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).     

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.     

Stable dry powder inhaler formulation of tranilast attenuated antigen-evoked airway inflammation in rats

Tranilast (TL) has been clinically used for the treatment of airway inflammatory diseases, although the clinical use of TL is limited because of its poor solubility and systemic side effects. To overcome these drawbacks, a novel respirable powder of TL (CSD/TL-RP) for inhalation therapy was developed using nanocrystal solid dispersion of TL (CSD/TL). Stability study on CSD/TL-RP was carried out with a focus on inhalation performance. Even after 6 months of storage at room temperature, there were no significant morphological changes in micronized particles on the surface of carrier particles as compared with that before storage. Cascade impactor analyses on CSD/TL-RP demonstrated high inhalation performance with emitted dose and fine particle fraction (FPF) of ca. 98% and 60%, respectively. Long-term storage of CSD/TL-RP resulted in only a slight decrease in FPF value (ca. 54%). Inhaled CSD/TL-RP could attenuate antigen-induced inflammatory events in rats, as evidenced by marked reduction of granulocytes in bronchoalveolar lavage fluid and inflammatory biomarkers such as eosinophil peroxidase, myeloperoxidase, and lactate dehydrogenase. These findings were consistent with decreased expression levels of mRNAs for nuclear factor-kappa B and cyclooxygenase-2, typical inflammatory mediators. Given these findings, inhalable TL formulation might be an interesting alternative to oral therapy for the treatment of asthma and other airway inflammatory diseases with sufficient dispersing stability.     

The development of a novel dry powder inhaler

A novel active and multi-dose dry powder inhaler (DPI) was developed and evaluated to deliver a small quantity (100-500 μg) of pure drug without any excipient. This dry powder inhaler utilized two compressed air flows to dispense and deliver drug powder: the primary flow aerosolizes the drug powder from its pocket and the secondary flow further disperses the aerosol. In vitro tests by Anderson Cascade Impactor (ACI) indicated that the fine particle fraction (FPF) (<4.7 μm) of drug delivery could reach over a range of 50-70% (w/w). Emitted dose tests showed that delivery efficiency was above 85% and its relative standard deviation (RSD) was under 10%. Confocal microscopy was used to confirm the deposition of fluorescently labeled spray-dried powder in rabbit lungs. Also, a chromatographic method was used to quantify drug deposition. The results of animal tests showed that 57% of aerosol deposited in the rabbit lung and 24% deposited in its trachea. All the results implied that this novel active dry powder inhaler could efficiently deliver a small quantity of fine drug particles into the lung with quite high fine particle fraction.     

Methacholine dry powder inhaler as a new tool for bronchial challenge test

BACKGROUND: The methacholine (MCH) challenge test is performed to detect bronchial hyperresponsiveness in subjects suffering from asthma. It is conducted by inhaling spasmogen substances at increasing doses and measuring FEV1-PD20 variation following the bronchoconstriction evoked. AIM: This paper describes a new method for MCH challenge test using pre-metered respirable powders of MCH at different doses for facilitating test execution. The availability of a series of pre-metered doses gives higher control over aerosolized dose and fine particle fraction (respirable dose), improving the accuracy and repeatability of the test. Dosimetric tests with MCH solution and pre-dosed powder challenge tests were clinically compared. METHODS AND MATERIALS: The inhalation powders were prepared by spray drying of solutions of methacholine, mannitol and hydroxypropylmethylcellulose in which different concentrations of MCH were included. The methacholine powders prepared were carefully characterized in terms of aerodynamic properties. RESULTS: Inhalation powders containing methacholine from 12.5 to 200 microg per metered dose, having a fine particle fraction between 40 and 60%, were prepared using mannitol and cellulose polymer. Eighteen subjects (12 hyperresponsive and six normal) were subjected to both the MCH solution and powder tests in random sequence. No significant differences in FEV1 and PD20 values were found between the challenge tests performed with liquid and powder formulations of methacholine. CONCLUSIONS: Powders of MCH having high respirability of the delivered doses can be prepared by spray drying. They allow for the performance of a challenge test using a dry powder inhaler. The powder dose series can be an alternative to the current dosimetric test with MCH solutions.     

Rheological profile of nesosteine: a new mucoactive agent

Nesosteine, a new agent shown to improve physical characteristics of bronchial mucus in animal models, has been studied in chronic bronchitic patients to confirm its effect on viscoelasticity of bronchial secretions. Sputum was collected from hypersecretory bronchitic patients in a stable condition before and after seven days of treatment with nesosteine (900 mg/day) or a placebo. At the end of treatment a significant (p less than 0.05) decrease was found in the viscosity in the nesosteine group: on the contrary, a slight, non-significant increase in viscosity was observed in the mucus samples of the placebo group. The improvement in rheological characteristics of the bronchial mucus in the patients treated with nesosteine was associated with an increase in mucus transport rate (mucociliary clearance) observed in the same samples. The findings indicate that nesosteine reduces mucus viscosity in chronic bronchitic patients and that this change induces also an improvement in mucociliary clearance.     

