Triple combination dry powder formulation of pretomanid, moxifloxacin, and pyrazinamide for treatment of multidrug-resistant tuberculosis.

Both latent and multidrug-resistant tuberculosis (TB) have been causing significant concern worldwide. A novel drug, pretomanid (PA-824), has shown a potent bactericidal effect against both active and latent forms of Mycobacterium tuberculosis (MTb) and a synergistic effect when combined with pyrazinamide and moxifloxacin. This study aimed to develop triple combination spray dried inhalable formulations composed of antitubercular drugs, pretomanid, moxifloxacin, and pyrazinamide (1:2:8 w/w/w), alone (PaMP) and in combination with an aerosolization enhancer, L-leucine (20 % w/w, PaMPL). The formulation PaMPL consisted of hollow, spherical, dimpled particles (<5 µm) and showed good aerosolization behaviour with a fine particle fraction of 70 %. Solid-state characterization of formulations with and without L-leucine confirmed the amorphous nature of moxifloxacin and pretomanid and the crystalline nature of pyrazinamide with polymorphic transformation after the spray drying process. Further, the X-ray photoelectron spectroscopic analysis revealed the predominant surface composition of L-leucine on PaMPL dry powder particles. The dose-response cytotoxicity results showed pyrazinamide and moxifloxacin were non-toxic in both A549 and Calu-3 cell lines up to 150 µg/mL. However, the cell viability gradually decreased to 50 % when the pretomanid concentration increased to 150 µg/mL. The in vitro efficacy studies demonstrated that the triple combination formulation had more prominent antibacterial activity with a minimum inhibitory concentration (MIC) of 1 µg/mL against the MTb H37Rv strain as compared to individual drugs. In conclusion, the triple combination of pretomanid, moxifloxacin, and pyrazinamide as an inhalable dry powder formulation will potentially improve treatment efficacy with fewer systemic side effects in patients suffering from latent and multidrug-resistant TB.

The quest to deliver high-dose rifampicin: can the inhaled approach help?

INTRODUCTION: Tuberculosis (TB) is a global health problem that poses a challenge to global treatment programs. Rifampicin is a potent and highly effective drug for TB treatment; however, higher oral doses than the standard dose (10 mg/kg/day) rifampicin may offer better efficacy in TB treatment. AREAS COVERED: High oral dose rifampicin is not implemented in anti-TB regimens yet and requires about a 3-fold increase in dose for increased efficacy. We discuss inhaled delivery of rifampicin as an alternative or adjunct to oral high-dose rifampicin. Clinical results of safety, tolerability, and patient compliance with antibiotic dry powder inhalers are reviewed. EXPERT OPINION: Clinical trials suggest that an approximately 3-fold increase in the standard oral dose of rifampicin may be required for better clinical outcomes. On the other hand, animal studies suggest that inhaled rifampicin can deliver a high concentration of the drug to the lungs and achieve approximately double the plasma concentration than that from oral rifampicin. Clinical trials on inhaled antibiotics suggest that dry powder inhalation is a patient-friendly and well-tolerated approach in treating respiratory infections compared to conventional treatments. Rifampicin, a well-known anti-TB drug given orally, is a good candidate for clinical development as a dry powder inhaler.

Repurposing ebselen as an inhalable dry powder to treat respiratory tract infections.

