The air conditioning in the nose of mammals depends on their mass and on their maximal running speed.

The nose of the mammals is responsible for filtering, humidifying, and heating the air before entering the lower respiratory tract. This conditioning avoids, notably, dehydration of the bronchial and alveolar mucosa. However, since this conditioning is not perfect, exercising in cold air can induce lung inflammation, both for human and non-human mammals. This work aims to compare the air conditioning in the noses of various mammals during inspiration. We build our study on computational fluid dynamics simulations of the heat exchanges in the lumen of the upper respiratory tract of these mammals. These simulations show that the efficiency of the air conditioning in the nose during inspiration does not relate only to the mass m of the mammal but also to its maximal running speed v. More precisely, the results allow establishing a scaling law relating the efficiency of air conditioning in the nose of mammals to the ratio v / log 10 ( m ) . The simulations also correlate the resistance to the flow in the nose to the efficiency of this air conditioning. The obtained scaling law allows predicting the air temperature at the top of the trachea during inspiration for nasal-breathing mammals, and thus notably for humans of various ages.

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.

Phage therapy is recognized to be a promising alternative to fight antibiotic-resistant infections. In the quest for oral dosage forms containing bacteriophages, the utilization of colonic-release Eudragit® derivatives has shown potential in shielding bacteriophages from the challenges encountered within the gastrointestinal tract, such as fluctuating pH levels and the presence of digestive enzymes. Consequently, this study aimed to develop targeted oral delivery systems for bacteriophages, specifically focusing on colon delivery and employing Eudragit® FS30D as the excipient. The bacteriophage model used was LUZ19. An optimized formulation was established to not only preserve the activity of LUZ19 during the manufacturing process but also ensure its protection from highly acidic conditions. Flowability assessments were conducted for both capsule filling and tableting processes. Furthermore, the viability of the bacteriophages remained unaffected by the tableting process. Additionally, the release of LUZ19 from the developed system was evaluated using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) model. Finally, stability studies demonstrated that the powder remained stable for at least 6 months when stored at +5 °C.

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

Introduction: This work aimed to develop chitosan-coated cubosomal nanoparticles intended for nose-to-brain delivery of paliperidone palmitate. They were compared with standard and cationic cubosomal nanoparticles. This comparison relies on numerous classical in vitro tests and powder deposition within a 3D-printed nasal cast. Methods: Cubosomal nanoparticles were prepared by a Bottom-up method followed by a spray drying process. We evaluated their particle size, polydispersity index, zeta-potential, encapsulation efficiency, drug loading, mucoaffinity properties and morphology. The RPMI 2650 cell line was used to assess the cytotoxicity and cellular permeation. An in vitro deposition test within a nasal cast completed these measurements. Results: The selected chitosan-coated cubosomal nanoparticles loaded with paliperidone palmitate had a size of 305.7 ± 22.54 nm, their polydispersity index was 0.166 ± 0.022 and their zeta potential was +42.4 ± 0.2 mV. This formulation had a drug loading of 70% and an encapsulation efficiency of 99.7 ± 0.1%. Its affinity with mucins was characterized by a ΔZP of 20.93 ± 0.31. Its apparent permeability coefficient thought the RPMI 2650 cell line was 3.00E-05 ± 0.24E-05 cm/s. After instillation in a 3D-printed nasal cast, the fraction of the injected powder deposited in the olfactory region reached 51.47 ± 9.30% in the right nostril and 41.20 ± 4.59% in the left nostril, respectively. Conclusion: The chitosan coated cubosomal formulation seems to be the most promising formulation for nose-to-brain delivery. Indeed, it has a high mucoaffinity and a significantly higher apparent permeability coefficient than the two other formulations. Finally, it reaches well the olfactory region.

Validation and Sensitivity analysis for a nasal spray deposition computational model.

Validating numerical models against experimental models of nasal spray deposition is challenging since many aspects must be considered. That being said, it is a critical step in the product development process of nasal spray devices. This work presents the validation process of a nasal deposition model, which demonstrates a high degree of consistency of the numerical model with experimental data when the nasal cavity is segmented into two regions but not into three. Furthermore, by modelling the flow as stationary, the computational cost is drastically reduced while maintaining quality of particle deposition results. Thanks to this reduction, a sensitivity analysis of the numerical model could be performed, consisting of 96 simulations. The objective was to quantify the impact of four inputs: the spray half cone angle, mean spray exit velocity, breakup length from the nozzle exit and the diameter of the nozzle spray device, on the three quantities of interest: the percentage of the accumulated number of particles deposited on the anterior, middle and posterior sections of the nasal cavity. The results of the sensitivity analysis demonstrated that the deposition on anterior and middle sections are sensitive to injection angle and breakup length, and the deposition on posterior section is only, but highly, sensitive to the injection velocity.

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.

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 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.

Proof of concept of a predictive model of drug release from long-acting implants obtained by fused-deposition modeling.

