old. Therefore, there is a real need to develop hospital preparations, especially in the hospital. Four oral pediatric solutions of furosemide (2 mg/Ml) were formulated. Two of those solutions did not contain ethanol. For each formulation, 12 batches of 1600.0 Ml were prepared and packaged in 250.0 Ml brown glass bottles with polypropylene screw caps. The physicochemical properties (visual appearance, pH, osmolarity, drug content) and microbiological quality of the finished product were determined on the freshly prepared solutions and after 90 days of storage at 30°C/65% RH. The physicochemical and microbiological characteristics of the freshly prepared solutions were within the prescribed specifications. After 90 days of storage at 30°C/65% RH, the solutions containing sucrose and those without ethanol showed a slight decrease in pH and furosemide content of about 2.5%-4.5% (w/w). Despite this slight decrease, the characteristics remained within the prescribed specifications. Based on the stability profile of the ethanol-free solution containing sorbitol, it could be implemented in hospitals for the care of pediatric patients.

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.

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 ±â€¯4% vs 61 ±â€¯4%), higher ghrelin entrapment efficiency (64 ±â€¯2% vs 55 ±â€¯4%), higher enzymatic protection against trypsin (26 ±â€¯2% vs 20 ±â€¯3%) and lower ghrelin storage degradation at 25 °C (2.67 ±â€¯1.1% vs 95.64 ±â€¯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 ±â€¯6 µm, a limited percentage of particles smaller than 10 µm of 4 ±â€¯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.

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.

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 110 µm and showed burst effect lower than 50% (w/w).

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

OBJECTIVES: The plasma pharmacokinetic profile in CD-1 mice of a novel 18ß-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 IC(50) 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 (t(1/2dist) of ∼3 min) but slowly eliminated (t(1/2elim) = ∼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.

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.