Respiratory tract infections (RTIs) are one of the leading causes of death globally, lately exacerbated by the increasing prevalence of antimicrobial resistance. While antimicrobial resistance could be overcome by developing new antimicrobial agents, the use of a safe repurposed agent having potent antimicrobial activity against various RTIs can be an efficient and cost-effective alternative to overcome the long and complex process of developing and testing new drugs. Ebselen, a synthetic organoselenium drug originally developed to treat noise-inducing hearing problems, has shown promising antimicrobial activity in vitro against several respiratory pathogens including viruses (e.g., SARS-CoV-2, influenza A virus) and bacteria (e.g., Mycobacterium tuberculosis, Streptococcus pneumoniae, and Staphylococcus aureus). Inhaled drug delivery is considered a promising approach for treating RTIs, as it can ensure effective drug concentrations at a lower dose, thereby minimizing the side effects that are often encountered by using oral or injectable drugs. In this study, we developed inhalable ebselen dry powder formulations using a spray-drying technique. The amino acids leucine, methionine, and tryptophan were incorporated with ebselen to enhance the yield and aerosolization of the dry powders. The amino acid-containing ebselen dry powders showed a better yield (37-56.4 %) than the amino acid-free formulation (30.9 %). All dry powders were crystalline in nature. The mass median aerodynamic diameter (MMAD) was less than 5 µm for amino acids containing dry powders (3-4 µm) and slightly higher (5.4 µm) for amino acid free dry powder indicating their suitability for inhalation. The aerosol performance was higher when amino acids were used, and the leucine-containing ebselen dry powder showed the highest emitted dose (84 %) and fine particle fraction (68 %). All amino acid formulations had similar cytotoxicity as raw ebselen, tested in respiratory cell line (A549 cells), with half-maximal inhibitory concentrations (IC50) between 100 and 250 µg/mL. Raw ebselen and amino acid-containing dry powders showed similar potent antibacterial activity against the Gram-positive bacteria S. aureus and S. pneumoniae with minimum inhibitory concentrations of 0.31 µg/mL and 0.16 µg/mL, respectively. On the other hand, raw ebselen and the formulations showed limited antimicrobial activity against the Gram-negative pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae. In summary, in this study we were able to develop amino-acid-containing inhalable dry powders of ebselen that could be used against different respiratory pathogens, especially Gram-positive bacteria, which could ensure more drug deposition in the respiratory tract, including the lungs. DPIs are generally used to treat lung (lower respiratory tract) diseases. However, DPIs can also be used to treat both upper and lower RTIs. The deposition of the dry powder in the respiratory tract is dependent on its physicochemical properties and this properties can be modulated to target the intended site of infection (upper and/or lower respiratory tract). Further studies will allow the development of similar formulations of individual and/or combination of antimicrobials that could be used to inhibit a number of respiratory pathogens.

Inhalable dry powder containing remdesivir and disulfiram: Preparation and in vitro characterization.

The respiratory tract, as the first and most afflicted target of many viruses such as SARS-CoV-2, seems to be the logical choice for delivering antiviral agents against this and other respiratory viruses. A combination of remdesivir and disulfiram, targeting two different steps in the viral replication cycle, has showed synergistic activity against SARS-CoV-2 in-vitro. In this study, we have developed an inhalable dry powder containing a combination of remdesivir and disulfiram utilizing the spray-drying technique, with the final goal of delivering this drug combination to the respiratory tract. The prepared dry powders were spherical, and crystalline. The particle size was between 1 and 5 µm indicating their suitability for inhalation. The spray-dried combinational dry powder containing remdesivir and disulfiram (RDSD) showed a higher emitted dose (ED) of >88% than single dry powder of remdesivir (RSD) (∼72%) and disulfiram (DSD) (∼84%), with a fine particle fraction (FPF) of ∼55%. Addition of L-leucine to RDSD showed >60% FPF with a similar ED. The in vitro aerosolization was not significantly affected after the stability study conducted at different humidity conditions. Interestingly, the single (RSD and DSD) and combined (RDSD) spray-dried powders showed limited cellular toxicity (CC50 values from 39.4 to >100 µM), while maintaining their anti-SARS-CoV-2 in vitro (EC50 values from 4.43 to 6.63 µM). In a summary, a combinational dry powder formulation containing remdesivir and disulfiram suitable for inhalation was developed by spray-drying technique which showed high cell viability in the respiratory cell line (Calu-3 cells) retaining their anti-SARS-CoV-2 property. In the future, in vivo studies will test the ability of these formulations to inhibit SARS-CoV-2 which is essential for clinical translation.

Spray-Dried Inhalable Microparticles Combining Remdesivir and Ebselen against SARS-CoV-2 Infection.

