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Papers by David Prime

Research paper thumbnail of Effect of Disease Severity in Asthma and Chronic Obstructive Pulmonary Disease on Inhaler-Specific Inhalation Profiles Through the ELLIPTA(®) Dry Powder Inhaler

Journal of aerosol medicine and pulmonary drug delivery, Jan 15, 2015

Two studies were undertaken to characterize the maximal effort inhalation profiles of healthy sub... more Two studies were undertaken to characterize the maximal effort inhalation profiles of healthy subjects and patients with asthma or chronic obstructive pulmonary disease (COPD) through a moderate-resistance dry powder inhaler (DPI). Correlations between inhaler-specific inhalation characteristics and inhaler-independent lung function parameters were investigated. Healthy subjects (n = 15), patients with mild, moderate, or severe asthma (n = 45), and patients with mild, moderate, severe, or very-severe COPD (n = 60) were included in the studies. Inhalation pressure drop versus time profiles were recorded using an instrumented ELLIPTA® DPI or bespoke resistor component with equivalent resistivity. Inhaler-independent lung function assessments included pharyngometry, spirometry, plethysmography, and diffusion. For the inhaler-specific inhalation profiles, the mean maximal effort peak inspiratory flow rates (PIFRs) varied across the subgroups from 65.8-110.6 L/min (range: 41.6-142.9). Pe...

Research paper thumbnail of In Vitro Dosing Performance of the ELLIPTA(®) Dry Powder Inhaler Using Asthma and COPD Patient Inhalation Profiles Replicated with the Electronic Lung (eLung™)

Journal of aerosol medicine and pulmonary drug delivery, Jan 15, 2015

To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive... more To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive pulmonary disease (COPD) therapies delivered via the ELLIPTA(®) dry powder inhaler across inhalation endpoints representative of the target patient population, using the Electronic Lung (eLung™) to replicate inhaler-specific patient inhalation profiles that were previously recorded in vivo. Selected profiles, representative of the range of inhalation endpoints achieved by patients with all severities of asthma and COPD, were replicated using the eLung breathing simulator in conjunction with an oropharyngeal cast. A Next Generation Impactor was coupled to the eLung to determine the aerodynamic particle size distribution of the ex-throat dose (ETD) of asthma and COPD therapies delivered via the ELLIPTA inhaler. Delivered dose (DD), ETD, and fine particle dose (FPD; defined as a mass of active substance less than 5 μm) were determined for fluticasone furoate (FF)/vilanterol (VI) 100/25 μg ...

Research paper thumbnail of Ex-Vivo Product Performance Of Fluticasone Furoate/Vilanterol Delivered From A Novel Dry Powder Inhaler, Using The Electronic Lung To Replicate Asthma And COPD Patient Inhalation Profiles

B41. COPD: PHARMACOLOGICAL TREATMENT, 2012

Research paper thumbnail of Latest advances in the development of dry powder inhalers

Pharmaceutical Science & Technology Today, 2000

The current market for dry powder inhalers (DPIs) has over 20 devices in present use and at least... more The current market for dry powder inhalers (DPIs) has over 20 devices in present use and at least another 30 under development. Clinicians recognize that DPIs are a suitable alternative to pressurized metered dose inhalers (pMDIs) for some patients but the relative performance of devices is often unclear. The problem is compounded by the need to reformulate pMDIs with new propellants, introducing further products to the market with associated variations in performance. This article reviews the DPIs currently available, the driving forces governing new designs, and the claimed advantages of DPIs in the development pipeline.

