Aerosol Synthesis of Inhalation Particles via a Droplet-to-Particle Method

Inhalation powders with consistent particle properties, including particle size, size distribution, and shape were produced with an aerosol synthesis method. Compared to conventional spray drying, the aerosol method provides better control of the thermal history and residence time of each droplet and product particle due to the laminar flow in the heated zone of the reactor where the droplet drying and particle formation take place. A corticosteroid, beclomethasone dipropionate, generally used for asthma treatment was chosen as a representative material to demonstrate the process. Spherical particles were produced with a droplet-to-particle method from an ethanolic precursor solution. The droplets produced with an ultrasonic nebulizer were carried to a heated zone of the reactor at 50-150°C where the solvent was evaporated and dry particles formed. The mass mean diameter of the particles were well within the respirable size range (approximately 2 μm). The geometric standard deviation (GSD) of produced particles was approximately 2. The particle surface structure varied from smooth to rough depending on the degree of particle crystallinity and was affected by the thermal history of the particle. Amorphous particles with smooth surface were most likely obtained due to the rapid evaporation of the solvent from the droplet combined with the slow diffusion of the beclomethasone dipropionate molecule. The amorphous particles were transformed slowly to crystalline particles in the open atmosphere. In addition, the particle surface structure changed from smooth to rough during storage. The process was accelerated by thermal post-annealing. However, additional heating also increased particle sintering. By optimizing the reactor parameters, and thus increasing the molecular diffusion, stable, crystalline particles were produced at 150°C.     

Evaluating the protective effects of radon inhalation or ascorbic acid treatment after transient global cerebral ischemic injury in gerbils

In this study, we compared the protective effects of radon inhalation and ascorbic acid administration on transient global cerebral ischemic injury in gerbils. Gerbils were treated with radon inhalation (2000 Bq/m³, 24 hours) or ascorbic acid (100, 300, or 500 mg/kg body weight). Then, transient global cerebral ischemia was induced by bilateral occlusion of the common carotid artery. Results showed that the number of damaged neurons was significantly increased in gerbils that underwent ischemia compared with that in control gerbils. However, the number of damaged neurons in gerbils treated with radon or 500 mg/kg of ascorbic acid before ischemia was significantly lower than gerbils who were subjected to ischemia without any pretreatment, and the protective effects of radon inhalation were similar to the effects of administering 500 mg/kg ascorbic acid. The levels of superoxide dismutase (SOD) and total glutathione (t-GSH) in brain tissue were increased to a similar extent by pretreatment with radon inhalation or 500 mg/kg of ascorbic acid. These findings suggested that radon inhalation has a protective antioxidative effect against transient global cerebral ischemic injury similar to 500 mg/kg ascorbic acid treatment.     

Advancements in Dry Powder Delivery to the Lung

The dry powder inhaler (DPI) has become widely known as a very attractive platform for drug delivery. Many patients have traditionally used DPIs to treat asthma and chronic obstructive pulmonary disease. Recently, the development of new DPIs for delivering therapeutic proteins such as insulin has been accelerated by patient demands, and innovative research. The current market for DPIs has over 20 devices presently in use, and many devices under development for delivering a variety of therapeutic agents. DPIs are recognized as suitable alternatives to pressurized metered dose inhalers for some patients, but the performance of DPI devices may vary according to a given patient's physiological condition. This variation can be associated with the necessary powder dispersion mechanism of each device. As such, much interest has focused on the development of efficient powder dispersion mechanisms, as this effectively minimizes the influence of interpatient variability. This article reviews DPI devices currently available, advantages of newly developed devices, outlines some requirements for future device design.     

The long and winding road to inhaled TB therapy: not only the bug’s fault

Not all of the issues impacting the success of tuberculosis (TB) treatment arise from pathogen-related disease characteristics. Nowadays, there is an increasing awareness that antibiotic treatment is not the only answer to the TB problem, promoting the search for alternative administration strategies and host-directed therapies. Among all the administration routes, being the lungs the main TB focus, inhalation is conceptually a logical solution to enhance treatment effectiveness and compliance. Nevertheless, research efforts and funding are almost entirely conveyed to conventional approaches. This review will critically evaluate the reasons constraining research in this field, providing some future perspectives. The most recent advances in inhalation approaches for TB will be discussed, either at the preclinical or clinical phase, illustrating the risk of failure and chances of success.     

Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis

A series of co-engineered macrolide–mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital^? inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200?mg of 50:50?w/w AZ: mannitol had 57.6%?±?7.6% delivery efficiency with a fine particle fraction (≤6.8?µm) of the emitted aerosol cloud being 80.4%?±?1.1%, with minimal throat deposition (5.3?±?0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide–mannitol therapy may provide a means of treating bronchiectasis.     

