Study Of The Preparation Of Oseltamivir Phosphate Dry Powder Inhalation

Pulmonary drug delivery system(PDDS)is a special drug delivery system which delivering the drug to the lung directly through the respiratory tract in order to act in the lung locally or throughout the whole body.PDDS has specific advantages due to the special physiological structure characteristics compared with traditional oral and injection ways.More and more attention has been paid on the antiviral drugs due to the appearance of COVID-19.Delivering antiviral drugs through PDDS is a hotspot in related areas.In this study,oseltamivir phosphate(OP),which was used to the precaution and treatment of Influenza A and B,was chosen as API.Lactoferrin,with the function of anti-virus and anti-bacteria,was added as well.Spray drying was chosen to prepare oseltamivir phosphate dry powder inhalation.Single factor and orthogonal factors of optimization method were adopted successively to study and optimize the formulation and spray drying process parameters of oseltamivir phosphate dry powder inhalation.The microstructure,yield,geometric diameter and its distribution,density and flowability,water content,crystal and so on of phosphate oseltamivir dry powder inhalation were tested.And the in-vitro lung deposition,cytotoxicity and anti-bacterial effect of the DPI were tested as well.In order to get particles with high sphericity and uniform particle size distribution,the optimal spray drying process parameters were:inlet temperature 120 ℃,intensity of cyclone 100%,feed rate about 6.4 m L/min,flow of compressed air about 473 L/h.And the optimal formulation in this preparation condition was:phosphate oseltamivir 500 mg,lactoferrin 50 mg,L-leucine 300 mg,concentration of drug solution 2.125%.And through the poor computing of orthogonal experiment,the order of factors for the affection of the properties of DPI was:the proportion of excipients,feed rate,concentration of drug solution and flow of compressed air.The optimized dry powder inhalation particles of OP were spherical with a wrinkled surface,and the dispersion of particles was good.The physio-chemical properties of DPI were suitable for the inhalation.The yield of spray drying process was about 65.99%.Mean geometric diameter of the DPI particle was 2.22μm.And the bulk density was 0.26 g/m L,tap density was 0.32 g/m L,Carr’s index was 21.06.The density and flowability all conformed to the general requirements of DPI.The content of free water was about 1.47%,and the particles were amorphous.When the concentration of the inhalation was lower than 600μg/m L,the inhalation did no harm to the HPAEpi C cell;the antibacterial rate was about 22.50%against Staphylococcus aureus with a concentration of 1 mg/mL.