Ambroxol Hydrochloride Dry Powder Inhaler Research

Inhalation therapy dates from several centuries b.c, which was applied after the first sprayer was invented in the early nineteenth century. Inhalation therapy did not catch on quickly until Medihaler and Dry Powder Inhalations (DPIs) were invented at the end of 20th century. It was admitted that inhalation therapy was one of four new drug deliveries in the preparation world of tomorrow.Ambroxol Hydrochloride (AH) is a pharmacologically active metabolite of bromhexine and is used as an expectorant which is more effective than bromhexine. AH was used to be the model drug in this study; the prescription of AH dry powder for inhalation was investigated systematically, the physicochemical properties of the powder were evaluated, and the pharmacokinetic of this preparation in rats was studied. DPIs were prepared in order to explore the possibility of increasing the curative effect, decreasing the side effect and enlarging the clinical serviceable range by formulation design.HPLC method was developed for the assay of AH in vitro. The stability, specificity and reproducibility of the method were good. The solubility of AH in different pH was determined. The solubility of AH is different in different pH, increasing as pH increases.Two types of evaluation index, including typical physicochemical properties of dry powders for inhalations (such as solubility, hygroscopicity, moisture content, morphology, particle size and distribution, density, compressibility, and angle of repose), and evaluation index on in-vitro deposition (such as deposition property in-vitro and empting ratio), were set to evaluate AH DPI.Spray-drying method was applied to prepare AH dry powders, emphasizing the research on formulations and procedure. The influence of ingredients including carbohydrate and amino acids on the physiochemical property of the AH dry powders was investigated. After the studying the category and dosage of ingredients, the formulation was set by the RSR method as follow: the ratio of AH:mannitol:L-leucine is 2.5:1:0.5. In the procedure study, based on the monofactorial investigation, the optimization of the preparation parameters was performed by using orthogonal design and Z-score method which employed four indices including powder yield, aerodynamic diameter, angle of repose and effective deposition percentage. The preparation condition was: inlet temperature: 110℃; pump speed: 1.8mL·min^-1; atomization pressure: 170KPa; air flow: 0.70m³·min^-1.The physicochemical property of AH dry powder showed that the product owned a little hygroscopicity, little poor flowability with the angle of repose 33.4±3.6°. The water content was 0.16±0.03%. Its aerodynamic diameter was about 3μm that signified the product could be fit for DPI. The solubility was consistent with correlated regulation. The results of empting ratio and effective deposition percentage demonstrated that most of the powders could be fit for DPI. Stability test showed that the product experienced no obvious change under 40±2℃, 75±5% RH for six months and 25±2℃, 60±10% RH for twelve months in respect of the external appearance, empting ratio, content and in vitro deposition property.HPLC method was developed for the assay of AH in the plasma and dialysate in vivo. The concentration of AH in the plasma and ELF was determined, respectively. The local pharmacokinetics and site-specific target efficiency of AH DPI were investigated by comparing lung epithelial lining fluid (ELF) and plasma AH levels after tracheal administration (TA) with those after intravenous administration. The pharmacokinetic model was used to describe the distribution of AH in vivo after TA. The (AUC_0-t)_ELF/ (AUC_0-tplasma ratio (1.85) after TA differed significantly from the ratio (0.034) observed after intravenous administration (P<0.05). The tendency of the predicted concentration points of AH by the pharmacokinetic model shown is identical with the concentration points of AH observed. Therefore, the parameters of the model could be acceptable, which is further confirmed by the goodness of fit metrics of the model. So it is inferred that the simulation model could be interesting. All these results indicate that AH DPI can be delivered to a specific targeted site and achieve high target efficiency in ELF.