Sustained Pulmonary Delivery Research Articles

Novel inhalable nano-based/microparticles for enhanced sustained pulmonary delivery of remdesivir - A patient malleable treatment for coronaviruses infection: In vitro aerosolization, cytotoxicity assays and antiviral activity studies

Remdesivir (RDV) is an antiviral used in potential treatment of SARS-COV-2 infection during the COVID-19 pandemic worldwide. However, it is still limited to IV administration for hospitalized patients. Therefore, we report herein successful development of RDV-loaded nanosuspensions (NS) using polycaprolactone and pluronic® F127, for the first time. The optimized RDV-NS was further loaded into inhalable nano-based/microparticles (OLN-microparticles) via co-spray drying with hyaluronic acid and mannitol. OLN-microparticles exhibited high yield value ∼80.56 %, with satisfactory entrapment efficiency and drug loading percent ∼97.27 ± 1.84 % and 3.92 ± 0.07 %, respectively. Carr's index was equal to 22.7 ± 11.67 % indicating good flowability properties. Scanning electron microscopic analysis showed spherical-shaped particles. Transmission electron microscope demonstrated grape-shaped clumps surface porosity. OLN-microparticles exhibited excellent aerodynamic features including; emitted fraction ∼97.46 ± 1.70 %, respirable particle fraction 53.77 ± 0.2 %, effective inhalation index 72.39 ± 1.40 %, and mass median aerodynamic diameter 2.25 ± 0.01 μm. Compared to plain RDV, OLN-microparticles showed significantly enhanced sustained release (p < 0.0001) with 1.5 and 1.9 fold increase at 24 and 48 h, respectively in Gamble's solution. OLN-microparticles also showed favorable cytotoxic profile with CC50 ∼ 252.0 μg/mL, inhibitory concentration (IC50) 13.08 μg/mL, and safety index (SI) 19.26 which is 1.3 fold higher compared to plain RDV. The Optimal release profile of OLN-microparticles enabled controlled and sustained release with enhanced cellular uptake. Hence, OLN-microparticles represented an efficient alternative form of dry powder for inhalation for deep and targeted pulmonary delivery of RDV, outweighing limitations accompanied with IV administration. It can provide self-administered and malleable access of treatment for SARS-COV-2 infected patients.

Evaluating the effect of sodium alginate and sodium carboxymethylcellulose on pulmonary delivery of levofloxacin spray-dried microparticles.

Patients with cystic fibrosis commonly suffer from lung infections caused by Pseudomonas aeruginosa. Recently, the Levofloxacin (LVF) nebulizing solution (Quinsair®) has been prescribed for the antimicrobial management. The sustained-release (SR) dry powder formulation of LVF is a convenient alternative to Quinsair®. It has the potential to enhance patient convenience and decrease the likelihood of drug resistance over time. In this paper, we set forth to formulate and evaluate the potential application of sodium alginate (SA) and sodium carboxymethylcellulose (SCMC) for sustained pulmonary delivery of LVF. The spray-dried (SD) LVF microparticles were formulated using SCMC and SA along with L-leucine (Leu). The microparticles were analyzed in terms of particle size, morphology, x-ray diffraction (XRD), in-vitro drug release, and aerodynamic properties. Selected formulations were further proceeded to short-term stability test. The polymer-containing samples displayed process yield of 33.31%-39.67%, mean entrapment efficiency of 89% and volume size within the range of 2-5 μm. All the hydrogel microparticles were amorphous and exhibited rounded morphology with surface indentations. Formulations with a drug-to-excipient ratio of 50:50 and higher, showed a 24-h SR. The aerodynamic parameters were fine particle fraction and emitted dose percentage ranging between 46.21%-60.6% and 66.67%-87.75%, respectively. The short-term stability test revealed that the formulation with a 50:50 drug-to-excipient ratio, containing SA, demonstrated better physical stability. The selected formulation containing SA has the potential to extend the release duration. However, further enhancements are required to optimize its performance.

