Spray-dried Formulations Research Articles

Fast onset of thrombolytic effect of efficiently inhalable spray-dried rivaroxaban powder formulations

Pulmonary embolism is a critical medical condition and can lead to cardiovascular arrest or death if left untreated. Pulmonary delivery of an anti-coagulant therapeutic could provide a locally limited and efficient therapy, moreover combined with a potentially fast onset of the therapeutic effect that is demanded in emergency situations. Rivaroxaban (riva) was formulated as an inhalable dry powder that can be administered directly to the lungs in order to reach high local drug doses. Particles obtained spray drying dichloromethane-methanol mixtures yielded an aerodynamic diameter of about or smaller than 5 µm and were found to reach an emitted fine particle fraction (FPFEF) of at least 60 %. Pulmonary administration to rats using a dry powder insufflator revealed a nearly immediate therapeutic onset confirmed by the anticoagulant effects after 5 min in the plasma followed by a plateau over the next 4 h. Such rivaroxaban particles were further formulated in binary blends using different lactose carriers (Inhalac® 70/251/400). These interactive blends resulted in high emitted fractions of at least 87 %, and furthermore, the highest fine particle fraction − total dose (FPFTD) (60 %) of all tested formulations was achieved by using Inhalac® 400 as a carrier. The data strongly suggest a significant therapeutic potential of a rivaroxaban dry powder formulation, combining fast onset and a plateau of plasma concentrations turning it into a potential first aid therapeutic.

New Insights on the Burst Release Kinetics of Spray-Dried PLGA Microspheres.

Spray drying is one of the leading manufacturing methods for active pharmaceutical ingredients (APIs) owing to its rapid, single-step, and cost-effective nature. It also has the capacity to generate microspheres capable of controlled release of APIs including biomolecules and vaccines. However, one of the key challenges of spray-dried formulations especially with poly(lactic-co-glycolic acid) (PLGA)-based controlled-release injectables is burst release, where a significant fraction of the API is released prematurely within a short period of time following administration, leading to detrimental impact on the performance and quality of end products. This study uses a model API, bovine serum albumin (BSA) protein, to identify the sources of burst release that may affect the kinetics and performance of long-acting injectable microsphere formulations. Spray-dried microspheres with various formulations (i.e., variable BSA/PLGA ratios) were characterized in terms of their morphology, particle size, surface area, thermal properties, moisture content, as well as chemical compositions and their distributions to investigate the impact of spray drying on the burst release phenomenon. The results suggest that a relatively high initial release (85%) observed is mainly attributed to the protein distribution close to the particle surface. Morphology analysis provided evidence that the microspheres retained their spherical structure during the burst release phase. X-ray photoelectron spectroscopy, hard X-ray photoelectron spectroscopy, and argon cluster sputtering-assisted time-of-flight secondary ion mass spectrometry analysis suggest an enrichment of PLGA on particle surfaces with buried BSA protein. The statistically significant difference in particle size and surface area between three different formulations may be responsible for an initial variation in release but did not seem to alter the overall burst release profile. Considering the suggested source of burst release, the two-fluid spray-drying method, characterized by a single liquid feed delivering a preprepared emulsion, generated matrix-type microspheres with a surface layer of PLGA, as evidenced by surface analysis. The PLGA surface layer proved to be prone to degradation and pore formation, allowing for faster diffusion of BSA out of the microspheres, resulting in a burst release. Increasing the polymer concentration did not seem to halt this process.

Absolute oral bioavailability of milvexian spray-dried dispersion formulation under fasted and fed conditions in healthy adult participants: An intravenous microtracer approach.

