Preparation of berberine hydrochloride dry powder inhalation and its effect on Staphylococcus aureus pneumonia / 中草药

Objective: To prepare berberine hydrochloride dry powder inhalation, and investigate its pharmacological effect on Staphylococcus aureus pneumonia after pulmonary administration. Methods: Berberine hydrochloride dry powder by spray drying and the experimental conditions was optimized by orthogonal experiment. The lung deposition, fluidity and appearance were characterized. The pharmacodynamic effects of the preparations on S. aureus pneumonia were performed with SD rats. Results: A berberine hydrochloride dry powder was prepared at an inlet temperature of 130 ℃ with a gas volume flow of 610 L/h and a feed volume flow of 3 mL/min. The berberine hydrochloride dry powder had a lung deposition rate (FPF) of 76.4% and an aerodynamic diameter of 4.61 μm. The stability index (SI) ≈ 1, the aeration energy ratio (AR) = 1.76 > 1, and the inflation energy (AE10) = 2.1 mJ < 10 mJ. Through the pharmacodynamic evaluation of S. aureus, we can know that the berberine hydrochloride dry powder inhalation effectively improved the pathological state of pneumonia rats, and significantly reduced (P < 0.05) the number of WBC, neutrophils, and the expression of inflammatory factors (TNF-α, IL-1β, and IL-6) in pneumonia rats. Conclusion: Berberine hydrochloride dry powder inhalation can directly reach the lesion site through pulmonary administration, so it has significant therapeutic effect on S. aureus pneumonia.

Formula Optimization of Rifampicin Dry Powder Inhalation with Chitosan-Xanthan Carrier Using Response Surface Methodology

This study was aimed to obtain an optimum formula of rifampicin dry powder inhalation (DPI) with chitosan-xanthan(CX) as a carrier by spray drying method using response surface methodology (RSM). Fourteen experimental formulaswere designed statistically by Box Behnken method by varying three parameters namely concentration of CX solution,rifampicin/CX ratio, and inlet temperature of the spray dryer. The entrapment efficiency (EE), particle size, and drugrelease in pH 7.4 (pulmonary condition) and pH 4.5 (pulmonary macrophages condition) of the rifampicin DPI werecharacterized. The optimum formula of rifampicin DPI was obtained using Design Expert software. The obtained DPIfrom those 14 formulas possessed EE of 112.00–149.08% and average particle sizes of 0.599–5.506 µm. Rifampicinrelease in phosphate buffer medium pH 7.4 was 6.54%–22.95% and in pH 4.5 was 12.02–48.60%. The DesignExpert predicted that the optimum formula would be obtained with a concentration of CX solution of 0.5%, a ratio ofrifampicin to CX 1:1, and inlet temperature of the spray dryer at 143°C. The optimized formula produced a rifampicinDPI with EE of 108.9%, the particle size of 1.177 µm, and the rifampicin release of 14.49% (at pH 7.4) and of 37.97%(at pH 4.5).

Preparation of resveratrol-DPPC liposomal dry powder inhalations and its antibacterial activities / 中草药

