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 drypowder 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.

Salvianolic acid B dry powder inhaler for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis(IPF)is a serious and fatal pulmonary inflammatory disease with an increasing incidenceworldwide.The drugs nintedanib and pirfenidone,are listed as conditionally recommended drugs in the“Evidence-Based Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis”.However,these two drugs have many adverse reactions in clinical application.Salvianolic acid B(Sal B),a water-soluble component of Salvia miltiorrhiza,could alleviate bleomycin-induced peroxidative stress damage,and prevent or delay the onset of IPF by regulating inflammatory factors and fibrotic cytokines during the disease’s progression.However,Sal B is poorly absorbed orally,and patient compliance is poor when administered intravenously.Therefore,there is an urgent need to find a new non-injection route of drug delivery.In this study,Sal B was used as model drug and l-leucine(LL)as excipient to prepare Sal B dry powder inhaler(Sal B-DPI)by spray drying method.Modern preparation evaluation methods were used to assess the quality of Sal B-DPI.Sal B-DPI is promising for the treatment of IPF,according to studies on pulmonary irritation evaluation,in vivo and in vitro pharmacodynamics,metabolomics,pharmacokinetics,and lung tissue distribution.

Preparation of slab-shaped lactose carrier particles for dry powder inhalers by air jet milling

Dry powder inhalers are often formulated by attaching micronized drug particles onto carrier particles, which are generally lactose. In this study, commercially available lactose was air jet milled to produce unique slab-like coarse carrier particles, which have larger and rougher surfaces compared to other commercially available lactose. Two key processing factors, i.e.,classifier speed and jet milling pressure, were systematically investigated. The largest fraction of slab-like particles in the resulting powder was obtained at a classifier speed of 3000 rpm.The slab-like coarse carrier particles are expected to exhibit superior performance than commercial lactose due to their unique surface properties.

Studies on the spray dried lactose as carrier for dry powder inhalation

The purpose of this study was to investigate the spray dried lactose as carrier for dry powder inhalation(DPI).The lactose particles were prepared by spray drying,then the particle size,shape and crystal form were characterized by laser diffraction,scanning electron microscopy(SEM),X-ray diffraction(XRD)and differential scanning calorimetry(DSC).The spray dried lactose particles were spherical and amorphous,but would transfer to crystal form when storage humidity was above 32%.Thus,the humidity of the storage environment should be controlled below 30%strictly in order to maintain the amorphous nature of spray dried lactose which is a great benefit to DPI development.

Effects of Direct Switching Dual Bronchodilators between Dry Powder and Soft Mist Inhalers in COPD Patients

Objective: Dual bronchodilation with long-acting muscarinic antagonist and long-acting β2-agonist combinations are available worldwide in COPD patients. However, the choice of agents remains under debate. We hypothesized that switching devices between dry powder and soft mist inhalers without a wash-out period to mimic clinical practice would improve clinical symptoms and lung function. The aim of this study was to examine the effects of switching between once-daily glycopyrronium/indacaterol (GLY/IND) or umeclidinium/vilanterol (UMEC/VI), dry powder inhalers, and tiotropium/olodaterol (TIO/OLO), a soft mist inhaler, in COPD patients. Methods: This was a prospective, open-label, 8-week, observational study with follow-up. Subjects included 57 COPD patients, who attended outpatient clinics at Shizuoka General Hospital for routine check-ups between February and December 2015, receiving GLY/IND (50/110 μg) or UMEC/VI (62.5/25 μg). After an 8-week run-in period, medications were switched to TIO/OLO (5/5 μg). Study outcomes included patient’s global rating (PGR), modified MRC (mMRC), COPD assessment test (CAT), and spirometric and forced oscillatory parameters after 8 weeks. PGR used in this study was a 7-point scale ranging from 1 to 7, with 4 in the middle. Patients who consented to switch from TIO/OLO to GLY/IND or UMEC/VI were followed-up thereafter. Results: In total, 53 patients completed the study (mean age, 75 years;48 males and 5 females;GOLD 1/2/3/4 = 19/27/6/1;mMRC 0/1/2/3/4 = 14/22/12/4/1;UMEC/VI 26, GLY/IND 27). PGR, mMRC, and CAT improved in 20 (38%), 9 (17%), and 15 patients (28%), respectively. Respiratory system resistance at 5 Hz (R5), 20 Hz (R20), and the difference between R5 and R20 (R5 - R20) significantly improved. In a follow-up of 16 patients after switching from TIO/OLO to UMEC/VI (9) or GLY/IND (7), PGR, mMRC, and CAT improved in 5 (31%), 3 (12%), and 4 patients (25%), respectively, and R20 significantly improved (p = 0.011). Conclusions: Switching dual bronchodilators between dry powder and soft mist inhalers improves symptoms and airway narrowing in some COPD patients.

