Lung Delivery Research Articles

Development and characterization of PLA nanoparticles for pulmonary drug delivery: Co-encapsulation of theophylline and budesonide, a hydrophilic and lipophilic drug

Drug encapsulated biodegradable polymeric nanoparticles are suitable for lung delivery of therapeutic molecules. The objective of the current study was to co-encapsulate a hydrophilic drug (theophylline) and a lipophilic drug (budesonide) in poly(lactic acid) (PLA) nanoparticles for pulmonary drug delivery. PLA nanoparticles were produced using a double emulsification solvent diffusion method and characterized for their particle size, zeta potential, drug loading, in vitro drug release, interactions with airway epithelial cell line (16HBE14o-) and in vitro deposition properties upon nebulization. The spherically-shaped mono- and co-encapsulated PLA nanoparticles were observed to have a particle size of 190–400 nm and a zeta potential of −10 to −16mV. Sustained drug release over 24 h was observed from the nanoparticles into a mixture of simulated lung fluid and methanol (1:1), measured using Franz diffusion cells and when assessed for permeability using 16HBE14o-cells. There was no significant reduction in cell viability after 24 h exposure to drug-encapsulated nanoparticles at nebulized concentrations (p > 0.05). Nebulization of co-encapsulated nanoparticles resulted in a fine particle fraction of 75% and 48% for theophylline and budesonide, respectively. From these observations it can be concluded that budesonide and theophylline drug-loaded PLA nanoparticles are suitable drug delivery systems for combination therapy of asthma and COPD.

Bioinspired polymer nanoparticles omit biophysical interactions with natural lung surfactant

Herein, we report the attenuated impact of bioinspired nanoparticles on the essential function of lung surfactant. Colloidal particles made from poly(lactide) caused a significant loss of surfactant protein B (and C) from a natural lung surfactant accompanied by a decline in surface activity under static conditions and surface area cycling. No such perturbation of lung surfactant composition and function was observed for polymer nanoparticles coated with bioinspired poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC). More specifically, increasing the PMPC-coating layer thickness (≥3 nm) and density (dense conformation, distance of individual polymer chains of ≤3 nm) on the polymer nanoparticle surface diminished bioadverse events. PMPC-coated poly(lactide) nanoparticles provoked a less severe perturbation of the utilized lung surfactant when compared to colloidal counterparts coated with poly(ethylene glycol). Overall, a steric shielding of colloidal drug delivery vehicles with bioinspired PMPC can be considered as a valuable approach for the rationale development of biocompatible nanomedicines intended for lung delivery.

Losartan-chitosan/dextran sulfate microplex as a carrier to lung therapeutics: Dry powder inhalation, aerodynamic profile and pulmonary tolerability

This study aims to obtain an inhalation powder with meaningful aerodynamic and safety profiles for the lung delivery of losartan (LS). For this, the capacity of self-assembly of chitosan (CS) and dextran sulfate (DS) to form CS/DS microplex (MC), incorporating high payload of hydrophilic LS was harnessed. Dry powder inhaler (LS-MC-DPI), prepared via spray drying of the best achieved LS-MC, was proposed to impart precise engineered inhalation characteristics. Micrometric robust CS/DS MC was revealed to offer the opportunity to heighten LS encapsulation, accounting for ~75%. LS-MC-DPI was successfully developed with high yield, flowability, respirable aerodynamic size and morphology which formed swellable and mucoadhesive network, facilitating intra-pulmonary delivery. Moreover, sustained release pattern, augmented deep lung deposition and safe histological profile were realized. Overall, the newly developed LS-MC DPI shows promises as an inhalation system. The aerodynamic performance and safety of LS-MC-DPI verify its suitability for further in vivo lung therapeutics.