Milvexian is an oral, small-molecule factor XIa inhibitor being developed to prevent thromboembolic events. This study assessed the absolute bioavailability (F) of milvexian following single doses of milvexian spray-dried dispersion (SDD) formulation under fed and fasted conditions, and milvexian solution, in healthy adult participants using an intravenous microtracer approach. This was a phase I, open-label, partially randomized, 4-sequence, 5-period crossover study. After fasting for ≥10 h, participants received milvexian 200-mg oral solution with a 100-μg 14C milvexian intravenous microtracer at the time of maximum observed plasma concentration. Following a 3-day washout, participants were randomized to 1 of 4 milvexian SDD treatment sequences in a crossover fashion: 25 mg fasted, 25 mg fed, 200 mg fasted, or 200 mg fed. Pharmacokinetic data were collected up to 72 h postdose. Seventeen participants were dosed, and 14 completed treatment. Under fasted conditions, milvexian F was ~100%, 58.2%, and 54.2% following administration of the oral solution, 25 mg SDD, and 200 mg SDD, respectively. Under fed conditions, milvexian F following 25 mg and 200 mg SDD was 44.3% and 75.6%, respectively. The milvexian SDD formulation at 25 mg and 200 mg resulted in similar F in a fasted state; under fed conditions, milvexian F decreased at 25 mg and increased at 200 mg. These findings clarify pharmacokinetic-related gaps observed in previous studies.

An aerosol nanocomposite microparticle formulation using rifampicin-cyclodextrin inclusion complexes for the treatment of pulmonary diseases

Rifampicin (RIF) is commonly used in the treatment of tuberculosis (TB), a bacterium that currently infects one fourth of the world’s population. Despite the effectiveness of RIF in treating TB, current RIF treatment regimens require frequent and prolonged dosing, leading to decreased patient compliance and, ultimately, increased mortality rates. This project aims to provide an alternative to oral RIF by means of an inhalable spray-dried formulation. TB uses alveolar macrophages to hide and replicate until the cells rupture, further spreading the bacteria. Therefore, delivering RIF directly to the lungs can increase the drug concentration at the site of infection while reducing off-site side effects. Cyclodextrin (CD) was used to create a RIF-CD inclusion complex to increase RIF solubility and biodegradable RIF-loaded NP (RIF NP) were developed to provide sustained release of RIF. RIF NP and RIF-CD inclusion complex were spray dried to form a dry powder nanocomposite microparticles (nCmP) formulation (RIF-CD nCmP). RIF-CD nCmP displayed appropriate aerosol dispersion characteristics for effective deposition in the alveolar region of the lungs (4.0 µm) with a fine particle fraction of 89 %. The nCmP provided both a burst release of RIF due to the RIF-CD complex and pH-sensitive release of RIF due to the RIF NP incorporated into the formulation. RIF-CD nCmP did not adversely affect lung epithelial cell viability and RIF NP were able to effectively redisperse from the nCmP after spray drying. These results suggest that RIF-CD nCmP can successfully deliver RIF to the site of TB infection while providing both immediate and sustained release of RIF. Overall, the RIF-CD nCmP formulation has the potential to improve the efficacy for the treatment of TB.

Effect of processing and formulation factors on Catalase activity in tablets

The manufacturing of tablets containing biologics exposes the biologics to thermal and shear stresses, which are likely to induce structural changes (e.g., aggregation and denaturation), leading to the loss of their activity. Saccharides often act as stabilizers of proteins in formulations, yet their stabilizing ability throughout solid oral dosage processing, such as tableting, has been barely studied. This work aimed to investigate the effects of formulation and process (tableting and spray-drying) variables on catalase tablets containing dextran, mannitol, and trehalose as potential stabilizers. Non-spray-dried and spray-dried formulations were prepared and tableted (100, 200, and 400 MPa). The enzymatic activity, number of aggregates, reflecting protein aggregation and structure modifications were studied. A principal component analysis was performed to reveal underlying correlations. It was found that tableting and spray-drying had a notable negative effect on the activity and number of aggregates formed in catalase formulations. Overall, dextran and mannitol failed to preserve the catalase activity in any unit operation studied. On the other hand, trehalose was found to preserve the activity during spray-drying but not necessarily during tableting. The study demonstrated that formulation and process variables must be considered and optimized together to preserve the characteristics of catalase throughout processing.

