Inhalable, Spray-Dried Terbinafine Microparticles for Management of Pulmonary Fungal Infections: Optimization of the Excipient Composition and Selection of an Inhalation Device

Terbinafine is a broad-spectrum antifungal agent with therapeutic potential against pulmonary aspergillosis. The main aim of the current study was to investigate the potential of l-leucine, alone and in combination with mannitol, to improve the performance of spray-dried terbinafine microparticles for inhalation. The study also aimed to investigate the potential of the low resistance Cyclohaler® and the high resistance Handihaler® as inhalation devices for spray-dried microparticles. To this end, eight powder inhalation formulations of terbinafine were prepared by nano spray drying via a factorial experimental design. The formulations were evaluated in vitro for their potential to deliver the antifungal drug to the lungs using the Cyclohaler® and the Handihaler®. Leucine was superior as an excipient to mannitol and to mixtures of leucine and mannitol. Using leucine as an excipient resulted in formulations with fine particle fractions of up to 60.84 ± 0.67% w/w and particle mass median aerodynamic diameters of down to 1.90 ± 0.20 μm, whereas using mannitol as an excipient resulted in formulations with fine particle fractions of up to 18.75 ± 3.46% w/w and particle mass median aerodynamic diameters of down to 6.79 ± 0.82 μm. When leucine was used as an excipient, using 50% w/w rather than 25% w/w ethanol in water as a spray solvent enhanced the dispersibility of the particles, with a mean absolute increase in the formulation fine particle fraction of 9.57% w/w (95% confidence interval = 6.40–12.73% w/w). This was potentially underlain by enrichment of the particle surfaces with leucine. The Cyclohaler® outperformed the Handihaler® as an inhalation device for the developed formulations, with a mean absolute increase in the fine particle fraction of 9.17% w/w (95% confidence interval = 8.17–10.16% w/w).

Pulmonary Drug Delivery of Antimicrobials and Anticancer Drugs Using Solid Dispersions

It is well established that currently available inhaled drug formulations are associated with extremely low lung deposition. Currently available technologies alleviate this low deposition problem via mixing the drug with inert larger particles, such as lactose monohydrate. Those inert particles are retained in the inhalation device or impacted in the throat and swallowed, allowing the smaller drug particles to continue their journey towards the lungs. While this seems like a practical approach, in some formulations, the ratio between the carrier to drug particles can be as much as 30 to 1. This limitation becomes more critical when treating lung conditions that inherently require large doses of the drug, such as antibiotics and antivirals that treat lung infections and anticancer drugs. The focus of this work article is to review the recent advancements in carrier free technologies that are based on coamorphous solid dispersions and cocrystals that can improve flow properties, and help with delivering larger doses of the drug to the lungs.

Comparison of User Satisfaction and Preference with Inhalant Devices Between a Pressurized Metered-Dose Inhaler and Ellipta in Stable Asthma Patients: A Randomized, Crossover Study

Introduction Inhalation therapy involves two types of adherence: adherence to the drug and adherence to the procedures for the inhalation device. User satisfaction and preference are key factors for maintaining good adherence of both types, and they should be evaluated based on three conditions being well maintained: asthma control level (ACL), adherence, and adequate device operability during usage duration. We compared user satisfaction and preference between a pressurized metered-dose inhaler (pMDI) and a dry powder inhaler (Ellipta), while maintaining the three conditions during usage in stable asthma patients. Methods In this open-label, randomized, two-way crossover study, patients with stable asthma [Asthma Control Questionnaire (ACQ) scores < 0.75] were classified into a 20–64-year age group (G1) and a ≥ 65-year age group (G2) and randomly assigned to either a formoterol/fluticasone combination (FFC) as the pMDI group or a vilanterol/fluticasone combination (VFC) as the Ellipta group. Satisfaction and preference levels were evaluated at week 4. ACL was measured using the ACQ and Japan Asthma Control Survey questionnaires at weeks 0 and 4. Device operability and respiratory resistance were also examined. Results Forty-four patients (23 G1, age 45.8 ± 1.9 years; 21 G2, 74.1 ± 1.3 years) were enrolled and maintained good ACL during the study. Adherence to FFC pMDI and VFC Ellipta was > 97% in all groups. Device operability did not differ significantly between FFC pMDI and VFC Ellipta in the G1 (p = 0.189) or G2 (p = 0.506) group. Overall satisfaction was marginally higher with the FFC pMDI than with the VFC Ellipta in G2 (p = 0.012) but non-significantly different in G1 (p = 0.733). Factors affecting overall satisfaction in G2 were difference of inhalation device and body mass index. Respiratory resistance did not change significantly over the study in G2. Conclusion Based on maintaining good ACL, adherence, and device operability, FFC pMDI showed significantly higher satisfaction and preference levels than VFC Ellipta in elderly persons. Trial Registration Japan Registry of Clinical Trials identifier, jRCTs041180001 (registered 21 August 2018).

Developing inhaled protein therapeutics for lung diseases

Biologic therapeutics such as protein/polypeptide drugs are conventionally administered systemically via intravenous injection for the treatment of diseases including lung diseases, although this approach leads to low target site accumulation and the potential risk for systemic side effects. In comparison, topical delivery of protein drugs to the lung via inhalation is deemed to be a more effective approach for lung diseases, as proteins would directly reach the target in the lung while exhibiting poor diffusion into the systemic circulation, leading to higher lung drug retention and efficacy while minimising toxicity to other organs. This review examines the important considerations and challenges in designing an inhaled protein therapeutics for local lung delivery: the choice of inhalation device, structural changes affecting drug deposition in diseased lungs, clearance mechanisms affecting an inhaled protein drug’s lung accumulation, protein stability, and immunogenicity. Possible approaches to overcoming these issues will also be discussed.

Maintenance Therapy with Nebulizers in Patients with Stable COPD: Need for Reevaluation

Patients with stable COPD rely heavily on inhaled bronchodilators and corticosteroids to control symptoms, maximize quality of life, and avoid exacerbations and costly hospitalizations. These drugs are typically delivered by hand-held inhalers or nebulizers. The majority of patients are prescribed inhalers due to their perceived convenience, portability, and lower cost, relative to nebulizers. Unfortunately, poor inhaler technique compromises symptom relief in most of these patients. In contrast to one or two puffs through an inhaler, nebulizers deliver a drug over many breaths, through tidal breathing, and hence are more forgiving to poor inhalation technique. To what extent susceptibility to errors in their use may influence the relative effectiveness of these two types of inhalation device has received little attention in COPD research. In 2005, a systematic review of the literature concluded that nebulizers and inhalers are equally effective in patients who are adequately trained to use their inhalation device. This conclusion was based on two small clinical trials that only examined objective measures of lung function. Since then, additional studies have found that maintenance therapy administered by nebulizers could improve patients’ reported feelings of symptom relief, quality of life, and satisfaction with treatment, compared to therapy administered by inhalers. Because it has been 15 years since the publication of the systematic review, in this article we summarize the results of studies that compared the effectiveness of inhalers with that of nebulizers in patients with stable COPD and discuss their implications for clinical practice and need for future research.