Biophysical model to predict lung delivery from a dual bronchodilator dry-powder inhaler

A biophysical lung model was designed to predict inhaled drug deposition in patients with obstructive airway disease, and quantitatively investigate sources of deposition variability. Different mouth-throat anatomies at varying simulated inhalation flows were used to calculate the lung dose of indacaterol/glycopyrronium [IND/GLY] 110/50 µg (QVA149) from the dry-powder inhaler Breezhaler®. Sources of variability in lung dose were studied using computational fluid dynamics, supported by aerosol particle sizing measurements, particle image velocimetry and computed tomography. Anatomical differences in mouth-throat geometries were identified as a major source of inter-subject variability in lung deposition. Lung dose was similar across inhalation flows of 30–120 L/min with a slight drop in calculated delivery at high inspiratory flows. Delivery was relatively unaffected by inhaler inclination angle. The delivered lung dose of the fixed-dose combination IND/GLY matched well with corresponding monotherapy doses. This biophysical model indicates low extra-thoracic drug loss and consistent lung delivery of IND/GLY, independent of inhalation flows. This is an important finding for patients across various ages and lung disease severities. The model provides a quantitative, mechanistic simulation of inhaled therapies that could provide a test system for estimating drug delivery to the lung and complement traditional clinical studies.

Lung delivery of nanoliposomal salbutamol sulfate dry powder inhalation for facilitated asthma therapy

The motive behind present work was to discover a solution for overcoming the problems allied with a deprived oral bioavailability of salbutamol sulfate (SS) due to its first pass hepatic metabolism, shorter half-life, and systemic toxicity at high doses. Pulmonary delivery provides an alternative route of administration to avoid hepatic metabolism of SS, moreover facilitated diffusion and prolonged retention can be achieved by incorporation into liposomes. Liposomes were prepared by thin film hydration technique using 32 full factorial design and formulation was optimized based on the vesicle size and percent drug entrapment (PDE) of liposomes. Optimized liposomal formulation exhibited an average size of about 167.2 ± 0.170 nm, with 80.68 ± 0.74% drug entrapment, and 9.74 ± 1.10 mV zeta potential. The liposomal dispersion was then spray dried and further characterized for in-vitro aerosol performance using Andersen Cascade Impactor. Optimized liposomal formulation revealed prolonged in-vitro drug release of more than 90% up to 14 h following Higuchi’s controlled release model. Thus, the proposed new-fangled liposomal formulation would be a propitious alternative to conventional therapy for efficient and methodical treatment of asthma and alike respiratory ailments.

Direct Intrabronchial Administration to Improve the Selective Agent Deposition Within the Mouse Lung.

Intratracheal (IT) administration of experimental agents is an essential technique in murine models of diffuse lung diseases, such as bleomycin-induced pulmonary fibrosis. However, distribution of intratracheally-administered agents to the distal mouse lung is often asymmetric, with lung parenchymal concentrations increased in the smaller (but equally accessible) left lung of the mouse. Described in this report is a novel intrabronchial (IB) approach to cannulate the left and/or right lungs of living mice non-operatively. It is also demonstrated how this approach can be used to selectively administer agents to one lung or adapted (via dose-adjusted IB delivery) to improve the left-right symmetry of lung delivery of experimental agents, thereby improving models of diffuse lung disease such as bleomycin-induced pulmonary fibrosis.

Inhalable chitosan microparticles for simultaneous delivery of isoniazid and rifabutin in lung tuberculosis treatment

The direct delivery of antibiotics to the lung has been considered an effective approach to treat pulmonary tuberculosis, which represents approximately 80% of total cases. In this sense, this work aimed at producing inhalable chitosan microparticles simultaneously associating isoniazid and rifabutin, for an application in pulmonary tuberculosis therapy. Spray-dried chitosan microparticles were obtained with adequate flow properties for deep lung delivery (aerodynamic diameter of 4 µm) and high drug association efficiencies (93% for isoniazid and 99% for rifabutin). The highest concentration of microparticles that was tested (1 mg/mL) decreased the viability of macrophage-differentiated THP-1 cells to around 60% after 24 h exposure, although no deleterious effect was observed in human alveolar epithelial (A549) cells. The release of LDH was, however, increased in both cells. Chitosan microparticles further evidenced capacity to activate macrophage-like cells, inducing cytokine secretion well above basal levels. Moreover, the propensity of macrophages to internalize microparticles was demonstrated, with uptake levels over 90%. Chitosan microparticles also inhibited bacterial growth by 96%, demonstrating that the microencapsulation preserved drug antibacterial activity in vitro. Overall, the obtained data suggest the potential of chitosan microparticles for inhalable lung tuberculosis therapy.