Improving the stability of spray-dried probiotic acerola juice: A study on hydrocolloids' efficacy and process variables

This study explores the optimization of spray drying conditions for fermented acerola juice powder, focusing on nutrient retention and probiotic viability. Acerola, a fruit high in vitamin C and phenolics, was fermented under varying conditions to support the growth of Lactobacillus gasseri. The fermentation of acerola juice was conducted at pH levels of 3.2(in natura), 5.0, and 7.0 to promote optimal bacterial growth. Spray drying was then performed at inlet temperatures of 120°C, 140°C, and 160°C, using varying concentrations of maltodextrin and gelatin as encapsulants. The powders were analyzed for vitamin C, phenolic content, and Lactobacillus gasseri cell concentration. Optimal bacterial growth occurred at pH 7.0. The spray drying process showed that lower temperatures (120°C) favored higher vitamin C (up to 6.2 mg/g) and phenolic retention (up to 59.9 mg/g), while higher temperatures (160°C) enhanced probiotic survival (up to 8.3 × 108 CFU/g). Hydrocolloids like maltodextrin and gelatin were crucial in enhancing nutrient and probiotic stability, showcasing their importance in optimizing spray-dried functional food formulations. Tailoring fermentation and spray drying conditions is crucial in producing functional fruit powders with high nutritional and probiotic value.

Design of Experiment (DoE) Approach for Developing Inhalable PLGA Microparticles Loaded with Clofazimine for Tuberculosis Treatment.

Tuberculosis (TB) is an airborne bacterial infection caused by Mycobacterium tuberculosis (M. tb), resulting in approximately 1.3 million deaths in 2022 worldwide. Oral therapy with anti-TB drugs often fails to achieve therapeutic concentrations at the primary infection site (lungs). In this study, we developed a dry powder inhalable formulation (DPI) of clofazimine (CFZ) to provide localized drug delivery and minimize systemic adverse effects. Poly (lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) containing CFZ were developed through a single emulsion solvent evaporation technique. Clofazimine microparticles (CFZ MPs) displayed entrapment efficiency and drug loading of 66.40 ± 2.22 %w/w and 33.06 ± 1.45 µg/mg, respectively. To facilitate pulmonary administration, MPs suspension was spray-dried to yield a dry powder formulation (CFZ SD MPs). Spray drying had no influence on particle size (~1 µm), zeta potential (-31.42 mV), and entrapment efficiency. Solid state analysis (PXRD and DSC) of CFZ SD MPs studies demonstrated encapsulation of the drug in the polymer. The drug release studies showed a sustained drug release. The optimized formulation exhibited excellent aerosolization properties, suggesting effective deposition in the deeper lung region. The in vitro antibacterial studies against H37Ra revealed improved (eight-fold) efficacy of spray-dried formulation in comparison to free drug. Hence, clofazimine dry powder formulation presents immense potential for the treatment of tuberculosis with localized pulmonary delivery and improved patient compliance.

A Retrospective Analysis of Polymer Selection Using Solvent Casting: Formulation and DoE Optimization of the Amorphous Solid Dispersion of Amoxicillin Trihydrate by a Spray Drying Method

Background. Amoxicillin trihydrate possesses poor solubility, compressibility, and flow behavior. Amorphous solid dispersion prepared by spray drying could solve all three problems at the same time. Objective. To prepare amorphous solid dispersion after screening of polymers by solvent casting method using a spray drying method. Methods. The solvent casting method was used to screen polymers, PVP/VA S-630, PVP K30, Soluplus, PEG 4000, HPMC AS, and HPMC HP55, in 1 : 1 and 2 : 3 ratios and followed by spray drying after polymer selection. Results. The dissolution performance of the formulation improved with time. The optimum feed rate and feed concentration were found to have an impact on the flow properties and particle size of spray-dried formulations, and they were selected as independent variables in a 32 full factorial statistical design. The ANOVA and regression analysis suggest that the developed regression model has a significant overall fit to the data and can explain a substantial proportion of the variability in the dissolution at 10 minutes. The optimized batch was selected based on the decisive factors of minimum and maximum values of response variables. Overall, the optimized batch demonstrated improved characteristics in terms of percentage yield (32.81%), dissolution at 10 min (49.70%), and angle of repose at 31.42°. Conclusion. This study provides valuable insights into optimizing formulation strategies for preserving the amorphous state of drugs and contributes to the development of stable pharmaceutical formulations.

