Zhengwei Huang

Nanoporous mannitol carrier prepared by non-organic solvent spray drying technique to enhance the aerosolization performance for dry powder inhalation

An optimum carrier rugosity is essential to achieve a satisfying drug deposition efficiency for the carrier based dry powder inhalation (DPI). Therefore, a non-organic spray drying technique was firstly used to prepare nanoporous mannitol with small asperities to enhance the DPI aerosolization performance. Ammonium carbonate was used as a pore-forming agent since it decomposed with volatile during preparation. It was found that only the porous structure, and hence the specific surface area and carrier density were changed at different ammonium carbonate concentration. Furthermore, the carrier density was used as an indication of porosity to correlate with drug aerosolization. A good correlation between the carrier density and fine particle fraction (FPF) (r2 = 0.9579) was established, suggesting that the deposition efficiency increased with the decreased carrier density. Nanoporous mannitol with a mean pore size of about 6 nm exhibited 0.24-fold carrier density while 2.16-fold FPF value of the non-porous mannitol. The enhanced deposition efficiency was further confirmed from the pharmacokinetic studies since the nanoporous mannitol exhibited a significantly higher AUC0-8h value than the non-porous mannitol and commercial product Pulmicort. Therefore, surface modification by preparing nanoporous carrier through non-organic spray drying showed to be a facile approach to enhance the DPI aerosolization performance.

Improved Gene Transfer with Functionalized Hollow Mesoporous Silica Nanoparticles of Reduced Cytotoxicity

Gene therapy is a promising strategy for treatment of genetically caused diseases. Successful gene delivery requires an efficient carrier to transfer the desired gene into host cells. Recently, mesoporous silica nanoparticles (MSNs) functionalized with 25 kD polyethyleneimine (PEI) were extensively used as gene delivery carriers. However, 25 kD PEI could significantly reduce the safety of the modified MSNs although it is efficient for intracellular delivery of nucleic acids. In addition, limited drug loading remains a challenge for conventional MSNs drug carriers. Hollow mesoporous silica nanoparticles (HMSNs) with high pore volume, tunable pore size, and excellent biocompatibility are attractive alternatives. To make them more efficient, a less toxic 1.8 kD PEI polymer was used to functionalize the HMSNs which have large pore size (~10 nm) and form PEI-HMSNs. Scanning and transmission electron microscopic images showed that HMSNs were spherical in shape and approximately 270 nm in diameter with uniform hollow nanostructures. The maximum loading capacity of green fluorescent protein labeled DNA (GFP-DNA) in PEI-HMSNs was found to be 37.98 mg/g. The loading capacity of PEI-HMSNs was nearly three-fold higher than those of PEI modified solid nanoparticles, indicating that both hollow and large pores contributed to the increase in DNA adsorption. The transfection of GFP-DNA plasmid loaded in PEI-HMSNs was increased two-fold in comparison to that of 25 kD PEI. MTT assays in Lovo cells showed that the cell viability was more than 85% when the concentration of PEI-HMSNs was 120 µg/mL, whereas the cell viability was less than 20% when the 25 kD PEI was used at the same concentration. These results indicated that PEI-HMSNs could be used as a delivery system for nucleic acids due to good biocompatibility, high gene loading capacity, and enhanced gene transfer efficiency.

Low density, good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement

ABSTRACT Background: The hygroscopicity of raffinose carrier for dry powder inhaler (DPI) was the main obstacle for its further application. Hygroscopicity-induced agglomeration would cause deterioration of aerosolization performance of raffinose, undermining the delivery efficiency. Methods: Cyclodextrin-raffinose binary carriers (CRBCs) were produced by spray-drying so as to surmount the above issue. Physicochemical attributes and formation mechanism of CRBCs were explored in detail. The flow property of CRBCs was examined by FT4 Powder Rheometer. Hygroscopicity of CRBCs was elucidated by dynamic vapor sorption study. Aerosolization performance was evaluated by in vitro deposition profile and in vivo pharmacokinetic profile of CRBC based DPI formulations. Results: The optimal formulation of CRBC (R4) was proven to possess anti-hygroscopicity and aerosolization performance enhancement properties. Concisely, the moisture uptake of R4 was c.a. 5% which was far lower than spray-dried raffinose (R0, c.a. 65%). R4 exhibited a high fine particle fraction value of 70.56 ± 0.61% and it was 3.75-fold against R0. The pulmonary and plasmatic bioavailability of R4 were significantly higher than R0 (p < 0.05). Conclusion: CRBC with anti-hygroscopicity and aerosolization performance enhancement properties was a promising approach for pulmonary drug delivery, which could provide new possibilities to the application of hygroscopic carriers for DPI.