Therapeutic Management of Pulmonary Tuberculosis by Mannosylated Chitosan Ascorbate Microspheres: Preparation and Characterization

Objective: In this study, biodegradable Chitosan Ascorbate Microsphere (CAMs) and mannosylated chitosan ascorbate microsphere (m-CAMs) prepared for targeting towards alveolar macrophages to treatment of pulmonary tuberculosis. 
 Significance: Ascorbic acid is an antioxidant and reported killing effect on mycobacterium by induces fenton reaction. This study enlightens the possible benefits of adding antioxidant properties of ascorbic acid with chitosan microsphere to an anti-tuberculosis regimen and mannosylation of microsphere significantly induce the targetability of antitubercular drug to alveolar macrophages.
 Methods: CAMs prepared by firstly salification of chitosan by ascorbic acid then ionic gelation with STPP and m-CAMs prepared by incubation method and purified for further studies. The physicochemical, in vitro and in vivo characterizations of both formulations were carried out.
 Results: The size of microspheres (both CAMs and m-CAMs) were found to be in range of 3.40-4.81µm. Evident changes were observed in crystallinity and structure of both carrier systems and depicted by Fourier transform infrared (FTIR), Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. In vitro lung deposition study of microspheres showed favourable aerodynamic properties for deep lung delivery (MMAD 2.0- 3.8 μm) and, thus, show potential for an application as inhalable tuberculosis therapy. The drug release showed the biphasic pattern of release, i.e., initial burst (30-45% up to 8 h) followed by a slower sustained release pattern (more than 80% up to 72 h) in both simulated lung fluids. Optimized formulations exhibited lower cytotoxicity and bio distribution studies demonstrated the efficiency of m-CAMs for spatial delivery of INH to alveolar tissues. CAMs and m-CAMs evidenced minor cytotoxicity on lung epithelial cells (A549 cell lines).
 Conclusion: m-CAMs thus has a promising potential to be explore as an effective carrier system for delivery of antitubercular drugs regimen.
 Key words: Targetability, alveolar macrophage, lung cancer A549 cells

Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.

Evaporation and particle formation from multi-solvent microdroplets containing solid excipients pertaining to spray-drying of therapeutic agents intended for lung delivery were studied. Various water and ethanol co-solvent systems containing a variety of actives and excipients (beclomethasone, budesonide, leucine, and trehalose) were considered. Numerical methods were used to predict the droplet evaporation rates and internal solute transfers, and their results verified and compared with results from two separate experimental setups. In particular, an electrodynamic balance was used to measure the evaporation rates of multicomponent droplets and a monodisperse droplet chain setup collected dried microparticles for further analytical investigations and ultramicroscopy. The numerical results are used to explain the different particle morphologies dried from solutions at different co-solvent compositions. The obtained numerical data clearly show that the two parameters controlling the general morphology of a dried particle, namely the Péclet number and the degree of saturation, can change with time in a multi-solvent droplet. This fact complicates product development for such systems. However, this additional complexity vanishes at what we define as the iso-compositional point, which occurs when the solvent ratios and other composition-dependent properties of the droplet remain constant during evaporation, similar to the azeotrope of such systems during distillation. Numerical and experimental analysis of multi-solvent systems indicate that spray-drying near the iso-compositional ratio simplifies the design and process development of such systems.

Nanocarriers in effective pulmonary delivery of siRNA: current approaches and challenges.