Nanoemulsion-based spray-dried formulation of essential oils, whey protein isolate, and maltodextrin: An approach for antifungal preservation of grated mozzarella cheese

An antifungal nanoemulsion-based formulation containing natural extracts encapsulated into whey protein isolate (WPI) and maltodextrin (MD) was spray-dried and applied on grated mozzarella cheese. Formulation efficiency was evaluated to extend the shelf-life and to inhibit spoilage fungi growth. The results of the spray-dried formulation (FP) showed a retention of 62% of the phenolic compounds, leading to a good encapsulation efficiency (72.3%). The sensory analysis results of grated mozzarella treated with FP revealed a powder concentration of ⩽2 g kg−1 was appreciated compared to the control. In situ evaluation of its antifungal capacity by challenge test revealed that FP showed an inhibitory effect similar to natamycin (FN) with a reduction of 3.4 log CFU g−1 after 56 days of storage (4 °C). The shelf-life result of grated mozzarella treated with FP and FN showed the onset of fungal growth on day 35 and day 56 in SA (air) and SL (nitrogen) packaging, respectively.

In silico guided pre-treatment of sugarcane juice with natural inhibitors of polyphenol oxidase (PPO) is a new and effective strategy for development of spray-dried formulation.

Sugarcane juice is a popular beverage and is also processed to produce sugar. The polyphenol oxidase (PPO) in sugarcane juice causes enzymatic browning and makes the process of sugar production complex and cumbersome. Storage of sugarcane juice is also hampered by the high sugar content and rapid microbial fermentation. The present research assessed the potential of lemon juice (LJ) and ginger extract (GE) as natural inhibitors of PPO. Enzyme kinetics and the mechanism of inhibition of LJ and GE were studied. Primary investigation was carried out using molecular docking approach to assess the inhibitory potential of LJ and GE and to determine the nature of interaction between the enzyme and inhibitors. Extracts were used as inhibitors and studies revealed that both reduced the PPO activity. Subsequently, pure bioactive inhibitors such as ascorbic acid, citric acid, and 6-shogaol present in these natural extracts were used to study the mode of inhibition of PPO. Citric acid decreased PPO activity by lowering pH, while ascorbic acid was found to be a competitive inhibitor of PPO with a Ki of 75.69µM. The proportion of LJ and GE required in sugarcane juice was optimized on the basis of browning index and sensory acceptance. Further, the sugarcane cane juice after inhibition of PPO under optimized conditions was spray dried and evaluated for reconstitution properties. The product formulated in the present study is a new and effective approach to address quality-compromising issues associated with long-term storage of cane juice.

Spray-Dried Mucoadhesive Re-dispersible Gargle of Chlorhexidine for Improved Response Against Throat Infection: Formulation Development, In Vitro and In Vivo Evaluation.

Drug delivery to the buccal mucosa is one of the most convenient ways to treat common mouth problems. Here, we propose a spray-dried re-dispersible mucoadhesive controlled release gargle formulation to improve the efficacy of chlorhexidine. The present investigation portrays an approach to get stable and free-flowing spray-dried porous aggregates of chlorhexidine-loaded sodium alginate nanoparticles. The ionic gelation technique aided with the chlorhexidine's positive surface charge-based crosslinking, followed by spray drying of the nanoparticle's dispersion in the presence of lactose- and leucine-yielded nano-aggregates with good flow properties and with a size range of about 120-350nm. Provided with the high entrapment efficiency (87%), the particles showed sustained drug release behaviors over a duration of 10h, where 87% of the released drug got permeated within 12h. The antimicrobial activity of the prepared formulation was tested on S. aureus, provided with a higher zone of growth inhibition than the marketed formulation. Aided with an appropriate mucoadhesive strength, this product exhibited extended retention of nanoparticles in the throat region, as shown by in vivo imaging results. In conclusion, the technology, provided with high drug retention and extended effect, could be a potential candidate for treating several types of throat infections.

Evaluation of a spray-dried amorphous solid dispersion formulation of ID11916, a new molecular entity with dual inhibition mechanisms targeting the androgen receptor and phosphodiesterase type-5

Evaluation of a spray-dried amorphous solid dispersion formulation of ID11916, a new molecular entity with dual inhibition mechanisms targeting the androgen receptor and phosphodiesterase type-5

In Vitro and In Vivo Performance of Pickering Emulsion-Based Powders of Omega-3 Polyunsaturated Fatty Acids.

