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.

Pulmonary delivery of mucus-traversing PF127-modified silk fibroin nanoparticles loading with quercetin for lung cancer therapy

The mucosal barrier remains a major barrier in the pulmonary drug delivery system,as mucociliary clearance in the airway accelerates the removal of inhaled nanoparticles(NPs).Herein,we designed and developed the inhalable Pluronic F127-modified silk fibroin NPs loading with quercetin(marked as QR-SF(PF127)NPs),aiming to solve the airway mucus barrier and improve the cancer therapeutic effect of QR.The PF127 coating on the SF NPs could attenuate the interaction between NPs and mucin proteins,thus facilitating the diffusion of SF(PF127)NPs in the mucus layer.The QR-SF(PF127)NPs had particle sizes of approximately 200 nm with negatively charged surfaces and showed constant drug release properties.Fluorescence recovery after photobleaching(FRAP)assay and transepithelial transport test showed that QR-SF(PF127)NPs exhibited superior mucus-penetrating ability in artificial mucus and monolayer Calu-3 cell model.Notably,a large amount of QR-SF(PF127)NPs distributed uniformly in the mice airway section,indicating the good retention of NPs in the respiratory tract.Themicemelanoma lungmetastasismodel was established,and the therapeutic effect of QR-SF(PF127)NPs was significantly improved in vivo.PF127-modified SF NPs may be a promising strategy to attenuate the interaction with mucin proteins and enhancemucus penetration efficiency in the pulmonary drug delivery system.

Inhalation Devices and Pulmonary Drug Delivery

Inhaled drug delivery is mainly used to treat pulmonary airway disorders by transporting the drug directly to its targeted location for action.This decreases the dose required to exert a therapeutic effect and minimizes any potential adverse effects.Direct drug delivery to air passages facilitates a faster onset of action;it also minimizes irritation to the stomach,which frequently occurs with oral medications,and prevents the exposure of drugs to pre-systemic metabolism that takes place in the intestine and liver.In addition to that,the lung is regarded as a route for transporting medications throughout the entire body's blood circulation.The type of medication and the device used to deliver it are both important elements in carrying the drug to its target in the lungs.Different types of inhalation methods are used in inhaled delivery.They differ in the dose delivered,inhalation technique,and other factors.This paper will discuss these factors in more detail.

In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug

This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide(BUD)as a model drug.The formulations investigated in this study are:(i)commercially available micronized BUD mixed with lactose(BUD-PT),(ii)BUD nanocrystal suspension(BUD-NC),(iii)BUD nanocrystals embedded hyaluronic acid microparticles(BUD-NEM).The deposition patterns of the three inhaled formulations in the rats’lungs were determined in vivo and in silico predicted,which were used as inputs in GastroPlus TM software to predict drug absorption following aerosolization of the tested formulations.BUD pharmacokinetics,estimated based on intravenous data in rats,was used to establish a drug-specific in silico absorption model.The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM,respectively.In the case of BUD-PT,the in silico model revealed significant gastrointestinal absorption of BUD,which could be overlooked by traditional in vivo experimental observation.This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations,which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.

Drug/polymer nanoparticles prepared using unique spray nozzles and recent progress of inhaled formulation

Inhaled formulations are promising for pulmonary and systemic non-pulmonary diseases.Functional engineered particles including drugs and drug-loaded nanocarriers have been anticipated because they can improve drug delivery efficacy against target sites in the lungs or blood.In this review,unique spray nozzles(e.g.,four-fluid spray nozzle and twosolution mixing type nozzle)for the preparation of nanocomposite particles which mean microparticles containing drug nanoparticles are described.These nozzles can produce nanocomposite particles in one-step and their spray drying system is suitable for scalingup.Nanocomposite particles are useful in improving drug absorption and delivery efficacy against alveolar macrophages.In addition,recent studies on several pulmonary diseases(tuberculosis,lung cancer,cystic fibrosis,pneumonia,vaccine and others)and related inhaled formulations were also reviewed.

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.

Protein microspheres for pulmonary drug delivery

A new supercritical fluid(SCF)technique was developed for the preparation of microspheres for pulmonary drug delivery(PDD).This technique,based on the anti-solvent process,has incorporated advanced engineering design features to enable improved control of the particle formation process.Human recombinant insulin(HRI)was used as a model compound to evaluate the efficiency of this SCF process.An aqueous solution of HRI with a co-solvent was sprayed into high pressure carbon dioxide that extracted the solvent and water,leading to a dry fine powder with good particle size distribution and near ideal morphology for pulmonary drug delivery.

