Dry Powder Formulation Research Articles

Dual targeting powder formulation of antiviral agent for customizable nasal and lung deposition profile through single intranasal administration

Unpredictable outbreaks due to respiratory viral infections emphasize the need for new drug delivery strategies to the entire respiratory tract. As viral attack is not limited to a specific anatomic region, antiviral therapy that targets both the upper and lower respiratory tract would be most effective. This study aimed to formulate tamibarotene, a retinoid derivative previously reported to display broad-spectrum antiviral activity against influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as a novel dual particle size powder formulation that targets both the nasal cavity and the lung by a single route of intranasal administration. Spray freeze drying (SFD) and spray drying (SD) techniques were employed to prepare tamibarotene powder formulations, and cyclodextrin was used as the sole excipient to enhance drug solubility. With the employment of appropriate atomizing nozzles, particles of size above 10 μm and below 5 μm could be produced for nasal and lung deposition, respectively. The aerosol performance of the powder was evaluated using Next Generation Impactor (NGI) coupled with a glass expansion chamber and the powder was dispersed with a nasal powder device. By blending powder of two different particle sizes, a single powder formulation with dual aerosol deposition characteristic in both the nasal and pulmonary regions was produced. The aerosol deposition fractions in the nasal cavity and pulmonary region could be modulated by varying the powder mixing ratio. All dry powder formulations exhibited spherical structures, amorphous characteristics and improved dissolution profile as compared to the unformulated tamibarotene. Overall, a novel dual targeting powder formulation of tamibarotene exhibiting customizable aerosol deposition profile was developed. This exceptional formulation strategy can be adopted to deliver other antimicrobial agents to the upper and lower airways for the prevention and treatment of human respiratory infections.

Dry Dosage Forms of Add-Value Bioactive Phenolic Compounds by Supercritical CO2-Assisted Spray-Drying.

Every year, grapevine pruning produces huge amounts of residue, 90% of which are from vine shoots. These are a rich source of natural antioxidants, mostly phenolic compounds, which, when properly extracted, can give rise to added-value products. However, their lack of solubility in aqueous media and high susceptibility to thermal and oxidative degradation highly limit their bioavailability. Encapsulation in suitable carriers may have a positive impact on their bioavailability and bioactivity. Previous data on vine-shoot extraction have identified gallic acid (GA) and resveratrol (RSV) as the main phenolic compounds. In this work, model dry powder formulations (DPFs) of GA and RSV using hydroxypropyl cellulose (HPC) as carriers were developed using Supercritical CO2-Assisted Spray Drying (SASD). A 32 full factorial Design of Experiments investigated the solid and ethanol contents to ascertain process yield, particle size, span, and encapsulation efficiency. Amorphous powder yields above 60%, and encapsulation efficiencies up to 100% were achieved, representing excellent performances. SASD has proven to be an efficient encapsulation technique for these phenolic compounds, preserving their antioxidation potential after three months in storage with average EC50 values of 30.6 µg/mL for GA–DPFs and 149.4 µg/mL for RSV–DPF as assessed by the scavenging capacity of the DPPH radical.

Formulation, characterization and evaluation of inhalable effervescent dry powder of Rifampicin nanoparticles

BackgroundDry powder inhaler is a popular approach to pulmonary drug delivery to treat tuberculosis. Spray dried Nanoparticles using lactose carrier is extensively used for pulmonary drug delivery. Though lactose nanoparticles show deep lung deposition, they fail to uniformly disperse nanoparticles in its original form in alveoli. Rifampicin is one of the first line drugs in tuberculosis treatment. Lung targeted drug delivery system is an approach to reduce dose related side effects of rifampicin. Inhalable nanoparticles also help to target alveolar macrophages, thus improving treatment efficiency. MethodologyThis study focuses on rifampicin nanosuspension formulation and optimization using nano-precipitation method followed by characterizing effervescent DPI of rifampicin nanoparticles with effervescent pair (citric acid and sodium bicarbonate). Preliminary studies showed suitability of 4:5 solvent: antisolvent ratio and lecithin (1%) as stabilizer. The drug and stabilizer concentration in nanoparticles was successfully optimized using 3 ∗ 2 factorial design using DESIGN EXPERT software. The rifampicin nanoparticles were further converted to spray dried powder using effervescent carrier. ResultThe effervescent pair formulation was monodisperse and had a particle size of 1.5 microns (polydispersity index 0.289), thus showing better redispersibility than lactose nanoparticles. The mass median aerodynamic diameter and fine particle diameter of both spray dried formulations were similar and suitable for deep lung deposition. ConclusionThese findings are suggestive that effervescent technique can be successfully employed to improve redispersibility of rifampicin nanoparticles.