Omega-3 polyunsaturated fatty acids (n-3 PUFA) are essential nutrients for human health and have been linked to a variety of health benefits, including reducing the risk of cardiovascular diseases. In this paper, a spray-dried powder formulation based on Pickering emulsions stabilized with cellulose nanocrystals (CNC) and hydroxypropyl methylcellulose (HPMC) has been developed. The formulation was compared in vitro and in vivo to reference emulsions (conventional Self-Emulsifying Drug Delivery System, SEDDS) to formulate n-3 PUFA pharmaceutical products, specifically in free fatty acid form. The results of in vivo studies performed in fasted dogs showed that Pickering emulsions reconstituted from powders are freely available (fast absorption) with a similar level of bioavailability as reference emulsions. In the studies performed with dogs in the fed state, the higher bioavailability combined with slower absorption observed for the Pickering emulsion, compared to the reference, was proposed to be the result of the protection of the n-3 PUFAs (in free fatty acid form) against oxidation in the stomach by the solid particles stabilizing the emulsion. This observation was supported by promising results from short-term studies of chemical stability of powders with n-3 PUFA loads as high as 0.8 g oil/g powder that easily regain the original emulsion drop sizes upon reconstitution. The present work has shown that Pickering emulsions may offer a promising strategy for improving the bioavailability and stability as well as providing an opportunity to produce environmentally friendly (surfactant free) and patient-acceptable solid oral dosage forms of n-3 PUFA in the free fatty acid form.

Understanding the impact of mannitol on physical stability and aerosolization of spray-dried protein powders for inhalation

Pulmonary delivery of protein-based therapeutics, including antibodies, is a promising option for treating respiratory diseases. Spray drying is a widely used method for producing dry powder formulations with mannitol being a commonly used excipient for these inhalation formulations. There is limited research available concerning the utilization of mannitol as an excipient in the spray drying of proteins and its impact on aerosol performance. This study highlights the importance to understand mannitol’s potential role and impact in this context. To investigate the impact of mannitol on physical stability and aerosolization of spray-dried protein formulations, bovine serum albumin (BSA) was employed as a model protein and formulated with different concentrations of mannitol via spray drying. The spray-dried solids were characterized for their particle size using Malvern mastersizer and aerodynamic particle size using next generation impactor (NGI). Additionally, the solids were characterized with solid-state Fourier-transform infrared spectroscopy (ssFTIR), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and solid-state nuclear magnetic resonance spectroscopy (ssNMR) to analyze the change in their secondary structure, crystallinity, particle morphology, and protein-excipient interaction, respectively. Size exclusion chromatography (SEC) was used to investigate changes in monomer content resulting from storage under stressed condition of 40 °C. Protein formulations containing more than 33 % mannitol by weight showed crystallization tendencies, causing an increase in monomer loss over time. ssNMR data also showed mixing heterogeneity of BSA and mannitol in the formulations with high mannitol contents. Futhermore, fine particle fraction (FPF) was found to decrease over time for the formulations containing BSA: Mannitol in the ratios of 2:1, 1:2, and 1:5, due to particle agglomeration induced by crystallization of mannitol. This study underscores the significant influence of excipients such as mannitol on the aerosol performance and storage stability of spray-dried protein formulations.

Subacute Toxicity of Microgranulated Myrmecodia platytyrea Aqueous Tuber Extract (gMPAE)

Introduction: Myrmecodia platytyrea, locally known as ‘Sarang Semut’, is an epiphytic plant native to Asia and the Asia Pacific. The tubers were traditionally used to manage cancer, hyperuricemia, and coronary heart diseases. Scientifically, the aqueous tuber extract has potential pharmacological benefits, including anti-cancer, anti-diabetic, and anti-inflammatory properties. Since the extract had no acute or subacute toxic effects, it might be used as a supplement to reduce inflammation and improve physiological functioning with better bioavailability than conventional preparations. This study aims to investigate the subacute toxicity of the microgranulated aqueous extract of M. platytyrea tuber (gMPAE). Methods: The formulation of the microgranules was established and analysed using a scanning electron microscope (SEM). The subacute oral toxicity study was carried out. The female nulliparous and non-pregnant ICR mice were divided into three groups (n=5), a group treated with normal saline (control group), a group treated with a placebo (blank microgranules), and a group treated with gMPAE, orally once daily for 28 days. Results: The gMPAE was produced using a spray-dry method and displayed microparticles with irregular shapes typical for spray-dried formulations. The sub-acute toxicity study showed no physical or behavioural changes in both placebo or gMPAE-treated mice compared to the control mice, with no mortality observed after 28 days of treatment and no signs of delayed occurrence of toxic effects 14 days post-treatment. Conclusion: Standardised spray-dried microgranules of M. platytyrea tuber aqueous extract were successfully developed to enhance the extract’s efficacy and are safe to be used as health supplements.

