2017-02-09全文追加 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18453号 / 医博第3908号 / 新制||医||1004(附属図書館) / 31331 / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂田 隆造, 教授 木村 剛, 教授 小池 薫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20081号 / 医博第4174号 / 新制||医||1018(附属図書館) / 33197 / 京都大学大学院医学研究科医学専攻 / (主査)教授 湊谷 謙司, 教授 福田 和彦, 教授 浅野 雅秀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Embargoed until July 2016. / Active Pharmaceutical Ingredients (APIs) are frequently prepared for delivery to the lung for local topical treatment of diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, or for systemic delivery. One of the most commonly used devices for this purpose is the pressurised metered dose inhaler (pMDI) whereby drugs are formulated in a volatile propellant held under pressure. The compound is aerosolised to a respirably sized dose on actuation, subsequently breathed in by the user. The use of hydrofluoroalkanes (HFAs) in pMDIs since the Montreal Protocol initiated a move away from chlorofluorocarbon (CFC) based devices has resulted in better performing products, with increased lung deposition and a concomitant reduction in oropharyngeal deposition. The physical properties of HFA propellants are however poorly understood and their capacity for solubilising inhaled pharmaceutical products (IPPs) and excipients used historically in CFCs differ significantly. There is therefore a drive to establish methodologies to study these systems in-situ and post actuation to adequately direct formulation strategies for the production of stable and efficacious suspension and solution based products. Characterisation methods have been applied to pMDI dosage systems to gain insight into solubility in HFAs and to determine forms of solid deposits after actuation. A novel quantitative nuclear magnetic resonance method to investigate the physical chemistry of IPPs in these preparations has formed the centrepiece to these studies, accessing solubility data in-situ and at pressure for the first time in HFA propellants. Variable temperature NMR has provided thermodynamic data through van’t Hoff approaches. The methods have been developed and validated using budesonide to provide limits of determination as low as 1 μg/mL and extended to 11 IPPs chosen to represent currently prescribed inhaled corticosteroids (ICS), β2-adrenoagonists and antimuscarinic bronchodilators, and have highlighted solubility variations between the classes of compounds with lipophilic ICSs showing the highest, and hydrophilic β2- agonist / antimuscarinics showing the lowest solubilities from the compounds under study. To determine solid forms on deposition, a series of methods are also described using modified impaction methods in combination with analytical approaches including spectroscopy (μ-Raman), X-ray diffraction, SEM, chromatography and thermal analysis. Their application has ascertained (i) physical form / morphology data on commercial pMDI formulations of the ICS beclomethasone dipropionate (QVAR® / Sanasthmax®, Chiesi) and (ii) distribution assessment in-vitro of ICS / β2-agonist compounds from combination pMDIs confirming co-deposition (Seretide® / Symbicort®, GlaxoSmithKline / AstraZeneca). In combination, these methods provide a platform for development of new formulations based on HFA propellants. The methods have been applied to a number of ‘real’ systems incorporating derivatised cyclodextrins and the co-solvent ethanol, and provide a basis for a comprehensive study of solubilisation of the ICS budesonide in HFA134a using two approaches: mixed solvents and complexation. These new systems provide a novel approach to deliver to the lung, with reduced aerodynamic particle size distribution (APSD) potentially accessing areas suitable for delivery to peripheral areas of the lung (ICS) or to promote systemic delivery.

No description available.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第23831号 / 薬科博第146号 / 新制||薬科||16(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 山下 富義, 教授 髙倉 喜信, 准教授 伊藤 美千穂 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

No description available.

No description available.