Development of a design space and predictive statistical model for capsule filling of low-fill-weight inhalation products

The objectives of this study were to develop a predictive statistical model for low-fill-weight capsule filling of inhalation products with dosator nozzles via the quality by design (QbD) approach and based on that to create refined models that include quadratic terms for significant parameters. Various controllable process parameters and uncontrolled material attributes of 12 powders were initially screened using a linear model with partial least square (PLS) regression to determine their effect on the critical quality attributes (CQA; fill weight and weight variability). After identifying critical material attributes (CMAs) and critical process parameters (CPPs) that influenced the CQA, model refinement was performed to study if interactions or quadratic terms influence the model. Based on the assessment of the effects of the CPPs and CMAs on fill weight and weight variability for low-fill-weight inhalation products, we developed an excellent linear predictive model for fill weight (R^2?=?0.96, Q^2?=?0.96 for powders with good flow properties and R^2?=?0.94, Q^2?=?0.93 for cohesive powders) and a model that provides a good approximation of the fill weight variability for each powder group. We validated the model, established a design space for the performance of different types of inhalation grade lactose on low-fill weight capsule filling and successfully used the CMAs and CPPs to predict fill weight of powders that were not included in the development set.     

Inhalation risk of indoor aerosol spray products commercially available in Bangladesh

Today, urbanised people spend most of their time in indoor environments, and the risk of exposure to toxic materials in an indoor environment is of great concern. This paper considers sources for the inhalation risk of aerosol sprays by measuring the particle size distributions of some of the most popular products that are commercially available in Bangladesh, and examines the degree of toxicity and the health risk via the respirability of the products. Results show that thoracic and respirable fractions of the suspended particulate matter are present in the tested samples and hence the spray products may pose a significant health risk.     

The in vitro and in vivo investigation of inhaled migraine therapies using a novel aerosol delivery system consisting of an air pressurized capsule device (APCD) in combination with a pMDI spacer for endotracheal dosing into beagle dogs

Abstract

Context: Aerosol delivery to animals in preclinical settings has historically been very challenging, requiring the use of techniques, such as intratracheal instillation and dry powder insufflation, that are somewhat invasive, inefficient and not representative of clinical inhalation.

Objective: The objective of this work is to develop a system to deliver dry powder to dogs in an efficient and effective manner for the study of new anti-migraine compounds in development.

Materials and methods: The new device uses a metered aliquot of a dry gas to force dry powder drug from a pre-filled HPMC capsule into an AeroChamber® spacer for subsequent inhalation by the animal.

Results: The delivery of two invesigational migraine drugs via the new device was assessed in vitro using abbreviated Andersen cascade impaction and showed the device is capable of generating a reproducible delivered dose of up to ～68% with more than 50% of the dose in the respirable range. In vivo studies have also been performed showing that this device effectively delivered the migraine drugs to spontaneously breathing dogs using a proprietary validated dog inhalation model.

Discussion: Results confirmed that the air pressurized capsule device (APCD) was effective in delivering the APIs to lungs of the animals. The in vivo data verified the advantages of inhaled delivery over oral delivery for this class of drugs and were used to establish the cardiopulmonary and respiratory side effect liability profile for these compounds.

Conclusions: This work has demonstrated the utility of this device for quick and accurate screening of prospective drug candidates, representing a significant improvement in ease of use and reprodicibility over current delivery methods.     

Inhaled PYY(3–36) dry-powder formulation for appetite suppression

Objective: Peptide YY3–36 [PYY(3–36)] has shown efficacy in appetite suppression when dosed by injection modalities (intraperitoneal (IP)/subcutaneous). Transitioning to needle-free delivery, towards inhalation, often utilizes systemic pharmacokinetics as a key endpoint to compare different delivery methods and doses. Systemic pharmacokinetics were evaluated for PYY3–36 when delivered by IP, subcutaneous, and inhalation, the systemic pharmacokinetics were then used to select doses in an appetite suppression pharmacodynamic study.

Methods: Dry-powder formulations were manufactured by spray drying and delivered to mice via nose only inhalation. The systemic plasma, lung tissue, and bronchoalveolar lavage fluid pharmacokinetics of different inhalation doses of PYY(3–36) were compared to IP and subcutaneous efficacious doses. Based on these pharmacokinetic data, inhalation doses of 70:30 PYY(3–36):Dextran T10 were evaluated in a mouse model of appetite suppression and compared to IP and subcutaneous data.

Results: Inhalation pharmacokinetic studies showed that plasma exposure was similar for a 2?×?higher inhalation dose when compared to subcutaneous and IP delivery. Inhalation doses of 0.22 and 0.65?mg/kg were for efficacy studies. The results showed a dose-dependent (not dose proportional) decrease in food consumption over 4?h, which is similar to IP and subcutaneous delivery routes.

Conclusions: The pharmacokinetic and pharmacodynamics results substantiate the ability of pharmacokinetic data to inform pharmacodynamics dose selection for inhalation delivery of the peptide PYY(3–36). Additionally, engineered PYY(3–36):Dextran T10 particles delivered to the respiratory tract show promise as a non-invasive therapeutic for appetite suppression.     

~(133)Xe吸入法双探头测量局部大脑血流量的简易装置

目前,国外用吸入~(133)Xe测量局部大脑血流量(rCBF)的方法已日趋完善,由多探头、多道分析器及电子计算机组成的测量装置已应用于临床。测量大脑各功能区的血流量,对缺血性脑血管病的诊断、病情估计及疗效观察都有重要意义。我们利用现有仪器和设备,组装一台可以同时测量大脑左右两个部位的血流量的简易装置,进行了吸入~(133)Xe测量rCBF方法的研究,并对106例正常健康人、22例功能性头痛患者及22例缺血性脑血管病人的rCBF值进行了检查,取得了有一定参考价值的数据。本装置组成简单,操作方便,在我国现有条件下有