Research on siRNA is increasing due to its wide applicability as a therapeutic agent in irreversible medical conditions. siRNA inhibits expression of the specific gene after its delivery from formulation to cytosol region of a cell. RNAi (RNA interference) is a mechanism by which siRNA is silencing gene expression for a particular disease. Numerous studies revealed that naked siRNA delivery is not preferred due to instability and poor pharmacokinetic performance. Nanocarriers based delivery of siRNA has the advantage to overcome physiological barriers and protect the integrity of siRNA from degradation by RNAase. Various diseases like lung cancer, cystic fibrosis, asthma, etc can be treated effectively by local lung delivery. The selective targeted therapeutic action in diseased organ and least off targeted cytotoxicity are the key benefits of pulmonary delivery. The current review highlights recent developments in pulmonary delivery of siRNA with novel nanosized formulation approach with the proven in vitro/in vivo applications.

Poly(lactide- co-glycolide) Nanoparticles for Prolonged Therapeutic Efficacy of Esculentin-1a-Derived Antimicrobial Peptides against Pseudomonas aeruginosa Lung Infection: in Vitro and in Vivo Studies.

Due to their excellent in vitro activity against multidrug resistant bacteria, antimicrobial peptides (AMPs) hold promise for treatment of Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) sufferers. In this work, poly(lactide- co-glycolide) (PLGA) nanoparticles for lung delivery of AMPs deriving from the frog-skin esculentin-1a, namely, Esc(1-21) and Esc(1-21)-1c (Esc peptides), were successfully developed. Improved peptide transport through artificial CF mucus and simulated bacterial extracellular matrix was achieved in vitro. The formulations were effectively delivered through a liquid jet nebulizer already available to patients. Notably, Esc peptide-loaded nanoparticles displayed an improved efficacy in inhibiting P. aeruginosa growth in vitro and in vivo in the long term. A single intratracheal administration of Esc peptide-loaded nanoparticles in a mouse model of P. aeruginosa lung infection resulted in a 3-log reduction of pulmonary bacterial burden up to 36 h. Overall, results unravel the potential of PLGA nanoparticles as a reliable delivery system of AMPs to lungs.

Co-Spray-Dried Urea Cross-Linked Hyaluronic Acid and Sodium Ascorbyl Phosphate as Novel Inhalable Dry Powder Formulation

The pathogenesis and progression of several lung disorders is propagated by inflammatory and oxidative processes, which can be controlled by adjunctive inhaled therapies. The present study aimed to develop an inhalable dry powder formulation consisting of co-spray-dried urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate (SD HA-CL–SAP), a novel combination which was recently shown to possess anti-inflammatory, antioxidant, and wound healing properties. Native HA and SAP were co-spray dried (SD HA–SAP) and evaluated as control formulation. Yield (Y%) and encapsulation efficiency (EE%) were 67.0 ± 4.8% and 75.5 ± 7.2% for SD HA–SAP, 70.0 ± 1.5% and 66.5 ± 5.7% for SD HA-CL–SAP, respectively. Both formulations were shown to be suitable for lung delivery in terms of morphology, particle size (median volumetric diameter ∼ 3.4 μm), physical and thermal stability, in vitro aerosol performance - respirable fraction: 30.5 ± 0.7% for SD HA–SAP and 35.3 ± 0.3% for SD HA-CL–SAP. SAP release was investigated using Franz cells and air-interface Calu-3 cell model (>90% of SAP transported within 4 h). The innovative SD HA-CL–SAP formulation holds potential as inhalable dry powder for the treatment of inflammatory lung disorders.

Development of a High-Flow Nasal Cannula and Pharmaceutical Aerosol Combination Device.

