Dry powder inhalers (DPIs) are used for delivering drugs to the airways. In addition to the drug, the formulations often contain a coarse carrier, most commonly alpha lactose monohydrate. The presence of fine lactose particles in the formulation is known to improve the formulation performance. The active site, drug-fines agglomeration and increased cohesion theories have been suggested to explain improved DPI performance upon addition of fine excipient particles. This project aimed to investigate the validity of those theories. The viability of the active sites theory in explaining the improved DPI performance was investigated by studying the impact of loaded drug dose on the in vitro performance for formulation series prepared with coarse carriers with different surface characteristics. The formulations prepared with the rougher lactose carrier were seen to outperform the formulations prepared with the smoother carrier at all drug concentrations. These findings were concluded to be non-compatible with the active sites theory. The impact of addition of lactose fines with different size distributions on powder flow and fluidisation properties and in vitro performance was studied. Powder cohesion increased independent of size distribution of the fines, but did not necessarily correspond to improved performance. Therefore, the increased cohesion theory was concluded not to be the sole explanation for the improvement in DPI performance in the presence of lactose fines. Instead, the increase in performance could be preliminarily attributed to the formation of agglomerated systems. The formation and co-deposition of drug-fines agglomerates, and consequential improvement in the DPI performance was proved using morphologically directed Raman spectroscopy. The project also aimed to develop a universal model for predicting DPI performance based on the lactose properties for a wide range of carriers with different properties. No simple linear correlations between any the lactose properties and the final DPI performance were found. Therefore no single parameter can be used as a universal predictor for DPI performance. To establish more complex relationships, artificial neural networks were used for modelling the importance of different lactose properties in determining DPI performance. The proportion of fine lactose particles (<4.5 μm) was identified as the most important parameter. However, this parameter was capable of explaining only approximately half of the variation seen in the formulation performance. The current study showed that to obtain more accurate predictions for the purposes of quality-by-design approach, also other lactose properties need to be characterised.

The influence of the size and morphology of carrier particles on drug dispersion performance from passive dry powder inhalers has been extensively studied topic, and a consensus has been reached regarding the adverse effect that larger carrier particle diameters impart to aerosol performance. However, previous studies have generally employed only a few carrier particle size fractions, generally possessing similar surface characteristics. Accordingly, theories developed to explain the influence of the physical characteristics of carrier particles on performance relied heavily on both extrapolation and interpolation. To fill in the gaps from the literature and simultaneously evaluate the influence of carrier particle size and morphology, a comprehensive study was undertaken using 4 lactose grades, each sieved into 13 contiguous sizes, to prepare 52 formulations incorporating a unique lactose grade-size population. The aerosol performance results indicated that large carrier particles possessing extensive surface roughness can improve drug dispersion, in contrast to what has been previously reported. It is proposed that this may be attributed to mechanical detachment forces arising from collisions between the carrier particle and inhaler during actuation. Based on these observations, a novel dry powder inhaler platform was developed, employing carrier particles much larger (> 1 mm) than previously explored in both the scientific and patent literature. Optimization of this technology required the judicious selection of a carrier material, and following an extensive screening process, low-density polystyrene was selected as a model candidate. Given its low mass, diameters in excess of 5-mm could be employed as carriers while still generating high detachment forces. To minimize drug particle aggregation, a novel drug-coating method employing piezo-assisted particle dispersion was developed to compensate for the reduced surface area of the novel carrier particles. In addition, the selection of a suitable inhalation device prototype was instrumental to the overall performance of the technology. In vitro testing of the novel large carrier particles yielded emitted fractions in excess of 85%, and overall drug delivery of up to 69% of the nominal dose. / text