Formulation and evaluation of inhaled Sildenafil-loaded PLGA microparticles for treatment of pulmonary arterial hypertension (PAH): A novel high drug loaded formulation and scalable process via hot melt extrusion technology (Part Ⅰ)

In recent years, several techniques were employed to develop a local sustained pulmonary delivery of sildenafil citrate (SC) as an alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). Most of these methods, however, need to be improved due to limitations of scalability, low yield production, low drug loading, and stability issues. In this study, we report the use of hot-melt extrusion (HME) as a scalable process for making Poly (lactic-co-glycolic acid) (PLGA) microparticles with high SC load. The prepared particles were tested in vitro for local drug delivery to the lungs by inhalation. Sodium bicarbonate was included as a porogen in the formulation to make the particles more brittle and to impart favorable aerodynamic properties. Six formulations were prepared with different formulation compositions. Laser diffraction analysis was used to estimate the geometric particle size distribution of the microparticles. In-vitro aerodynamic performance was evaluated by the next-generation cascade impactor (NGI). It was reported in terms of an emitted dose (ED), an emitted fraction (EF%), a respirable fraction (RF%), a fine particle fraction (FPF%), a mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). The formulations have also been characterized for surface morphology, entrapment efficiency, drug load, and in-vitro drug release. The results demonstrated that PLGA microparticles have a mean geometric particle size between 6 and 14 µm, entrapment efficiency of 77 to 89 %, and SC load between 17 and 33 % w/w. Fifteen percent of entrapped sildenafil was released over 24 h from the PLGA microparticles, and seventy percent over 7 days. The aerodynamic properties included fine particle fraction ranging between 19 and 33 % and an average mass median aerodynamic diameter of 6–13 µm.

Inhalable cryptotanshinone spray-dried swellable microparticles for pulmonary fibrosis therapy by regulating TGF-β1/Smad3, STAT3 and SIRT3 pathways

Cryptotanshinone (CTS) is a promising therapeutic option for pulmonary fibrosis (PF). However, clinical applications of CTS are limited owing to high photosensitivity and poor oral bioavailability. Pulmonary drug delivery, especially sustained pulmonary drug delivery, is promising for local treatment of chronic lung diseases. In this study, CTS was encapsulated in an optimized chitosan/L-leucine-based swellable microparticles (SMs) system, which exhibited an appropriate aerosolization performance, sustained release and storage stability. SMs enhanced the in vitro anti-fibrosis efficacy of CTS as shown by the improved cellular uptake. The effect of PF status on in vivo fate of the pulmonary delivered drug was also assessed. Pharmacokinetics and tissue distribution of oral and pulmonary delivery CTS in bleomycin-induced PF rats were compared. Pulmonary delivery exhibited high drug concentrations in pulmonary lesion areas, with reduced exposure to blood and non-targeted tissues after administration at a significantly lower dose compared with oral delivery. Moreover, PF pathological status enhanced activity of SMs, implying that pulmonary delivery was highly effective for PF treatment. Compared to oral delivery, Inhaled SMs showed comparable or even better efficacies at approximately 60-fold low dose compared with oral delivery. A sustained efficacy was observed under a prolonged administration interval (corresponding to half the total dose). Inhalation safety of SMs was established, and important mechanism-related signaling pathways against PF were investigated in vitro and in vivo. In summary, the findings showed that the developed CTS-loaded sustained pulmonary delivery system is a safe and effective strategy for chronic PF treatment.

Design and evaluation of novel inhalable sildenafil citrate spray-dried microparticles for pulmonary arterial hypertension