Background: Aerosol drug delivery to the lungs is known to be very inefficient during all forms of noninvasive ventilation, especially when the aerosol is administered simultaneously with high-flow nasal cannula (HFNC) therapy. The objective of this study was to develop a new combination device based on vibrating mesh nebulizers that can provide continuously heated and humidified HFNC therapy as well as on-demand pharmaceutical aerosols with high efficiency. Methods: The combination device implemented separate mesh nebulizers for generating humidity (humidity nebulizer) and delivering the medical aerosol (drug nebulizer). Nebulizers were actuated in an alternating manner with the drug nebulizer delivering the medication during a portion of an adult inhalation cycle. Aerosol entered a small-volume mixing region where it was combined with ventilation gas flow and then entered a heating channel to produce small particles that are desirable for nose-to-lung administration and potentially excipient enhanced growth delivery. Three assessment methods (analytical calculations, computational fluid dynamics [CFD] simulations, and in vitro experiments in three-dimensional [3D] printed devices) were used to improve the mixer-heater design to minimize depositional drug losses, maintain a small device volume, ensure sufficient droplet evaporation, and control the outlet thermodynamic conditions. Results: For an initial configuration (Design 1), good agreement in performance metrics was found using the three assessment methods. Based on insights gained from the CFD simulations of Design 1, two new designs were developed and produced with 3D printing. Experimental analysis indicated that the new designs both achieved <5% depositional loss in the mixer-heater even with cyclic operation and sufficiently dried the aerosol from an initial size of 5.3 μm to an outlet size of ∼1.0 μm. A combination of the applied methods indicated that the desired thermodynamic conditions of HFNC therapy were also met. Conclusions: Multiple methodological approaches were used concurrently to develop a new combination device for administering HFNC therapy and simultaneous on-demand pharmaceutical aerosols to the lungs with high efficiency. The use of a small-volume mixer-heater (<100 mL), synchronization of the drug nebulizer with inhalation, and small outlet particle size should enable high efficiency lung delivery of the aerosol.

Recent Developments in mRNA-Based Protein Supplementation Therapy to Target Lung Diseases.

Protein supplementation therapy using invitro-transcribed (IVT) mRNA for genetic diseases contains huge potential as a new class of therapy. From the early ages of synthetic mRNA discovery, a great number of studies showed the versatile use of IVT mRNA as a novel approach to supplement faulty or absent protein and also as a vaccine. Many modifications have been made to produce high expressions of mRNA causing less immunogenicity and more stability. Recent advancements in the invivo lung delivery of mRNA complexed with various carriers encouraged the whole mRNA community to tackle various genetic lung diseases. This review gives a comprehensive overview of cells associated with various lung diseases and recent advancements in mRNA-based protein replacement therapy. This review also covers a brief summary of developments in mRNA modifications and nanocarriers toward clinical translation.

HPLC Quantification of Dexamethasone Palmitate in Bronchoalveolar Lavage Fluid of Rat after Lung Delivery with Large Porous Particles

A high-performance liquid chromatography (HPLC) method has been developed and validated for the determination of dexamethasone palmitate (DXP) in bronchoalveolar fluid lavage samples (BALF). DXP in rat BALFs containing the internal standard (IS), testosterone decanoate (TD), was extracted using a mixture of chloroform and methanol (9:1, v/v). Extracts were then centrifuged, dried and dissolved in acetonitrile. A chromatographic separation based on an isocratic elution was done using acetonitrile and water (85:15, v/v) as a mobile phase at a flow rate of 1.2 mL/min. The graph of the developed method was linear within the tested calibration range of 0.5 - 40 μg/mL. The overall extraction recovery of DXP from BALF samples was 84.3% ± 1.6%. The accuracy (relative error) and precision (coefficient of variation) values were within the pre-defined limits of ≤15% at all concentrations. This methodology has been applied to determine levels of DXP in BALF samples collected from rats treated with DXP large porous particles. The measured concentrations were successfully evaluated using a non-compartment pharmacokinetic model. Since the developed method requires only a microvolume (100 μL) of BALF sample for analysis, it is therefore particularly suitable for the evaluation of drug biodistribution in lung.