Currently available dry powder inhalers (DPIs) for drug delivery to the lungs require turbulent energy to generate and disperse aerosol particles in the respirable range ≤5μm during inhalation. The patient's inspiratory effort together with the resistance inside the device creates this energy. Different inhalers provide varying degrees of resistance to inhalation flow and require different inhalation techniques for the generation and delivery of drug fine particles in respirable size range to the lungs. The aim of this research programme was to identify the influence of inhalation flow, inhalation volume and the number of inhalations per dose on the ex-vivo dose emission and the in-vitro aerodynamic dose emission characteristics of the salbutamol Accuhaler®, Easyhaler®, and Clickhaler® and the terbutaline Turbuhaler® DPIs. A high-performance liquid chromatography method for the assay of salbutamol sulphate and terbutaline sulphate in aqueous samples was modified and accordingly validated. In-vitro dose emission of the four different DPIs was measured using the pharmacopoeia method with modifications to simulate varying inhalation flows within patient and between patients. The ranges of the total emitted dose (% nominal dose) at the inhalation flow range of 10 - 60 Lmin-1, following one and two inhalations per metered dose for 2L and 4L inhaled volumes were as follows: the Accuhaler (52.64- 85.11; 61.88-85.11 and 59.23-85.11; 62.81-85.11); the Easyhaler (68.35-91.99; 79.94-91.99 and 73.83-92.51; 80.40-92.51); the Clickhaler (46.55-96.49; 51.12-96.49 and 51.18-101.39; 59.71-101.39) as well as the Turbuhaler (46.08-88.13; 51.95-88.13 and 48.05-89.22; 48.64-89.22). The results highlight that the four inhalers have flow-dependent dose emission property to a varying degree using 2L and 4 L inhaled volumes. There was no significant difference in the total emitted dose between a 2L inhaled volume and a 4L inhaled volume at each inhalation flow. Furthermore, the total emitted dose from the Easyhaler®, Clickhaler®, and Turbuhaler® was significantly (p≤0.001) greater with two inhalations than one inhalation per metered dose across the range of inhalation flow (10-60) Lmin-1. This effect was only observed at inhalation flow less than 30 Lmin-1 with the Accuhaler®. Overall there is a significant difference in the total emitted dose. The ex-vivo dose emission of the four different DPIs has been determined using the In- Check Dial device to train twelve non-smoking healthy adult volunteers to inhale at slow (30 Lmin-1) and fast (60 L min-1) inhalation flows through the device with its dial set corresponding to each inhaler. Subsequently each volunteer inhaled at the trained inhalation flows through each active inhaler. The local ethics committee approval was obtained prior to the study and all volunteers gave signed informed consent. The results obtained demonstrate that the studied inhalers have flow-dependent dose emission, thereby enhancing confidence in the use of the In-Check Dial® to identify a patient's inhalation flows through a variety of DPIs. Also the total emitted dose determined by ex-vivo methodology was significantly (p≤0.05) greater with two inhalations than one inhalation per metered dose. The results of the in-vitro aerodynamic dose emission characteristics highlight that the fine particle dose (FPD) from the four studied inhalers is flow dependent. Also the minimum inhalation flow to generate the (FPD) with the appropriate characteristics for lung deposition has been identified to be 20 L min⁻¹ for the Accuhaler®, Easyhaler® and Clickhaler®, while that for the Turbuhaler® is about 30 L min⁻¹. Also the inhalation volume above 2L and the number of inhalations for each dose have respectively no significant (p≤0.05) influence on the FPD emitted from the four studied inhalers. The results support the present instructions to patients using these inhalers to inhale once for each dose as fast as they can.

Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major health burdens on the global population. To treat diseases of the lung, topical therapies using dry powder inhalers (DPIs) have been employed. However, a relatively small amount of dose (5.5 - 28 %) reaches the lung during DPI therapy leading to high inter-patient variability in therapy response and oropharyngeal deposition. Strategies were assessed to take patient variability in inhalation performance into account when developing devices to reduce throat deposition and to mitigate flow rate dependency of the emitted aerosol. A cyclone-spacer was manufactured and evaluated with marketed and in-house manufactured formulations. An in vivo study showed that a high resistance inhaler would produce longer inhalation times in lung disease patients and that a spacer with high resistance may prove a suitable approach to address inter-patient variability. Two spacer prototypes were evaluated with cohesively- and adhesively-balanced particle blends. The data suggested that the throat deposition dramatically decreased for the emitted particles when the spacers were used with the inhalers (e.g. 18.44 ± 2.79% for salbutamol sulphate, SS 4 kPa) due to high retention of the formulation within the spacer (87.61 ± 2.96%). Moreover, variation in fine particle fraction and dose was mitigated when increasing the flow rate (82.75 ± 7.34 %, 92.2 ± 7.7 % % and 77.0 ± 10.1 % at 30, 45 and 60 Lmin-1, respectively). The latter was an improvement over previous proposed DPI spacers, where variability in emitted dose due to airflow rate was a major issue. Due to the different physicochemical properties of the active pharmaceutical ingredients used in the formulation, throat deposition and respirable fraction for adhesively-balanced particles (e.g. SS) were double that of the cohesively- balanced particles (salmeterol xinafoate, SX) (e.g. 65.83 ± 8.99 % vs. 45.83 ± 5.04 % for SS:Coarse Lactose (CL) and SX:CL, respectively). Scanning electron microscopy revealed that surface-bound agglomerates were more freely removed from the carrier, but subject to decreased impaction-type deagglomeration forces in the spacer than for carrier-bound drug. An ex vivo study using breath profiles from healthy volunteers identified the minimization of differences between adhesively- and cohesively-balanced blends when full breath profiles were studied compared to square-wave airflow. Therefore the use of constant flow for in vitro testing should not be the sole flow regime to study aerosolization when developing new inhalation devices and formulations.