Preparation of Ultra-fine Salbutamol Sulfate Particles by Reactive Precipitation and Characterization of Dry Powder Inhalant

The preparation of ultra-fine particles of salbutamol sulphate （SS） was accomplished with a reactive precipitation pathway, in which salbutamol and sulphuric acid were Used as reactants with the solvents of ethanol.The effects of sulphuric acid concentration, reaction temperature, stirring rate, and reaction time onthesize of the particle were investigated. A binary mixture composed of lactose and SS was prepared to evaluate SS. The results showed that ultra-fine SS particles with controlled diameters ranging between 3 μm and 0.8 μm and with a narrow distribution could be achieved. The morphology consisting of clubbed particles wassuccess.fully obtained. The purity of the particles reached above 98% with-UV detection. The dose- of dry powder inhalation was obtained by blending the particles with recrystallized lactose, which acted as a carrier. The deposition quantity of the drug in breathing tract was estimated using a twin imPinger apparatus. Compared with the Shapuer powder （purchased in the market）, the results showed that SS_particles had more quantifies.subsided in simulative lung.. _

The effect of ethanol on the habit and in vitro aerodynamic results of dry powder inhalation formulations containing ciprofloxacin hydrochloride

In the case of dry powder inhalation systems(DPIs),the development of carrierfree formulations has gained increased attention.Thereby,spray-drying is a promising technology and is widely used to produce carrier-free DPIs.Numerous works have been published about the co-spray-drying of active ingredients with various solid excipients and their effect on the physicochemical characteristics and aerodynamic properties of the formulations.However,only a few studies have been reported about the role of the solvents used in the stock solutions of spray-dried formulations.In the present work,DPI microcomposites containing ciprofloxacin hydrochloride were prepared by spray-drying in the presence of different ethanol concentrations.The work expresses the roughness,depth and width of the dimples for particle size as a novel calculation possibility,and as a correlation between the MMAD/D_(0.5)ratio and correlating it with cohesion work,these new terms and correlations have not been published–to the best of our knowledge–which has resulted in gap-filling findings.As a result,different proportions of solvent mixtures could be interpreted and placed in a new perspective,in which the influence of different concentrations of ethanol on the habit of the DPI formulations,and thus on in vitro aerodynamic results.Based on these,it became clear why we obtained the best in vitro aerodynamic results for DPI formulation containing 30%ethanol in the stock solution.

Swirling flow and capillary diameter effect on the performance of an active dry powder inhalers

For patients with lung disease,dry powder inhalers(DPI)are profoundly beneficial.The current study introduces and develops a series of dry powder inhalers(DPIs).A capsule-based(size 0)active DPI was considered.The study aims to investigate whether swirling flow and outlet capillary diameter(dc_out)affect the percentage of emitted doses(ED)released from the capsule.Spiral vanes were added to the capillary inlet to produce a swirling flow.Computational fluid dynamics(CFD)was applied to simulate the problem.The results were compared with previous in vitro and numerical studies to validate the results.Based on the derived results,the small swirl parameter(SP)enhances the secondary flow and recirculation zone.It increases the central jet flow,which increases the ED value by about 5–20%compared to no-swirl flow.However,as the airflow rate increases,the recirculation zone enlarges,vorticities become dominant,and asymmetrical flow patterns emerge.Consequently,ED%drops significantly(more than 50%).As d_(c_out)decreases,the vorticities around the outlet capillary become more potent,which is undesirable.Indeed,the emptying of the capsule does not happen ideally.The research provides a perspective on the device's design and DPI performance.