Development and evaluation of nanoemulsion and microsuspension formulations of curcuminoids for lung delivery with a novel approach to understanding the aerosol performance of nanoparticles

Extensive research has demonstrated the potential effectiveness of curcumin against various diseases, including asthma and cancers. However, few studies have used liquid-based vehicles in the preparation of curcumin formulations. Therefore, the current study proposed the use of nanoemulsion and microsuspension formulations to prepare nebulised curcuminoid for lung delivery. Furthermore, this work expressed a new approach to understanding the aerosol performance of nanoparticles compared to microsuspension formulations. The genotoxicity of the formulations was also assessed. Curcuminoid nanoemulsion formulations were prepared in three concentrations (100, 250 and 500 µg/ml) using limonene and oleic acid as oil phases, while microsuspension solutions were prepared by suspending curcuminoid particles in isotonic solution (saline solution) of 0.02% Tween 80. The average fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of the nebulised microsuspension formulations ranged from 26% and 7.1 µm to 40% and 5.7 µm, for 1000 µg/ml and 100 µg/ml respectively. In a comparison of the low and high drug concentrations of the nebulised nanoemulsion, the average FPF and MMAD of the nebulised nanoemulsion formulations prepared with limonene oil ranged from 50% and 4.6 µm to 45% and 5.6 µm, respectively; whereas the FPF and MMAD of the nebulised nanoemulsion prepared with oleic acid oil ranged from 46% and 4.9 µm to 44% and 5.6 µm, respectively. The aerosol performance of the microsuspension formulations were concentration dependent, while the nanoemulsion formulations did not appear to be dependent on the curcuminoids concentration. The performance and genotoxicity results of the formulations suggest the suitability of these preparations for further inhalation studies in animals.

High-Efficiency Nose-to-Lung Aerosol Delivery in an Infant: Development of a Validated Computational Fluid Dynamics Method.

Background: Computational fluid dynamics (CFD) provides a powerful tool for developing new high-efficiency aerosol delivery strategies, such as nose-to-lung (N2L) aerosol administration to infants and children using correctly sized aerosols. The objective of this study was to establish numerically efficient CFD solution methods and guidelines for simulating N2L aerosol administration to an infant based on comparisons with concurrent in vitro experiments. Materials and Methods: N2L administration of a micrometer-sized aerosol (mass median aerodynamic diameter [MMAD] = 1.4 μm) was evaluated using concurrent CFD simulations and in vitro experiments. Aerosol transport and deposition was assessed in a new nasal airway geometry of a 6-month-old infant with a streamlined nasal cannula interface, which was constructed as a CFD mesh and three-dimensionally printed to form an identical physical prototype. CFD meshes explored were a conventional tetrahedral approach with near-wall (NW) prism elements and a new polyhedral mesh style with an equally refined NW layer. The presence of turbulence in the model was evaluated using a highly efficient low-Reynolds number (LRN) k-ω turbulence model, with previously established NW corrections that accounted for anisotropic wall-normal turbulence as well as improved NW velocity interpolations and hydrodynamic particle damping. Results: Use of the new polyhedral mesh was found to improve numerical efficiency by providing more rapid convergence and requiring fewer control volumes. Turbulent flow was found in the nasal geometry, generated by the inlet jets from the nasal cannula interface. However, due to the small particle size, turbulent dispersion was shown to have little effect on deposition. Good agreement was established between the CFD predictions using the numerically efficient LRN k-ω model with appropriate NW corrections and in vitro deposition data. Aerosol transmission efficiencies through the delivery tube, nasal cannula, and infant nasal model, based on experimental and CFD predictions, were 93.0% and 91.5%, respectively. Conclusions: A numerically efficient CFD approach was established to develop transnasal aerosol administration to infants and children. Small particle aerosols with aerodynamic diameters of ∼1.5 μm were confirmed to have low inertial depositional loss, and have low deposition from turbulent dispersion, making them ideal for high-efficiency lung delivery through an infant nasal cannula interface.

