Optimization and Application of an Efficient and Stable Inhalation Exposure System for Rodents.

Inhalation is a promising and challenging method in pharmaceutical and biological science research. A stable environment is critical in dynamic inhalation administration. However, the establishment of a stable inhalation system is very challenging. Indacaterol glycopyrronium bromide inhalation powder (IM/GP mixed powder) is composed of indacaterol maleate and glycopyrronium bromide powder to treat chronic obstructive pulmonary disease (COPD). The aim of this study is to build suitable inhalation conditions and then to evaluate the pulmonary safety of this drug in Sprague-Dawley(SD) rats. In the research, through the coordination of the atomization flow, air pump flow, and scraper speed, aerosols were stabilized at 200 ± 20% mg/m3, and then rats were nose-only administered with the IM/GP mixed powder, Ultibro, and lactose-magnesium stearate mixed powder at 2.6 mg/kg/day for 14 days and 14 days of recovery period, respectively. After exposure, hematology, inflammatory cytokines in rats bronchoalveolar lavage fluid (BALF) and serum, histopathological examination were performed. Results showed that the stability of powder aerosols can be realized under the atomization generation flow: 10 L/min, sampling flow: 2 L/min, system pumping capacity: 10 L/min and powder scraper speed: 8-10 L/min, and there were no significant adverse effects on body weight, clinic signs, hematology, and pathology in rats. Overall, the results suggested that the IM/GP mixed powder inhalation at the dose of 2.6 mg/kg/d can be reached when the aerosol concentration is within the range of 200 ± 20% mg/m3, and there were no pulmonary toxicity effects in rats.

Exploring the influence of drug content on DPI powder properties and potential prediction of pulmonary drug deposition.

Based on dry powder inhaler (DPI) inhalation process, powder properties have a key influence on fluidization and deagglomeration behavior during aerosol generation. The aim of this study was to explore the influence of drug content on DPI powder properties and further reveal the correlations between powder properties and pulmonary deposition efficiency. Using salbutamol sulfate as a model drug, Lactohale® 100 as carrier, carrier-based binary mixtures were prepared at drug content from 0.5 to 10% (w/w), characterized with powder rheometer, faraday cage and Next Generation Impactor. It was demonstrated that drug content had a remarkable influence on powder behavior, and good correlations between powder properties and fine particle fraction (FPF) were established in drug content range 0.5-7%. A negative correlation between basic flowability energy and FPF, reflected a good flowability is beneficial for powder fluidization. Further properties characterization, including aeration ratio, permeability, pre-shear stress and aerodynamic specific charge, suggested a strong interaction is beneficial for powder deagglomeration. It's the first time that interaction indicator and flowability indicator were extracted with principal component analysis (PCA). In conclusion, drug content has a significant influence on powder properties. DPI formulations with a stronger interaction and meanwhile a better flowability are desirable for enhanced pulmonary drug delivery.

Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective κ opioid receptor agonists.

A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a-maj-3u were synthesized and evaluated in vitro for their binding affinity at κ-opioid receptors. Maj-3c displayed the highest affinity for κ-opioid receptors (Ki = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent (Ki = 0.0059 nM) κ-opioid receptor agonist among the four stereoisomers. Maj-3c produced significant antinociception (ED50 = 0.000406 mg kg(-1)) compared to U-50,488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED50 = 0.000568 mg kg(-1)) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent κ-opioid receptor agonist (Ki = 35.13 nM). More importantly, the dose for the sedative effect (ED50 = 9.29 mg kg(-1)) of maj-11a was significantly higher than its analgesic dose (ED50 = 0.392 mg kg(-1)), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.

[Technology study on extraction and purification of alkaloid from Stemona japonica].

OBJECTIVE: In order to obtain the optimal conditions for separating the alkaloids from the extract of Stemona japonica by selecting appropriate cation exchange resins. METHODS: Seven types of cation exchange resins were evaluated in separating efficiency with measuring the adsorption ratio and eluting ratio of total alkaloids as indices, and the content of total alkaloids from Stemona japonica was determined as an index by spectrophotometry to choose the optimal technological parameters. RESULTS: The optimal result of extraction was obtained as Stemona japonica shattered into thick powder, adding eight times amount of 90% alcohol and refluxing and extracting for 3 h (totally extracting for 3 times). Each gram of D004 cation exchange resin could absorb 0.5003 mg of the total alkaloid, and the desorption ratio was 68.45%. The transfer rate of total alkaloids was 58.70%. the product purity of alkaloids was up to 70%. CONCLUSION: The D004 cation exchange resin can be used for purificating total alkaloids from Stemona japonica and the established procedure is simple and feasible.

Pharmacokinetics of forsythoside after intravenous administration in beagle dogs.

A high-performance liquid chromatography with ultraviolet detection method was established and validated for quantification of forsythoside concentrations in dog plasma. Following a single-step protein precipitation with perchloric acid, the forsythoside and internal standard were separated on a reversed-phase C18 column with water-glacial acetic acid-methanol as mobile phase at a flow rate of 1 mL/min with ultraviolet detection at 326 and 278 nm for forsythoside and IS, respectively. The calibration curve for forsythoside was linear over a range of 0.052-13.33 microg/mL with correlation coefficient of 0.999. The within- and between-batch precisions of analysis were < 8 % and accuracy was 95-107%. After intravenous administration of forsythoside at the doses of 5, 10, and 20 mg/kg, the C(max) values for forsythoside were estimated to be of 12.33, 22.90 and 54.45 microg/mL, respectively. The AUC increased with the increasing of doses, and the mean AUC(o-t) values were 5.69, 11.80, and 18.66 mg x h/L, respectively. Forsythoside was eliminated quickly and the mean T(1/2) values at doses of 5, 10, and 20 mg/kg were 1.36, 1.49, and 0.71 h, respectively. The pharmacokinetics of forsythoside in beagle dogs complied with linear kinetic course in the dose range.