<p>Dry Powder inhalers (DPIs) have been one of the most promising developments in pulmonary drug delivery systems. In general, DPIs are more effective than systemic administrations and convenient to use. However, delivering high-dose antibiotics through a DPI is still a challenge because high powder load may need a very large inhaler or increase the incidence of local adverse effects. Spray drying has been increasingly applied to produce DPI formulations for high-dose antibiotics; nevertheless, many spray-dried particles are amorphous and physically unstable during storage, particularly under the humid environment. </p> <p> </p> <p>My research focuses on addressing critical challenges in physical stability of DPIs for spray-dried high-dose antibiotics. The effects of moisture-induced crystallization on physical stability and aerosol performance of spray-dried amorphous Ciprofloxacin DPI formulations stored at different humidity conditions were studied. Our study not only provided a mechanistic understanding in the impact of crystallization on aerosol performance but also developed novel approaches for improving stability of spray-dried formulations used in DPI.</p> <p> </p> <p>Our work has shown that recrystallization of amorphous spray-dried Ciprofloxacin led to significant changes in aerosol performance of DPIs upon storage, which cause critical quality and safety concerns. These challenges have been solved through co-spray-drying Ciprofloxacin with either excipient such as leucine or synergistic antibiotic like Colistin. Co-spray-drying Ciprofloxacin with Colistin not only improved physical and aerosol stability but also enhanced antibacterial activity which is a great advantage for treating ‘difficult to cure’ respiratory infections caused by multidrug resistant bacteria.</p> <p> </p> <p>My research work is a sincere effort to maximize the utility and efficacy of high-dose DPI, an effective delivery tool for treating severe resistant bacterial respiratory infections.</p>

No description available.

No / Purpose The relative lung bioavailability of salbutamol sulfate particles produced using supercritical fluids (SEDS¿) and delivered by dry powder inhaler (DPI) was compared with the performance of a conventional micronized drug DPI using the same device design (Clickhaler¿, Innovata Biomed). Materials and Methods Twelve healthy volunteers and 11 mild asthmatic patients completed separate four-way randomised cross-over studies, assessing the relative bioavailability of salbutamol sulfate (urinary excretion method), formulated as SEDS¿ particles (three batches) and micronized particles (Asmasal¿ inhaler, UCB Pharma Ltd). Post-treatment improvements in patient lung function were assessed by measuring FEV1. Physicochemical evaluation of the three SEDS¿ batches revealed inter-batch differences in particle size and shape. Results There was no significant difference in the relative lung bioavailability of salbutamol and its bronchodilator response between the best performing SEDS¿ formulation and the Asmasal¿ inhaler in volunteers and patients, respectively. SEDS¿ salbutamol sulfate showing wafer like morphology gave greater fine particle dose, relative lung bioavailability and enhanced bronchodilation compared to other SEDS¿ batches containing elongated particles. Conclusions Active Pharmaceutical Ingredient (API) manufactured using supercritical fluids and delivered by DPI can provide similar lung bioavailability and clinical effect to the conventional micronized commercial product. Product performance is however notably influenced by inter-batch differences in particle characteristics.

No / Previously, dose emission below 30 L min(-1) through DPI has not been routinely determined. However, during routine use some patients do not achieve 30 L min(-1) inhalation flows. Hence, the aim of the present study was to determine dose emission characteristics for low inhalation flows from terbutaline sulphate Turbuhaler. Total emitted dose (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) of terbutaline sulphate Turbuhaler were determined using inhalation flows of 10-60 L min(-1) and inhaled volume of 4 L. TED and FPD increase significantly with the increase of inhalation flows (p <0.05). Flows had more pronounced effect on FPD than TED, thus, faster inhalation increases respirable amount more than it increases emitted dose. MMAD increases with decrease of inhalation flow until flow of 20L min(-1) then it decreases. In vitro flow dependent dose emission has been demonstrated previously for Turbuhaler for flow rates above 30 L min(-1) but is more pronounced below this flow. Minimal FPD below 30 L min(-1) suggests that during routine use at this flow rate most of emitted dose will impact in mouth. Flow dependent dose emission results suggest that Pharmacopoeias should consider the use variety of inhalation flows rather than one that is equivalent to pressure drop of 4 KPa.