There is a continuous effort to develop efficient treatments for coronavirus disease 2019 (COVID-19) and other viral respiratory diseases. Among the different strategies, inhaled treatment is considered one of the most logical and efficient approaches to treating COVID-19, as the causative "SARS-CoV-2 virus RNA" predominantly infects the respiratory tract. COVID-19 treatments initially relied on repurposed drugs, with a few additional strategies developed during the last two years, and all of them are based on monotherapy. However, drug combinations have been found to be more effective than monotherapy in other viral diseases such as HIV, influenza, and hepatitis C virus. In the case of SARS-CoV-2 infection, in vitro studies have shown synergistic antiviral activity combining remdesivir with ebselen, an organoselenium compound. Therefore, these drug combinations could ensure better therapeutic outcomes than the individual agents. In this study, we developed a dry powder formulation containing remdesivir and ebselen using a spray-drying technique and used L-leucine as an aerosolization enhancer. The prepared dry powders were spherical and crystalline, with a mean particle size between 1 and 3 µm, indicating their suitability for inhalation. The emitted dose (ED) and fine particle fraction (FPF) of remdesivir- and ebselen-containing dry powders were ~80% and ~57% when prepared without L-leucine. The ED as well as the FPF significantly increased with values of >86% and >67%, respectively, when L-leucine was incorporated. More importantly, the single and combinational dry powder of remdesivir and ebselen showed minimal cytotoxicity (CC50 > 100 µM) in Calu-3 cells, retaining their anti-SARS-CoV-2 properties (EC50 2.77 to 18.64 µM). In summary, we developed an inhalable dry powder combination of remdesivir and ebselen using a spray-drying technique. The spray-dried inhalable microparticles retained their limited cytotoxicity and specific antiviral properties. Future in vivo studies are needed to verify the potential use of these remdesivir/ebselen combinational spray-dried inhalable microparticles to block the SARS-CoV-2 replication in the respiratory tract.

Inhalable Combination Powder Formulations for Treating Latent and Multidrug-Resistant Tuberculosis: Formulation and In Vitro Characterization.

Tuberculosis (TB) is an infectious disease resulting in millions of deaths annually worldwide. TB treatment is challenging due to a huge number of global latent infections and due to multidrug-resistant forms of TB. Inhaled administration of anti-TB drugs using dry powder inhalers has various advantages over oral administration due to its direct drug delivery and minimization of systemic side effects. Pretomanid (PA-824, PA) is a relatively new drug with potent activity against both active and latent forms of Mycobacterium tuberculosis (Mtb). It is also known for its synergistic effects in combination with pyrazinamide (PYR) and moxifloxacin (MOX). Fixed-dose combination powder formulations of either PYR and PA or PYR and MOX were prepared for inhaled delivery to the deep lung regions where the Mtb habitats were located. Powder formulations were prepared by spray drying using L-leucine as the aerosolization enhancer and were characterized by their particle size, morphology and solid-state properties. In vitro aerosolization behaviour was studied using a Next Generation Impactor, and stability was assessed after storage at room temperature and 30% relative humidity for three months. Spray drying with L-leucine resulted in spherical dimpled particles, 1.9 and 2.4 µm in size for PYR-PA and PYR-MOX combinations, respectively. The powder formulations had an emitted dose of >83% and a fine particle fraction of >65%. PA and MOX showed better stability in the combination powders compared to PYR. Combination powder formulations with high aerosolization efficiency for direct delivery to the lungs were developed in this study for use in the treatment of latent and multidrug-resistant TB infections.

A review of formulations and preclinical studies of inhaled rifampicin for its clinical translation.

