压力定量吸入剂的质量评价与影响因素

综述在设计和制备压力定量吸入剂产品时,其质量评价内容及处方和装置的影响因素。压力定量吸入剂的处方设计包括药物、抛射剂、表面活性剂、助溶剂等的应用,对产品的质量起着至关重要的作用,尤其是氯氟烃类抛射剂逐步被淘汰后,其替代品种呈现多元化,致使处方因素对产品质量的影响变得复杂和不可预知。     

吸入气雾剂中水分的摄入及其对产品性能的影响

氟利昂(CFC)是定量吸入气雾剂(MDI)中常用的抛射剂,近年来逐渐被氢氟烷烃(HFA)所替代.由于HFA的亲水性比CFC强,因此在生产和贮存过程中HFA-MDI中更易引入水分.然而,水分可能影响MDI产品质量,特别是对于混悬型MDI.本文讨论了MDI中水分的摄入机制并分析了影响水分渗入MDI中的因素.简要介绍了欧美法规对MDI中水分的要求;总结了水分对MDI产品性能的影响及防止MDI水分摄入的措施.     

In Vitro Investigation of Drug Particulates Interactions and Aerosol Performance of Pressurised Metered Dose Inhalers

Purpose To determine a relationship between adhesive and cohesive inter-particulate forces of interactions and in vitro performance in pressurised metered dose inhalers (pMDIs) suspension formulations.Methods Interparticulate forces of salbutamol sulphate (SS), budesonide (BUD) and formoterol fumarate dihydrate (FFD) were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H, 3H perfluoropentane (HPFP). Experimental data were analysed using the recently developed cohesive/adhesive analysis method (CAB) and compared with in vitro deposition performances in pMDIs systems using Andersen cascade impactor (ACI).Results The in vitro investigation suggested that the micronised drug materials had significantly different aerosolisation profiles when manufactured as single or combination formulations. In general, the greatest significant differences were observed between SS single drug and SS-BUD and SS-FFD combinations. Analysis of the in vitro performance for the SS only formulation suggested that the cohesive nature of SS (as predicted by the CAB and observed with AFM) led to tightly bound flocs that did not fully deaggregate upon aerosolisation.Conclusions It is suggested that the relationship between interparticulate interactions and in vitro performance of pMDIs suspension systems, when compared to direct measurement of the adhesion/cohesion forces, indicated good correlation. This approach may be useful in expediting the development of pMDI formulation and predicting performance.     

Investigations into the Formulation of Metered Dose Inhalers of Salmeterol Xinafoate and Fluticasone Propionate Microcrystals

PURPOSE: To investigate the aerosolization and behaviour of microparticles of salmeterol xinafoate (SX) and fluticasone propionate (FP) suspended in hydrofluoroalkane (HFA) propellant. METHODS: Microcrystals of SX and FP were produced from poly(ethylene glycol) by antisolvent crystallization. The suspension behaviour and aerosolization of the microcrystals when formulated as metered dose inhalers (MDIs) in HFA 134a propellant was compared with that of microparticles produced by micronization (mSX and mFP) using a glass twin stage impinger and by laser light diffraction using a pressurized cell. RESULTS: FP microparticles underwent non-reversible aggregation in suspension as seen by a doubling in the volume median diameter compared to the raw material. The degree of aggregation of SX particles in suspension was found to decrease as the particle size of the original particles increased. However, because the SX aggregate size was lowest for the particles with the smallest initial size (mSX), the highest fine particle fraction (FPF) of SX was obtained from a suspension of mSX. The FPFs following aerosolization of FP suspensions were similar although the FPF was lowest for particles with the largest original size. CONCLUSIONS: The size of the aggregates in the HFA suspensions was found to correlate directly with the FPFs determined by impaction.     

The Influence of Flow Rate on the Aerosol Deposition Profile and Electrostatic Charge of Single and Combination Metered Dose Inhalers

Purpose  

The capability of the electrostatic next generation impactor (eNGI) has been investigated as a tool capable of measuring the electrostatic charge of single (Flixotide™; containing fluticasone propionate (FP)) and combination (Seretide™; FP and salmeterol xinafoate (SX)) pressurised metered dose inhalers (pMDIs) at different flow rates.     

