Study On The Lung Targeting Dexamethasone Acetate Lipid Nanoparticle Lyophilized Injection

Glucocorticoid is the first choice for curing the idiopathic interstitial pneumonia. In addition, it is often used to cure such pulmonary diseases as acute lung injury, acute respiratory distress syndrome, pulmonary contusion, and pulmonary fibrosis. It is also one of major measures for treatment of infective atypical pneumonia. However, Glucocorticoid may lead to a series of systemic side effects, e.g. infection, bleeding, hyperglycemia, and ulcer. Long-term use of ultra-large dosage of glucocorticoid may cause serious adverse reactions, including osteonecrosis, double infection, diabetes, and psychological block of suicide, to patients. Due to the systemic side effects and serious adverse reactions, the clinical application of glucocorticoid is restricted. Dexamethasone acetate(DXM) is a kind of synthetic glucocorticoid, which has a strong anti-inflammatory ability. Clinically, it is often used to cure serious inflammation, pulmonary fibrosis, bronchial asthma, and dyspnea, etc. Since it has a weaker water solubility but a stronger liposolubility, it is suitable to be made into solid lipid nanoparticle preparations.Solid lipid nanoparticle is a kind of drug carrier to which people attach much attention in recent years. It can control the release of drug and change the in vivo biodistribution of drug. It is also a suitable carrier for targeting drug delivery system including lung-targeting, brain-targeting et al. At the same time, such carrier can decrease the toxicity and increase the therapeutic effect of the drug. Also it can be made on the basis of industrialized production by using the high pressure homogenization method.In this study, the DXM solid lipid nanoparticles(DXM-SLN) were made by adopting film evaporating & high pressure homogenization method, with DXM as model drug. With particle size and span as index, a single-factor experiment was used to investigate the effect of category and dosage of surfactants, homogenization pressure & temperature, proportion between drug and phosphatide, and tristearin content on the preparation of lipid nanoparticles. Based on the single-factor experiment, a Central Composite Design was adopted to optimize the prescription. According to the optimized DXM-SLN formulation, DXM-SLN was prepared, resulting in a particle size of 172nm,drug-loading of 8.82% and entrapment ratio of 92.87%. The measured value is only a little different from the estimated value. Moreover, all indices of dexamethasone acetate lipid nanoparticle prepared through prescription optimization were satisfactory. This proves that the optimization is successful.In order to better preserve lipid nanoparticle colloidal solutions, the prescriptions for lyophilized injection were well selected in this study. The DXM-SLN lyophilized powder was prepared , resulting in a particle size of 340nm, drug-loading of 7.10%, entrapment ratio of 92.10% and zeta potential of -25.2mV. Preliminary stability experiments had proved that the lyophilized injection prepared in accordance with the prescription selected had stable properties.In-vzvo release of lyophilized injection showed that it fitted for the Pepas equation.The results of in-vivo biodistribution study demonstrated that DXM-SLN were uptaken mainly by lung after i.v administration to mice. The AUC is 17 times larger than that free drug. The relative distribution efficiency (R_Te) of lung is 5.20 and that of liver is 0.02. For the rest of visceral organs, their relative distribution efficiency is a negative value. By comparison, visceral organs stand in this sequence with regard to the value of targeting efficiency ( r_e) : lung > liver > heart > kidney > spleen > blood. In regard to the total targeting coefficient, the sequence of visceral organs is: lung>liver>heart> kidney > spleen > blood.This study proves that the dexamethasone acetate lipid nanoparticle made by using film emulsification & high pressure homogenization method can change the distribution of DXM in mice. The drug can be targeted to the lung which may have potential for intensify DXM's anti-inflammatory and anti-fibrosis function. Compared to exisiting DXM preparations, the lung targeting DXM-SLN lyophilized injection can abate systemic side effects hormone, and mitigate reverse actions of drugs.