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.

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.

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.

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.

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.

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.

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.

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.

Dry powder platform for pulmonary drug delivery

The phenomenon of particle interaction involved in pulmonary drug delivery belongs to a wide variety of disciplines of particle technology, in particular, fluidization. This paper reviews the basic concepts of pulmonary drug delivery with references to fluidization research, in particular, studies on Geldart group C powders. Dry powder inhaler device-formulation combination has been shown to be an effective method for delivering drugs to the lung for treatment of asthma, chronic obstructive pulmonary disease and cystic fibrosis. Even with advanced designs, however, delivery efficiency is still poor mainly due to powder dispersion problems which cause poor lung deposition and high dose variability. Drug particles used in current inhalers must be 1–5 μm in diameter for effective deposition in small-diameter airways and alveoli. These powders are very cohesive, have poor flowability, and are difficult to disperse into aerosol due to cohesion arising from van der Waals attraction. These problems are well known in fluidization research, much of which is highly relevant to pulmonary drug delivery.

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).

A real-time and modular approach for quick detection and mechanism exploration of DPIs with different carrier particle sizes

Dry powder inhalers(DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes(PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform(MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes(CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device,an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation,detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.

A homogenous nanoporous pulmonary drug delivery system based on metal-organic frameworks with fine aerosolization performance and good compatibility

Pulmonary drug delivery has attracted increasing attention in biomedicine,and porous particles can effectively enhance the aerosolization performance and bioavailability of drugs.However,the existing methods for preparing porous particles using porogens have several drawbacks,such as the inhomogeneous and uncontrollable pores,drug leakage,and high risk of fragmentation.In this study,a series of cyclodextrin-based metal-organic framework(CD-MOF)particles containing homogenous nanopores were delicately engineered without porogens.Compared with commercial inhalation carrier,CDMOF showed excellent aerosolization performance because of the homogenous nanoporous structure.The great biocompatibility of CD-MOF in pulmonary delivery was also confirmed by a series of experiments,including cytotoxicity assay,hemolysis ratio test,lung function evaluation,in vivo lung injury markers measurement,and histological analysis.The results of ex vivo fluorescence imaging showed the high deposition rate of CD-MOF in lungs.Therefore,all results demonstrated that CD-MOF was a promising carrier for pulmonary drug delivery.This study may throw light on the nanoporous particles for effective pulmonary administration.

Novel approach for real-time monitoring of carrier-based DPIs delivery process via pulmonary route based on modular modified Sympatec HELOS

An explicit illustration of pulmonary delivery processes(PDPs)was a prerequisite for the formulation design and optimization of carrier-based DPIs.However,the current evaluation approaches for DPIs could not provide precise investigation of each PDP separately,or the approaches merely used a simplified and idealized model.In the present study,a novel modular modified Sympatec HELOS Real-time monitoring;Modular modification;Carrier;Air flow rate;Mechanism of drug delivery(MMSH)was developed to fully investigate the mechanism of each PDP separately in real-time.An inhaler device,artificial throat and pre-separator were separately integrated with a Sympatec HELOS.The dispersion and fluidization,transportation,detachment and deposition processes of pulmonary delivery for model DPIs were explored under different flow rates.Moreover,time-sliced measurements were used to monitor the PDPs in real-time.The Next Generation Impactor(NGI)was applied to determine the aerosolization performance of the model DPIs.The release profiles of the drug particles,drug aggregations and carriers were obtained by MMSH in real-time.Each PDP of the DPIs was analyzed in detail.Moreover,a positive correlation was established between the total release amount of drug particles and the fine particle fraction(FPF)values(R^2=0.9898).The innovative MMSH was successfully developed and was capable of illustrating the PDPs and the mechanism of carrier-based DPIs,providing a theoretical basis for the design and optimization of carrier-based DPIs.