Research paper thumbnail of The influence of carrier and drug morphology on drug delivery from dry powder formulations

International Journal of Pharmaceutics, 2003

Lactose was crystallised either from neutralised Carbopol 934 gel or from water-ethanol solution ... more Lactose was crystallised either from neutralised Carbopol 934 gel or from water-ethanol solution without stirring, with a view to obtaining lactose alpha-monohydrate of favourable shape and smooth surface, suitable for use as carriers in formulations for dry powder inhalers (DPIs). Crystallisation of salbutamol sulphate was carried out in the presence of water, lecithin and ethanol to form salbutamol crystals with defined shape and smooth surface. The crystals formed were needle-shaped, with a length of less than 6 microm and a width between 0.5 and 1 microm. DSC and TGA showed that lactose crystals produced from Carbopol gel or from water-ethanol solution existed as alpha-lactose monohydrate. The DSC thermograms of micronised and crystallised salbutamol sulphate showed two similar endothermic transitions at 200 and 290 degrees C, respectively. The first transition was initially thought to correspond to the melting of salbutamol sulphate. However, the shape of the particles as observed by optical microscopy was not altered after heating the sample to 250 degrees C, suggesting that no transition from solid to liquid state occurred at 200 degrees C. This was confirmed by observations made using hot stage microscopy. The two endothermic transitions are suggested to correspond to the decomposition of the salbutamol sulphate molecule. The elongation ratio of the commercial lactose crystals, lactose crystallised from Carbopol and from water-ethanol were 1.69+/-0.05, 2.01+/-0.13 and 6.25+/-0.17, respectively. As the elongation ratio increased the flow properties of the carrier were affected detrimentally and this consequently reduced the content uniformity of salbutamol sulphate and drug emission from the inhaler device. Whereas, increasing the elongation ratio of the carrier or drug improved the deposition profiles of salbutamol sulphate, suggesting that the more elongated particles would be more aerodynamic and favour deep lung penetration.

Research paper thumbnail of Comparison Of Inhalation Profiles Through A Novel Dry Powder Inhaler (nDPI) And Lung Function Measurements For Healthy Subjects, Asthma And Chronic Obstructive Pulmonary Disease (COPD) Patients

B41. COPD: PHARMACOLOGICAL TREATMENT, 2012

Research paper thumbnail of Analysis of polycyclic aromatic hydrocarbons in metered dose inhaler drug formulations by isotope dilution gas chromatography/mass spectrometry

Journal of Pharmaceutical and Biomedical Analysis, 1995

Organic compounds extracted into metered dose inhalers (MDIs) from the rubber components of the m... more Organic compounds extracted into metered dose inhalers (MDIs) from the rubber components of the metering valve are of increasing interest in the development of these formulations. Polycyclic aromatic hydrocarbons (PAHs) are a class of extractable organic compounds whose source is the carbon black commonly used as a reinforcing agent in rubber. The analytical method for PAHs described in this report

Research paper thumbnail of A Critical Comparison of the Dose Delivery Characteristics of Four Alternative Inhalation Devices Delivering Salbutamol: Pressurized Metered Dose Inhaler, Diskus Inhaler, Diskhaler Inhaler, and Turbuhaler Inhaler

Journal of Aerosol Medicine, 1999

Salbutamol is a short-acting beta 2 agonist which is effective as a rescue therapy in the treatme... more Salbutamol is a short-acting beta 2 agonist which is effective as a rescue therapy in the treatment of asthma. This study uses in vitro test methods to compare the capability of four alternative devices to deliver an accurate and precise dose of salbutamol. It is demonstrated that the conventional metered dose inhaler (MDI) achieves excellent accuracy and precision in dose delivery. Additionally, it is the most efficient inhaler in terms of generating in-vitro a fine particle fraction from the dose. A spacer device has been shown to further enhance the dosing characteristics. When tested over a wide range of inspiratory air flow rates, the Diskus (GlaxoWellcome, Hertfordshire, UK) has comparable accuracy and precision to the MDI tested at 60 L/min, and it offers an advantage over two alternative dry powder inhalers (DPIs), delivering a more consistent dose across the range of flow rates tested and being more efficient at generating a fine particle fraction than either Turbuhaler (Astra, Lund, Sweden) or Diskhaler (GlaxoWellcome) at both 28 and 60 L/min inspiratory flow rates. Diskus, Diskhaler, Ventolin, Volumatic, and Rotadisk are trademarks of the GlaxoWellcome Group of companies. The Accuhaler is the alternative to the Diskus in those countries where the Diskus trademark is not available. Inspiryl and Turbuhaler are trademarks of the Astra Group of companies.