Inhaled drug delivery is a promising approach to achieving high lung drug concentrations to facilitate efficient treatment of tuberculosis (TB) and to reduce the overall duration of treatment. Rifampicin is a good candidate for delivery via the pulmonary route. There have been no clinical studies yet at relevant inhaled doses despite the numerous studies investigating its formulation and preclinical properties for pulmonary delivery. This review discusses the clinical implications of pulmonary drug delivery in TB treatment, the drug delivery systems reported for pulmonary delivery of rifampicin, animal models, and the animal studies on inhaled rifampicin formulations, and the research gaps hindering the transition from preclinical development to clinical investigation. A review of reports in the literature suggested there have been minimal attempts to test inhaled formulations of rifampicin in laboratory animals at relevant high doses and there is a lack of appropriate studies in animal models. Published studies have reported testing only low doses (≤ 20 mg/kg) of rifampicin, and none of the studies has investigated the safety of inhaled rifampicin after repeated administration. Preclinical evaluations of inhaled anti-TB drugs, such as rifampicin, should include high-dose formulations in preclinical models, determined based on allometric conversions, for relevant high-dose anti-TB therapy in humans.

In vitro Dissolution Testing of Rifampicin Powder Formulations For Prediction of Plasma Concentration-Time Profiles After Inhaled Delivery.

PURPOSE: The purpose of this study was to evaluate the in vitro lung dissolution of amorphous and crystalline powder formulations of rifampicin in polyethylene oxide (PEO) and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), and to predict the in vivo plasma concentration-time profiles using the in vitro data. METHODS: The in vitro dissolution and permeation profiles of respirable rifampicin particles were studied using a custom-made dissolution apparatus. Data from the in vitro dissolution test were used to estimate the parameters to be used as the input for the simulation of in vivo plasma concentration-time profiles using STELLA® software. For prediction of in vivo profiles, a one-compartment model either with a first order elimination or with a Michaelis-Menten kinetics-based elimination was used. RESULTS: Compared to the crystalline formulation, the amorphous formulation showed rapid in vitro dissolution suggesting their possible faster in vivo absorption and higher plasma concentrations of rifampicin following lung delivery. However, the simulations suggested that both powder formulations would result in similar plasma-concentration time profiles of rifampicin. CONCLUSIONS: Use of an in vitro dissolution test coupled with a simulation model for prediction of plasma-concentration time profiles of an inhaled drug was demonstrated in this work. These models can also be used in the design of inhaled formulations by controlling their release and dissolution properties to achieve desired lung retention or systemic absorption following delivery to the lungs.

Amorphicity and Aerosolization of Soluplus-Based Inhalable Spray Dried Powders.

Soluplus is a polymer that has been explored to prepare nanocomposites for pulmonary drug delivery and is non-toxic. However, its aerosolization attributes when spray-dried have not been investigated. Hence, this work aimed to investigate the aerosol performance of soluplus-based spray-dried powders. In addition, the potential use of leucine to improve the aerosolization of such particles was also investigated by including leucine at 10 or 20% w/w. 4% w/w salbutamol was used as a model drug in all the formulations primarily to aid quantification during aerosolization evaluation and for assessing the interaction between the drug and soluplus using infrared spectroscopy with the multivariate analysis approach of principal component analysis (PCA). Three formulations (4% salbutamol/96% soluplus, 4% salbutamol/86% soluplus/10% leucine, 4% salbutamol/76% soluplus/20% leucine) were prepared. The formulations were characterized in terms of solid-state, water content, particle size/morphology, and aerosolization. Similarly, two additional formulations (14% salbutamol/86% soluplus and 24% salbutamol/76% soluplus) were prepared to assess potential non-covalent interactions between salbutamol and soluplus. The formulations with only salbutamol and soluplus were amorphous, as evident from X-ray diffraction. Leucine was crystalline in the formulations. All the spray-dried formulations were irregular spheres with surface corrugation. The 96% soluplus powder showed an emitted fraction (EF) and fine particles fraction (FPF) of 91.9 and 49.8%, respectively. The inclusion of leucine at 10% did not increase the EF; however, an increase in FPF (69.7%) was achieved with 20% leucine. PCA of the infrared spectra suggested potential non-covalent interactions between salbutamol and soluplus. It hinted at the potential involvement of ketone groups of the excipient. This study concludes that soluplus-based spray-dried powder with or without leucine can potentially be utilized for pulmonary drug delivery. In addition, PCA can effectively be utilized in assessing interactions and overcoming limitations associated with visual assessment of the spectra of such formulations.