In the pharmaceutical field, there is a growing interest in manufacturing of drug delivery dosage forms adapted to the needs of a large variety of patients. 3D printing has proven to be a powerful tool allowing the adaptation of immediate drug delivery dosage forms. However, there are still few studies focusing on the adaptation of long-acting dosage forms for patient suffering of neurological diseases. In this study, paliperidone palmitate (PP) was chosen as a model drug in combination with different polymers adapted for fused-deposition modeling (FDM). The impact of different printing parameters on the release of PP were investigated. The layer thickness and the infill percentage were studied using a quality by design approach. Indeed, by defining the critical quality attributes (CQA), a proof of concept of a prediction system, and a quality control system were studied through designs of experiments (DoE). The first part of this study was dedicated to the release of PP from a fix geometry. In the second part, the prediction system was developed to require only surface and surface to volume ratio. From that point, it was possible to get rid of a fix geometry and predict the amount of PP released from complex architectures.

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.

A Design of Experiment Approach to Optimize Spray-Dried Powders Containing Pseudomonas aeruginosaPodoviridae 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.

This review aims to cement three hot topics in drug delivery: (a) the pre-formulation of new products intended for nose-to-brain delivery; (b) the development of nasal casts for studying the efficacy of potential new nose-to-brain delivery systems at the early of their development (pre-formulation); (c) the use of 3D printing based on a wide variety of materials (transparent, biocompatible, flexible) providing an unprecedented fabrication tool towards personalized medicine by printing nasal cast on-demand based on CT scans of patients. This review intends to show the links between these three subjects. Indeed, the pathway selected to administrate the drug to the brain not only influence the formulation strategies to implement but also the design of the cast, to get the most convincing measures from it. Moreover, the design of the cast himself influences the choice of the 3D-printing technology, which, in its turn, bring more constraints to the nasal replica design. Consequently, the formulation of the drug, the cast preparation and its realisation should be thought of as a whole and not separately.

Long-acting implantable dosage forms containing paliperidone palmitate obtained by 3D printing.

In this work, the versatility of pressure extrusion-based printing (PEBP) was used as 3D printing process to create long-acting implantable dosage forms. Different release profiles were achieved based on the drug concentration, the way of preparation and the design of the final implants. Polycaprolactone (PCL) was used as the polymer to sustain the release of the loaded drug. Paliperidone palmitate (PP), a BCS Class II drug, used in the treatment of schizophrenia, was used as the model drug. Two PP concentrations (e.g. 5 and 10% w/w) as well as two methods of preparation before the 3D printing process, mortar and pestle and cryogenic milling, were evaluated. The amorphous state of PP was obtained by using cryogenic milling and it was maintained after printing. Two designs were printed by PEBP, a ring and a disk, to evaluate their impact on the release profile of PP. During the in vitro dissolution tests, the implant design, the amount of PP, as well as the crystalline or amorphous state of PP have shown to influence the drug release profile. During the successive steps of preparation of the long-acting implants, blends and raw materials were characterized by DSC and XRD.

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.

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.

Feasibility study into the potential use of fused-deposition modeling to manufacture 3D-printed enteric capsules in compounding pharmacies.

The purpose of this work was to investigate the feasibility to manufacture enteric capsules, which could be used in compounding pharmacies, by fused-deposition modeling. It is well-known that conventional enteric dip coating of capsules in community pharmacies or hospitals is a time-consuming process which is characterized by an erratic efficacy. Fused-deposition modeling was selected as a potential 3D printing method due its ease and low-cost implementation. Before starting to print the capsules, an effective sealing system was designed via a computer-aided design program. Hot melt extrusion was used to make printable enteric filaments. They were made of the enteric polymer, a plasticizer and a thermoplastic polymer, namely Eudragit® L100-55, polyethylene glycol 400 and polylactic acid, respectively. Riboflavine-5'-phosphate was selected as a coloured drug model to compare the efficacy of the 3D printed capsules to that of enteric dip coated capsules as they are currently produced in community pharmacies and hospitals. Different parameters of fabrication which could influence the dissolution profile of the model drug, such as the layer thickness or post-processing step, were studied. It was demonstrated that our 3D printed enteric capsules did not release the drug for 2 h in acid medium (pH 1.2). However, they completely dissolved within 45 min at pH 6.8 which allowed the release of a minimal amount of 85% w/w of drug as it was recommended by the European Pharmacopoeia 9th Edition for enteric products.

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.

Development and evaluation of an omeprazole-based delayed-release liquid oral dosage form.

Modified-release oral dosage forms are commonly used in pharmaceutics to delay or sustain the release of drugs. Nowadays, they are only marketed as solid dosage forms such as capsules or tablets. Therefore, the development of a liquid oral dosage form with modified-release properties has been keenly awaited to increase the compliance of patients with a swallowing impairment, such as paediatric, older or critically ill patients. In this study, a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup, using omeprazole as a model drug. The coating procedure was optimized to obtain a yield of minimum 90% w/w and a mean diameter below 500 µm. Eudragit® E100 and Eudragit® L100-55 were used to prevent the early release of omeprazole in the syrup and in the acidic environment of the stomach, respectively. These polymers allowed the stability of the coated particles to be ensured when dispersed in a liquid and the enteric release of the drug to be targeted. It was demonstrated that our new system presented similar release performances to existing marketed enteric dosage forms. It is able to protect omeprazole for 2 h in acidic medium at pH 1.2, while omeprazole was entirely released at pH 6.8 within 45 min. Once the final suspension is prepared extemporaneously, it presents sufficient stability to guarantee the administration of multiple doses filled into a syrup bottle and kept for a limited storage time at room temperature (e.g. up to 10 doses to be administered within 10 days).

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.