Investigation of Electrostatic Behavior of a Lactose Carrier for Dry Powder Inhalers

Purpose  This study aims to elucidate the electrostatic behavior of a model lactose carrier used in dry powder inhaler formulations by examining the effects of ambient relative humidity (RH), aerosolization air flow rate, repeated inhaler use, gelatin capsule and tapping on the specific charge (nC/g) of bulk and aerosolized lactose. Materials and Methods  Static and dynamic electrostatic charge measurements were performed using a Faraday cage connected to an electrometer. Experiments were conducted inside a walk-in environmental chamber at 25°C and RHs of 20% to 80%. Aerosolization was achieved using air flow rates of 30, 45, 60 and 75 L/min. Results  The initial charges of the bulk and capsulated lactose were a magnitude lower than the charges of tapped or aerosolized lactose. Dynamic charge increased linearly with aerosolization air flow rate and RH. Greater frictional forces at higher air flow rate induced higher electrostatic charges. Increased RH enhanced charge generation. Repeated inhaler use significantly influenced electrostatic charge due to repeated usage. Conclusions  This study demonstrated the significance of interacting influences by variables commonly encountered in the use DPI such as variation in patient’s inspiratory flow rate, ambient RH and repeated inhaler use on the electrostatic behavior of a lactose DPI carrier.     

The Impact of Inspiratory Flow Rate on Drug Delivery to the Lungs with Dry Powder Inhalers

Current marketed dry powder inhalers utilize the energy from patient inspiration to fluidize and disperse bulk powder agglomerates into respirable particles. Variations in patient inspiratory flow profiles can lead to marked differences in total lung dose (TLD), and ultimately patient outcomes for an inhaled therapeutic. The present review aims to quantitate the flow rate dependence in TLD observed for a number of drug/device combinations using a new metric termed the Q index. With this data in hand, the review explores key attributes in the design of the formulation and device that impact flow rate dependence. The review also proposes alternative in vitro methods to assess flow rate dependence that more closely align with in vivo observations. Finally, the impact of variations in flow rate on lung function for inhaled bronchodilators is summarized.     

Twin-Screw Continuous Mixing Can Produce Dry Powder Inhalation Mixtures for Pulmonary Delivery

The feasibility of twin-screw corotating extruder as a continuous process mixer to prepare dry powder inhalation (DPI) powders was investigated. Interactive mixtures of 1% micronized budesonide, 0.3% magnesium stearate and 98.7% alpha-lactose monohydrate were manufactured using a Leistritz Nano-16 extruder at various processing conditions. One set of GFM (grooved mixing) elements were included in the screw profile to provide distributive mixing of conveyed powders with the goal of resulting in a homogeneous mixture. Residence time in the twin-screw mixer was modelled to quantify mixing efficiency. Comparative powders were also prepared using either low or high-shear batch mixing to compare the effect of mixing methods on the properties of the budesonide dry powder inhalation formulation. Twin screw mixing results in homogeneous mixtures with aerosol performance comparable to that of high-shear batch mixing. Scanning electron microscopy confirmed that twin screw mixing produces particles with morphology like that of low and high-shear batch mixing. X-ray diffraction (XRD) analysis verified that there was no form change of the drug due to twin-screw processing. Statistical regression was used to probe the relationship between twin screw mixing process parameters such as screw speed and feed rate and aerosol performance. The twin screw mixing process was found to be robust, as no significant differences in aerosol performance were found for various processing parameters.     

Freeze-Dried Mannitol for Superior Pulmonary Drug Delivery via Dry Powder Inhaler

Purpose

To show for the first time the superior dry powder inhaler (DPI) performance of freeze dried mannitol in comparison to spray dried mannitol and commercial mannitol.

Methods

Different mannitol powders were sieved to collect 63–90 μm particles and then analyzed in terms of size, shape, surface morphology, solid state, density, flowability. Salbutamol sulphate-mannitol aerosol formulations were evaluated in terms of homogeneity, SS-mannitol adhesion, and in vitro aerosolization performance.