Dissolution and Absorption of Inhaled Drug Particles in the Lungs.

Dry powder inhalation therapy has been effective in treating localized lung diseases such asthma, chronic obstructive pulmonary diseases (COPD), cystic fibrosis and lung infections. In vitro characterization of dry powder formulations includes the determination of physicochemical nature and aerosol performance of powder particles. The relationship between particle properties (size, shape, surface morphology, porosity, solid state nature, and surface hydrophobicity) and aerosol performance of an inhalable dry powder formulation has been well established. However, unlike oral formulations, there is no standard dissolution method for evaluating the dissolution behavior of the inhalable dry powder particles in the lungs. This review focuses on various dissolution systems and absorption models, which have been developed to evaluate dry powder formulations. It covers a summary of airway epithelium, hurdles to developing an in vitro dissolution method for the inhaled dry powder particles, fine particle dose collection methods, various in vitro dissolution testing methods developed for dry powder particles, and models commonly used to study absorption of inhaled drug.

Inhalable ceftazidime-roflumilast powder targeting infection and inflammation: Influence of incorporating roflumilast into ceftazidime-leucine co-amorphous formulation.

Co-amorphization of a single drug with amino acid is a technique to improve aerosolization of inhalable spray-dried formulation for inhalation therapy. However, the incorporation of a second drug molecule into drug-amino acid co-amorphous particles to prepare combination formulations has not been explored. Here, we prepared combination powders using two model drugs, ceftazidime and roflumilast, which when concurrently used can potentially improve therapeutic outcome in non-cystic fibrosis bronchiectasis by counteracting both infection and inflammation. The study was performed using a two-step approach. The first step involved the identification of an amino acid and its concentration (% w/w) for the best aerosolization enhancement of ceftazidime by varying the ratios of leucine and tryptophan in combination (0-25 % w/w). In the second step, roflumilast (5-20 % w/w) was incorporated into the formulation containing the selected concentration of the amino acid to understand the impact of introducing a second drug into ceftazidime-amino acid(s) co-amorphous particles. In total, 10 formulations were prepared and characterized in terms of solid-state and aerosol performance. Leucine introduced surface asperity which correlated well with improved aerosolization of the particles. The best fine particle fraction (FPF) (75 %) was achieved with 25 % leucine; hence, leucine was selected as the ideal amino acid at the given concentration to understand the impact of roflumilast inclusion on ceftazidime-leucine system. The ceftazidime-roflumilast powder retained their anti-bacterial and anti-inflammatory properties following formulation. However, inclusion of roflumilast at 5 % dramatically decreased the FPF to 55 % and higher roflumilast concentration did not have much effect on FPF. The decrease in FPF ascribed to the change in particle surface as roflumilast was found to decrease surface asperity. In addition, leucine crystallized with inclusion of roflumilast. This study indicates that inclusion of a second drug into drug-amino acid amorphous matrix particles can affect its solid-state dynamics and aerosol performance; hence, such parameters should be cautiously considered while undertaking similar endeavors of preparing combination formulations.

Solid state of inhalable high dose powders.

High dose inhaled powders have received increased attention for treating lung infections. These powders can be prepared using techniques such as spray drying, spray-freeze drying, crystallization, and milling. The selected preparation technique is known to influence the solid state of the powders, which in turn can potentially modulate aerosolization and aerosolization stability. This review focuses on how and to what extent the change in solid state of high dose powders can influence aerosolization. It also discusses the commonly used solid state characterization techniques and the application of potential strategies to improve the physical and chemical stability of the amorphous powders for high dose delivery.