Objective To prepare the resveratrol-DPPC liposomal dry powder inhalations (RDLDPIs), and solve the problem of lower bioavailability of resveratrol after oral administration. Methods The RDLDPIs were prepared by film-dispersion and freeze drying. The formulation was optimized by orthogonal design. The particle size, entrapment efficiency, electric potential, in vitro release, and lung deposition were characterized. The broth microdilution method was used to evaluate the antibacterial activity and determine the minimal inhibitory concentration (MIC) in vitro. Results The optimized ratio of DPPC/cholesterol, resveratrol/DPPC, and mannitol/DPPC was 3:1, 1:3, and 2:1 in the prescription of RDLDPIs, respectively; And hydration time was 15 min. The entrapment efficiency of RDLDPIs was (69.8 ± 1.6)%, the drug loading was (2.4 ± 0.9)%, the particle size was (191.5 ± 4.5) nm, and the zeta potential was (12.4 ± 1.5) mV. The aerodynamic particle size of the powder was (3.2 ± 0.2) μm and the in vitro pulmonary deposition ratio was 28.1% in vitro. The antibacterial activity against Staphylococcus aureus, Acinetobacter baumannii, Streptococcus pneumoniae, and Pseudomonas aeruginosa was evaluated in vitro. The crude drug group had no antibacterial activity in four species of bacteria, while RDLDPIs had antibacterial activity of Staphylococcus aureus and Acinetobacter baumannii, and MIC was 4 mg/mL and 2 mg/mL, respectively. Conclusion The prepared RDLDPIs have small size and uniform distribution with good stability and high lung deposition rate and in vitro antibacterial activity against Staphylococcus aureus and Acinetobacter baumannii, which is expected to be an substitute for traditional antibiotics for the treatment of bacterial pneumonia.

Novel dry powder inhalation carrier:drug-carried lactose microparticles with flower shape and nanoporous structure / 药学学报

This work was designed to study a novel dry powder inhalation (DPI) carrier for drug loading and release of tiotropium bromide (asthma medicine). The synthesized lactose drug-carrier with a flower shape was crystalline. The carrier with a micro-meso-macroporous structure had advantages of high pore surface area, high capacity of drug loading and fast release of drug. In the study of loading tiotropium bromide, the drug was distributed at the core of carrier using the solution-based method, while the morphology was changed a little and the amount of loaded drug was 5% (w/w). Using the crystallization-based method, the drug was distributed at the shell of carrier, while the morphology was changed a lot and the amount of loaded drug was 49% (w/w). In addition, with the impact of carrier structure, the drug release rate was increased first and then decreased thereafter using the solution-based method, while the drug release rate was decreased first and then increased thereafter using the crystallization-based method. Thus, the lactose microparticles can be used as a novel drug carrier for dry powder inhalation.

Preparation of dry powder inhalation of yuanhuacine and its tissue distribution in rats / 中国药科大学学报

The aim of the present study was to increase distribution of yuanhuacine in the lungs and achieve the purpose of reducing toxicity and increasing efficiency.Therefore,yuanhuacine was designed to be dry powder inhalers innovatively and directly delivered to the lungs.Accordingly,inhaled lactose was used as a carrier to adsorb yuanhuacine on the surface of lactose.Fine particle fraction (FPF) was utilized as evaluation index to filtrate the optimal prescription for pulmonary administration.Besides,an UHPLC-MS/MS method was established for the analysis of heart,liver,spleen,lung,kidney,brain and reproductive system of rats.Intravenous injection was taken as reference to investigate the distribution of yuanhuacine and calculate relevant targeting parameters.The experimental result indicated that the prescription (rough lactose ∶fine lactose =10 ∶ 1) has the highest FPF,which can be chosen as the most suitable prescription for pulmonary administration of yuanhuacine.Moreover,by comparing the distribution of yuanhuacine through pulmonary administration and intravenous injection,it was found that the concentration of yuanhuacine in the lung tissue was greatly increased by pulmonary administration,which decreased the distribution in heart,liver,spleen,kidney,brain and reproductive system,thus sequentially reducing the toxicity in other tissues and increased the efficiency.

Inhalable oridonin-loaded poly(lactic--glycolic)acid large porous microparticles fortreatment of primary non-small cell lung cancer