Inhalable microparticles as drug delivery systems to the lungs in a dry powder formulations

Inhalation-administrated drugs remain an interesting possibility of addressing pulmonary diseases.Direct drug delivery to the lungs allows one to obtain high concentration in the site of action with limited systemic distribution,leading to a more effective therapy with reduced required doses and side effects.On the other hand,there are several difficulties in obtaining a formulation that would meet all the criteria related to physicochemical,aerodynamic and biological properties,which is the reason why only very few of the investigated systems can reach the clinical trial phase and proceed to everyday use as a result.Therefore,we focused on powders consisting of polysaccharides,lipids,proteins or natural and synthetic polymers in the form of microparticles that are delivered by inhalation to the lungs as drug carriers.We summarized the most common trends in research today to provide the best dry powders in the right fraction for inhalation that would be able to release the drug before being removed by natural mechanisms.This review article addresses the most common manufacturing methods with novel modifications,pros and cons of different materials,drug loading capacities with release profiles,and biological properties such as cytocompatibility,bactericidal or anticancer properties.

Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers

Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler(LCD) for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 μm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.

Influence of physical properties of carrier on the performance of dry powder inhalers

Dry powder inhalers(DPIs) offer distinct advantages as a means of pulmonary drug delivery and have attracted much attention in the field of pharmaceutical science. DPIs commonly contain micronized drug particles which, because of their cohesiveness and strong propensity to aggregate, have poor aerosolization performance. Thus carriers with a larger particle size are added to address this problem. However, the performance of DPIs is profoundly influenced by the physical properties of the carrier, particularly their particle size, morphology/shape and surface roughness. Because these factors are interdependent, it is difficult to completely understand how they individually influence DPI performance.The purpose of this review is to summarize and illuminate how these factors affect drug–carrier interaction and influence the performance of DPIs.

Practical,regulatory and clinical considerations for development of inhalation drug products

The formulation and device collectively constitute an inhalation drug product.Development of inhaled drugs must consider the compatibility between formulation and device in order to achieve the intended pharmaceutical performance and usability of the product to improve patient compliance with treatment instruction.From the points of formulation,device and patient use,this article summarizes the inhalation drugs,including pressurized metered dose inhaler(pMDI),dry powder inhaler(DPI),and nebulizer that are currently available in the US and UK markets.It also discusses the practical considerations for the development of inhalers and provides an update on the corresponding regulations of the FDA(U.S.Food and Drug Administration)and the EMA(European Medicines Agency).

Three-dimensional DEM-CFD analysis of air-flow-induced detachment of API particles from carrier particles in dry powder inhalers

Air flow and particle-particle/wall impacts are considered as two primary dispersion mechanisms for dry powder inhalers(DPIs).Hence,an understanding of these mechanisms is critical for the development of DPIs.In this study,a coupled DEM-CFD(discrete element method-computational fluid dynamics)is employed to investigate the influence of air flow on the dispersion performance of the carrier-based DPI formulations.A carrier-based agglomerate is initially formed and then dispersed in a uniformed air flow.It is found that air flow can drag API particles away from the carrier and those in the downstream air flow regions are prone to be dispersed.Furthermore,the influence of the air velocity and work of adhesion are also examined.It is shown that the dispersion number(i.e.,the number of API particles detached from the carrier)increases with increasing air velocity,and decreases with increasing the work of adhesion,indicating that the DPI performance is controlled by the balance of the removal and adhesive forces.It is also shown that the cumulative Weibull distribution function can be used to describe the DPI performance,which is governed by the ratio of the fluid drag force to the pull-off force.

Optimizing aerosolization of a high-dose L-arginine powder for pulmonary delivery

In this study a carrier-free dry powder inhalation(DPI)containing L-arginine(ARG)was developed.As such,it is proposed that ARG could be used for adjunctive treatment of cystic fibrosis and/or tuberculosis.Various processing methods were used to manufacture highdose formulation batches consisting various amounts of ARG and excipients.The formulations were evaluated using several analytical methods to assess suitability for further investigation.Several batches had enhanced in vitro aerolization properties.Significant future challenges include the highly hygroscopic nature of unformulated ARG powder and identifying the scale of dose of ARG required to achieve the response in lungs.