Pulmonary delivery of vasodilators is a promising alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). The aim of this study was to design and evaluate hydrogel microparticles as a carrier for sustained pulmonary delivery of sildenafil citrate. Spray dried hydrogel microparticles containing biodegradable sodium carboxymethyl cellulose, sodium alginate, and sodium hyaluronate polymers at variable concentrations were prepared. A design of experiment using the “Extreme Vertices Mixture” design was executed. The design was used to study the influence of polymer concentration and their interactions on the physicochemical properties of the formulations in terms of particle size, particle size distribution, product yield, entrapment efficiency, and in-vitro drug release. Selected formulations were also evaluated for swelling, biodegradation, moisture content, in-vitro aerodynamic performance, and cytotoxicity. In addition, a lung deposition and pharmacokinetic study was conducted in rats to study drug accumulation in lungs and blood after intratracheal administration of the spray dried inhalable hydrogel microparticles in comparison to orally administered Viagra®. The results demonstrated that formulated microparticles had a mean geometric particle size between 2 and 5 μm, entrapment efficiency of >80%, and yield ranging between 47 and 66% w/w. The in-vitro drug release profiles showed a sustained drug release of sildenafil citrate for over 24 h. The statistical design showed a significant influence of the microparticulate composition on the physicochemical properties. Furthermore, selected formulations were evaluated for their aerodynamic properties. The aerodynamic properties included fine particle fraction ranging between 24 and 30%, dose recovery percent of 68–8 5%, and average mass median aerodynamic diameter of 4.6–4.8 μm. The in-vivo pharmacokinetic study showed that inhaled spray dried hydrogel microparticles (M6) formulation had significantly higher lung/blood Cmax, AUC, extended half-life, and mean residence time in comparison to orally administered sildenafil citrate of the same dose. In conclusion, the formulated drug-loaded spray dried hydrogel microparticles showed promising in-vitro and in-vivo results for the pulmonary delivery of sildenafil citrate. The spray dried hydrogel microparticles formulation can be considered as a potential alternative of oral sildenafil citrate for treatment of PAH.

Nanometric ion pair complexes of tobramycin forming microparticles for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis

Sustained pulmonary delivery of tobramycin from microparticles composed of drug/polymer nanocomplexes offers several advantages against traditional delivery methods. Namely, in patients with cystic fibrosis, microparticle delivery can protect the tobramycin being delivered from strong mucoadhesive interactions, thus avoiding effects on its diffusion toward the infection site. Polymeric ion-pair complexes were obtained starting from two synthetic polyanions, through impregnation of their solid dissociated forms with tobramycin in aqueous solution. The structure of these polymeric systems was characterized, and their activities were examined against various biofilm-forming Pseudomonas aeruginosa. Once dried, the nanocomplexes can change their aggregation state, to form microparticle-based aggregates with a spherical shape and a micrometer size. In aqueous dispersions, the ion-pair complexes produced had nanometric size, negative ζ potential, and high biocompatibility toward human bronchial epithelium cells. The antibiofilm activity of these formulations was more efficient than for free tobramycin, with the antibiofilm activity against P. aeruginosa mucoid and nonmucoid end-stage strains isolated from cystic fibrosis lungs being of particular relevance.

Methods of Fabrication of Chitosan-Based Nano-in-Microparticles (NMPs).

Chitosan nano-in-microparticles (NMPs) are promising carrier systems that have gained recently more interest aiming to combine advantages of both the nano- and microsystems. They have been employed for various purposes including sustained pulmonary delivery of drugs and pulmonary delivery of peptides, proteins, or genes or as injectable scaffolds for simultaneous delivery of stem cells and supporting growth factors. Among these delivery systems, chitosan was a common ingredient due to its biocompatibility, biodegradability, and ability to sustain the release of drugs and improving their bioavailability. Here we introduce a method for the development of chitosan self-assembly nanoparticles and the incorporation of these nanoparticles into chitosan microparticles via spray drying.

From the printer to the lungs: Inkjet-printed aerogel particles for pulmonary delivery

Inkjet printing is as an emerging technique in the biomedical field offering cost-effective solutions for flexible production and the engineering of personalized medicine solutions. Thermal inkjet printing technology in the “drop on demand” mode allows the design of fully automated deposition patterns with high spatial resolution for applications ranging from microparticles in drug formulations to cell deposition in regenerative medicine. In particular, novel formulations in the form of porous particles are sought for the treatment of respiratory disorders and the systemic administration of bioactive compounds using the pulmonary route. Aerogel particles, i.e. highly porous and light-weight nanoporous powders, are particularly promising as carriers for the pulmonary route. In this work, the preparation of aerogel microspheres by thermal inkjet printing followed by supercritical drying is presented for the first time to overcome the current processing limitations. Alginate aerogel particles were loaded with salbutamol sulphate, a bronchodilator used for the treatment of asthma attacks and chronic obstructive pulmonary disease, as a model drug for sustained pulmonary delivery. The optimized processing method allowed the preparation of reproducible nanostructured microparticles with modified salbutamol sulphate release profile and aerodynamic performance of relevance for oral inhalation purposes.