Performance of Pressurized Metered‐Dose Inhalers at Extreme Temperature Conditions

The performance of pressurized metered‐dose inhalers (pMDIs) under a variety of temperature conditions was investigated. The effects of both inhaler temperature and ambient temperature were considered. The inhaler temperature ranged from −13.0°C to 41.7°C and the ambient temperature ranged from −12.0°C to 41.7°C. The in vitro lung dose was measured for four widely available pMDIs: Airomir^TM, QVAR^TM, Symbicort®, and Ventolin®. The in vitro lung dose through an Alberta Idealized Throat was measured by gravimetric assay, which was verified by UV spectroscopic assay. A decrease in the in vitro lung dose was observed for all evaluated pMDIs when ambient temperature and device temperature were simultaneously reduced, decreasing on average by 70% at the coldest temperatures, whereas increasing on average by 25% at the elevated temperature condition. In vitro lung dose is strongly dependent on both inhaler temperature and ambient temperature with the tested pMDIs.     

Effect of Oropharyngeal Length in Drug Lung Delivery via Suspension Pressurized Metered Dose Inhalers

Purpose To determine the effect of the oropharyngeal length in adults on the lung dose of a suspension pressurized metered dose inhaler, and whether employing small volume spacers can alter this role. Methods Depositions of Ventolin™ Evohaler™ (100) μg in the oropharyngeal models of two healthy adult subjects with 17.1 cm (short cast) and 19.9 cm (long cast) centerline lengths via three small volume spacers [two spacers with 3 cm effective length but one with 6.5 cm² (L3) and the other with 24.6 cm² (L3W) cross sections, and the Optimiser] were studied. Results Without using spacers, lung dose of the long cast (19.52 ± 2.32 μg, mean ± standard deviation) was significantly larger than that for the short cast (8.08 ± 1.01 μg, p < 0.006). However, using the L3 spacer with the short cast made the lung dose (18.59 ± 3.33 μg) similar to that for the long cast alone. Lung doses of the short cast (20.43 ± 1.42 μg) and the long cast (30.81 ± 1.84 μg) with the L3W spacer were similar to those with the L3 spacer. However, using the Optimiser spacer increased the lung dose for the short cast (22.27 ± 6.03 μg) and significantly for the long cast (35.61 ± 2.19 μg, p < 0.006) compared to those for the L3 spacer. Using spacers increased drug deposition in the oropharynx part of the short cast, and this reduced the lung dose compared to that for the long cast. Conclusion The oropharyngeal length in adults may affect the lung dose via the pMDIs, which may not be eliminated by using small volume spacers.     

A Novel High-Speed Imaging Technique to Predict the Macroscopic Spray Characteristics of Solution Based Pressurised Metered Dose Inhalers

Purpose

Non-volatile agents such as glycerol are being introduced into solution-based pMDI formulations in order to control mean precipitant droplet size. To assess their biopharmaceutical efficacy, both microscopic and macroscopic characteristics of the plume must be known, including the effects of external factors such as the flow generated by the patient’s inhalation. We test the hypothesis that the macroscopic properties (e.g. spray geometry) of a pMDI spray can be predicted using a self-similarity model, avoiding the need for repeated testing.

Methods

Glycerol-containing and glycerol-free pMDI formulations with matched mass median aerodynamic diameters are investigated. High-speed schlieren imaging is used to extract time-resolved velocity, penetration and spreading angle measurements of the pMDI spray plume. The experimental data are used to validate the analytical model.

Results

The pMDI spray develops in a manner characteristic of a fully-developed steady turbulent jet, supporting the hypothesis. Equivalent glycerol-containing and non glycerol-containing formulations exhibit similar non-dimensional growth rates and follow a self-similar scaling behaviour over a range of physiologically relevant co-flow rates.

Conclusions

Using the proposed model, the mean leading edge penetration, velocity and spreading rate of a pMDI spray may be estimated a priori for any co-flow conditions. The effects of different formulations are captured in two scaling constants. This allows formulators to predict the effects of variation between pMDIs without the need for repeated testing. Ultimately, this approach will allow pharmaceutical scientists to rapidly test a number of variables during pMDI development.     