Research paper thumbnail of Characterisation and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolised salbutamol sulfate from dry powder inhalers

European Journal of Pharmaceutical Sciences, 2003

Lactose particles with different elongation ratio, roundness, polymorphic form and crystallinity ... more Lactose particles with different elongation ratio, roundness, polymorphic form and crystallinity were prepared by a one-step crystallisation process using varying ratios of acetone/water. The crystals were characterised using image analysis optical microscopy, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The elongation ratio was found to increase with increasing acetone ratio which therefore, appears to accelerate the growth in length rather than width and/or thickness. The crystallinity and polymorphic forms were also acetone-concentration dependent. For example, the crystals formed using 65-80% v/v acetone were almost all of the alpha-form whereas at 85% v/v a small amount of beta-form was precipitated, as detected by a peak at the reflection angle 2 theta=10.4 in the X-ray diffractogram. When 90% v/v acetone was incorporated a mixture of alpha- and beta-forms were produced in almost equal quantity, whereas, with 95% v/v acetone the beta-form predominated. At high acetone concentration (90 and 95% v/v), the crystallisation proceeded rapidly leading to the creation of some amorphous content. The 63-90-microm sieve cut of either commercial grade lactose (CL) or crystallised lactose was mixed with salbutamol sulfate and dispersibility was determined using the twin stage liquid impinger. All the formulations containing carrier particles generated by crystallization from solvent showed higher dispersibility and fine particle fraction (FPF) of the drug compared to the formulation made containing CL. The carrier that showed the highest elongation ratio (produced from an 85% acetone 15% water solution), when mixed with salbutamol sulfate produced the highest dispersibility (38.5%) and highest FPF (29.24%). These parameters were six times higher than the values obtained with the formulation containing CL.

Research paper thumbnail of Review of dry powder inhalers

Advanced Drug Delivery Reviews, 1997

The search for alternatives to metered-dose inhalers has accelerated recently in a bid to find ef... more The search for alternatives to metered-dose inhalers has accelerated recently in a bid to find effective products that do not use chlorofluorocarbon (CFC) propellants. This paper reviews the factors to be considered in developing dry powder inhalers (DPIs), particularly the formulation, metering design and flow path in the device. The advantages and disadvantages of current DPIs are discussed and possible future approaches outlined.

Research paper thumbnail of Studies of the Human Oropharyngeal Airspaces Using Magnetic Resonance Imaging. III. The Effects of Device Resistance with Forced Maneuver and Tidal Breathing on Upper Airway Geometry

Journal of Aerosol Medicine, 2005

The anatomical geometry of the upper airways of 20 volunteers has been studied using three-dimens... more The anatomical geometry of the upper airways of 20 volunteers has been studied using three-dimensional (3D)inhalation-gated magnetic resonance imaging (MRI)for four separate dummy inhalation devices of varying diameters and resistances. The only anatomical parameters showing a consistent dependence upon device characteristics were the total airway and buccal volumes between large and small mouthpieces and the distance from the back of the teeth to the first solid obstacle encountered. Individual subjects showed varied device dependent changes: 45% having an increase in regional airway volumes, particularly in the nasopharynx (+46% volume increase)and laryngo-pharynx (+36% volume increase)for the high-resistance devices compared with the low-resistance ones. However, 30% of subjects showed the opposite behavior, a reduction in naso-pharynx volume (-17%), laryngo-pharynx volume (-17%), and laryngeal cavity (-11%). 25% showed no significant difference in airway volume between high- and low-resistance devices. There was a correlation between maximum inspiratory pressure (MIP)and change in airway volume for high-resistance devices, with those exhibiting expansion having generally lower MIP than the group showing contraction (with the non-responders intermediate). Mean airway minimum and maximum cross-sectional areas and radii were not influenced by device. The geometric mean radius at the epiglottis was 5.1 mm (standard deviation [SD] 1.1) and 5.7 mm (SD 1.1) at the vocal cords. Significant differences observed between males and females included MIP for high-resistance devices, the volume and minimum and maximum radii of the laryngeal and laryngeo-pharynx regions, and total airway volume. A cadaver cast exhibited a number of striking differences in comparison with the in vivo data, most notably a significantly greater total volume.

