When it comes to dry powder inhalation (DPI), adhesive mixtures are the most widely used formulation type. Various techniques have been developed to generate inhaled drug particles and improve the delivery efficiency of DPI formulations. For dry powder inhaler formulations (DPIs), micronized drug powders are usually mixed with lactose carriers to improve powder handling during manufacturing and powder aerosol delivery during patient use. The performance of DPI systems is strongly dependent on several formulation factors, the construction of the delivery device and the inhalation technique. There is a growing interest in DPI in new medical areas such as vaccines and antibiotics which requires further development and challenges to ensure physical and aerosolization stability of DPI.  This project aims to discuss the development of inhalation therapy, the challenges during formulation processes, the mixing process and the use of excipients in pulmonary drug delivery in DPIs. Further, the project is covered by experiments based on the literature overview and performed at the Department of Pharmaceutical Biosciences at Uppsala University. Bulk density was measured on three series of adhesive mixtures with increasing amounts of fine particles. In two series, small amounts of Magnesium Stearate, 0,1% and 0,01% were added.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and asthma constitute the majority of the pulmonary disease burden in the United States. Various kinds of inhalers are used for treating both these conditions, and Medicare is the biggest payer for them. We analyze the trend in prescriptions and associated expenses of various inhaler prescriptions from 2014 to 2018 using the Medicare part D database. METHODS: Medicare part D data is analyzed for the years 2014-2018. Inhalers are grouped based on their drug class. The number of beneficiaries and the associated expenses for each inhaler and the groups were calculated separately and analyzed using statistical software. RESULTS AND CONCLUSION: Some 85 million beneficiaries received inhalers through Medicare part D over the four years. Medicare spent 50.5 billion US dollars on these prescriptions, which showed an increase of 130% users and 128% expenditure over the four years. Medicare's expense for inhaler prescriptions is growing and is expected to increase even more in the near future.

Many respiratory patients misuse their inhaler. Although training improves their inhaler technique, patients do forget the correct inhaler use with time. In the current work, three clinical studies investigated novel tools designed with feedback mechanisms to ensure patients use the correct inhalation method when using their inhaler. Research Ethics Committee approval was obtained and all the participants signed an informed consent form. In the first study, the recruited asthmatic children (n=17) and adults (n=39) had their metered dose inhaler (MDI) technique assessed. Those who attained the recommended inhalation flow rate (IFR) of < 90 l/min through their MDI formed the control group. Whilst those who had a poor MDI technique with an IFR ¿ 90 l/min were randomized into either the verbal counselling (VC) group; or the 2ToneTrainer (2TT) group that, in addition to the verbal training, received the 2ToneTrainer MDI technique training device equipped with an audible feedback mechanism of correct inhalation flow. All the participants were assessed on two occasions (6 weeks apart) for their inhalation flow rate, asthma control and quality of life. The study showed that the 2ToneTrainer tool was as efficient as verbal training in improving and maintaining the asthmatic patients¿ MDI technique, particularly using the recommended slow inhalation flow through the MDI. Although statistically insignificant, potential improvement in quality of life was demonstrated. The 2ToneTrainer tool has the advantage of being available to the patients all the time to use when they are in doubt of their MDI technique. In the second research study, the inhalation profiles of asthmatic children (n=58) and adults (n=63), and of COPD patients (n=63) were obtained when they inhaled through the novel Spiromax dry powder inhaler (DPI) which was connected to an electronic pressure change recorder. From these inspiratory profiles; the peak inhalation flow, inhalation volume and inhalation acceleration rate were determined. The variability (23% - 58%) found in these inhalation profile parameters among various patient groups would be expected in all DPIs. The effect of the inhalation acceleration rates and volumes on dose emission characteristics from DPIs should be investigated. Attention, though, should be paid to the patients¿ realistic inhalation profile parameters, rather than the recommended Pharmacopoeial optimal inhalation standard condition, when evaluating the in-vitro performance of DPIs. Finally, in preschool asthmatic children, the routine use of the current AeroChamber Plus spacer (n=9) was compared with that of a novel version; the AeroChamber Plus with Flow-Vu spacer (n=10) over a 12-week period. The Flow-Vu spacer has a visual feedback indicator confirming inhalation and tight mask-face seal. The study showed that the new AeroChamber Plus with Flow-Vu spacer provided the same asthma control as the AeroChamber Plus in preschool children and maintained the same asthma-related quality of life of their parents. However, the parents preferred the new Flow-Vu spacer because its visual feedback indicator of inhalation reassured them that their asthmatic children did take their inhaled medication sufficiently.