Development of vitamin B12 containing pullulan-bovine serum albumin microparticles designed dry powder inhaler: In-vitro and in-vivo study

The poor permeability and low bioavailability of vitamin B12 (vit. B12) through the mucosal lining of lungs are required substitutes. Therefore, the present work aims to develop a dry powder inhaler (DPI) of (Vit.B12) encapsulated into bovine serum albumin (BSA) followed by pullulan coated micro particles (Vit.B12-Pull-BSA) through spray drying. Briefly, pullulan was used as a mucoadhesive agent whereas BSA was used as an encapsulating agent. The obtained Vit.B12-Pull-BSA micro-particles were characterized using different in-vitro spectroscopic techniques, in vitro dissolution, mucoadhesion study, particle size analysis, etc. As a result, the surface morphology of Vit.B12-Pull-BSA micro-particles shows spherical micro-particle with circular surface morphology that can be suitable for pulmonary drug delivery. The PXRD study reveals the conversion of the crystalline nature of vitamin B12 to amorphous nature. Particle size showed 590.1 nm and zeta potential of microparticles was −27.3 mV respectively, which indicates the good stability of particles. The in-vitro assessment of Vit.B12-Pull-BSA microparticles using cascade Impactor revealed that 90.8 ± 1.1% of dry powder formulation was emitted from the device whereas 64.1 ± 6.8% of vitamin B12 loaded particles were reached at a fine stage that suggests preferential delivery of micro-particle. Male Wister rats were utilized for pharmacokinetic analysis through intratracheal administration of Vit.B12-Pull-BSA micro-particles that confirmed the increase in the permeability. Accordingly, it increases the 4.5 folds' relative bioavailability of vitamin B12. In conclusion, the Vit.B12-Pull-BSA micro-particles-based DPI offers improved permeability and bioavailability that can provide the alternative for conventional drug delivery.

In Vitro Analysis of Nasal Interface Options for High-Efficiency Aerosol Administration to Preterm Infants.

Background: An infant air-jet dry powder inhaler (DPI) platform has recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high-efficiency aerosolization with low actuation air volumes. The objective of this study was to investigate modifications to the nasal interface section of this platform to improve the aerosol delivery performance through preterm nose-throat (NT) models. Methods: Aerosol delivery performance of multiple nasal interface flow pathways and prong configurations was assessed with two in vitro preterm infant NT models. Two excipient-enhanced growth (EEG) dry powder formulations were explored containing either l-leucine or trileucine as the dispersion enhancer. Performance metrics included aerosol depositional loss in the nasal interface, deposition in the NT models, and tracheal filter deposition, which was used to estimate lung delivery efficiency. Results: The best performing nasal interface replaced the straight flexible prong of the original gradual expansion design with a rigid curved prong (∼20° curvature). The prong modification increased the lung delivery efficiency by 5%-10% (absolute difference) depending on the powder formulation. Adding a metal mesh to the flow pathway, to dissipate the turbulent jet, also improved lung delivery efficiency by ∼5%, while reducing the NT depositional loss by a factor of over twofold compared with the original nasal interface. The platform was also found to perform similarly in two different preterm NT models, with no statistically significant difference between any of the performance metrics. Conclusions: Modifications to the nasal interface of an infant air-jet DPI improved the aerosol delivery through multiple infant NT models, providing up to an additional 10% lung delivery efficiency (absolute difference) with the lead design delivering ∼57% of the loaded dose to the tracheal filter, while performance in two unique preterm airway geometries remained similar.