Research paper thumbnail of Effect of Disease Severity in Asthma and Chronic Obstructive Pulmonary Disease on Inhaler-Specific Inhalation Profiles Through the ELLIPTA(®) Dry Powder Inhaler

Journal of aerosol medicine and pulmonary drug delivery, Jan 15, 2015

Two studies were undertaken to characterize the maximal effort inhalation profiles of healthy sub... more Two studies were undertaken to characterize the maximal effort inhalation profiles of healthy subjects and patients with asthma or chronic obstructive pulmonary disease (COPD) through a moderate-resistance dry powder inhaler (DPI). Correlations between inhaler-specific inhalation characteristics and inhaler-independent lung function parameters were investigated. Healthy subjects (n = 15), patients with mild, moderate, or severe asthma (n = 45), and patients with mild, moderate, severe, or very-severe COPD (n = 60) were included in the studies. Inhalation pressure drop versus time profiles were recorded using an instrumented ELLIPTA® DPI or bespoke resistor component with equivalent resistivity. Inhaler-independent lung function assessments included pharyngometry, spirometry, plethysmography, and diffusion. For the inhaler-specific inhalation profiles, the mean maximal effort peak inspiratory flow rates (PIFRs) varied across the subgroups from 65.8-110.6 L/min (range: 41.6-142.9). Pe...

Research paper thumbnail of In Vitro Dosing Performance of the ELLIPTA(®) Dry Powder Inhaler Using Asthma and COPD Patient Inhalation Profiles Replicated with the Electronic Lung (eLung™)

Journal of aerosol medicine and pulmonary drug delivery, Jan 15, 2015

To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive... more To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive pulmonary disease (COPD) therapies delivered via the ELLIPTA(®) dry powder inhaler across inhalation endpoints representative of the target patient population, using the Electronic Lung (eLung™) to replicate inhaler-specific patient inhalation profiles that were previously recorded in vivo. Selected profiles, representative of the range of inhalation endpoints achieved by patients with all severities of asthma and COPD, were replicated using the eLung breathing simulator in conjunction with an oropharyngeal cast. A Next Generation Impactor was coupled to the eLung to determine the aerodynamic particle size distribution of the ex-throat dose (ETD) of asthma and COPD therapies delivered via the ELLIPTA inhaler. Delivered dose (DD), ETD, and fine particle dose (FPD; defined as a mass of active substance less than 5 μm) were determined for fluticasone furoate (FF)/vilanterol (VI) 100/25 μg ...

Research paper thumbnail of Ex-Vivo Product Performance Of Fluticasone Furoate/Vilanterol Delivered From A Novel Dry Powder Inhaler, Using The Electronic Lung To Replicate Asthma And COPD Patient Inhalation Profiles

B41. COPD: PHARMACOLOGICAL TREATMENT, 2012

Research paper thumbnail of Latest advances in the development of dry powder inhalers

Pharmaceutical Science & Technology Today, 2000

The current market for dry powder inhalers (DPIs) has over 20 devices in present use and at least... more The current market for dry powder inhalers (DPIs) has over 20 devices in present use and at least another 30 under development. Clinicians recognize that DPIs are a suitable alternative to pressurized metered dose inhalers (pMDIs) for some patients but the relative performance of devices is often unclear. The problem is compounded by the need to reformulate pMDIs with new propellants, introducing further products to the market with associated variations in performance. This article reviews the DPIs currently available, the driving forces governing new designs, and the claimed advantages of DPIs in the development pipeline.

