Improvement of asthma therapy by a novel budesonide multidose dry powder inhaler

The objective of the present post-marketing surveillance (PMS) was the evaluation of efficacy, tolerability and acceptance of the novel budesonide (CAS 51333-22-3) multidose dry powder inhaler (MDPI) Novopulmon 200 Novolizer. A total of 3,057 patients suffering from allergic, non-allergic or mixed bronchial asthma were included in the PMS. The study medication was administered by inhalation at a median dosage of 2 x 200 micrograms budesonide/day. In order to evaluate the efficacy of the novel budesonide MDPI, pulmonary functions (peak expiratory flow rate (PEFR) and FEV1) were measured at the start of the treatment and after 4 weeks of treatment. Severity of the following symptoms was evaluated on a four-score scale: cough, wheezing, diurnal dyspnea, nocturnal dyspnea and dyspnea on physical effort. Furthermore, the patients' satisfaction in dealing with the control mechanisms (optical, acoustic, sensory, dose counter, overdose prevention) of this innovative MDPI was assessed. Patients who already had used another inhalation system assessed the control mechanisms of the novel budesonide MDPI in comparison with their previous inhalation system (e.g. fluticasone premetered dose MDPI, non-refillable budesonide MDPI). The patients' compliance and any improvement of compliance by the control mechanisms according to physicians' assessments were evaluated. The novel budesonide MDPI was shown to lead to a decrease in the severity of symptoms. The median total symptom score (0 = no symptoms, 15 = all symptoms severe) decreased from 8 before therapy to 2 after therapy. Pulmonary function measurements supported a relief of the patients' symptoms: The median PEFR increased from 5 l/s before therapy to 6.3 l/s at the end of therapy, with a median individual increase of 1 l/s. The median FEV1 increased from 2250 ml before therapy to 2700 ml at the end of therapy, with a median individual increase of 310 ml. The majority of patients were satisfied with the control mechanisms. 97% of the patients were satisfied with the optical control mechanism, 94% with the acoustic, 78% with the sensory mechanism, 92% with the dose counter and 81% with the overdose prevention. Compliance was assessed by the physicians to be good in 84% of the patients, to be satisfactory in 14% and to be not satisfactory in 2%. An improvement in compliance by the control mechanisms of the inhaler was observed in 80% of the patients. 97% of the patients were satisfied with the control mechanisms, the optical and acoustic mechanisms were confirmed as being the most important ones. The vast majority of patients assessed the control mechanisms of the novel MDPI to be better or much better than those of a previously used inhaler (e.g. 41.2% and 52.1%, respectively, of patients who had previously used a non-refillable budesonide MDPI; 38.7% and 44.7%, respectively, of patients who had previously used a fluticasone premetered dose MDPI). Overall, the novel budesonide MDPI was shown to be efficient in the relief of asthma symptoms and improvement of lung function. The MDPI's control mechanisms were shown to be well accepted by the patients and considered by the physicians as an important contributor to an improvement of patient compliance.     

Improvement of asthma therapy by a novel formoterol multidose dry powder inhaler

The objective of this post-marketing surveillance (PMS) was the evaluation of efficacy, tolerability, and acceptance of the advanced formoterol (CAS 73573-87-2) multidose dry powder inhaler (MDPI) Formatris 6 microg/12 microg Novolizer (FN) in asthmatic patients (n = 5219) in a real-life setting. A total of 2727 patients (52%) received concomitant anti-inflammatory treatment exclusively via a budesonide Novolizer (BN). Efficacy of the FN was assessed by measurement of peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) before and after 4 weeks of therapy. The severity of cough, wheezing, diurnal dyspnea, nocturnal dyspnea and dyspnea on physical effort were assessed on a four-point scale, and a severity sum score was calculated. The patients' satisfaction with the multiple feedback mechanisms, handling and safety of the FN was also assessed. The physicians judged the patient compliance and any improved inhalation reassurance due to FN control mechanisms in comparison with other inhalation systems. FN use (n = 2727) was associated with improved lung function. After 4 weeks, PEF increased by 26% (from 270 L/min to 340 L/min) and the median FEV1 increased by 24% (from 2.1 L to 2.6 L). The median severity sum score decreased from 8.0 before therapy to 3.0 after therapy. Most patients assessed the control mechanisms and safety functions of the FN as 'very good' or 'good'. 96% of patients were satisfied with the optical control mechanism, 92% with the acoustic mechanism, 70% with the taste feedback, 89% with the dose counter and 76% with the overdose prevention. The majority of patients (95%) confirmed that the multiple feedback mechanisms reassured correct drug intake, with 83% rating the FN as 'much better' or 'better' than previously used inhalers. The physicians confirmed that in contrast to previously used inhalers the FN ensured correct inhalation in 87% of all patients. The physicians were satisfied with the patients' compliance in 95% of cases. Finally, the majority of patients (98%) were highly satisfied with the correct inhalation feedback mechanism. 94% of patients intended to continue FN therapy beyond the study. Overall, FN reduced the patients' asthma symptoms and improved lung function, possibly due to improved compliance with therapy. The correct inhalation feedback mechanisms and safety functions of the device were assessed very positively by patients and were considered by the physicians to be important in improving inhalation reassurance and patient compliance.     