Results

Freeze dried mannitol demonstrated superior DPI performance with a fine particle fraction believed to be highest so far reported in literature for salbutamol sulphate under similar protocols (FPF?=?46.9%). To lesser extent, spray dried mannitol produced better aerosolization performance than commercial mannitol. Freeze dried mannitol demonstrated elongated morphology, α-+β-+δ- polymorphic forms, and poor flowability whereas spray dried mannitol demonstrated spherical morphology, α-+β- polymorphic forms, and excellent flowability. Commercial mannitol demonstrated angular morphology, β- polymorphic form, and good flowability. Freeze dried mannitol demonstrated smoother surface than spray dried mannitol which in turn demonstrated smoother surface than commercial mannitol. FPF of SS increased as mannitol powder porosity increase.

Conclusions

Freeze drying under controlled conditions can be used as a potential technique to generate aerodynamically light mannitol particles for superior DPI performance.     

Suitability of the Upper Airway Models Obtained from MRI Studies in Simulating Drug Lung Deposition from Inhalers

No HeadingPurpose. In this study, the suitability of the upper airway models, obtained by applying a magnetic resonance imaging method, in simulating in vivo aerosol deposition data is determined.Methods. Depositions of salbutamol sulfate from two nebulizers in two models, one with constriction at the oropharynx (the constricted cast) and another model without that constriction (the wide cast), were determined.Results. For the Sidestream and Ventstream nebulizer, 76 ± 3% (mean ± standard deviation) and 81 ± 2% of the emitted dose deposited in the constricted cast, whereas 51 ± 2% and 49 ± 3% of the emitted dose deposited in the wide cast, respectively. These values were in good agreement with in vivo data. Mostly, increasing nebulizer charge volume (by normal saline) from 2.5 ml to 5 ml increased significantly the lung dose. However, the lung doses from the Sidestream and Ventstream nebulizer with 2.5 ml charge volume via the wide cast were (1.37 ± 0.06 and 1.38 ± 0.05 mg) significantly larger than those for the constricted cast with 5 ml charge volume (0.87 ± 0.15 and 0.86 ± 0.21 mg, respectively) (p = 0.005).Conclusions. The upper airway models closely simulated the in vivo deposition data. Optimizing the upper airway posture during inhalation via the nebulizers would be more efficient in increasing drug lung delivery than diluting their contents.     

Development and Comparison of New High-Efficiency Dry Powder Inhalers for Carrier-Free Formulations

High-efficiency dry powder inhalers (DPIs) were developed and tested for use with carrier-free formulations across a range of different inhalation flow rates. Performance of a previously reported DPI was compared with two new designs in terms of emitted dose (ED) and aerosolization characteristics using in vitro experiments. The two new designs oriented the capsule chamber (CC) at different angles to the main flow passage, which contained a three-dimensional (3D) rod array for aerosol deaggregation. Computational fluid dynamics simulations of a previously developed deaggregation parameter, the nondimensional specific dissipation (NDSD), were used to explain device performance. Orienting the CC at 90° to the mouthpiece, the CC₉₀-3D inhaler provided the best performance with an ED = 73.4%, fine particle fractions (FPFs) less than 5 and 1 μm of 95.1% and 31.4%, respectively, and a mass median aerodynamic diameter (MMAD) = 1.5 μm. For the carrier-free formulation, deaggregation was primarily influenced by capsule aperture position and the NDSD parameter. The new CC-3D inhalers reduced the percent difference in FPF and MMAD between low and high flows by 1–2 orders of magnitude compared with current commercial devices. In conclusion, the new CC-3D inhalers produced extremely high-quality aerosols with little sensitivity to flow rate and are expected to deliver approximately 95% of the ED to the lungs.     

Effects of Device and Formulation on In Vitro Performance of Dry Powder Inhalers

The study examined the sensitivity of DPI in vitro performance to formulation and device changes. Rotahaler/Rotacaps was selected as the reference DPI drug product, and Aerolizer was selected as the test device. Since the test device was recognized to have much greater efficiency of dispersion, simple modifications to both formulation and device were made in an effort to provide a closer match to the in vitro performance of the reference product. The modifications included varying the drug and lactose particle sizes and/or lactose fine particle content in the test formulations, as well as lowering the specific resistance of the test device. These modifications were intended to address variables important for drug product performance for a defined experimental design and were not intended to mimic the extensive formulation and device design strategies that are employed in an industrial setting. Formulation and device modifications resulted in a modified test product that approached the reference product in the in vitro performance.     