A dry powder formulation for peripheral lung delivery and absorption of an anti-SARS-CoV-2 ACE2 decoy polypeptide

One of the strategies proposed for the neutralization of SARS-CoV-2 has been to synthetize small proteins able to act as a decoy towards the virus spike protein, preventing it from entering the host cells. In this work, the incorporation of one of these proteins, LCB1, within a spray-dried formulation for inhalation was investigated. A design of experiments approach was applied to investigate the optimal condition for the manufacturing of an inhalable powder. The lead formulation, containing 6% w/w of LCB1 as well as trehalose and L-leucine as excipients, preserved the physical stability of the protein and its ability to neutralize the virus. In addition, the powder had a fine particle fraction of 58.6% and a very high extra-fine particle fraction (31.3%) which could allow a peripheral deposition in the lung. The in vivo administration of the LCB1 inhalation powder showed no significant difference in the pharmacokinetic from the liquid formulation, indicating the rapid dissolution of the microparticles and the protein capability to translocate into the plasma. Moreover, LCB1 in plasma samples still maintained the ability to neutralize the virus. In conclusion, the optimized spray drying conditions allowed to obtain an inhalation powder able to preserve the protein biological activity, rendering it suitable for a systemic prevention of the viral infection via pulmonary administration.

Mechanistic evaluation of the initial burst release of leuprolide from spray-dried PLGA microspheres

Spray-dried poly(lactic-co-glycolic acid) (PLGA) peptide-loaded microspheres have demonstrated similar long-term in vitro release kinetics compared to those produced by the solvent evaporation method and commercial products. However, the difficult-to-control initial burst release over the first 24 h after administration presents an obstacle to product development and establishing bioequivalence. Currently, detailed information about underlying mechanisms of the initial burst release from microspheres is limited. We investigated the mechanism and extent of initial burst release using 16 previously developed spray-dried microsphere formulations of the hormone drug, leuprolide acetate, with similar composition to the commercial 1-month Lupron Depot® (LD). The burst release kinetics was measured with a previously validated continuous monitoring system as well as traditional sample-and-separate methods. The changes in pore structure and polymer permeability were investigated by SEM imaging and the uptake of a bodipy-dextran probe. In vitro results were compared to pharmacokinetics in rats over the same interval. High-burst, spray-dried microspheres were differentiated in the well-mixed continuous monitoring system but reached an upper limit when measured by the sample-and-separate method. Pore-like occlusions observed by confocal microscopy in some formulations indicated that particle swelling may have contributed to probe diffusion through the polymer phase and showed the extensive internal pore structure of spray-dried particles. Continuous monitoring revealed a rapid primary (1°) phase followed by a constant-rate secondary (2°) release phase, which comprised ∼80% and 20% of the 24-hr release, respectively. The ratio of 1° phase duration (t1°) and the characteristic probe diffusion time (τ) was highly correlated to 1° phase release for spray dried particles. Of the four spray-dried formulations administered in vivo, three spray-dried microspheres with similar polymer density showed nearly ideal linear correlation between in vivo absorption and well-mixed in vitro release kinetics over the first 24 h. By contrast, the more structurally dense LD and a more-dense in-house formulation showed a slight lag phase in vivo relative to in vitro. Furthermore, in vitro dimensionless times (tburst/τ) were highly correlated with pharmacokinetic parameters for spray-dried microspheres but not for LD. While the correlation of increases in effective probe diffusion and 1° phase release strongly suggests diffusion through the polymer matrix as a major release mechanism both in vitro and in vivo, a fixed lower limit for this release fraction implies an alternative release mechanism. Overall, continuous monitoring release and probe diffusion appears to have potential in differentiating between leuprolide formulations and establishing relationships between in vitro release and in vivo absorption during the initial burst period.