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. Traditional chemotherapy for this disease leads to serious side effects. Here we prepared an inhalable oridonin-loaded poly(lactic--glycolic)acid (PLGA) large porous microparticle (LPMP) fortreatment of NSCLC with the emulsion/solvent evaporation/freeze-drying method. The LPMPs were smooth spheres with many internal pores. Despite a geometric diameter of ~10 µm, the aerodynamic diameter of the spheres was only 2.72 µm, leading to highly efficient lung deposition.studies showed that most of oridonin was released after 1 h, whereas the alveolar macrophage uptake of LPMPs occurred after 8 h, so that most of oridonin would enter the surroundings without undergoing phagocytosis. Rat primary NSCLC models were built and administered with saline, oridonin powder, gemcitabine, and oridonin-loaded LPMPsairway, respectively. The LPMPs showed strong anticancer effects. Oridonin showed strong angiogenesis inhibition and apoptosis. Relevant mechanisms are thought to include oridonin-induced mitochondrial dysfunction accompanied by low mitochondrial membrane potentials, downregulation of BCL-2 expressions, upregulation of expressions of BAX, caspase-3 and caspase-9. The oridonin-loaded PLGA LPMPs showed high anti-NSCLC effects after pulmonary delivery. In conclusion, LPMPs are promising dry powder inhalations fortreatment of lung cancer.

Simulation and validation of computational fluid dynamics used for selected inhalation device of Rehmanniae Radix oligosaccharide dry powder inhalation / 中草药

Objective: To simulate the kinematics of drug particles in two kinds of dry powder inhalation devices for Rehmanniae Radix oligosaccharide dry powder inhalation (RRODPI) by computational fluid dynamics (CFD), and to compare simulation results with the in vitro deposition results in order to verify the accuracy of the results. Methods: NGI was used to carry out in vitro deposition experiments, and the relative experiment data were obtained. UGNX 10.0 software was adopted to establish three-dimensional models of two kinds of dry powder inhalation devices according to their actual sizes, and then the models were imported into ICEM CFD software to divide mesh. After checking mesh quality, mesh was imported to Fluent software and the related parameters were set. When the data was in steady state after iteration and convergence, the data analysis was carried out; Finally the kinematics results of drug particles at three kinds of particle sizes in two kinds of dry powder inhalation devices were gained. The kinematics results were compared with the in vitro deposition results to verify the simulation results. Results: In vitro deposition experiment results showed that the effective deposition rate in twister was higher than that in osmohaler. CFD results showed that drug particles at different sizes in twister could all reach the outlet but for drug particles in osmohaler, it could not reach the outlet at a certain range of sizes. The two results showed that twister was more suitable for the dry powder inhaler device of RRODPI. Conclusion: It is comparatively intuitive to use CFD to carry out the kinematics simulation of drug particles in two kinds of dry powder inhalation devices and the result is consistent with the in vitro deposition experiment results, which can well predict the motion state of drug particles in the two dry powder inhalation devices.

Optimization for preparation process of fanhuncaoin dry powder for inhalation / 中国药学杂志

OBJECTIVE: To optimize the preparation process conditions of fanhuncaoin dry powder for inhalation by orthogonal design. METHODS: Fanhuncaoin dry powder was prepared by spray-drying method. Following spray-drying, particle size analysis was performed by laser diffraction. Resultant powders were characterized using scanning electron microscopy. The aerosolisation performance was determined using twin-stage liquid impinger. And moisture content was examined by thermogravimetric analysis. The preparation process conditions were optimized with orthogonal design combined with multi-index test. The powder yield, aerodynamic diameter, moisture content and respirable fraction were used as indices for orthogonal design. RESULTS: The results of optimized process parameters were confirmed with atomization pressure of 210 kPa, feed flow rate of 9.1 mL·min-1, aspiration speed of 0.6 m3·min-1 and inlet temperature of 130℃. As a result, 51.19% yield, 2.92 μm aerodynamic diameter, 4.18% moisture content and 54.45% respirable fraction are obtained by the optimal process conditions. CONCLUSION: Orthogonal design combined with multi-index test can be used to optimize the preparation process of fanhuncaoin dry powder for inhalation.

