Cinnamon Oil Dry Powder Inhalers For The Treatment Of Bacterial Pneumonia

Objective:To prepare cinnamon oil dry powder inhalers for the effective therapy of various bacterial pneumonia.Methods:Loose and light calcium carbonate particles were prepared after screening of formulations and preparation processes.Cinnamon oil pickering emulsions were prepared after the oil was high-speed stirred with the stabilizer,i.e.,calcium carbonate particles,which were freeze-dried to CODPIs.In another method,cinnamon oil-β-cyclodextrin inclusion complexes（CO-β-CD）were prepared after cinnamon oil andβ-cyclodextrin were mixed,which were also freeze-dried to CODPIs.Cinnamon oil should be included into the hydrophobic cavity ofβ-CD,reducing its volatilization during preparation and storage,and increasing drug loads.The bulk density,tap density,geometric particle size,and aerodynamic diameter（D_a）of CO-β-CD powders were investigated to verify their suitability for inhalation.In vitro antibacterial experiments were conducted for testing of the antimicrobial ability of CO-β-CD on Staphylococcus aureus,Methicillin resistant Staphylococcus aureus（MRSA）,Pseudomonas aeruginosa,and Meropenem resistant Pseudomonas aeruginosa（MRPA）.The administration dose of CO-β-CD was found out by in vivo experiments.Five days post-intraperitoneal injection of dexamethasone,bacterial solutions were intratracheally（i.t.）administered to mice to obtain bacterial pneumonia models,and then CO-β-CD,penicillin,and meropenem were i.t.administered once a day for3 continual days.The therapeutic efficiencies of them were obtained according to the survival rates of the mice,the appearance of lung tissues,the hematoxylin and eosin（H&E）stained sections of lung tissues,the numbers of white blood cells and neutrophils in the blood,and the levels of inflammatory factors（Tumor necrosis factor-α（TNF-α）and Interleukin-6（IL-6））.Results:Calcium carbonate particles were prepared with the following conditions:CO₃^2-from sodium bicarbonate of 0.2 mol·L^-1and reaction under ultrasound.However,the loads of cinnamon oil in the CODPIs was only 5.87%,indicating that most of the drugs volatilized during freeze-drying.The optimal formulation and preparation process of肉桂油β-CD was as follows:the freeze-drying method,β-CD/water（1:4,w/w）,and cinnamon oil/β-CD（1:8,w/w）.The drug loads of CO-β-CD was 10.30%according to the high performance liquid chromatography（HPLC）and the encapsulation efficiency was hight to92.71%.The bulk density of CO-β-CD powders was 0.09 g/cm³,the tap density was 0.15g/cm³,the D₅₀ was 3.50μm,and the D_a was 1.34μm.It is known that the particles of 1-5μm D_a can reach the deep site of the lung by inhalation.Therefore,CODPIs from CO-β-CD is suitable for inhalation treatment of bacterial pneumonia.In vitro antibacterial experiments showed that the minimum bactericidal concentration（MBC）of CO-β-CD against Staphylococcus aureus and MRSA were the same as 2 mg·mL^-1,and the MBC against Pseudomonas aeruginosa and MRPA was 10 mg·mL^-1 and 6 mg·mL^-1,respectively.These values were higher than that of penicillin and meropenem.The toxic concentration of inhaled CO-β-CD was more than100 mg·kg^-1 to mice.The pharmacodynamics experiment showed that all the treatments alleviated the lung injury of mice and significantly increased the survival rates.Compared with penicillin and meropenem,CO-β-CD significantly attenuated the infiltration of inflammatory cells in the lung tissue;moreover,the numbers of leukocytes and neutrophils in the blood,as well as the levels of TNF-αand IL-6 in lung tissues,were comparable to those in the healthy mice with no significant difference,indicating that CO-β-CD had the capability of immune regulation and anti-inflammation besides the antibacterial effect in vivo.Conclusion:The drug loads of CODPIs from by Pickering emulsions were low.Loose and high drug-loading CO-β-CD powders was prepared.CO-β-CD not only had good antibacterial ability in vivo and in vitro,but also had obvious immunomodulatory and anti-inflammatory effects.CODPIs showed high therapeutic effect on various types of bacterial pneumonia.CODPIs are a promising inhalation preparation for the treatment of bacterial pneumonia.