| Budesonide(BN) and formoterolfumarate(FM) are the common drugs used to maintenance treatment for patients with chronic obstructive pulmonary disease(COPD) and asthma.So BN and FM have been choosen as objects to prepare a kind of inhalation liquid formulation which BN is suspended in water and FM is dissolved in it. The formulation was atomized by a self-made nebulizer and evaluated systematically in vitro.Firstly, HPLC analytical methods were established and validated for determination of the two drugs and their related substances.Secondly, the formulation optimization was performed and the stability of the formulation was carried out. The components of formulation were decided using the change of drugs content, related substances, p H value and drop size distribution as indexes and finally decided the component is : BN 0.1%,FM 0.0045%,Tween-80 0.01%,sodium chloride 0.85%,citric acid 0.03%,sodium citrate 0.06% and EDTA-2Na 0.01%. Water is solvent and disperse under ultrasonic, then adjust p H value up to 5.0 using sodium hydroxide solution. The stability of the formulation was carried out at 25℃ for 3 months and 4℃ for 6 months respectively. No significant changes were detected for the items.At last,the optimal formulation was evaluated in vitro,including observing by the microscope, measuring the particle size, caculating nebulized velocity, evaluating of the aerodynamic particle size distribution(APSD) and measuring the dosage of deposite.Three kinds of equipments, including twin-stage impactor, next generation impactor and Anderson cascade impactor were used to measure the dosage of deposite. Some factors such as temperature, air flow rate, mouth-throat configuration and nebulizer were studied to explore the influence on the dosage of deposite. Measures have been taken to simulate the in vivo process by controlling the factors above.According to the results, the formulation showed homogeneous apperence and no aggregation. The mean particle diameter was(2.24±0.24)μm, and there were(98.2±0.62)% of the particles whose size were less than 5μm.The formulation atomized by a self-made nebulizer was at a appropriate velocity.In TOF test, the mass median aerodynamic diameter(MMAD) of the formulation was(2.65±0.05μ)m,and geometry standard deviation(GSD) was 2.37±0.06 determined by TOF.In biopolar impactor test, with the increasing of air flow rate, the residue in nebulizer of the two drugs increased and the fine particle fraction(FPF) of the formulation decreased. When the air flow rate was 15L/min, the FPF of the two drugs were(19.75±2.20)%and(21.28±4.43)%.In breath simulation mode, the FPF of two drugs using the self-made nebulizerwere(34.35±4.17)%and(33.63±5.75)%,while using PARI were(23.31±1.03)%and(24.39±1.88)%。In NGI test, with the increasing of temperature, the residue in nebulizer of the two drugs decreased and the fine particle fraction(FPF) of the formulation increased. When the temperature was37℃, the FPF of the two drugs were(19.75±2.20)%and(21.28±4.43)%.In the mode of breath simulation, compared with PARI nebulizer the self-made one had obvious advantage. In breath simulation mode, the FPF of two drugs using the self-made nebulizer were(30.29±2.93)%and(33.20±2.81)%,while using PARI were(20.90±1.07)%and(22.25±1.62)%。In ACI test, idealized throat had more residue than USP pipe, while the breath simulation mode had less residue in mouth-throat than continuous atomization mode. |
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