Inhaled therapy for COVID-19: Considerations of drugs, formulations and devices.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for the COVID-19 pandemic, has outspread at full tilt across the world. Although several effective vaccines continue to be deployed, reliable antiviral treatments have yet to be developed against this disease. Currently, available therapeutics for COVID-19 include repurposed, and a few novel drugs. Many drugs have been promising in preclinical studies, but a majority of these drugs have shown little or no efficacy in clinical studies. One of the major reasons is the insufficient drug concentration in the lung, the primary target site of infection for SARS-CoV-2, from the administration of drugs through oral or intravenous routes. Higher effective doses administered through these routes could also lead to adverse side effects. For this reason, inhaled treatments are being tested as an efficient approach for COVID-19, allowing lower doses of drugs ensuring higher concentrations of the drug(s) in the lung. The inhaled treatment combining two or more antiviral drugs will increase potency and reduce the possibility of selecting for SARS-CoV-2 variants with reduced drug susceptibility. Finally, the appropriate drug combination needs to be delivered using a suitable system. Here, we review the current treatment for COVID-19 and their limitations, discussing the advantages of mono and combinational inhaled therapy with a brief outline of the recently reformulated anti-SARS-CoV-2 agents as inhaled formulations. The selection of appropriate delivery devices for inhalation and associated key considerations including the formulation challenges are also discussed.

Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder.

SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved anti-parasitic drug, was originally shown to inhibit SARS-CoV-2 replication in vitro, albeit at relatively high concentrations, which is difficult to achieve in the lung. In this study, we tested the spray-drying conditions to develop an inhalable dry powder formulation that could ensure sufficient antiviral drug concentrations, which are difficult to achieve in the lungs based on the oral dosage used in clinical trials. Here, by using ivermectin as a proof-of-concept, we evaluated spray-drying conditions that could lead to the development of antivirals in an inhalable dry powder formulation, which could then be used to ensure sufficient drug concentrations in the lung. Thus, we used ivermectin in proof-of-principle experiments to evaluate our system, including physical characterization and in vitro aerosolization of prepared dry powder. The ivermectin dry powder was prepared with a mini spray-dryer (Buchi B-290), using a 23 factorial design and manipulating spray-drying conditions such as feed concentration (0.2% w/v and 0.8% w/v), inlet temperature (80 °C and 100 °C) and presence/absence of L-leucine (0% and 10%). The prepared dry powder was in the size range of 1−5 µm and amorphous in nature with wrinkle morphology. We observed a higher fine particle fraction (82.5 ± 1.4%) in high feed concentration (0.8% w/v), high inlet temperature (100 °C) and the presence of L-leucine (10% w/w). The stability study conducted for 28 days confirmed that the spray-dried powder was stable at 25 ± 2 °C/<15% RH and 25 ± 2 °C/ 53% RH. Interestingly, the ivermectin dry powder formulation inhibited SARS-CoV-2 replication in vitro with a potency similar to ivermectin solution (EC50 values of 15.8 µM and 14.1 µM, respectively), with a comparable cell toxicity profile in Calu-3 cells. In summary, we were able to manipulate the spray-drying conditions to develop an effective ivermectin inhalable dry powder. Ongoing studies based on this system will allow the development of novel formulations based on single or combinations of drugs that could be used to inhibit SARS-CoV-2 replication in the respiratory tract.

An expert opinion on respiratory delivery of high dose powders for lung infections.

INTRODUCTION: High dose powder inhalation is evolving as an important approach to to treat lung infections. It is important to its identify applications, consider the factors affecting high dose powder delivery, and assess the effect of high dose drugs in patients. AREA COVERED: Both current and pipeline high dose inhalers and their applications have been summarized. Challenges and opportunities to high dose delivery have been highlighted after reviewing formulation techniques in the context of factors affecting aerosolization, devices, and patient factors. EXPERT OPINION: High dose inhaled delivery of antimicrobials is an innovative way to increase treatment efficacy of respiratory infections, tackle drug resistance, and the scarcity of new antimicrobials. The high dose inhaled technology also has potential for systemic action; however, innovations in formulation strategies and devices are required to realize its full potential. Advances in formulation strategies include the use of excipients or the engineering of particles to decrease the cohesive property of microparticles and their packing density. Similarly, selection of a synergistic drug instead of an excipient can be considered to increase aerosolization and stability. Device development focused on improving dispersion and loading capacity is also important, and modification of existing devices for high dose delivery can also be considered.