Evaluation of Granulated Lactose as a Carrier for Dry Powder Inhaler Formulations 2: Effect of Drugs and Drug Loading

Previously, granulated lactose carriers were shown to improve uniformity and aerosolization of a low-dose model drug. In the present study, the blending uniformity and aerosol dispersion performance were assessed for 2 model drugs salbutamol sulfate (SS) and rifampicin (RIF), blended at high loadings (10% or 30% drug) with granulated lactose carriers. The model drug powders differed in particle size distribution, morphology, density, and surface energies. Content uniformity of RIF blends was better than that of SS. Aerosolization studies showed that all blend formulations had acceptable emitted fractions (>70%). The SS blends showed low induction-port deposition (6%-10%) compared to RIF (5%-30%). This difference was greater at high flow rates. At 90 L/min, the low induction port deposition of SS blends allowed high fine particle fraction (FPF) of 73%-81%, whereas the FPF of the RIF blends was around 43%-45% with higher induction port deposition. However, SS blends exhibited strong flow rate–dependent performance. Increasing the flow rate from 30 L/min to 90 L/min increased SS FPF from approximately 20% to 80%. Conversely, RIF blends were flow rate and drug loading independent. It was concluded that the aerosolization of high drug–loaded dry powder inhaler formulations using granulated lactose, particularly flow rate dependency, varies with active pharmaceutical ingredient properties.     

Effect of Device Design on the In Vitro Performance and Comparability for Capsule-Based Dry Powder Inhalers

This study investigated the effect of modifying the design of the Cyclohaler on its aerosolization performance and comparability to the HandiHaler at multiple flow rates. The Cyclohaler and HandiHaler were designated as model test and reference unit-dose, capsule-based dry powder inhalers (DPIs), respectively. The flow field, pressure drop, and carrier particle trajectories within the Cyclohaler and HandiHaler were modeled via computational fluid dynamics (CFD). With the goal of achieving in vitro comparability to the HandiHaler, the CFD results were used to identify key device attributes and to design two modifications of the Cyclohaler (Mod 1 and Mod 2), which matched the specific resistance of the HandiHaler but exhibited different cyclonic flow conditions in the device. Aerosolization performance of the four DPI devices was evaluated by using the reference product''s capsule and formulation (Spiriva capsule) and a multistage cascade impactor. The in vitro data showed that Mod 2 provided a closer match to the HandiHaler than the Cyclohaler and Mod 1 at 20, 39, and 55 l/min. The in vitro and CFD results together suggest that matching the resistance of test and reference DPI devices is not sufficient to attain comparable aerosolization performance, and the improved in vitro comparability of Mod 2 to the HandiHaler may be related to the greater degree of similarities of the flow rate of air through the pierced capsule (Q_c) and the maximum impact velocity of representative carrier particles (V_n) in the Cyclohaler-based device. This investigation illustrates the importance of enhanced product understanding, in this case through the CFD modeling and in vitro characterization of aerosolization performance, to enable identification and modification of key design features of a test DPI device for achieving comparable aerosolization performance to the reference DPI device.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-012-9379-9) contains supplementary material, which is available to authorized users.KEY WORDS: computational fluid dynamics, device design, dry powder inhaler, in vitro comparability, in vitro performance     

Development and Characterisation of Supramolecular Autovectoring System for Selective Drug Delivery

Abstract

Supramolecules since ages have been characterised as self-associating systems emanating the properties directly related to the mode of molecular association. Similar to supramolecules, liquid crystals may also be considered as an associated system. The liquid crystals are defined as the state of matter with the characterstic order of the crystal and the mobility of liquid. The system has been compared to the transporting form of cholesterol in body. The present study reports autovectoring potentials of the drug liquid crystals using diclofenac diethylammonium (DD) as a model.