Airmax: a multi-dose dry powder inhaler

Airmax is a multi-dose dry powder inhaler. An internal pump measures out the drug dose using controlled air pressure. Inhalation transports the drug into a cyclone separator (where active drug is separated from the lactose carrier) and then into the patient airway. In vitro studies indicate that Airmax may be less dependent on airflow than Turbuhaler for drug delivery; greater dose consistency was seen with administration of budesonide via Airmax than via Turbuhaler. At a low flow rate, the lung deposition of budesonide administered via Airmax was greater than that of budesonide administered via Turbuhaler or a pressurised metered dose inhaler in patients with asthma. In cumulative-dose studies, the mean forced expiratory volume in 1 second (FEV(1)) achieved with salbutamol (albuterol) or formoterol administered via Airmax was equivalent to that achieved with twice the dose administered via dry powder inhalers. black triangle In randomised, double-blind studies, budesonide administration via Airmax was equivalent to administration via Turbuhaler with regards to FEV(1) and improvement in asthma symptoms in both adults and children with asthma. The concentration of adenosine monophosphate producing a 20% fall in FEV(1) increased from pretreatment levels by a greater extent with budesonide administered via Airmax, compared with Turbuhaler. Both adults and children preferred Airmax to Turbuhaler, and more found Airmax easier to use. In one study, the majority of children found learning how to use Airmax trade mark easier than learning how to use Turbuhaler.     

Novolizer: a multidose dry powder inhaler

Novolizer is a multidose breath-actuated dry powder inhaler (DPI) approved for use with salbutamol (albuterol) and budesonide. It has multiple patient feedback mechanisms and an inspiratory flow rate threshold designed to optimise dosage. In two studies, children aged 4-11 years with asthma correctly used Novolizer and generated mean peak inspiratory flow rates (PIFRs) through Novolizer of 76 and 92.7 L/min, well above the Novolizer threshold of 35-50 L/min. In healthy volunteers, median lung deposition of budesonide administered via Novolizer was 19.9-32.1% at mean PIFRs of 54-99 L/min. In a randomised, double-blind, single-dose study in patients with chronic obstructive pulmonary disease (COPD) and asthma, the 1-hour improvement from baseline in mean maximum forced expiratory volume in 1 second (FEV(1)) was 21.3% with inhalation of salbutamol through Novolizer, and 19.5% through Sultanol pressurised metered-dose inhaler (MDI). FEV(1) increased significantly in patients with asthma and COPD treated for 4 weeks in a randomised, open-label comparison of salbutamol through either Novolizer or Sultanol MDI. A randomised open-label study in adults with asthma treated with inhaled budesonide found equivalent improvements in FEV(1) and symptoms with Novolizer and Turbuhaler. Novolizer was well accepted overall. Most patients preferred it to previously used MDIs or DPIs. Only 4-5% found the taste feedback unacceptable. Physicians observed improved compliance over 4 weeks in 80% of patients with asthma using Novolizer.     

新型环索奈德胶囊型干粉吸入剂的研制及其质量研究

目的:研制用于治疗哮喘的环索奈德胶囊型干粉吸入剂,建立其含量测定方法,并对其稳定性进行初步考察。方法:用高效液相色谱-紫外法检测环索奈德干粉吸入剂中主药环索奈德及其有关物质的含量。将主药与辅料混合后,以含量均匀度和肺部沉积率为指标进行处方筛选,考察制剂的有关物质和影响因素,并进行了加速稳定性和长期留样稳定性试验。结果:建立的高效液相色谱法,色谱条件如下:色谱柱为Alltima C18(250 mm×4.6mm,5μm);流动相为乙醇-水(65∶35);流速为1.2 mL.min-1;检测波长为243 nm。最后选择乳糖作为辅料,确定了最佳处方和工艺,获得了较好的含量均匀度和肺部沉积率(约19%)。稳定性结果显示,本制剂应置于阴凉、干燥处保存,在室温下保存至少在1年内稳定,长期放置稳定性在继续考察。结论:建立的高效液相色谱法适合于环索奈德胶囊型干粉吸入剂的日常质量控制,研制的制剂处方稳定。     