Amino acids improve aerosolization and chemical stability of potential inhalable amorphous Spray-dried ceftazidime for Pseudomonas aeruginosa lung infection.

Pseudomonas aeruginosa infection is common in cystic fibrosis as well as non-cystic fibrosis bronchiectasis. The pathogen presents challenges for treatment due to its adaptive antibiotic-resistance, mainly pertaining to its biofilm-forming ability, as well as limitations associated with conventional drug delivery in achieving desired therapeutic concentration in the infection site. Hence, therapeutic approach has shifted towards the inhalation of antibiotics. Ceftazidime is a potent antibiotic against the pathogen; however, it is currently only available as a parenteral formulation. Here, spray dryer was employed to generate inhalable high dose ceftazidime microparticles. In addition, the use of amino acids (valine, leucine, methionine, phenylalanine, and tryptophan) to improve aerosolization as well as chemical stability of amorphous ceftazidime was explored. The particles were characterized using X-ray diffraction, infrared (IR) spectroscopy, calorimetry, electron microscopy, particle size analyzer, and next generation impactor. The chemical stability at 25 °C/<15% was assessed using chromatography. All co-spray dried formulations were confirmed as monophasic amorphous systems using calorimetry. In addition, principal component analysis of the IR spectra suggested potential interaction between tryptophan and ceftazidime in the co-amorphous matrix. Inclusion of amino acids improved aerosolization and chemical stability in all cases. Increase in surface asperity was clear with the use of amino acids which likely contributed to the improved aerosol performance, and potential interaction between amino acids and ceftazidime was plausibly the reason for improved chemical stability. Leucine offered the best aerosolization enhancement with a fine particle fraction of 78% and tryptophan showed stabilizing superiority by reducing chemical degradation by 51% over 10 weeks in 1:1 M ratio. The protection against ceftazidime degradation varied with the nature of amino acids. Additionally, there was a linear relationship between degradation protection and molar mass of amino acids or percentage weight of amino acids in the formulations. None of the amino acids were successful in completely inhibiting degradation of ceftazidime in amorphous spray-dried powder to prepare a commercially viable product with desired shelf-life. All the amino acids and ceftazidime were non-toxic to A549 alveolar cell line.

Optimization of methionine in inhalable High-dose Spray-dried amorphous composite particles using response surface Method, infrared and low frequency Raman spectroscopy.

The influence of amino acids, other than leucine, in improving aerosolization of inhalable powders has not been widely explored. This detailed study focused on the use of methionine, another promising endogenous amino acid, in high dose spray-dried co-amorphous powders by investigating the influence of methionine proportion (0 - 20% w/w), and feed concentration (0.2 - 0.8% w/v) on aerosolization of kanamycin, a model drug, using a design of experiment approach. Low frequency Raman spectroscopy was used to assess the stability of the powders stored at 25 °C/53% relative humidity over 28 days. An increase in concentration of methionine was associated with an increase in fine particle fraction (FPF), with the highest FPF of 84% being achieved at 20% w/w and 0.2% w/v feed concentration. With an increase in feed concentration, both yield and particle size increased for all formulations; the FPF did not change except for kanamycin only formulation in which it decreased. During storage at high humidity, similar aerosolization stabilities were offered by different proportions of methionine although methionine crystallized out in all formulations. Furthermore, the crystallization was accompanied by surface enrichment of methionine on the particles. This study suggests that there is a direct relationship between methionine content and aerosolization for kanamycin-methionine amorphous matrices but feed concentration has little effect. In addition, methionine proportion has no effect on physical stability of such matrices at high humidity.

Alcohol-based hand sanitizer - composition, proper use and precautions.