Curcumin Acetate Nanocrystals for sustained Pulmonary Delivery: Preparation, Characterization and In Vivo Evaluation.

The main objective of this study was to test the hypothesis that inhaled nanocrystals of a highly lipophilic drug could be used as a novel approach for producing sustained pulmonary delivery. Curcumin acetate, an ester prodrug of curcumin, was utilized as a highly lipophilic model drug. Curcumin acetate was subjected to wet ball milling to produce different particle sizes of nanocrystals and microparticles, and the milled curcumin acetate was spray-dried to yield similar inhalable microparticles. Following intrapulmonary administration in rats, pharmacokinetic experiments indicated that curcumin acetate significantly extended the pulmonary absorption time by 7.2-fold compared to curcumin, possibly due to the high lipophilicity of the former. The biodistribution data showed that aerosolized curcumin acetate nanocrystals 123.7 nm in size not only prolonged pulmonary retention, with the AUC value of curcumin acetate being 7.62-fold higher than that of the microparticles 1120 nm in size, but also increased the local in vivo release rate by 3.3-fold and the local availability of converted curcumin by 25.1-fold. In addition, the improved local availability resulted in better pharmacological efficacy in a monocrotaline-induced rat model of pulmonary arterial hypertension. This study was the first to demonstrate that inhalable nanocrystals are a feasible means for the sustained pulmonary delivery of highly lipophilic drugs.

Respirable controlled release polymeric colloid (RCRPC) of bosentan for the management of pulmonary hypertension: in vitro aerosolization, histological examination and in vivo pulmonary absorption

Bosentan is an endothelin receptor antagonist (ERA) prescribed for patients with pulmonary arterial hypertension (PAH). The oral delivery of bosentan possesses several drawbacks such as low bioavailability (about 50%), short duration of action, frequent administration, hepatotoxicity and systemic hypotension. The pulmonary administration would circumvent the pre-systemic metabolism thus improving the bioavailability and avoids the systemic adverse effects of oral bosentan. However, the short duration of action and the frequent administration are the major drawbacks of inhalation therapy. Thus, the aim of this work is to explore the potential of respirable controlled release polymeric colloid (RCRPC) for effective, safe and sustained pulmonary delivery of bosentan. Central composite design was adopted to study the influence of formulation and process variables on nanoparticles properties. The particle size, polydispersity index (PDI), entrapment efficiency (EE) and in vitro bosentan released were selected as dependent variables. The optimized RCRPC showed particle size of 420 nm, PDI of 0.39, EE of 60.5% and sustained release pattern where only 31.0% was released after 16 h. The in vitro nebulization of RCRPC indicated that PLGA nanoparticles could be incorporated into respirable nebulized droplets better than drug solution. Pharmacokinetics and histopathological examination were determined after intratracheal administration of the developed RCRPC to male albino rats compared to the oral bosentan suspension. Results revealed the great improvement of bioavailability (12.71 folds) and sustained vasodilation effect on the pulmonary blood vessels (more than 12 h). Bosentan-loaded RCRPC administered via the pulmonary route may therefore constitute an advance in the management of PAH.