Novel dry powder inhaler particle-dispersion systems

Dry powder inhalers are a diverse family of devices that have emerged as a rapidly growing segment of the respiratory therapeutics area. The forces that these devices must impart into dry powder formulations for effective dispersion performance and reproducibility of delivery are relatively large, and multiple mechanisms have been developed in attempts to improve the efficiency of these systems. In this review, we address the reasons for the proliferation of dry powder inhalers, beginning with an abbreviated introduction on the basic inter-particulate forces that need to be disrupted to achieve successful powder dispersion and effective lung delivery. From this background, we survey the diversity of inhaler designs, starting from marketed devices, before introducing some of the novel device designs under development, both patient driven (passive) and device driven (active), as we attempt to link the themes of the device design features to the present understanding of the dynamics governing powder dispersion. Finally, we conclude by providing some assessment on the future of the wide range of device designs and mechanisms that have evolved by considering technical, regulatory and market forces.     

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI.
Methods A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30  min following inhalation of 2×100  μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin^® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24  h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body.
Results The mean (s.d.) 30  min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9)  μg, respectively ( P <0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24  h period after inhalation was 187.9 (77.6) and 137.6 (40.0)  μg ( P <0.05).
Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.     

Gamma scintigraphic evaluation of a novel budesonide dry powder inhaler using a validated radiolabeling technique.

A scintigraphic study was carried out to compare the lung deposition of budesonide delivered via Clickhaler and Turbuhaler dry powder inhalers in healthy volunteers. Validation of Technetium-99m ((99m)Tc) radiolabeling of the budesonide/lactose blend used in the Clickhaler and excipient-free budesonide used in the Turbuhaler was carried out using a multistage liquid impinger, and compared with reference unlabeled devices. Budesonide was quantified using high-performance liquid chromatography and (99m)Tc by scintillation counting. The percentages (SD) of fine particles (<5.5 microm diameter) from radiolabeled and unlabeled devices were not significantly different (p > 0.05). Mean values for drug and radiolabel, respectively, were 34.6% (2.5) and 31.6% (3.8) for the Clickhaler, and 29.8% (5.5) and 31.4% (5 6) for the Turbuhaler. Fifteen healthy male volunteers received a single dose (2 x 200 microg actuations) from both devices in a double-blinded, double dummy, crossover study. During dosing, each inhalation maneuver was recorded using a computer-linked pressure transducer. To permit accurate determination of radiolabeled drug deposition, the lung margins of each volunteer were determined by Krypton-81m ((81m)Kr) gas imaging. Mean [SD] lung deposition for the Clickhaler (26.8% [6.8], RSD 25.2) was significantly greater (p < 0.001) than for the Turbuhaler (15.8% [6.6], RSD 42.2). Inspiratory flow rate parameters were similar for both devices with peak and mean values of 73 and 51 L/min for the Clickhaler, and 73 and 47 L/min for the Turbuhaler, respectively. These results indicate that, in healthy volunteers, budesonide lung deposition was higher and more consistent with the Clickhaler than with the Turbuhaler.     

The development of a sensitive methodology to characterise hard shell capsule puncture by dry powder inhaler pins

In order for hard-shell capsules to function effectively as drug reservoirs in dry powder inhalers, the capsule must be punctured with sharpened pins to release the powdered medicament upon inspiration. Capsule performance in this setting is poorly understood. This study aims to develop a methodology to characterise hard shell capsule penetration by needles from commercial dry powder inhalers, to determine whether changes to capsule materials impact on their performance.     

干粉吸入剂的有效性及质量评价

综述了影响干粉吸入剂有效性的因素,并对其体内外测定方法及质量控制进行了概述.     

Experimental observations of dry powder inhaler dose fluidisation

Dry powder inhalers (DPIs) are widely used to deliver respiratory medication as a fine powder. This study investigates the physical mechanism of DPI operation, assessing the effects of geometry, inhalation and powder type on dose fluidisation. Patient inhalation through an idealised DPI was simulated as a linearly increasing pressure drop across three powder dose reservoir geometries permitting an analysis of shear and normal forces on dose evacuation. Pressure drop gradients of 3.3, 10 and 30 kPa s(-1)were applied to four powder types (glass, aluminium, and lactose 6 and 16% fines) and high speed video of each powder dose fluidisation was recorded and quantitatively analysed. Two distinct mechanisms are identified, labelled 'fracture' and 'erosion'. 'Fracture' mode occurs when the initial evacuation occurs in several large agglomerates whilst 'erosion' mode occurs gradually, with successive layers being evacuated by the high speed gas flow at the bed/gas interface. The mechanism depends on the powder type, and is independent of the reservoir geometries or pressure drop gradients tested. Both lactose powders exhibit fracture characteristics, while aluminium and glass powders fluidise as an erosion. Further analysis of the four powder types by an annular shear cell showed that the fluidisation mechanism cannot be predicted using bulk powder properties.     