During the COVID-19 pandemic, the use of alcohol-based hand sanitizers (ABHS) increased worldwide among the public as well as the health care workers in pursuit to prevent the spread of SARS-CoV-2, the causative virus of COVID-19. Hand hygiene is one of the primary preventive measures to prevent the spread of harmful germs. Although ABHS are effective hand hygiene products and help reduce the transmission of pathogenic microorganisms, appropriate use of such products is necessary to ensure the maximum killing of pathogens and to prevent hazards associated with ABHS. The effectiveness of ABHS against different microorganisms, including SARS-CoV-2 is also documented, but proper knowledge on hand hygiene techniques, selection of appropriate hand sanitizer product, and safe handling of ABHS are required to avoid their adverse effects such as allergies, skin irritation, lung injury, fire hazards, and toxicities. The effectiveness of ABHS is dependent on several factors including its appropriate usage, manufacturing methods, the choice of active agents, and the appropriateness of the agent on the target pathogen. This article highlights the importance of proper usage, handling, and appropriate ABHS selection for maximum efficacy against intended pathogens and safe use of ABHS. User awareness can help promote the appropriate usage of ABHS and prevent its hazards, which ultimately can help in preventing the transmission of pathogenic microorganisms.

Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization.

Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and potentially circumvent the associated toxicity. Roflumilast was cospray-dried with trehalose and L-leucine with varied feed concentrations and spray-gas flow rates to produce the desired dry powder. A Next-Generation Impactor (NGI) was used to assess the aerosolization efficiency. In addition, different devices (Aerolizer, Rotahaler, and Handihaler) and flow rates were used to investigate their effects on the aerosolization efficiency. A cytotoxicity assay was also performed. The powders produced under optimized conditions were partially amorphous and had low moisture content. The powders showed good dispersibility, as evident by the high emitted dose (>88%) and fine particle fraction (>52%). At all flow rates (≥30 L/min), the Aerolizer offered the best aerosolization. The formulation exhibited stable aerosolization after storage at 25 °C/15% Relative Humidity (RH) for one month. Moreover, the formulation was non-toxic to alveolar basal epithelial cells. A potential inhalable roflumilast formulation including L-leucine and trehalose has been developed for the treatment of COPD. This study also suggests that the choice of device is crucial to achieve the desired aerosol performance.

Pharmacokinetics of rifampicin after repeated intra-tracheal administration of amorphous and crystalline powder formulations to Sprague Dawley rats.

Rifampicin is one of the key drugs used to treat tuberculosis and is currently used orally. The use of higher oral doses of rifampicin is desired for better therapeutic efficacy, but this is accompanied by increased risk of systemic toxicity thus limiting its recommended oral dose to 10 mg/kg per day. Inhaled delivery of rifampicin is a potential alternative mode of delivery, to achieve high drug concentrations in both the lung and potentially the systemic circulation. In addition, rifampicin exists either as amorphous or crystalline particles, which may show different pharmacokinetic behaviour. However, disposition behaviour of amorphous and crystalline rifampicin formulations after inhaled high-dose delivery is unknown. In this study, rifampicin pharmacokinetics after intra-tracheal administration of carrier-free, amorphous and crystalline powder formulations to Sprague Dawley rats were evaluated. The formulations were administered once daily for seven days by oral, intra-tracheal and oral plus intra-tracheal delivery, and the pharmacokinetics were studied on day 0 and day 6. Intra-tracheal administration of the amorphous formulation resulted in a higher area under the plasma concentration curve (AUC) compared to the crystalline formulation. For both formulations, the intra-tracheal delivery led to significantly higher AUC compared to the oral delivery at the same dose suggesting higher rifampicin bioavailability from the inhaled route. Increasing the intra-tracheal dose resulted in a more than dose proportional AUC suggesting non-linear pharmacokinetics of rifampicin from the inhaled route. Upon repeated administration for seven days, no significant decrease in the AUCs were observed suggesting the absence of rifampicin induced enzyme auto-induction in this study. The present study suggests an advantage of inhaled delivery of rifampicin in achieving higher drug bioavailability compared to the oral route.