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.

Curcuminoids have strong anticancer activities but have low bioavailability. The highest rate of cancer deaths comes from lung tumours; therefore, inhaled curcuminoids could treat lung cancer locally. To date, there are no nebulised formulations of curcuminoids, and there are no inhalable curcuminoids particles without excipients using air jet mill and sonocrystallisation methods for DPI formulations. It is the first time; the aerodynamic parameters of curcumin, demethoxycurcumin and bisdemethoxycurcumin were measured individually using NGI. The size, shape, free surface energy, and the crystal polymorphism of the produced inhalable curcuminoid particles were characterised using laser diffraction, SEM, IGC, DSC and XRPD, respectively. Several DPI formulations with a variable particle size of curcuminoids were prepared in two drug-carrier ratios (1:9 and 1:67.5). The best performance of the DPI formulations of the sonocrystallised particles, which exist in crystal structure form1, were obtained from ethanol- heptane, as illustrated FPF 43.4%, 43.6% and 43.4% with MMAD of 3.6µm, 3.5µm and 3.4µm, whereas the best DPI formulation of the air jet milled particles was presented FPF 38.0%, 38.9%, and 39.5% with MMAD of 3.6µm, 3.4µm and 3.2µm for curcumin, demethoxycurcumin and bisdemethoxycurcumin, respectively. Nebulised curcuminoids using nanoemulsion and microsuspension formulations were prepared. The physical properties, such as osmolality, pH and the viscosity of the aerosolised nanoemulsion and the microsuspension formulations were determined. The FPF% and MMAD of nebulised nanoemulsion ranged from 44% to 50% and from 4.5µm to 5.5µm respectively. In contrast, the FPF% of microsuspension ranged from 26% to 40% and the MMAD from 5.8µm to 7.05µm. A HPLC method was developed and validated in order to be used in the determination of curcuminoids from an aqueous solution.

No / The objective of this study was to develop SEDS-engineered budesonide particles suitable for dry powder inhalation delivery and to evaluate their aerosol performance across a range of passive dry powder inhalers (DPI). SEDS budesonide powders were manufactured in Nektar's SCF manufacturing plant and compared to the micronized drug and commercial powder (Pulmicort Turbuhaler, AstraZeneca). Aerosol performance was evaluated by determining emitted dose (ED) by a variation of the USP method and fine particle fraction (FPF) using Andersen cascade impaction. The SCF powder dispersed best in the Turbospin and Eclipse devices, exhibiting high EDs (70%-80%) and relatively low variability (RSD 8%-13%). Regardless of the device, the SEDS material outperformed both the micronized drug and the commercial powder, while exhibiting good batch-to-batch reproducibility (RSD <5%). All powders exhibited flow rate-dependent ED, albeit for the SEDS material it was minimized at reduced fill weights. This was attributed to inadequate and variable powder clearance from the capsules at low inspiratory flow rates, which was more pronounced in the Eclipse and Cyclohaler. The results demonstrate that SEDS is an attractive particle-engineering process that may enhance pulmonary performance of budesonide and possibly facilitate development of other small molecule pulmonary products in passive DPI.