Development and clinical trial of nano-atropine sulfate dry powder inhaler as a novel organophosphorous poisoning antidote

The aim of the work was to develop, characterize, and carry out a clinical trial with nano-atropine sulfate (nano-AS) dry powder inhaler (DPI), because this route may offer several advantages over the conventional intramuscular route as an emergency treatment, including ease of administration and more rapid bioavailability. Different batches of nanoparticles of AS were produced using variants of nanoprecipitation method. The influence of the process parameters, such as the types and quantity of solvent and nonsolvent, the stirring speed, the solvent-to-nonsolvent volume ratio, and the drug concentration, was investigated. The methodology resulted in optimally sized particles. Bulk properties of the particles made by the chosen methodology were evaluated. A clinical trial was conducted in six healthy individuals using a single DPI capsule containing 6 mg nano-AS DPI in lactose. Early blood bioavailability and atropinization pattern confirmed its value as a potential replacement to parenteral atropine in field conditions. The formulation seems to have the advantage of early therapeutic drug concentration in blood due to absorption through the lungs as well as sustained action due to absorption from the gut of the remaining portion of the drug.     

Development of liposomal amphotericin B dry powder inhaler formulation

The purpose of our study was to prepare and optimize liposomal Amphotericin B (AMB) dry powder inhaler (DPI) formulation for treatment of invasive lung fungal infection. Liposomes were prepared by reverse phase evaporation technique using ethyl acetate and ethanol (1:1) as organic solvents to avoid a possible risk for human health and to impart adequate stability of the vesicles. Drug lipid ratio was 1:10 with membrane composition of hydrogenated soyaphosphatidylcholine; cholesterol and either saturated soyaphosphatidylglycerol (7:3:0.5) or stearylamine (1:1:0.1) was used to prepare negatively (AMB1) and positively (AMB2) charged liposomes, respectively. Liposomes were extruded through 2 microm polycarbonate membrane, separated from unentrapped drug and subjected to lyophilization using Tris buffer containing cryoprotectants in various mass ratios. Sucrose was found to be the best cryoprotectant for liposomal AMB in a mass ratio of lipid: sucrose at 1:5 for AMB1 and AMB2, respectively. Sorbolac 400 and sieved Pharmatose 325 M (500#) in varying mass ratios were used as carriers to prepare the liposomal DPI formulations and subjected to determination of angle of repose, compressibility index, dispersiblity index, water content, scanning electron microscopy, and fine particle fraction (FPF). Carrier blend of Sorbolac 400 and 10% sieved Pharmatose 325 M (liposome: carrier ratio to be 1:6) resulted in 22.6 +/- 2.2% and 16.8 +/- 2.2% FPF for AMB1 and AMB2, respectively with significantly different (p >.05) device fraction. Percent dug retention studies were conducted at different storage conditions and demonstrated a shelf life over 1 year at refrigerated storage condition (2-8 degrees C).     

Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder

Purpose. To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere® powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs). Methods. Budesonide PulmoSphere (PS_bud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 g budesonide PulmoSphere inhaled from Eclipse® DPI at target PIF of 25 L·min^-1 (PS_bud25), and 50 L·min^-1 (PS_bud50), and 800 g of pelletized budesonide from Pulmicort® Turbuhaler® at 60 L·min^-1(TH_bud60). PS_bud powder was radiolabeled with ^99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation. Results. Pulmonary deposition (mean ± sd) of PS_bud was 57 ± 7% and 58 ± 8% of the nominal dose at 25 and 50 L·min^-1, respectively. Mean peak plasma budesonide levels were 4.7 (PS_bud25), 4.0 (PS_bud50), and 2.2 ng·ml^-1 (TH_bud60). Median t_max was 5 min after both PS_bud inhalations compared to 20 min for Turbuhaler (P < 0.05). Mean AUCs were comparable after all inhalations, 5.1 (PS_bud25), 5.9 (PS_bud50), and 6.0 (TH_bud60) ng·h·ml^-1. The engineered PS_bud powder delivered at both flow rates from the Eclipse® DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L·min^-1 from the Turbuhaler. Intersubject variability was also dramatically decreased for PS_bud relative to TH_bud. Conclusion. Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.     