Preparation and characterization of budesonide-loaded solid lipid nanoparticles for pulmonary delivery

To increase the solubility and adsorption of budesonide（BUD）,budesonide-loaded solid lipid nanoparticles（BUD-SLNs） were prepared and characterized in this study.Glycerin monostearate（GMS）was selected to be the matrix lipid material after calculation the differences of partial solubility parameters.An emulsification-ultrasound diffusion method was employed and formula was optimized in the BUD-SLNs preparation.The entrapment efficiency（ee%）of BUD-SLNs was（97.77±2.60）%, and the mean particle size was 147.3 nm（PDI=0.228）.Uniform and sphere particles were observed under TEM.The in vitro release of BUD-SLNs could be well explained by the biphasic release dynamics equation.The spectrums of DSC and X-ray diffraction indicated that BUD molecules were dispersed mainly into the lipids to form homogeneous matrix structure.Our results provide fundamental data for the application of SLNs in pulmonary delivery system.

Increasing stiffness promotes pulmonary retention of ligand-directed dexamethasone-loaded nanoparticle for enhanced acute lung inflammation therapy

Inhaled nanoparticles(NPs)need to penetrate the bronchial mucosa to deliver drug payloads deeply in the lung for amplified local therapy.However,the bronchial mucociliary barrier eliminates NPs rapidly,which considerably limits their mucosal penetration.In this study,we find that surface ligand modification and stiffness adjustment of NPs contribute to the significantly enhanced bronchial mucosal absorption and pulmonary retention of inhaled drugs.We utilize neonatal Fc receptor ligand(FcBP)to modify the rationally designed low stiffness NPs(Soft-NP)and high stiffness NPs(Stiff-NP)to target bronchial mucosa.In an acute lung inflammation rat model,after intranasal administration with dexamethasone-loaded NPs,Stiff-NP endowed with FcBP displays superior therapeutic effects.The in vitro data demonstrate that the promotion effect of FcBP to bronchial mucosal absorption of Stiff-NP dominates over Soft-NP.This could be attributed to the higher affinity between ligand-receptor when incorporating FcBP on the Stiff-NP surface.Meanwhile,high stiffness modulates more actin filaments aggregation to mediate endocytosis,along with strengthened Ca2+signal to enhance exocytosis.Conclusively,we highlight that FcBP-modified NPs with higher stiffness would be a potential pulmonary drug delivery system.

Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma,chronic obstructive pulmonary diseases and respiratory infections,and systemic diseases such as diabetes.Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit.The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration,but also enhance the clinical benefits to the patients with improved therapeutic outcomes.This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines.It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure,which is followed by recent advances in various strategies to overcome these barriers.Finally,the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.

Flow behavior and deposition study of pollen-shape carrier particles in an idealized inhalation path model

Pollen-shape （spiked sphere） hydroxyapatite （HA） particles for drug carrier application are studied. The particle shape and size effect on flow characteristics and deposition are assessed. The pollen-shape HA particles are synthesized to have comparable size as typical carrier particles with mean diameter of 30-50 μm and effective density less than 0.3 g/cm^3. The flow behaviors of HA and commonly used lactose （LA） carrier particles are characterized by the Carr＇s compressibility index （CI）. The HA particles have lower CI than the LA particles for the same size range. The flow fields of HA and LA carrier particles are measured in an idealized inhalation path model using particle image velocimetry （PLY） technique. The particle streamlines indicate that a large portion of particles may deposit at the bending section due to inertial impaction and gravitational deposition. The flow field result shows that HA particles give smaller separation regions than the LA particles for the same size range. The pollen-shape HA particles are found to be able to follow the gas flow in the model and minimize undesired deposition. Deposition result confirms the bending section to have the most deposition. Deposition is found to be a function of particle properties. An empirical correlation is derived for the deposition efficiency of the pollen-shape particles as a function of particles Stokes number.

Applications of the crystallization process in the pharmaceutical industry

The applications of the crystallization technique in the pharmaceutical industry as a purification and separation process for the isolation and synthesis of pure active pharmaceutical ingredients(API),co-crystals,controlled release pulmonary drug delivery,and separation of chiral isomers are briefly discussed using a few case studies.The effect of process variables and solvent on the polymorphism and morphology of stavudine is discussed.The implementation of external control in the form of feedback and real-time optimal control using cooling and antisolvent crystallization of paracetamol in water-isopropyl alcohol is introduced.Two methods to prepare micronsized drug particles,namely,micro-crystallization and polymer-coated API-loaded magnetic nanoparticles for pulmonary drug delivery,are discussed.The significance of co-crystals in drug administration is highlighted using the theophylline-nicotinamide co-crystal system.Resolution of chloromandelic acid derivatives,a racemic compound,is achieved using direct crystallization and diastereomeric salts crystallization.The crystal structures of diastereomeric salts of chloromandelic acid and phenylethylamine are determined.The structure comparison between the less soluble and more soluble salts shows that weak interactions such as CH/πinteractions and van der Waals forces contribute to chiral recognition when the hydrogen bonding patterns are similar.