Development of porous particles using dextran as an excipient for enhanced deep lung delivery of rifampicin

This study aimed to develop a dry powder inhaler (DPI) formulation for enhanced deep lung delivery of rifampicin using dextrans of different molecular weights. Porous particles were formed by a spray-drying method, which was designed based on the Peclet number. The morphology of particles containing both rifampicin and dextran was dependent on the dextran concentration. The D50 values of SDPs containing rifampicin and dextran 40 or 70 at ratios of less than 1:10 were below 5 μm. The specific surface area values of spray-dried particles containing rifampicin and dextran 40 or 70 of more than 1:10 were over 20 m2/g, assuming that an increase in specific surface area was indicative of an increase in the formation ratio of a porous structure. DPI formulations that contained higher amounts of dextran had higher rifampicin contents. Thus, the formulations containing a dextran: rifampicin ratio of 1:20 had approximately 100% drug encapsulation.The formation of the porous particles can be explained by the related Peclet number, which correlates with the viscosity and surface tension of the ethanol-water solution used in preparing the particles. It was noted that the existence ratio of the porous particles increased as the viscosity of the mixed solution was increased. Furthermore, an increase in the proportion of dextran resulted in higher rifampicin loading into the particles and the formation of finer particle fractions (FPF) (<7.0 μm at a rate of 28.3 L/min, <4.8 um at a rate of 60.0 L/min). The formulations containing rifampicin and both dextrans at a ratio of more than 1:10 consisted of approximately 50% FPF at a rate of 28.3 L/min and 60.0 L/min. The results indicate that dextran is suitable to obtain porous particles via spray-drying. Additionally, the existence ratio of the porous particles can be improved by increasing the viscosity of the solution used in the preparation of the particles.

Spray-drying of konjac glucomannan to produce microparticles for an application as antitubercular drug carriers

Spray-drying is proposed in this work as the technique to produce konjac glucomannan microparticles aimed at an application in lung tuberculosis therapy. Microparticles were developed to provide direct lung delivery of an association of two first-line antitubercular drugs, isoniazid and rifabutin, by inhalation. Mannitol or leucine were incorporated as spray-drying excipients to verify their effect on the final properties of drug-loaded konjac glucomannan microparticles. The obtained results indicate that konjac glucomannan is a suitable material for the preparation of inhalable microparticles for antitubercular therapy upon processing by spray-drying. The incorporation of excipients revealed no benefit on the characterized properties. Isoniazid and rifabutin were mostly associated to microparticles with success (efficiencies of 88–104%). However, the presence of mannitol was found to decrease the capacity to associate isoniazid (efficiency of 43%). The excipients further promoted the acceleration of drug release. Moreover, general absence of toxicity was observed for microparticles in Calu-3 and A549 cells, with cell viabilities above 70%. The results of the work suggest that microparticles composed only of KGM display the most appropriate characteristics.

Micro/nanostructured inhalable formulation based on polysaccharides: Effect of a thermoprotectant on powder properties and protein integrity

Combined micro- and nanosystems are appealing for pulmonary protein delivery, fulfilling the specific physiological requirements for efficient outcomes in-vivo. However, fabrication of protein formulations may impose stresses perturbing protein conformational stability and, hence, biological activity. Herein, a protein, insulin (INS), was nanoencapsulated inside chitosan nanoparticles (CS NPs) by ionic gelation. By spray drying, the resultant protein-loaded NPs were further encapsulated with a thermoprotectant into powders bearing adequate aerodynamic properties for lung delivery. Structural modifications and interactions of the protein/carrier system were investigated following processing, with special emphasis on protein integrity. Accordingly, physicochemical, elemental, structural and thermal experiments were performed. The analyses revealed the localization of a proportion of the protein on the NPs’ surface following nanoencapsulation, and the involved molecular interactions between the NPs and thermoprotectant after microencapsulation. Protein integrity was conserved throughout the preparation processes. This highlights the non-invasiveness of the fabrication techniques, particularly spray drying, for preparing micro-nanosystems for effective administration of inhalable macromolecules.