The drug based liquid crystals of DD were prepared employing temperature induced transformation of isotropic form to the liquid crystal form. The prepared liquid crystal systems were incubated with 1% phosphatidylcholine in order to stabilise the surface and restrict it into the liquid crystalline state. The system was characterised for viscosity variation, X-ray diffraction pattern, partitioning behaviour and in vitro diffusion profile. In vivo vectorising potential of the developed system was evaluated using rats as test animal and studying for the organ level distribution and drug compartmentalisation.

The system exhibited satisfactory vecterisation as significant amount of administered dose was localised selectively in liver.     

Effect of Device Design and Formulation on the In Vitro Comparability for Multi-Unit Dose Dry Powder Inhalers

The focus of this investigation was to understand the design space to achieve comparable in vitro performance of two multi-unit dose dry powder inhalers (DPIs)—Flixotide® Accuhaler® (reference product) and MultiHaler® (test product). Flow field, pressure drop and particle trajectories within the test and reference DPI devices were modelled via computational fluid dynamics (CFD). Micronized fluticasone propionate (FP) was characterized to determine particle size distribution (PSD), specific surface area (SSA) and surface interfacial properties using cohesive-adhesive balance (CAB). CFD simulations suggested that the pressure drop and airflow velocity in the MultiHaler® were greater than Accuhaler®. Two modified test devices (MOD MH 1 and MOD MH 2) were manufactured with the introduction of by-pass channels in the airflow path, which achieved comparable specific resistance and airflow path between the test and reference devices. Assessment of reference product formulation in modified test devices suggested that MOD MH 2 achieved comparable in vitro performance to the reference product. CAB analysis suggested that adhesion of all FP batches to lactose was different, with batch D showing greatest and batch A least adhesion to lactose. Test DPI formulations were manufactured using four different batches of FP with milled or sieved lactose, and showed that batch A FP formulated with sieved lactose in MOD MH 2 device demonstrated the highest degree of similarity to the Accuhaler® in vitro deposition. Application of CFD modelling and material characterization of formulation raw materials enabled the modification of device and formulation critical material attributes to create an in vitro comparable device/formulation system to the reference product.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9775-z) contains supplementary material, which is available to authorized users.Key words: aerosolization, computational fluid dynamics, device design, dry powder inhaler, in vitro comparability, in vitro performance     

InVitro Evaluation of Optimal Inhalation Flow Patterns for Commercial Dry Powder Inhalers and Pressurized Metered Dose Inhalers With Human Inhalation Flow Pattern Simulator

This study aimed at developing a novel analytical method to identify optimal inhalation flow patterns for commercial dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs). As typical commercial DPI and pMDI, Pulmicort^® Turbuhaler^®, and Sultanol^® Inhaler were evaluated by an in vitro inhalation performance testing system with a flow pattern simulator. An 8-stage Andersen cascade impactor (ACI) or twin stage liquid impinger (TSLI) was applied to determine the inhalation performance. The peak flow rate (PFR) of the inhalation flow pattern was set from 15 to 80 L/min in reference to our previous study. From TSLI test results, a higher PFR improved the inhalation performance of the DPI, while the performance of the pMDI was less affected by the PFR. Conversely, from ACI test results, the pMDI performance decreased with a higher PFR, while the DPI followed a similar pattern as in the TSLI test results, because ACI is a finer aerodynamic classification apparatus than TSLI. These results suggested that our in vitro system using a human inhalation flow pattern simulator successfully detected different optimal inhalation patterns between DPI and pMDI. That is, the higher PFR is better for Pulmicort^® Turbuhaler^® (DPI). Conversely, lower PFR is desirable for Sultanol^® Inhaler (pMDI).     

Design of Improved Permeation Enhancers for Transdermal Drug Delivery

This article has been retracted. The correct revised version may be found at DOI:21940. We apologize for the error.     

Particle Aerosolisation and Break-up in Dry Powder Inhalers 1: Evaluation and Modelling of Venturi Effects for Agglomerated Systems

Purpose  

This study utilized a combination of computational fluid dynamics (CFD) and standardized entrainment tubes to investigate the influence of turbulence on the break-up and aerosol performance of a model inhalation formulation.     