Preparation of organic-solvent free liposome of Piper albi Linn extract in solution and powder form

Piperine is bioactive alkaloid extracted from white pepper (Piper albi Linn) with several beneficial pharmacological activities. It is also known to enhance the bioavailability of several limited solubilities of other compounds such as curcumin and resveratrol. Nevertheless, due to its poorly water-soluble character, piperine and extract of white pepper are less applied among other plant extracts. Therefore, our research focussed on the engineering of white pepper extract standardized to piperine in liposome solution and liposome powder for further preparation of various pharmaceutical dosage forms.Our research in preparation of extracted white pepper in liposome delivery system successfully prepared spheric liposome solution with 98.92%±1.17% and an average size of 398.7 nm. The liposome was also successfully prepared in dry powder form with sucrose as a carrier for liposome protection. The rehydration is successfully forming a spheric shape with a similar profile to the initial liposome solution. This research paves the way for scalable white pepper extract liposome preparation without the utilization of toxic organic solvent, to produce the commercial solvent-free product in the future.Keywords: Piperine, Piper albi Linn, liposome, extract, organic solvent-free, drug delivery system, spray dry

Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline.

Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir–theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature–composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 μm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.

Effects of Anthocyanin Supplementation and Ageing Time on the Volatile Organic Compounds and Sensory Attributes of Meat from Goat Kids.

Simple SummaryAlternative animal feed sources are being used for the rearing of small ruminants. Among them, the use of agri-food by-products stands out. This strategy meets the demands of consumers towards natural products, offering beneficial effects on meat quality linked to their antioxidant activity properties. In addition, meat ageing allows substantial improvements in palatability attributes, especially tenderness and flavour.The aim of this study was to assess the effects of dietary anthocyanin addition on volatile compounds of meat from goat kids during ageing. For this work, 60 male and female kids were divided into two groups: red orange and lemon extract (RLE group; n = 30), which received an RLE extract (90 mg/kg of live weight); and control (CON group; n = 30). The phytoextract in dry powder form was rich in bioflavonoids such as flavanones (about 16%) and anthocyanins (about 3%). After slaughtering, the longissimus thoracis et lumborum muscle was aged at 4 °C. The volatile organic compound (VOC) and sensorial analyses were carried out at 1, 3 and 7 days. A total of 10 chemical families were identified during the ageing process. Aldehydes were the most abundant VOC, followed by ketones and alcohols. Their contents increased during the process, showing after 7 days of ageing mean values of 20,498, 2193 and 1879 ng/g of meat, respectively. Regarding dietary effects, carboxylic acids, hydrocarbons and thiols presented significant differences between treatments, with higher carboxylic acid contents observed in RLE samples (437 vs. 467 ng/g of meat for CON and RLE batches, respectively; p < 0.05). On the contrary, hydrocarbons (436 vs. 254 ng/g of meat for CON and RLE batches, respectively) and thiols (160 vs. 103 ng/g of meat for CON and RLE batches, respectively) displayed significantly (p < 0.01) higher amounts in CON compared to the RLE group. Regarding ageing time, the tenderness, juiciness, odour and overall assessment parameters showed significantly higher scores at the end of the whole process (p < 0.05). On the other hand, only odour displayed significant differences between treatments, reaching higher scores in CON samples (p < 0.05). Therefore, ageing time improved the sensorial properties (tenderness, juiciness, odour and overall assessment) and the VOC content, whereas the inclusion of anthocyanins in the kids’ diet did not have a great impact on the properties of aged meat.