Pulmonary disposition of budesonide from liposomal dry powder inhaler

The Purpose of this study was to establish the use of a developed dry powder inhaler of budesonide liposomes in pulmonary drug delivery. Budesonide liposomes composed of egg phosphatidyl choline (EPC) and cholesterol were prepared using a lipid-film hydration technique. The liposomal dispersion was freeze dried and formulated to a dry powder inhaler. The entrapped drug values (91.79% to 78.99%) of freeze dried liposomes were estimated in prepared batches after purification from the free drug by centrifugation of the rehydrated vesicles. In vitro drug retention was evaluated using methanolic phosphate buffer saline and bronchoalveolar lavage, following incubation at 37 degrees C. All batches were found to retain more than 63.54% of budesonide within liposomes at the end of 24 h. Rehydrated budesonide liposomes or nonencapsulated budesonide was delivered to rat lungs by intratracheal administration. The pulmonary drug disposition was assessed by simultaneous monitoring of drug levels in the bronchoalveolar lavage and lung tissue. After intratracheal administration, cumulative drug levels in the lung tissue indicated that the targeting factor was at least 1.66 times higher in liposomes. The maximal drug concentration in the lung homogenate for the liposomal dry powder inhaler was 36.64 micrograms as compared to 78.56 micrograms with the plain drug. Similarly, the time for maximum drug concentration in the lung homogenate for the liposomal dry powder inhaler was 9-12 h as compared to 3 h for that of the plain drug. Hence, the use of a developed liposomal budesonide dry powder inhaler was found to provide desired drug levels in the lungs for a prolonged period of time, which is expected to enhance the therapeutic index of the drug and probably reduce the dose and cost of therapy as well.     

干粉吸入剂的粉末定量分装设备浅析

干粉吸入剂是一种新兴呼吸道给药剂型,其吸入粉末的分装装置不同于常见的口服固体粉末分装装置。本文综述国际上常用的干粉吸入剂的粉末定量分装装置,包括标准定量器装置装置、真空滚筒分装装置、Xcelodose精确粉末微定量装置等,同时介绍几种较新的、处于研发阶段的粉末分装装置。     

A dry powder inhaler with reduced mouth-throat deposition.

A novel, compact, and highly efficient dry powder inhaler (DPI) with low mouth-throat deposition is described. The performance of this DPI was evaluated by measuring both (1) the total aerosol deposition in and distal to an idealized mouth-throat cast and (2) the fine particle fraction (FPF) using a standard Mark II Anderson impactor. Ultraviolet (UV) spectroscopy techniques were used in the aerosol deposition measurements. Two inhalation aerosol powders, namely budesonide (extracted from a Pulmicort/Turbuhaler multi-dose device, 200 microg/dose) and ciprofloxacin + lipid + lactose (in-house), were dispersed by the DPI at a steady inhalation flow rate of 60 L/min. The newly developed DPI had a total aerosol delivery distal to the mouth-throat cast of 50.5% +/- 3.04% and 69.7% +/- 1.5% for the budesonide and ciprofloxacin + lipid + lactose aerosols, respectively. This is a significant improvement over the Turbuhaler original device delivery of 34.5% +/- 5.2%, particularly considering that in vitro mouth-throat deposition dropped from 27.5% +/- 5.4% with the budesonide Turbuhaler to 11.0% +/- 3.5% with the present inhaler. The different lung deliveries from the same inhaler for the two formulations above also confirm that the overall performance of an inhaler is optimizable via powder formulations.     

Rational design of a dry powder inhaler: device design and optimisation

Objectives As part of the development of a dry powder inhalation system for the treatment of asthma and chronic obstructive pulmonary disease, this work specifically aimed at the systematic, however, cost-effective and efficient development of an inhalation device. Methods Based on theoretical design considerations and an initial inhaler prototype, the concept of a modular inhaler was developed. The modular inhaler was used for the systematic evaluation of the influence of the inhaler's inner dimensions on the resistance to the air flow and the in-vitro deposition characteristics of the inhalation system by using statistical design of experiments and cascade impaction analysis. Key findings A reliable statistical model enabled the accurate prediction of the device resistance of any combination of inner dimensions of the inhaler. In conjunction with results from in-vitro deposition studies, this allowed for the definition of optimised inner dimensions of the inhaler to maximise the fine particle fraction and minimise oropharyngeal deposition within the desired range of the inhaler's resistance to air flow. Conclusions The concept of the modular inhaler and statistical design and evaluation of experiments proved to be important tools for an efficient and successful product development. Eventually, the approaches described and the knowledge obtained enabled the cost-effective development and design of a technically feasible and competitive dry powder inhaler.