No / In vitro dissolution testing as a form of quality control has become a necessity in the pharmaceutical industry. As such, the need to establish a method that investigates the in vitro dissolution profile of inhaled products should be taken into account. The prime focus in this study was to examine the in-vitro in-vivo correlation utilising a modified version of the Twin Stage Impinger and to promote an in vitro dissolution model by enhancing the Fine Particle Dose (FPD) collection method for dry powder inhalers. The Twin Impinger was modified by inserting a stainless steel membrane holder disk in the base of the lower chamber. The design, with optimum drug deposition, was adopted for the dissolution study of budesonide and salbutamol. Afterwards, the membrane holder system was placed in the bottom of the dissolution vessel. Phosphate buffer saline (PBS), simulated lung fluid (SLF, Gamble solution) and Phosphate buffer (PB) were used in the study. The paddle dissolution apparatus, containing 300 mL of the medium, was operated at 75 rpm paddle speed. Samples were collected at defined time intervals and analysed using a validated HPLC method. The largest proportion of the budesonide dose was dissolved in PBS compared to PB and SLF. This was due to the presence of surfactant (0.2% w/v polysorbate), which enhances the wettability and the solubility of the poorly soluble drug (budesonide). The similarity factors for PBS and PB were 47.6 and 69.7, respectively, using SLF as a reference, whereas the similarity factor for salbutamol dissolution between PB and SLF was 81.3, suggesting PB is a suitable substitute. Comparison using both the predicted and actual in vivo pharmacokinetics (PK) values of the two drugs, as well as the pattern of their Concentration-Time (c-t) profiles, showed good similarity, which gave an indication of the validity of this in vitro dissolution method.

Dry Powder Inhalers (DPIs) have great potential in pulmonary drug delivery; the granular powder, used as active ingredient in DPIs, is ozone friendly and the operation of DPIs ensures coordination between dose release and patient inhalation. However, the powder fluidisation mechanisms are poorly understood which leads to low efficiency of DPIs with 10-35 % of the dose reaching the site of action. The main aim of this thesis is to study the hydrodynamics of powder fluidisation in DPIs, using experimental and computational approaches. An experimental test rig was developed to replicate the process of transient powder fluidisation in an impinging air jet configuration. The powder fluidisation chamber was scaled up resulting in a two dimensional particle flow prototype, which encloses 3.85 mm glass beads. Using optical image processing techniques, individual particles were detected and tracked throughout the experimental time and domain. By varying the air flow rate to the test section, two particle fluidisation regimes were studied. In the first fluidisation regime, the particle bed was fully fluidised in less than 0.25 s due to the strong air jet. Particle velocity vectors showed strong convective flow with no evidence of diffusive motion triggered by inter-particle collisions. In the second fluidisation regime, the particle flow experienced two stages. The first stage showed strong convective flow similar to the first fluidisation regime, while the second stage showed more complex particle flow with collisional and convective flow taking place on the same time and length scales. The continuum Two Fluid Model (TFM) was used to solve the governing equations of the coupled granular and gas phases for the same experimental conditions. Sub-models for particle-gas and particle-particle interactions were used to complete the model description. Inter-particle interactions were resolved using models based on the kinetic theory of granular flow for the rapid flow regime and models based on soil mechanics for the frictional regime. Numerical predictions of the first fluidisation regime showed that the model should incorporate particle-wall friction and minimise diffusion, simultaneously. Ignoring friction resulted in fluidisation timing mismatch, while increasing the diffusion resulted in homogenous particle fluidisation in contrast to the aggregative convective fluidisation noticed in the experiments. Numerical predictions of the second fluidisation regime agreed well with the experiments for the convection dominated first stage of flow up to 0.3 s. However, later stages of complex particle flow showed qualitative discrepancies between the experimental and the computational approaches suggesting that current continuum granular models need further development. The findings of the present thesis have contributed towards better understanding of the mechanics of particle fluidisation and dense multiphase flow in DPI in particular, and particle bed fluidisation using impinging air jet in general. The use of TFM for predicting high speed convective granular flows, such as those in DPIs, is promising. Further studies are needed to investigate the form of particle-particle interactions within continuum granular flow models.

No description available.