Quantification of Buckminsterfullerene (C60) in non-graphitizing carbon and a microstructural comparison of graphitizing and non-graphitizing carbon via Small Angle Neutron Scattering

In this article we present the first experimental evidence confirming a global presence of Buckminsterfullerene (C60) in non-graphitizing polymeric carbon, along with its volume fraction calculations. Partially stacked carbon fragments featuring weak or strong curvatures constitute the structural units in non-graphitizing carbons. It has been proposed that a certain fraction of completely closed spherical fullerenes, such as C60, is also present in these materials. Strongly curved structures are not expected to exist in graphitizing carbons. We report on a Small Angle Neutron Scattering (SANS) investigation conducted at the Institut Laue-Langevin, Grenoble, France, that enables us to (i) quantify C60 in a non-graphitizing carbon, (ii) investigate the evolution patterns of graphitizing and non-graphitizing carbons, and (iii) perform a detailed SANS analysis of pure crystalline C60 in dry powder form. We also revisit the formation patterns of slightly larger structures (3–5 nm) such as graphitic crystallites and voids in both classes of polymeric carbon. These results provide a strong evidence in support of the fullerene-like microstructural models of non-graphitizing carbon, adding that the curved structural units are not just “fullerene-like”, but also spherical fullerenes, C60 in particular.

PRELIMINARY STUDY OF INSULIN DRY POWDER FORMULATION: CRITICAL PROCESS PARAMETERS ON SPRAY-FREEZE-DRYING AND CRITICAL MATERIAL ATTRIBUTE OF TREHALOSE AND INULIN AS STABILIZER

Objective: The aim of this study was to obtain recommendations about critical process parameters (CPP) and optimal ratio of trehalose and inulin as critical material attribute (CMA) on insulin dry powder formulation with spray-freeze-drying (SFD) method.&#x0D; Methods: Inulin dry powder was formulated with the SFD method, which consisted of an atomization process and freeze-drying (FD). SFD processes were optimized in order to obtain dry powder and CPP was analyzed. All seven variations of formulas proceeded with physicochemical characterization to obtain the optimal formula.&#x0D; Results: In the early optimization, there was a slight time lag between the atomization process and FD; as a result, some of the powder coagulated and crystallized. Another critical parameter was that the FD process should not be interrupted for at least 50 h of FD. Dry powder proceeded with physicochemical characterization, a formula without inulin showed semicrystalline properties, while six formulas had amorphous properties due to its combination. All formulas had a spherulite shape and rough surface. Five formulas with the combination of trehalose and inulin obtained dry powders with a diameter range of 30-43 μm, moisture content below 3.5% and high encapsulation efficiency (EE). Formula with the ratio of 1:1 (F4) showed optimal properties with moisture content and EE of 2.62% and 99.68%, respectively.&#x0D; Conclusion: This study concluded that there were two critical process parameters in the SFD method. There should be no time lag in SFD process and FD time which should not be interrupted. The optimal ratio for trehalose and inulin was shown by F4 with ratio of 1:1.

Influence of Polymer Modifiers on Selected Properties and Microstructure of Cement Waterproofing Mortars.

This paper presents the results of research on the influence of polymer modifiers: styrene-acrylic copolymer, vinyl acetate/ethylene (EVA), vinyl acetate/acrylic copolymer (VAAc), and VA/VeoVa/acrylic terpolymer on the water permeability and adhesion of cement-containing waterproofing mortars in concrete. The content of the polymers in the composition of the mortars was 15, 20 and 26% (m/m) in relation to the weight of the dry ingredients. Using microscopic methods, an attempt was made to analyse the relationship between the microstructure of the mortars and the properties of these polymers. The EVA and the vinyl acetate/acrylic copolymer, which were used in the form of dry powders, had the most favourable effect on water permeability and adhesion to the concrete substrate. They may prove to be useful for the production of one-component cement-containing waterproofing mortars. On the other hand, the VA/VeoVa/acrylic terpolymer modifier had the least favourable effect on the tested properties. For mortars with this modifier, the desired water-permeability parameters were not achieved. Depending on the amount of polymer modifier, the mortars were characterized by differences in watertightness, as established on the basis of changes in porosity and differences in the adhesion of the cement-polymer paste to the surface of aggregate grains. It was determined that the type of polymer and its dispergation properties influence the water permeability of mortars, as well as their adhesion to concrete substrates.

Spray-Dried Powder Formulation of Capreomycin Designed for Inhaled Tuberculosis Therapy.