丙酸倍氯米松及其溶剂化合物在三氯—氟甲烷的结晶生长动力学对定量气雾剂行为的影响

本文研究了丙酸倍氯米松及其醋酸乙酯和三氯－氟甲烷溶剂化物微粉在三氯－氟甲烷中的结晶生长行为，给出了结晶生长曲线并计算了结晶生长动力学参数，结晶生长的趋势及速度为丙酸倍氯米松＞丙酸倍氯米松醋酸乙酯溶剂化物＞丙酸倍氯米松三氯－氟溶剂化物。15℃时丙酸倍氯米松及40℃丙酸倍氯米松醋酸乙酯溶剂化物的结晶生长动力学参数（K值）分别为0．1637um.min^-1及0．0138um.min^-1，同时观察并计算了最终平衡粒径，双冲程实验结果表明用丙酸倍氯米松，丙酸倍氯米松醋酸乙酯溶剂化物及丙酸倍氯米松三氯－氟甲烷溶剂微粉制备的定量气雾剂在深肺部的沉积为8％，54％及59％，在40％，75％RH条件下贮存两周后，降至2％，40％及57％。     

Spray Pattern Analysis for Metered Dose Inhalers: Effect of Actuator Design

Purpose This study was conducted to identify the device factors influencing spray pattern and particle size to gain a more complete understanding of spray plume measurements. Methods A statistically designed experiment was used to investigate the influence of three actuator features (orifice diameter, expansion chamber depth, and orifice length) on spray pattern and particle size profiles. Custom-built actuators were manufactured and analyzed with laser light sheet illumination methods for spray patterns and laser diffraction for particle size analysis. Results In addition to orifice size, spray patterns were significantly influenced by the actuator orifice length and sump depth. Particle size analysis of the plumes generated from actuators used in these studies showed that all actuator features (orifice size, length, and sump depth) were significant factors influencing particle size. Conclusions The performance of propellant-based metered dose inhaler aerosols seems to be significantly related to sump depth and orifice length, in addition to orifice size. Rational design of propellant-based metered dose inhalers should therefore consider these variables in addition to formulation strategies and simply modifying orifice diameter.     

The Interaction Between the Oropharyngeal Geometry and Aerosols via Pressurised Metered Dose Inhalers

Purpose  

This study investigated the effect of oropharyngeal geometry on inhaled aerosol characteristics via pressurised metered dose inhalers (pMDIs), both with or without spacers.     

Loading Effect on Particle Size Measurements by Inertial Sampling of Albuterol Metered Dose Inhalers

Purpose. The purpose of this study is to investigate the albuterol loading effect on particle size measurements by studying the effect of the amount of albuterol delivered, the number of puffs used, and the sampling techniques used in particle size measurement. Methods. Particle size distribution profiles for different albuterol loadings were evaluated using an 8-stage cascade impactor and a sensitive HPLC electrochemical assay method. A commercial albuterol MDI (Proventil^R) and other specially prepared albuterol MDIs were used in the study. Results. As the amount of albuterol was increased, either by increasing the number of puffs or the amount delivered per puff, the measured MMAD increased. This increase was more prominent in some formulations (Proventil^R) than others. Further, albuterol particles previously deposited on the valve and/or actuator didn't play a role in the observed multi-puff/loading effect. Conclusions. The collection of the least amount of aerosol in a cascade impactor provides a better estimate of MMAD, as it minimizes modifications of the collection surfaces.     

中药复方气雾剂喘立停中麻黄碱和伪麻黄碱含量及微粒分数的测定

用HPLC法测定中药复方气雾剂喘立停中麻黄碱和伪麻黄碱的含量,双冲程取样器法测定气雾剂中有效成分的微粒分数(FPF)。盐酸麻黄碱和盐酸伪麻黄碱的平均回收率为100.4%和99.60%,RSD为1.47%和0.72%。随处方中乙醇含量的增加或贮存温度的降低,制品FPF减小。     

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).     

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     

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.     