Preparation of dry powder inhalation based on phytosomes-chitosan microspheres by spray-drying method and study on its characterization / 中草药

Objective: To prepare a dry powder inhalation based on phytosomes-chitosan microspheres and to investigate the possibility for pulmonary delivery. Methods: Curcumin was selected to be model drug. The curcumin-phytosomes loaded chitosan microspheres (Cur-PS-CMs) were prepared by spray-drying method. The technology was optimized using drug loading, angle of repose, moisture uptake, theoretical aerodynamic diameter, and aerodynamic behavior in vitro as evaluation indexes. The optimized Cur-PS-CMs were characterized by SEM, DSC, and X-ray diffraction. Results: The drug loading of optimized Cur-PS-CMs was (11.79 ± 0.82)%, and the theoretical aerodynamic diameter was (3.93 ± 0.53) μm. The fine particle fraction and emitted dose were (59.36 ± 5.17)% and (98.55 ± 0.60)%, respectively. The humidity uptake was less than 10% but the powder flowability was poor. SEM showed that Cur-PS-CMs were spherical with smooth surface. DSC and X-ray diffraction verified that Cur was not released from PS in CMs. Conclusion: The PS-CMs prepared by spray-drying method may have a potential to be used as a dry powder inhalation for pulmonary delivery.

Physicochemical property and stability of zanamivir dry powder inhalation / 中国药学杂志

OBJECTIVE: To study the physicochemical property and stability of zanamivir dry powder inhalation (ZDI). METHODS: ZDI was prepared by spray-drying method. The hygroscopicity, relative humidity, particle size, powder morphology, emptying rate and deposition rate of the inhalation were determined. Water contents were analyzed by TGA. The stability of ZDI was determined by accelerated test and long-term test. RESULTS: The resultant powder inhalation exhibited the following properties: critical relative humidity was 67%, and average aerodynamic diameter dae was 90%, and deposition rate was >30% for thress batches of samples; the accelerated test and the long-term test indicated that zanamivir dry powder inhalation was stable. CONCLUSION: Zanamivir dry powder inhalation is stable and suitable for drug delivery.

The formulation factors of influencing the aerosolizing and deposition properties of dry powder inhalation / 国际药学研究杂志

Recently, dry powder inhalation (DPI) has become a hotspot in the research area of pulmonary drug delivery (PDD). With the development of drug micronization technology and the emergence of innovative inhaler device, DPI has now been widely applied. This article introduces the formulation composition of DPI, which consists of micronized drug particles, carrier and inhaler device, and the formulation factors of influencing the aerosolizing and deposition properties are emphatically reviewed.

Investigation on pharmacokinetics and bioavailabiUty of insulin dry powder inhalation / 中华内分泌代谢杂志

Objective To study the characteristics of pharmacokinetics and pharmacodynamics of insulin dry powder inhalation and its relative bioavailability as compared with subcutaneous injection of regular insulin. Methods In this open,single-center,randomized,two-period,cross-over,euglycemic glucose clamp study,18 healthy volunteers(14 men and 4 women),aged(24.9?1.7)years,with body mass index(20.6?1.2)kg/m~2, received the insulin dry powder inhalatin(80 U)or regular insulin(15 U)subcutaneous administration.The blood samples of this study at 0,20,30,40,50,60,70,80,90,100,110,120,135,150,165,180,195, 210,225,240,270,300,330,360,390,420,450 and 480 rain were taken for serum insulin measurement, meanwhile,glucose infusion rates(GIR)were determined per 5 minutes over a period of 8 hours.Results The C_(max)were(57.9?17.8 vs 114.5?29.7)mU/L(tested vs reference preparation),T_(max)were(46.7?45.6 vs 107.8?33.7)min,GIR_(max)were(3.35?0.98 vs 5.17?1.75)mg?kg~(-1)?min~(-1)and T_(GIRmax)were(88.3?17.0 vs 151.9?34.6)min.The relative bioavailability was(10.26?2.25)%,and the relative bioefficacy was(14.33?7.26)%.Conclusion The study shows that insulin dry powder inhalation is absorbed via lungs and its action sets in earlier than that of the regular insulin injected subcutaneously.These pharmacokinetie and pharmacodynamic data may provide a reliabe guide for further clinical trial.