Currently available dry powder inhalers (DPIs) for drug delivery to the lungs require turbulent energy to generate and disperse aerosol particles in the respirable range ¿5¿m during inhalation. The patient's inspiratory effort together with the resistance inside the device creates this energy. Different inhalers provide varying degrees of resistance to inhalation flow and require different inhalation techniques for the generation and delivery of drug fine particles in respirable size range to the lungs. The aim of this research programme was to identify the influence of inhalation flow, inhalation volume and the number of inhalations per dose on the ex-vivo dose emission and the in-vitro aerodynamic dose emission characteristics of the salbutamol Accuhaler®, Easyhaler®, and Clickhaler® and the terbutaline Turbuhaler® DPIs. A high-performance liquid chromatography method for the assay of salbutamol sulphate and terbutaline sulphate in aqueous samples was modified and accordingly validated. In-vitro dose emission of the four different DPIs was measured using the pharmacopoeia method with modifications to simulate varying inhalation flows within patient and between patients. The ranges of the total emitted dose (% nominal dose) at the inhalation flow range of 10 - 60 Lmin-1, following one and two inhalations per metered dose for 2L and 4L inhaled volumes were as follows: the Accuhaler (52.64- 85.11; 61.88-85.11 and 59.23-85.11; 62.81-85.11); the Easyhaler (68.35-91.99; 79.94-91.99 and 73.83-92.51; 80.40-92.51); the Clickhaler (46.55-96.49; 51.12-96.49 and 51.18-101.39; 59.71-101.39) as well as the Turbuhaler (46.08-88.13; 51.95-88.13 and 48.05-89.22; 48.64-89.22). The results highlight that the four inhalers have flow-dependent dose emission property to a varying degree using 2L and 4 L inhaled volumes. There was no significant difference in the total emitted dose between a 2L inhaled volume and a 4L inhaled volume at each inhalation flow. Furthermore, the total emitted dose from the Easyhaler®, Clickhaler®, and Turbuhaler® was significantly (p¿0.001) greater with two inhalations than one inhalation per metered dose across the range of inhalation flow (10 ¿ 60) Lmin-1. This effect was only observed at inhalation flow less than 30 Lmin-1 with the Accuhaler®. Overall there is a significant difference in the total emitted dose. The ex-vivo dose emission of the four different DPIs has been determined using the In- Check Dial device to train twelve non-smoking healthy adult volunteers to inhale at slow (30 Lmin-1) and fast (60 L min-1) inhalation flows through the device with its dial set corresponding to each inhaler. Subsequently each volunteer inhaled at the trained inhalation flows through each active inhaler. The local ethics committee approval was obtained prior to the study and all volunteers gave signed informed consent. The results obtained demonstrate that the studied inhalers have flow-dependent dose emission, thereby enhancing confidence in the use of the In-Check Dial® to identify a patient¿s inhalation flows through a variety of DPIs. Also the total emitted dose determined by ex-vivo methodology was significantly (p¿0.05) greater with two inhalations than one inhalation per metered dose. The results of the in-vitro aerodynamic dose emission characteristics highlight that the fine particle dose (FPD) from the four studied inhalers is flow dependent. Also the minimum inhalation flow to generate the (FPD) with the appropriate characteristics for lung deposition has been identified to be 20 L min-1 for the Accuhaler®, Easyhaler® and Clickhaler®, while that for the Turbuhaler® is about 30 L min-1. Also the inhalation volume above 2L and the number of inhalations for each dose have respectively no significant (p¿0.05) influence on the FPD emitted from the four studied inhalers. The results support the present instructions to patients using these inhalers to inhale once for each dose as fast as they can.

This study provides, for the first time, an ex vivo comparative evaluation of formulations of budesonide with crystallised β-form mannitol, commercial DPI grade mannitol and lactose. The lactose-budesonide was the marketed Easyhaler® 200 g formulation. Ex vivo assessment of deposition using the Easyhaler® multi-dose high resistance inhaler with reservoir was compared with the RS01® single dose capsule low resistance inhaler at two different inhalation rates. Aerodynamic characteristics, flow and surface energies were investigated together with in vitro and ex vivo assessment of drug deposition. Dose emission was greater for all formulations with higher inhalation flow, indicating greater detachment of drug from carrier, and greater with the Easyhaler®, highlighting the importance of correct device for formulation. Emission was lowest at both inhalation rates for crystallised mannitol due to poor flowability associated with elongated particle shape which resulted in interception deposition. Surface energies were also implicated; closely matched polar surface energy of carrier and drug may be an important inhibiting factor. The promising aerodynamic characteristics of crystallised mannitol with the RS01® inhaler and lactose-budesonide from in vitro assessment were not supported by ex vivo results, highlighting the need for careful selection of device.