Research paper thumbnail of The influence of carrier and drug morphology on drug delivery from dry powder formulations

International Journal of Pharmaceutics, 2003

Lactose was crystallised either from neutralised Carbopol 934 gel or from water-ethanol solution ... more Lactose was crystallised either from neutralised Carbopol 934 gel or from water-ethanol solution without stirring, with a view to obtaining lactose alpha-monohydrate of favourable shape and smooth surface, suitable for use as carriers in formulations for dry powder inhalers (DPIs). Crystallisation of salbutamol sulphate was carried out in the presence of water, lecithin and ethanol to form salbutamol crystals with defined shape and smooth surface. The crystals formed were needle-shaped, with a length of less than 6 microm and a width between 0.5 and 1 microm. DSC and TGA showed that lactose crystals produced from Carbopol gel or from water-ethanol solution existed as alpha-lactose monohydrate. The DSC thermograms of micronised and crystallised salbutamol sulphate showed two similar endothermic transitions at 200 and 290 degrees C, respectively. The first transition was initially thought to correspond to the melting of salbutamol sulphate. However, the shape of the particles as observed by optical microscopy was not altered after heating the sample to 250 degrees C, suggesting that no transition from solid to liquid state occurred at 200 degrees C. This was confirmed by observations made using hot stage microscopy. The two endothermic transitions are suggested to correspond to the decomposition of the salbutamol sulphate molecule. The elongation ratio of the commercial lactose crystals, lactose crystallised from Carbopol and from water-ethanol were 1.69+/-0.05, 2.01+/-0.13 and 6.25+/-0.17, respectively. As the elongation ratio increased the flow properties of the carrier were affected detrimentally and this consequently reduced the content uniformity of salbutamol sulphate and drug emission from the inhaler device. Whereas, increasing the elongation ratio of the carrier or drug improved the deposition profiles of salbutamol sulphate, suggesting that the more elongated particles would be more aerodynamic and favour deep lung penetration.

Research paper thumbnail of Comparison Of Inhalation Profiles Through A Novel Dry Powder Inhaler (nDPI) And Lung Function Measurements For Healthy Subjects, Asthma And Chronic Obstructive Pulmonary Disease (COPD) Patients

B41. COPD: PHARMACOLOGICAL TREATMENT, 2012

Research paper thumbnail of Analysis of polycyclic aromatic hydrocarbons in metered dose inhaler drug formulations by isotope dilution gas chromatography/mass spectrometry

Journal of Pharmaceutical and Biomedical Analysis, 1995

Organic compounds extracted into metered dose inhalers (MDIs) from the rubber components of the m... more Organic compounds extracted into metered dose inhalers (MDIs) from the rubber components of the metering valve are of increasing interest in the development of these formulations. Polycyclic aromatic hydrocarbons (PAHs) are a class of extractable organic compounds whose source is the carbon black commonly used as a reinforcing agent in rubber. The analytical method for PAHs described in this report

Research paper thumbnail of A Critical Comparison of the Dose Delivery Characteristics of Four Alternative Inhalation Devices Delivering Salbutamol: Pressurized Metered Dose Inhaler, Diskus Inhaler, Diskhaler Inhaler, and Turbuhaler Inhaler

Journal of Aerosol Medicine, 1999

Salbutamol is a short-acting beta 2 agonist which is effective as a rescue therapy in the treatme... more Salbutamol is a short-acting beta 2 agonist which is effective as a rescue therapy in the treatment of asthma. This study uses in vitro test methods to compare the capability of four alternative devices to deliver an accurate and precise dose of salbutamol. It is demonstrated that the conventional metered dose inhaler (MDI) achieves excellent accuracy and precision in dose delivery. Additionally, it is the most efficient inhaler in terms of generating in-vitro a fine particle fraction from the dose. A spacer device has been shown to further enhance the dosing characteristics. When tested over a wide range of inspiratory air flow rates, the Diskus (GlaxoWellcome, Hertfordshire, UK) has comparable accuracy and precision to the MDI tested at 60 L/min, and it offers an advantage over two alternative dry powder inhalers (DPIs), delivering a more consistent dose across the range of flow rates tested and being more efficient at generating a fine particle fraction than either Turbuhaler (Astra, Lund, Sweden) or Diskhaler (GlaxoWellcome) at both 28 and 60 L/min inspiratory flow rates. Diskus, Diskhaler, Ventolin, Volumatic, and Rotadisk are trademarks of the GlaxoWellcome Group of companies. The Accuhaler is the alternative to the Diskus in those countries where the Diskus trademark is not available. Inspiryl and Turbuhaler are trademarks of the Astra Group of companies.