Development of ciclesonide dry powder inhalers and the anti-asthmatic efficacy in guinea pigs

Ciclesonide is a new corticosteroid currently in clinical development for the treatment of asthma by oral inhalation. The objectives of the present study were to develop ciclesonide dry powder inhalers （DPIs, 80 μg） and investigate the anti-asthmatic effect in animals. For preparing a ciclesonide capsule-type DPI, sphere-shaped lactose was used as a diluent carrier, mixed with micronized ciclesonide, and filled into a capsule, and then put into a dry powder inhaler for oral inhalation. The asthmatic model was established with guinea pigs, and the therapeutic efficacy of ciclesonide was performed on the asthmatic guinea pig model. Results showed that the pulmonary deposition ratio of ciclesonide DPIs was approximately 26% and their content uniformity met the requirements of China Pharmacopoeia. The established pathological model exhibited the typical features of asthma with a widened pulmonary alveolar interval, narrowed alveolar space and detached bronchial mucosal epithelium with topical necrosis, goblet cell hyperplasia, and inflammatory cell infiltration. After treating with ciclesonide, the impaired indicators in asthmatic guinea pigs were significantly recovered or alleviated, exhibiting decreased total cells, decreased eosinophils and a decreased IL-5 level while there was an increased IFN-γ level in the bronchoalveolar lavage fluid （BALF）. This study develops a new pulmonary ciclesonide delivery system for treating asthma, and proves the therapeutic efficacy in asthmatic guinea pigs.

DEM analysis of the effect of electrostatic interaction on particle mixing for carrier-based dry powder inhaler formulations

Particle interactions play a significant role in controlling the performance of dry powder inhalers （DPIs）, which mainly arise through van der Waals potentials, electrostatic interactions, and capillary forces. Our aim is to investigate the influence of electrostatic charge on the performance of DPIs as a basis for improv- ing the formulation of the particle ingredients. The mixing process of carrier and active pharmaceutical ingredient （API） particles in a vibrating container is investigated using a discrete element method （DEM）. The number of APl particles attaching to the carrier particle （i.e., contact number） increases with increas- ing charge and decreases with increasing container size. The contact number decreases with increasing vibrational velocity amplitude and frequency. Moreover, a mechanism governed by the electrostatic force is proposed for the mixing process. This mechanism is different from that previously proposed for the mixing process governed by van der Waals forces, indicating that long-range and short-range adhesive forces can result in different mixing behaviours.

干粉吸入剂体内外评价技术的研究进展

肺部给药已成为肺部疾病药物及某些蛋白类全身作用药物的重要给药方式。本文结合影响干粉吸入剂(DPI)性能的两大因素,即装置与微粒,就其体内、外评价体系的几种新颖的技术手段,如颗粒分布撞击器、电动力学悬浮模拟微粒与细胞表面作用的装置、液压肺技术,以及小鼠气管内吹入装置等进行了重点阐述,为DPI的研究与开发提供评价技术方面的参考。

高剪切一步法制备微晶乳糖研究

采用高剪切压(1.15×102～2.30×102 Pa)下一步微晶法,通过后续的离心、冷冻干燥、过筛制备药用微晶乳糖,然后使用激光粒度仪、X射线衍射(XRD)和扫描电镜(SEM)来分析样品的形态学特征,并通过进行舒喘宁(SS)体外沉积实验,比较了实验制备的微晶乳糖与商业化微晶乳糖(Sorbolac 400)对于药物粉末体外沉积性能的影响。本研究中SS的体外沉积实验是使用Rotahaler投递后用二级沉积装置进行收集,最后通过HPLC法分析药物含量。结果表明,在舒喘宁干粉吸入剂的沉积性能方面,制备的微晶乳糖相比Sorbolac 400性能更优越,因此高剪切压能够为干粉吸入剂制备载体微晶乳糖提供一种可行的方法。

基层医务人员规范使用干粉吸入剂的干预方法研究

目的探讨基层医务人员规范使用干粉吸入剂(DPI)的干预方法。方法随机选取泰州市二级及其以下医疗机构的80名基层医务人员,按随机数字表法分为干预组(41名)和对照组(39名)。干预组给予多手段联合干预,对照组给予常规干预。比较干预前及干预完成0,3,6个月时的DPI操作规范性评分。结果干预组干预完成时的DPI操作规范性评分显著高于对照组(P<0.01);与干预完成时比较,两组干预完成3个月时的DPI操作规范性评分无显著差异(P>0.05),干预组干预完成6个月时的DPI操作规范性评分显著降低(P<0.01)。结论多手段联合干预法提高基层医务人员DPI操作规范性的效果明显优于常规干预法,知识保留程度有待进一步研究。

吸入疗法在可逆性气道阻塞性疾病应用的进展

吸入疗法是治疗可逆性气道阻塞性疾病的常用方法。本文就吸入装置的改进、吸入方法的新认识及临床应用等方面的进展作一综述。