Multi-drug-resistant tuberculosis (MDR-TB) is a huge public health problem. The treatment regimen of MDR-TB requires prolonged chemotherapy with multiple drugs including second-line anti-TB agents associated with severe adverse effects. Capreomycin, a polypeptide antibiotic, is the first choice of second-line anti-TB drugs in MDR-TB therapy. It requires repeated intramuscular or intravenous administration five times per week. Pulmonary drug delivery is non-invasive with the advantages of local targeting and reduced risk of systemic toxicity. In this study, inhaled dry powder formulation of capreomycin targeting the lung was developed using spray drying technique. Among the 16 formulations designed, the one containing 25% capreomycin (w/w) and spray-dried at an inlet temperature of 90 °C showed the best overall performance with the mass median aerodynamic diameter (MMAD) of 3.38 μm and a fine particle fraction (FPF) of around 65%. In the pharmacokinetic study in mice, drug concentration in the lungs was approximately 8-fold higher than the minimum inhibitory concentration (MIC) (1.25 to 2.5 µg/mL) for at least 24 h following intratracheal administration (20 mg/kg). Compared to intravenous injection, inhaled capreomycin showed significantly higher area under the curve, slower clearance and longer mean residence time in both the lungs and plasma.

Respirable spray dried vancomycin coated magnetic nanoparticles for localized lung delivery

Bacterial pneumonia is a common pulmonary infection responsible for premature death. Biomaterials based-carriers loaded with antibiotics enhance drug potency through localizing the therapy, minimizing the associated adverse effects, and improving patient compliance. Herein, this study reports the preparation of an inhalable dry powder formulation composed of a nano-in-microparticles. Vancomycin was adsorbed on the core of magnetic nanoparticles followed by spray drying into lactose/dextran to optimize the aerodynamic performance and allow the local delivery of the drug into the bacterial pneumonia infection site. Lactose and Dextran are polysaccharides commonly used for pulmonary delivery due to their optimum aerodynamic performance and biocompatibility. The preparation of the nano-in-micro particles with optimum properties was confirmed using FTIR, TEM, SEM, Laser-diffraction, ICP-AES and TGA. The TEM micrographs confirmed the formation of spherical magnetic nanoparticles with a diameter 14.7 ± 5.9 nm and a coating thickness 3 – 16 nm, while laser diffraction showed that outer microparticles exhibited a mean diameter < 5 µm. The formulations demonstrated a promising activity against S. aureus and MRSA and better biocompatibility using MTT assay. In vivo safety and pharmacokinetic studies confirmed the localization of VAN in lung tissue and minimized adverse effects compared to free VAN. Therefore, the developed nano-in-microparticles confers a good potential for eradication of lung infections.

Design and Characterization of Atorvastatin Dry Powder Formulation as a potential Lung Cancer Treatment

Lung cancer is the leading cause of cancer death. Many studies have shown the beneficial effects of Atorvastatin in decreasing the mortality risk and improving survival among patients with lung cancer. This research paper focuses on improving AVT cytotoxic activity and cellular uptake by developing mannitol microcarriers as a promising drug delivery system for lung cancer treatment and, studying the impact of improving inhalation deposition on the delivery and Dry Powder formulations efficiency. The AVT loaded mannitol (AM) microparticles (AVT-AM) formulation was prepared by spray drying and characterized for its physicochemical properties and aerodynamic deposition. The results revealed that the AVT-AM formulation has good flow properties and aerosol deposition with a particle size of 3418 nm ± 26.86. The formulation was also assessed in vitro for cytotoxicity effects (proliferation, apoptosis, and cell cycle progression) on A549 human lung adenocarcinoma. Compared with free AVT, the AVT-AM formulation has significantly higher cellular uptake and anti-cancer properties by disrupting cell cycle progression via either apoptosis or cell cycle arrest in the G2/M phase. This study shows that AVT loaded mannitol microcarriers may provide a potentially effective and sustained pulmonary drug delivery for lung cancer treatment.

Targeting of Inhaled Therapeutics to the Small Airways: Nanoleucine Carrier Formulations.

Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of the current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.