Portable ultrasonic humidifiers add moisture into room air, but they simultaneously add exposure risks of aerosolized metals from drinking water used as fill water. The inhalation exposure from emitted metals can be overlooked, and thus, co-exposure of inhalation and ingestion and co-exposure to multiple inorganic metals is investigated. The objectives of this work are: 1) predict airborne metal concentrations and particle sizes in four realistic room scenarios (33 m3 small or 72 m3 large, with varying ventilation rates from 0.2/hr -1.5/hr), and the investigated metals are arsenic, cadmium, chromium, copper, lead, and manganese; 2) characterize exposure doses and consequent risks for adults and 0.25, 1, 2.5, and 6 yr old children, when using identical drinking water ingested and as fill water, including inhalation of fine, respirable particles generated at the frequency of 8 hrs/day (equals 121.67 days/yr) and daily ingestion, under four realistic room scenarios. The risk assessment includes non-cancer [calculation of average daily dose (ADD) and hazard quotient (HQ)] and cancer risk evaluation; 3) quantify deposition fraction and deposited doses of multiple metals in human adult's and children's respiratory tract, using multi-path particle dosimetry (MPPD) model. Results show airborne-particle-bound metal concentrations increase proportionally with water metals, and a poorly ventilated room causes greater exposure. Ingestion ADDs are 2 magnitudes higher than inhalation ADD, at identical water metal concentrations and daily exposure frequency. However, in the worse-case scenario of 33 m3 small room with low air exchange rate, the consequent inhalation HQs are all greater than 1 for children and adults, except for lead, indicating significant non-cancer risks when exposed to humidifier particles under the worse-case scenario. The cancer risks for arsenic, cadmium, chromium, and lead metals reveal are greater than acceptable one case in a million population (1E-6) produced from inhalation of the humidifier emitted metal-containing particles only. The MPPD model results indicate inhaled metal-containing airborne particles deposit primarily in head and pulmonary regions, and a greater dose (unit in µg/kg body weight/day) deposits in children than adults. Inhalation of ultrasonic humidifier aerosolized metals results in additional, and potentially greater risks (indicated by HQinhalation >1, and greater deposited dose) than ingestion at the same aqueous metal concentration, especially for children. Room conditions (i.e. volume and ventilation) influence risks. Both inhalation and ingestion exposures require consideration for eliminating multiple metal exposures and health-based environmental policy making. Consumers should be aware that they may be degrading their indoor air quality by using ultrasonic humidifiers even when filling with acceptable water quality for drinking. / Doctor of Philosophy / The purpose of this work is to investigate the exposure from use of ultrasonic humidifiers filled with drinking water containing inorganic metals. Typical exposure pathway of drinking water metals is ingestion. However, inhalation of aerosolized metals can cause undesirable health effects towards metal exposure, when fill water of ultrasonic humidifiers is the same drinking water, and the inhalation of aerosolized metals exposure pathway can be overlooked. Emitted airborne particles are composed of soluble metals in drinking water, and are respirable with diameters between 100-200 nm. PM2.5 (particulate matter with aerodynamic under 2.5 µm) concentrations increase from approximately 2 µg/m3 to hundreds of µg/m3 in a common-sized room, exceeding the USEPA's regulatory level of 15 µg/m3 for ambient air PM2.5. The resulting air metal concentrations increase with increasing metals in the fill water, and/or lower ventilation rates in a household room. In addition, children receive greater average daily exposure doses than adults (i.e. average daily dose and deposited dose, in unit of µg/kg body weight/day), when assuming daily inhalation exposure of 8 hr/day and daily ingestion exposure. The ingestion doses from various metals are greater than inhalation doses, however, the inhalation risks may be greater for certain metals than ingestion. Even when using acceptable drinking water quality that meets regulations for metals, the indoor air quality is still degraded and can pose adverse health effects. In conclusion, the dissertation work presents a framework to estimate risks developed from multi-media and single or multi-metals exposure. The addition from inhalation of aerosolized metals in drinking water should be considered in an overall risk assessment, especially for the susceptible population of young children. Consumers should be aware that they may be degrading their indoor air quality by using ultrasonic humidifiers even when filling with acceptable water quality for drinking.

Inhalation av torrt pulver är en populär metod för administrering av aerosolläkemedel vid luftvägssjukdomar som Astma och KOL. På den svenskamarknaden finns det flera olika inhalatorer att välja emellan men är alla lika effektiva?    I denna litteraturstudie jämförs femton originalartiklar som söktes via Pubmed med syfte att inhämta information om aerosoliserings-förmåga och kapacitet för inhalatorerna Diskus, Easyhaler, Ellipta, Nexthaler, Spiromax och Turbuhaler.   Resultaten indikerar att alla inhalatorer har en effektiv aerosolisering, men när det gäller mängden läkemedel som når lungorna, framkommer att Nexthaler och Turbuhaler presterar bäst. Artiklarna visar att inhalatorer som underlättar de-aggregation har en högre andel läkemedel som når lungorna jämfört med de som saknar denna förmåga. En artikel visade också att genom att byta läkemedlet från en inhalators formulering till en annan inhalators formulering förbättrades inhalatorns prestanda.   Denna kunskap är av betydelse vid utveckling av inhalatorer och läkemedelsformuleringar för inhalation. Då målet är att öka effektiviteten vid administrering av aerosolläkemedel, med en högre andel läkemedelspartiklar som når lungorna och mindre går förlorad.

Yes / Background Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). Tobramycin nebulizer solution (TNS) is indicated for maintenance therapy in CF patients. TOBI® is a tobramycin nebulizer solution (TNS) approved by FDA for maintenance therapy for patient with CF. Adherence to recommended therapy in CF has always been a challenge and new generation nebulizers are increasingly used “off label” to reduce the time required for inhalation, potentially improving patient compliance. Objectives To assess the performance of selected recent nebulizer delivery systems for determination the optimum combinations to deliver TOBI®. Using the relative lung bioavailability of TOBI® to the lungs in healthy volunteers, following inhalation from selected nebulizer delivery systems, using a urinary pharmacokinetics method. In vitro aerodynamic characteristics of the nebulized dose were also determined. Methods Serial urine samples were collected from 12 healthy volunteers up to 24 h post-inhalation of TOBI® inhaled solution following delivery by Pari LC Plus®, Sidestream®, NE-U22-E Omron® and Aeroneb® Go nebulizers. In vitro aerodynamic characteristics of the nebulized dose were also determined according to the CEN (Committee European de Normalization) method. Results The mean (SD) relative lung bioavailability from Pari LC Plus®, Sidestream®, Omron®, and Aeroneb® Go nebulizers was 4.9 (0.5), 3.9 (0.5), 7.1 (1.3), and 7.7 (0.7) %, respectively. The mean (SD) mass median aerodynamic diameter (MMAD) of the drug particles from the same systems was 2 (0.2), 2 (0.2), 1.2 (0.03) and 2.0 (0.1) μm, and the corresponding fine particle doses (FPD) were 2.2 (0.23), 1.5 (0.2), 3.44 (0.3) and 2.8 (0.3) mg. Conclusion The data obtained from in-vitro and in-vivo studies reflect poor relative lung bioavailability of tobramycin following jet nebulization.