Research paper thumbnail of Characterisation and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolised salbutamol sulfate from dry powder inhalers

European Journal of Pharmaceutical Sciences, 2003

Lactose particles with different elongation ratio, roundness, polymorphic form and crystallinity ... more Lactose particles with different elongation ratio, roundness, polymorphic form and crystallinity were prepared by a one-step crystallisation process using varying ratios of acetone/water. The crystals were characterised using image analysis optical microscopy, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The elongation ratio was found to increase with increasing acetone ratio which therefore, appears to accelerate the growth in length rather than width and/or thickness. The crystallinity and polymorphic forms were also acetone-concentration dependent. For example, the crystals formed using 65-80% v/v acetone were almost all of the alpha-form whereas at 85% v/v a small amount of beta-form was precipitated, as detected by a peak at the reflection angle 2 theta=10.4 in the X-ray diffractogram. When 90% v/v acetone was incorporated a mixture of alpha- and beta-forms were produced in almost equal quantity, whereas, with 95% v/v acetone the beta-form predominated. At high acetone concentration (90 and 95% v/v), the crystallisation proceeded rapidly leading to the creation of some amorphous content. The 63-90-microm sieve cut of either commercial grade lactose (CL) or crystallised lactose was mixed with salbutamol sulfate and dispersibility was determined using the twin stage liquid impinger. All the formulations containing carrier particles generated by crystallization from solvent showed higher dispersibility and fine particle fraction (FPF) of the drug compared to the formulation made containing CL. The carrier that showed the highest elongation ratio (produced from an 85% acetone 15% water solution), when mixed with salbutamol sulfate produced the highest dispersibility (38.5%) and highest FPF (29.24%). These parameters were six times higher than the values obtained with the formulation containing CL.

Research paper thumbnail of Review of dry powder inhalers

Advanced Drug Delivery Reviews, 1997

The search for alternatives to metered-dose inhalers has accelerated recently in a bid to find ef... more The search for alternatives to metered-dose inhalers has accelerated recently in a bid to find effective products that do not use chlorofluorocarbon (CFC) propellants. This paper reviews the factors to be considered in developing dry powder inhalers (DPIs), particularly the formulation, metering design and flow path in the device. The advantages and disadvantages of current DPIs are discussed and possible future approaches outlined.

Research paper thumbnail of Studies of the Human Oropharyngeal Airspaces Using Magnetic Resonance Imaging. III. The Effects of Device Resistance with Forced Maneuver and Tidal Breathing on Upper Airway Geometry

Journal of Aerosol Medicine, 2005

The anatomical geometry of the upper airways of 20 volunteers has been studied using three-dimens... more The anatomical geometry of the upper airways of 20 volunteers has been studied using three-dimensional (3D)inhalation-gated magnetic resonance imaging (MRI)for four separate dummy inhalation devices of varying diameters and resistances. The only anatomical parameters showing a consistent dependence upon device characteristics were the total airway and buccal volumes between large and small mouthpieces and the distance from the back of the teeth to the first solid obstacle encountered. Individual subjects showed varied device dependent changes: 45% having an increase in regional airway volumes, particularly in the nasopharynx (+46% volume increase)and laryngo-pharynx (+36% volume increase)for the high-resistance devices compared with the low-resistance ones. However, 30% of subjects showed the opposite behavior, a reduction in naso-pharynx volume (-17%), laryngo-pharynx volume (-17%), and laryngeal cavity (-11%). 25% showed no significant difference in airway volume between high- and low-resistance devices. There was a correlation between maximum inspiratory pressure (MIP)and change in airway volume for high-resistance devices, with those exhibiting expansion having generally lower MIP than the group showing contraction (with the non-responders intermediate). Mean airway minimum and maximum cross-sectional areas and radii were not influenced by device. The geometric mean radius at the epiglottis was 5.1 mm (standard deviation [SD] 1.1) and 5.7 mm (SD 1.1) at the vocal cords. Significant differences observed between males and females included MIP for high-resistance devices, the volume and minimum and maximum radii of the laryngeal and laryngeo-pharynx regions, and total airway volume. A cadaver cast exhibited a number of striking differences in comparison with the in vivo data, most notably a significantly greater total volume.