A technology evaluation of CVT-301 (Inbrija): an inhalable therapy for treatment of Parkinson’s disease

Introduction The most widely used pharmacological treatment for Parkinson’s disease is levodopa, the precursor for dopamine formation in the brain. With time, the effectiveness of levodopa declines, and patients experience motor fluctuations, or OFF periods. A levodopa formulation administered via a capsule-based oral inhaler provides a new delivery mechanism for levodopa that provides rapid relief of OFF periods. Areas covered CVT-301 is a dry powder formulation designed to supply levodopa to the systemic circulation via pulmonary absorption. The technology, pharmacokinetics, efficacy, and safety data of this formulation are presented. Expert opinion Oral inhalation is a novel method of administration for levodopa that bypasses the gastrointestinal tract, allowing levodopa to enter the systemic circulation rapidly and more reliably than oral medications. Gastrointestinal dysfunction, a common feature of Parkinson’s disease, can lead to impaired absorption of oral medications. Pulmonary delivery rapidly elevates levodopa plasma concentrations to provide relief of OFF periods for patients receiving oral levodopa.

Production of Organically Selenium Yeast by Fermentation and Analysis by Atomic Absorption Spectrophotometry

Objectives: The objective of this study was to perform selenium yeast production and analyze the selenium and protein contained in selenium yeast obtained. Methods: Selenium yeast production was carried out by incubating the stationary phase culture of yeast with selenium solution for 24 hr, and yeast biomass was dried by Freeze-dryer to produce selenium yeast in powder form, then the selenium yeast was determined to the selenium content with atomic absorption spectrophotometer at a wavelength of 196 nm and protein content analyzing by the Bradford method at a wavelength of 595 nm using UV-Vis spectrophotometer. Results: Selenium yeast production reached 2.5 g of selenium yeast in powder form. The selenium and protein content of selenium yeast was 4258.0096 (±278.39) μg Se/g and 0.8505 (±0.0045) mg/mL, respectively. The method was easy, simple, and can prove that selenium yeast can still be produced and analyzed for the selenium and protein content. Conclusion: The present study demonstrated that production of selenium yeast in the form of dry powder could be carried out using the stationary phase culture of S. cerevisiae incubated with 30 μg/mL selenium solution, and the resulting selenium yeast can be analyzed for selenium content using atomic absorption spectrophotometer and protein content by Bradford method using UV-Vis spectrophotometer.

Safety, tolerability, and pharmacokinetics (PK) of treprostinil palmitil inhalation powder (TPIP): a phase 1, randomised, double-blind, single- and multiple-dose study

Abstract Background/Introduction Use of treprostinil in the treatment of pulmonary arterial hypertension (PAH) is limited by a short half-life and dose-limiting adverse events. TPIP, a dry powder formulation of the treprostinil prodrug treprostinil palmitil, is under investigation for PAH. In preclinical models, TPIP provided sustained treprostinil release in the lung and demonstrated sustained reduction of pulmonary arterial pressures. Purpose To examine the safety, tolerability, and PK of single- and multiple-dose administration of once-daily (QD) TPIP in healthy volunteers. Methods In this phase 1 study, healthy adults (aged 18–45 years) were randomised to receive single or multiple QD inhalation doses of TPIP. Single-dose participants received TPIP 112.5, 225, 450, or 675 μg (n=6 per dose) or placebo (n=2). Multiple-dose participants received TPIP 225 μg QD for 7 days (n=6), 112.5 μg QD for 4 days followed by 225 μg QD for 3 days (n=6), or placebo for 7 days (n=4). Results Of 42 randomly assigned participants who received ≥1 dose, 41 (97.6%) completed the study. Of the single-dose TPIP–treated participants, 70.8% (n=17/24) experienced a treatment-emergent adverse event (TEAE) vs 0% (0/2) of placebo-treated participants; the most common TEAEs (≥15%) among TPIP-treated participants were cough (45.8%), dizziness (29.2%), throat irritation (20.8%), nausea (16.7%), and hypotension (16.7%). Of the multiple-dose TPIP–treated participants, 83.3% (n=10/12) experienced a TEAE vs 50.0% of placebo-treated participants (2/4); the most common TEAEs were cough (58.3% TPIP vs 50.0% placebo), headache (50.0% vs 0%), nausea (33.3% vs 0%), and dizziness (25.0% vs 0%). Overall, 69.0% of participants (29/42) experienced mild TEAEs and 16.7% (7/42) experienced moderate TEAEs; no severe or serious TEAEs occurred. TEAEs were more frequent with increasing TPIP doses. Participants titrated from TPIP 112.5 μg QD to 225 μg QD experienced fewer TEAEs than those who received 225 μg QD at treatment initiation; all TEAEs were mild. After single-dose TPIP treatment, treprostinil exposure was dose proportional, with mean (CV%) Cmax = 78.4–717 pg/mL (38.6-72.9%) and AUC(0–∞) = 1.09–5.48 h·ng/mL (11.5–30.0%). At steady-state (225 μg), the mean (CV%) of Cmax, Cmin, and AUC(0–t) were 193–228 pg/mL (32.9–46.4%), 17.6–22.8 ng/mL (43.7%-64.4%) and 1.68–1.82 ng·h/mL (28.7–36.6%), respectively. No steady-state accumulation was observed. Elimination t1/2 was 8.7–11.6 h after a single dose and 6.8–8.8 h at steady state. Plasma concentrations of treprostinil palmitil were below the limit of quantification (100 pg/mL) at all time points measured. Conclusions In this phase 1 study, single and multiple TPIP dosing was generally well tolerated in healthy volunteers, with a PK profile that supports QD dosing. TEAEs were dose related; most were mild, none were severe or serious, and a titration schedule improved tolerability. These results support further examination of TPIP in patients with PAH. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Insmed Incorporated