Anhydrous reverse micelle nanoparticles: new strategy to overcome sedimentation instability of peptide-containing pressurized metered-dose inhalers

Abstract The objective of this study was to develop a novel anhydrous reverse micelle nanoparticles (ARM-NPs) system to overcome the sedimentation instability of peptide-containing pressurized metered-dose inhalers (pMDIs). A bottom-up method was utilized to fabricate ARM-NPs. Tertiary butyl alcohol (TBA)/water system, freeze-drying and lipid inversion method were successively used to produce the ARM-NPs for pMDI. Various characteristics of ARM-NPs were investigated including particle size, morphology, secondary structure of the peptide drug, aerosolization properties and storage stability. As revealed by the results, ARM-NPs with spherical shape possessed 147.7 ± 2.0 nm of particle size with 0.152 ± 0.021 PdI. The ARM-NPs for pMDI had satisfactory fine particle fraction (FPF) value of 46.99 ± 1.33%, while the secondary structure of the peptide drug was unchanged. Stability tests showed no pronounced sedimentation instability for over 12 weeks at 4–6 °C. Furthermore, a hypothesis was raised to explain the formation mechanism of ARM-NPs, which was verified by the differential scanning calorimetry analysis. The lecithin employed in the reverse micelle vesicles could serve as a steric barrier between peptide drugs and bulk propellant, which prevented the instability of peptide drugs in hydrophobic environment. Homogenous particle size could avoid Ostwald ripening phenomenon of particles in pMDIs. It was concluded that the ARM-NPs for pMDI could successfully overcome sedimentation instability by the steric barrier effect and homogeneous particle size.

An Endotracheal Aerosolization Device for Laboratory Investigation of Pulmonary Delivery of Nanoparticle Suspensions: in vitro and in vivo Validation

The objective of this study was to perform the in vitro and in vivo validation of an endotracheal aerosolization (ETA) device (HRH MAG-4, HM). Solid lipid nanoparticle suspension (SLNS) formulations with particle sizes of approximately 120, 240, 360, and 480 nm were selected as model nanoparticle suspensions for the validation. The emission rate (ER) of the in vitro aerosolization and the influence of aerosolization on the physicochemical properties were investigated. A high ER of up to 90% was obtained, and no significant alterations in physicochemical properties were observed after the aerosolization. The pulmonary deposition of model drug budesonide in Sprague-Dawley rats was determined to be approximately 80%, which was satisfactory for pulmonary delivery. Additionally, a fluorescent probe with aggregation-caused quenching property was encapsulated in SLNS formulations for in vivo bioimaging, after excluding the effect of aerosolization on its fluorescence spectrum. It was verified that SLNS formulations were deposited in the lung region. The results demonstrated the feasibility and reliability of the HM device for ETA in laboratory investigation.

Thermo-sensitive gel in glaucoma therapy for enhanced bioavailability: In vitro characterization, in vivo pharmacokinetics and pharmacodynamics study

Aims: Glaucoma is a chronic ophthalmic disease, which has become one of the leading causes to progressive and irreversible blindness. Current ophthalmic drug delivery to treat glaucoma is mostly eyedrop, whose rapid elimination on corneal surface can lead to poor bioavailability. The present study was aimed to develop a timolol maleate loaded thermo‐sensitive gel (TM‐TSG) with improved bioavailability to treat glaucoma. Main methods: TM‐TSG was prepared by homogeneously dispersing 0.3% (w/v) timolol maleate, 24.25% (w/v) poloxamer 407 (P407) and 1.56% (w/v) poloxamer 188 (P188) into phosphate buffer solution (pH=7.4) and the formulated TM‐TSG was characterized. Key findings: TM‐TSG was stored in liquid form at room temperature (25°C) and transited to semisolid gel at physiological temperature (32°C). The rheological property of TM‐TSG was in favor of uniform distribution of drug. TM‐TSG showed good stability at different conditions including centrifugation, autoclaving and different temperature. In vivo pharmacokinetic studies indicated that TM‐TSG could enhance absorption of TM in aqueous humor and improve the ocular bioavailability in comparison of commercial TM eyedrops. In vivo experiment result showed that TM‐TSG had greater effect in treating glaucoma than TM eyedrops by sustainably lowering intraocular pressure (IOP) for a week. Moreover, slit lamp test and histopathological analysis demonstrated that TM‐TSG had excellent biocompatibility. Significance: TM‐TSG could be a promising ophthalmic delivery system for glaucoma therapy. HIGHLIGHTSThe liquid‐solid phase transition of thermo‐sensitive gel facilitates administration and prolongs the drug retention time.Enhanced bioavailability is achieved by the prolonged retention and drug release compared with TM commercial eyedrops.