Influence of the moisture on the performance of a new dry powder inhaler

An accelerated stability test was carried out on two prototypes of a new dry powder inhaler (DPI) to verify the influence of moisture uptake on the performance of the device. The prototypes were stored at 40 degrees C and 75% relative humidity (RH) for different storage times and their performance was assessed in terms of emitted dose and respirable fraction (Twin Impinger). At the same time intervals, the water content of the powder contained in the drug reservoir was evaluated using Karl Fischer's method. The respirable fraction was strongly influenced by the moisture content of the powder, on the contrary, the dosing precision and reproducibility is independent of this variable. The results show that a suitable protection from the external environment is necessary to prevent moisture uptake in the powder and the consequent loss of efficiency of the delivery device.     

Optimization of a dry powder inhaler of ciprofloxacin-loaded polymeric nanomicelles by spray drying process

Ciprofloxacin is a commonly prescribed antibiotic for treatment of pulmonary infections. Nanocarriers such as nanomicelles can increase the drug residence time in the lungs and enhance their antibacterial effects. Dry powder inhalers (DPIs) are the preferred pulmonary drug delivery system and preparation of an optimum nanoaggregate from nanomicelles by means of spray drying would be valuable. The two-level full factorial design was performed in 16 runs. The effects of carrier type, anti-adhesion agent type, carrier to nanoparticle ratio and anti-adhesion agent to carrier ratio on the size of the microparticles, their in vitro pulmonary deposition, and redispersibility were investigated. Its antibacterial effects against Pseudomonas aeruginosa, Klebsiella pneumoniae, and Streptococcus pneumoniae also were investigated. All independent variables were fitted into two-factorial interaction models. The optimum nanoaggregate was prepared using mannitol and L-phenylalanine with a D_0.5 of 1.7?µm and 60% fine particles. The process had no negative effect on the stability or drug release profile of the nanomicelles. The antibacterial effects of ciprofloxacin against microorganisms increased significantly. This spray drying process could be used for preparation of an optimum DPI from polymeric nanomicelles. This formulation could increase the efficacy of ciprofloxacin for treatment of pulmonary infections.     

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.     

Pulmonary delivery of liposomal dry powder inhaler formulation for effective treatment of idiopathic pulmonary fibrosis

Dry powder inhaler Liposomes were prepared to investigate the effectiveness of pulmonary delivery of Colchicine and Budesonide for Idiopathic Pulmonary fibrosis. Budesonide (BUD) and Colchicine (COL) liposomes were prepared by thin layer film hydration method (TFH) using 1,2-Dipalmitoyl-sn-glycero-3- phosphoglycerol sodium (DPPG), Hydrogenated Soyaphosphotidylcholine (HSPC), Soyaphosphatidylcholine (SPC), cholesterol (CHOL) and drug in different weight ratios. The optimum lipid composition for BUD (74.22 ± 0.97%) was DPPG: HSPC: CHOL (4:5:1) and for COL (50.94 ± 2.04%) was DPPG: SPC: CHOL (3:6:1). These compositions retained drug for a longer period of time so selected for further study. Liposomes were found to be spherical in shape with mean size below 100 nm. Liposomes lyophilized using Mannitol as carrier and cryoprotectant showed high entrapment efficiency (97.89 - 98.6%). The powder was dispersed through an Andersen cascade impactor to evaluate the performance of the aerosolized powder. It was found that prepared liposomal dry powder inhaler (DPIs) sustained the drug release up to 24 hours. Optimized Budesonide DPI Formulation B2 (86.53 ± 1.9%), Colchicine DPI Formulation C2 (90.54 ± 2.3 %) and BUD and COL DPI Combination M2 (89.91 ± 1.8%, 91.23 ± 1.9%). Histopathological results, measurements of lung hydroxyproline content, Myeloperoxidase activity indicated that liposomal dry powder inhaler administration attenuates lung fibrosis induced by bleomycin. Long term stability studies indicated that lyophilised BUD and COL liposomes were stable for 6 months at (25 °C ± 2 °C, 60% ± 5% RH) and refrigerated conditions (2 - 8 °C). These results supported that combination of budesonide and colchicine liposomal dry powder inhaler pulmonary drug delivery for treatment of idiopathic Pulmonary Fibrosis exhibits prolonged drug retention at targeted site and reduces the systemic exposure.     

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.     

Pharmacodynamic study of procaterol hydrochloride dry powder inhaler: evaluation of pharmacodynamic equivalence between procaterol hydrochloride dry powder inhaler and procaterol hydrochloride metered-dose inhaler in asthma patients in a randomized, double-dummy, double-blind crossover manner

Therapeutic equivalence between procaterol hydrochloride dry powder inhaler (Meptin DPI) and procaterol hydrochloride metered-dose inhaler (Meptin MDI), the currently marketed formulation, was assessed in 16 patients with bronchial asthma. The study was conducted in a randomized, double-dummy, double-blind crossover manner, using forced expiratory volume in the first second (FEV1) as an index of bronchodilatory effect. In Period I, the patients received 20 mcg of either Meptin DPI or Meptin MDI, and then crossed over in Period II after a washout interval of 3--28 days. Pharmacodynamic equivalence was accessed using AUC (FEV1)/h and peak FEV1 as indices, and the data were analyzed by analysis of variance (ANOVA). Factors used for the analysis were the treatment group and/or carryover effect, patients within each group, period, and treatment. The 90% confidence intervals for the differences between the two treatments were --0.0995 to --0.0204 (L) for mean AUC (FEV1)/h and --0.102 to --0.022 (L) for mean peak FEV1, both within the acceptance criteria of --0.15 to 0.15 (L). Meptin DPI was therefore assessed as being equivalent to the current Meptin MDI.     

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.