Thin-film freeze-drying of a bivalent Norovirus vaccine while maintaining the potency of both antigens

A bivalent Norovirus vaccine candidate has been developed that contains Norovirus strain GI.1 Norwalk-virus like particles (VLP) and strain GII.4 Consensus VLP adsorbed on aluminum (oxy)hydroxide. The Norwalk and Consensus antigens have different stability profiles, making it challenging to prepare a dry powder form of the Norovirus vaccine while maintaining the potency of both antigens. In the present study, we tested the feasibility of converting the vaccine from a liquid suspension to dry powders by thin-film freeze-drying (TFFD). With the proper amount of trehalose and/or sucrose as cryoprotectant (i.e. sucrose alone at 4.55% or 5.55%, w/v, or trehalose at 3–4% with 0.55% of sucrose), TFFD can be applied to successfully convert the Norovirus vaccine candidate into dry powders without causing antigen loss or particle aggregation, while maintaining the relative potency of both antigens within a specified acceptable range. In an accelerated stability study, the potency of the antigens was also maintained in the specified acceptable range after the dry powders prepared by TFFD in the presence of 5.55% (w/v) of sucrose were stored for eight weeks at 40 °C, 75% relative humidity. It is concluded that it is feasible to apply TFFD to convert the Norovirus vaccine from a liquid suspension to stable dry powders.

Inhalable hydrophilic molecule-loaded liposomal dry powder formulations using supercritical CO2 – assisted spray-drying

Liposomes are known to be one of the most promising drug delivery systems for carrying and delivering biopharmaceuticals. Yet, both liposomes and biopharmaceuticals are susceptible to destabilization during storage, and thus require cold supply and efficient distribution chains. This drawback can be overcome, though, by converting liposomal suspension into solid form dosage capable of administration via different routes, including the lungs. In this work, we present a synergy between pharmaceutical and supercritical carbon dioxide technologies to assist in liposome drying. Liposomes, encapsulating 5(6)- carboxyfluorescein (CF) as a marker of the internal aqueous phase, were produced and then dried using supercritical CO2 - assisted spray-drying (SASD). CF-loaded liposomal dry powder formulations were thus obtained. After resuspension in water to remove the trehalose, the liposomes maintained their structure and the CF encapsulation efficiency remained above 95 %. To optimize the process, a quality-by-design approach using the design of experiments tool was used. Then, the powders were submitted to storage stability assays at relative humidity of 4 %, 50 % and 78 % for 30 days. Results showed that the dry powder formulations were able to maintain liposome stability at relative humidity of 4 % and 50 % at 20 °C for 30 days.