Study On The Zanamivir Dry Powder Inhaler

Zanamivir is neuraminidase inhibitors, selectively inhibits the activity of neuraminidase through combining with the activity of influenza virus neuraminidase. It can prevent virus particles aggregation and release in infected cells, so as to achieve the effect of the treatment and prevention of influenza. Zanamivir has strong molecular polarity, high solubility in water and poor tissue penetration capacity. Oral inhalation, nasal spray or intranasal were mainly used in clinically and oral inhalation was used in the treatment of type A and type B influenza. In this study, zanamivir was used to be the model drug, and zanamivir dry powder inhalation was investigated systematically.HPLC analysis method for the assay of Zanamivir was established in content and in vitro deposition. The stability, specificity, reproducibility and accuracy of the method were good. Two types of evaluation index, including typical physicochemical properties of dry powder inhaler and evalution index on in vitro deposition were established to evaluate the zanamivir dry powder inhalation. Physicochemical properties of the powder comprising a plurality of evaluation indexes, such as: particle morphology, crystal form, particle size, angle of repose, hygroscopicity, moisture, tap density. And the evaluation indexed of in vitro deposition mainly include fine particle fraction, aerodynamic diameter, emptying vitro deposition rate and delivery dose uniformity, which can inflect the aerosolization performance and also can simulation the deposition of particle in the respiratory tract.Powders were first prepared via spray drying using excipients such as carbohydrate, amino acids and surfactant to obtain suitable excipients. The optimum conditions were as follows: inlet temperature of 150° C, feeding speed of 1.67ml/min, air flow of 0.5m 3 / min, atomization pressure of 140 kPa, which was obtained through process optimization. And then we optimized the formulations of the selected excipients via the response surface methodology using a 53 central composite design. The optimal formulation was zanamivir: excipients=1:4, and mannitol: leucine: poloxamer 188= 2.4: 2.22: 0.05 in the excipients. Then the physicochemical characteristics and the in vitro powder deposition of the optimal formulation were also investigated. The final optimized powders, characterized with an angle of repose 37.48°, an aerodynamic diameter of 2.346 μm and in vitro deposition of 58.54%. And the powder which was a hollow spherical particle with an extremely wrinkled surface has a good flowability, fine aerosolization performance, low moisture and slight hygroscopicity.After making the prescription and technology research, the study went on during the preparation of dry powder inhaler conducted a preliminary exploration, and enlarged three batches. The three batches characterized with the in vitro powder deposition of 57.31%, 56.96% and 56.91%, respectively. Through the one-factor analysis of variance of the three batches, P-value is 0.8438. Then we can know that there was no significant difference in the three batches and they have fine aerosolization performance, stabilization technology and good reproduction quality. The next step for the stability of the product conducted a preliminary study including influencing factor, accelerate text and long-time stability. Influencing factor were investigated the main factors to text the change in the powder-filled capsule, the high temperature, high humidity and light conditions placed occurred. The results showed that the products under the condition of light and high temperature was stable, and there was no significant difference on the powder state and aerosolization performance, but the products were more sensitive to humidity, and need to add the ribbon to moisture. Stability tests showed that the product’s appearance and aerosolization performance were no significant changed after accelerating test and long-term stability test under the conditions of(40 ± 2) °C(75 ± 5)% RH and at room temperature.Finally, the product was prepared pharmacokinetic and in vivo fluorescent imaging texts after endotracheal administration using penn-century powder insufflators, investigating the distribution and metabolism in the body. The AUC0-8h was 4498.03± 1038.42(ng/ml)*h and 2944.90±1756.93(ng/ml)*h for intravenous and endotracheal administration, respectively, the absolute bioavailability was 89.54%. The powder can quickly be absorbed and entered the bloodstream by avoiding the liver after pulmonary system.The fluorescence could be detected in rats following the pulmonary administration of the dry powder. The dry powders successfully reached the lungs after administration, which might be due to the dissolution of Cy7. The fluorescence strength in the lungs reached a maximum at 1.5 h and then decreased with time. The fluorescence in the liver was observed at approximately 2 h and increased gradually.