Aerosol Electrostatics I: Properties of Fine Powders Before and After Aerosolization by Dry Powder Inhalers

Purpose. To evaluate the dependence of fine particle dose charge (FPD charge) generated from powder inhalers on physico-chemical properties of the inhalation powder, inhaler type, deaggregation mechanism, dose number and/or retained powder. Methods. Electrostatic charges were determined on micronized powders and aerosolized fine particle doses withdrawn from two, high efficiency, multidose powder inhalers, Turbohalerand prototype Dryhaler. The behavior of terbutaline sulfate, budesonide, albuterol (sulfate and base), beclomethasone dipropionate and lactose was assessed before and after aerosolization. Results. Both inhalers conferred triboelectric FPD charges during aerosolization in the range –400 pC through +200 pC. Specific charges (charge/unit mass) on the fine particle doses of budesonide from Dryhaler were significantly less than those from Turbohaler (p < 0.01). Electrostatic charges on the potentially respirable cloud of terbutaline sulfate generated by Bricanyl Turbohaler were positive and/or negative and unpredictable. With Pulmicort Turbohaler, FPD charges on budesonide were always positive. Dryhaler was used to determine the chemical dependence of fine particle triboelectrification during the aerosolization of pure materials. A triboelectric series was constructed from the Dryhaler results ranking the powders from positive to negative as budesonide > lactose > albuterol sulfate > terbutaline sulfate albuterol beclomethasone dipropionate. Conclusions. While there was no evidence of FPD charge dependence upon dose number with either inhaler, FPD charges were dependent upon the powder under investigation, as well as the construction and deaggregation mechanism of the inhaler. The specific charge on the fine particle dose of budesonide from Turbohaler corresponded to approximately 200 electronic charges per particle, a value which is known to affect both total and regional aerosol deposition in the human lung. Electrostatic charge effects may be important determinants of aerosol behavior and should not be neglected.     

Parametric Two-Tier Sequential Quality Assurance Test of Delivery Dose Uniformity of Multiple-Dose Inhaler and Dry Powder Inhaler Drug Products

The delivery dose uniformity is one of the most critical requirements of dry powder inhaler and metered dose inhaler products. In 1998, the U.S. Food and Drug Administration recommended a two-tier acceptance sampling plan in the Draft Guidance of Metered Dose Inhaler and Dry Powder Inhaler Drug Products Chemistry, Manufacturing and Controls. The two-tier procedure is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity. It employed a zero tolerance criterion. In addition, it has a near-zero probability acceptance at the second tier. In this article, a two-tier sequential tolerance interval approach is proposed that is equivalent to a two-tier two one-sided testing procedure. It controls the probability of the product delivering below a prespecified effective dose and the probability of the product delivering over a prespecified safety dose.     

Use of a Fundamental Approach to Spray-Drying Formulation Design to Facilitate the Development of Multi-Component Dry Powder Aerosols for Respiratory Drug Delivery

Purpose

A fundamental approach incorporating current theoretical models into aerosol formulation design potentially reduces experimental work for complex formulations. A D-amino acid mixture containing D-Leucine (D-Leu), D-Methionine, D-Tryptophan, and D-Tyrosine was selected as a model formulation for this approach.

Methods

Formulation design targets were set, with the aim of producing a highly dispersible D-amino acid aerosol. Particle formation theory and a spray dryer process model were applied with boundary conditions to the design targets, resulting in a priori predictions of particle morphology and necessary spray dryer process parameters. Two formulations containing 60% w/w trehalose, 30% w/w D-Leu, and 10% w/w remaining D-amino acids were manufactured.

Results

The design targets were met. The formulations had rugose and hollow particles, caused by deformation of a crystalline D-Leu shell while trehalose remained amorphous, as predicted by particle formation theory. D-Leu acts as a dispersibility enhancer, ensuring that both formulations: 1) delivered over 40% of the loaded dose into the in vitro lung region, and 2) achieved desired values of lung airway surface liquid concentrations based on lung deposition simulations.

Conclusions

Theoretical models were applied to successfully achieve complex formulations with design challenges a priori. No further iterations to the design process were required.