Spray drying robot for high-throughput combinatorial fabrication of multicomponent solid dispersions

During the development of pharmaceutical spray-dried formulations, many samples must be prepared for physico-chemical characterisation and dissolution testing by systematically varying parameters such as drug loading or the grades and ratios of excipients (polymers, surfactants, etc.). When spray drying from organic solvents in a traditional laboratory set-up, the process must be stopped after producing each sample and then re-started, which makes combinatorial exploration of the formulation design space rather time-consuming. The present work reports a new approach using a device built around a commercially available laboratory spray dryer, which enables the preparation of powder samples with systematically varying composition within a single spray drying run. The device consists of three main parts whose purpose is to achieve: i) automatic combinatorial preparation of feed mixtures from up to 9 different stock solutions; ii) removal of adhered particles from the internal glass walls of the cyclone to minimise sample cross-contamination; and iii) automatic collection of individual powder samples in sealed vials without breaking the inert atmosphere. To validate the device operation and to demonstrate its ability to produce sets of powder samples in a short time, two cases studies were conducted: a model system with ternary mixtures of coloured lactose, and a pharmaceutical co-amorphous formulation with two actives and a polymeric excipient. The case studies show that an identical set of samples can be produces by up to 8× faster compared to manual screening, while keeping sample cross-contamination at around 1%. Ultimately, this can significantly increase the throughput of data collection and analysis during powder formulation studies.

Enhanced powder dispersion of dual-excipient spray-dried powder formulations of a monoclonal antibody and its fragment for local treatment of severe asthma

The advent of biologics has brought renewed hope for patients with severe asthma, a condition notorious for being hampered by poor response to conventional therapies and adverse drug reactions owing to corticosteroid dependence. However, biologics are administered as injections, thereby precluding the benefits inhalation therapy could offer such as increased bioavailability at the site of action, minimal systemic side effects, non-invasiveness, and self-administration. Here, 2-hydroxypropyl-beta-cyclodextrin and ʟ-leucine were co-spray-dried, as protein stabiliser and dispersion enhancer, respectively, at various weight ratios to produce a series of formulation platforms. Powder aerosolisation characteristics and particle morphology were assessed for suitability for pulmonary delivery. The selected platform with the best aerosol performance, a 1:1 ratio of the excipients, was then incorporated with a monoclonal antibody directed against IL-4 receptor alpha or its antigen-binding fragment. The dual-excipient antibody formulations exhibited emitted fraction of at least 80% and fine particle fraction exceeding 60% in cascade impactor study, while the residual moisture content was within a desirable range between 1% and 3%. The in vitro antigen-binding ability and inhibitory potency of the spray-dried antibody were satisfactorily preserved. The results from this study corroborate the viability of inhaled solid-state biomacromolecules as a promising treatment approach for asthma.

Inhalable ciprofloxacin/polymyxin B dry powders in respiratory infection therapy

The current study focused on the formulation, physicochemical characterization, and antibacterial susceptibility testing of inhalable spray dried powders containing ciprofloxacin (CIP) and polymyxin B sulfate (PMB). CIP nanosuspensions with an average particle diameter of 435.9 ± 9.3 nm were initially obtained using the wet-milling protocol and subsequently co-spray dried with PMB solutions to yield inhalable dry powders. The Powder X-Ray Diffraction (P-XRD) results showed that the wet-milled CIP nanoparticles were in a 4.8 hydrate state, which were transformed to 3.7 hydrates and amorphous materials after co-spray drying. The PMB remained in an amorphous state in the dry powders. Differential Scanning Calorimetry (DSC) analyses revealed that the glass transition temperatures (Tgs) of the co–spray dried formulations were higher than the Tg of CIP, but lower than the Tg of PMB. Fourier Transform Infrared Spectrometer (FTIR) studies suggested the existence of π - π interactions between CIP and PMB in the co-spray dried powders. These powders also retained antimicrobial effects against Pseudomonas aeruginosa strain PAO1. In addition, the spray-dried powder formulations exhibited satisfactory solid-state stability and aerodynamic characteristics when stored under 3% relative humidity and 20 ± 5 °C for 4 months. Overall, the newly developed inhalable CIP/PMB dry powders are a promising therapeutic strategy for respiratory tract infections.