Nanocrystals embedded in chitosan-based respirable swellable microparticles as dry powder for sustained pulmonary drug delivery

In this study, nanocrystals embedded in microparticles were designed to achieve sustained pulmonary drug delivery of hydrophobic drugs. Chitosan based microparticles were engineered to allow sustained drug release via swelling and mucoadhesive properties of the polymer. Taking cinaciguat as a hydrophobic model drug, drug nanocrystals were prepared by high pressure homogenization and then encapsulated in chitosan microparticles via spray drying. Through various in vitro characterizations, it was shown that drug loaded microparticles had a high drug loading with promising aerosolization characteristics (mean volume diameter (Dv50) 3–4μm, experimental mass mean aerodynamic diameter (MMADe) 4–4.5μm, fine particle fraction (FPF%) 40–45%, emitted dose (ED%) 94–95%). The microparticles showed high swelling capacity within 5min, with various sustained drug release rates depending on chitosan concentration and molecular weight. Furthermore, aerosolization performances under various inhalation conditions were investigated. It was found that both inspiratory flow rate and volume had an influence on the aerosolization of developed microparticles, indicating actual inhalation efficiency might be compromised under disease conditions. Taken together, in vitro data indicate that chitosan based swellable microparticles could potentially be useful as nanocrystal carrier to achieve sustained pulmonary delivery. To complete the feasibility assessment of this formulation principle, future in vivo safety and efficacy studies are needed.

Solid lipid nanoparticles for sustained pulmonary delivery of Yuxingcao essential oil: Preparation, characterization and in vivo evaluation

The objective of this study was to prepare solid lipid nanoparticles (SLNs) for sustained pulmonary delivery of Yuxingcao essential oil (YEO). Three YEO loaded SLNs (SLN-200, SLN-400 and SLN-800) with different particle size were prepared and separated following a high-shear homogenization technique using Compritol 888 ATO as lipid and polyvinyl alcohol as an emulsifier. The particle size, zeta potential, drug encapsulation efficiency and drug loading of the SLNs were determined to be between 171 and 812nm, −17.1 and −19.3mV, between 76.6 and 90.2% and between 2.34 and 3.12%, respectively whereas the in vitro release data showed that the SLNs led to sustained drug release up to 48h. In addition, the SLN suspensions after nebulization conferred the fine particle fractions (<5.4μm) of 67.4–75.8%. Following intratracheal administration to rats, YEO loaded SLNs not only prolonged pulmonary retention up to 24h, but also increased AUC values (15.4, 18.2 and 26.3μg/gh for SLN-200, SLN-400 and SLN-800, respectively) by 4.5-7.7 folds compared to the intratracheally dosed YEO solution and by 257–438 folds to the intravenously dosed YEO solution, respectively. The present results were the first to show that YEO loaded SLNs may sustain YEO inhalation delivery and improve local bioavailability, representing a promising inhalable carrier to attain once daily application.

Development of a nano–micro carrier system for sustained pulmonary delivery of clarithromycin

Abstract To overcome the limitations of nanoparticles for respiratory drug delivery, we prepared nano-composites containing micro-particles as drug carriers for targeting the lungs. The aim of present study was preparation of Clarithromycin (CLM) loaded poly Lactide-co-Glycolide (PLGA) nanoparticles (NPs) and evaluation of aerodynamic behavior of co-spray dried NPs with different carriers. Mannitol and lactose were employed as dry powder carriers for inhalation and the effects of l -leucine as a third component for increasing the yield and fine particle fraction (FPF) of powders were investigated. PLGA was employed as a GRAS (Generally Regarded As Safe) polymer and the NPs were prepared by emulsification solvent evaporation technique in different conditions. We assessed physicochemical characteristics of the NPs in terms of particles' size, poly dispersity index (PDI), entrapment efficiency, drug loading, release profile, thermal behavior, morphology and aerodynamic performance. Particle size of NPs was between 78 and 347 nm and drug loading of NPs varied from 0.08% to 7.44% in different formulations. Thermal analysis demonstrated the merging of drug into the polymer matrix and drug release profiles appeared to consist of two phases with an initial rapid release followed by a slower exponential stage. After co-spray drying of NPs with sugar based carriers, spherical particles with size range of 5.3 to 8.9 μm were harvested. The presence of l -leucine in formulations resulted in significant increase of yield as well as FPF of particles.