Manipulation of Corticosteroid Release from a Transiently Supersaturated Topical Metered Dose Aerosol Using A Residual Miscible Co-Solvent

Purpose  The creation of supersaturation transiently after application overcomes the issue of drug instability. However, if the solvents used to drive supersaturation evaporate too quickly, drug recrystallisation or rapid film drying can occur which will inhibit drug release. As such the effects of a residual solvent, poly(ethylene glycol) 400 (PEG), on the release, mobility and supersaturation kinetics of a transiently supersaturated formulation were studied. Materials and Methods  Metered dose aerosol (MDA) formulations consisting of hydrofluoroalkane 134a, ethanol, poly(vinyl pyrrolidone) K90, beclomethasone dipropionate (BDP), and 0%, 5% or 10% w/w PEG were prepared in canisters sealed with metered dose valves and tested for release and adhesion over time. Results  The addition of 10% PEG to the MDA formulation resulted in a significant reduction (p < 0.05) in steady state drug release rate (230.4 ± 17.3 μg/cm²/h for 0% PEG MDA, 83.6 ± 4.9 μg/cm²/h for 10% PEG MDA). The presence of PEG caused a delay in dose depletion (2 h for 0% PEG MDA versus 4 h for 10% PEG), retarded supersaturation kinetics and increased film drying time. Conclusion  Whilst equivalent amounts of BDP were released, the residual solvent altered the drug release profile to achieve more constant delivery.     

Introduction of the Electrical Next Generation Impactor (eNGI) and Investigation of its Capabilities for the Study of Pressurized Metered Dose Inhalers

Purpose

To introduce the design of the electrical Next Generation Impactor (eNGI), and validate its proposed function as a method of electrostatic characterization for pressurized metered dose inhaler (pMDI) formulations.

Methods

Flixotide® (fluticasone propionate), Ventolin® (salbutamol sulphate), and QVAR® (beclomethasone dipropionate) were used as model pMDIs in this study. At an airflow rate of 30 l/min, five individual actuations of each pMDI were introduced into the electrical low-pressure impactor (ELPI), Next Generation Impactor (NGI), and the eNGI. Charge profiles for each actuation were measured by the ELPI and eNGI, while mass profiles were recorded by the all three impactors.

Results

The difference in estimated mass median aerodynamic diameters and geometric standard deviations for all pMDIs using the NGI and eNGI were not found to be statistically significant (p?     

The Equivalent Bronchodilator Effects of Salbutamol Formulated in Chlorofluorocarbon and Hydrofluoroalkane-134a Metered Dose Inhalers on the Histamine-Induced Pulmonary Response in Dogs

Purpose. The bronchodilator effect of salbutamol formulated in hydrofluoroalkane-134a (HFA-134a), a Chlorofluorocarbon (CFC)-free propellant for metered dose inhalation (MDI) devices, was compared with that of salbutamol formulated in CFC in anesthetized dogs. Methods. Bronchospasms were induced by the intravenous injection of histamine, and bronchial resistance was measured by the method of Konzett and Rossler. Results. While the placebo vehicles (HFA-134a and CFC propellants) had no significant effect on histamine-induced bronchospasms, the salbutamol/HFA-134a and salbutamol/CFC MDI formulations had equivalent dose-related inhibitory effects. Conclusions. These data indicated that salbutamol formulated in HFA-134a and that in CFC propellant are bioequivalent.     

Influence of Crystal Habit on Trimethoprim Suspension Formulation

Purpose. The role of crystal habit in influencing the physical stability and pharmacokinetics of trimethoprim suspensions was examined. Methods. Different habits of trimethoprim (TMP) were obtained by recrystallizing the commercial sample (PD) utilizing solvent-change precipitation method. Four distinct habits (microscopic observation) belonging to the same polymorphic state (DSC studies) were selected for studies. Preformulation and formulation studies were carried out on suspension dosage forms containing these crystals. The freshly prepared suspensions were also evaluated for their pharmacokinetic behaviour on healthy human volunteers using a cross over study. Results. Variation of crystallization conditions produces different habits of TMP. Among the different crystal habits exhibiting same polymorphic state, the most anisometric crystal showed best physical stability in terms of sedimentation volume and redispersibility. However, habit did not significantly affect the extent of TMP excreted in urine. Conclusions. Modification of surface morphology without significantly altering the polymorphic state can be utilized for improving physical stability of TMP suspensions. However, the pharmacokinetic profile remains unaltered.