喷雾冷冻干燥法制备布地奈德富马酸福莫特罗干粉吸入颗粒及其特性评价
|
摘要
现有的复方干粉吸入剂产品,通常使用各活性药物成分的微粉化颗粒和乳糖载体物理混合而得,不同活性成分颗粒的大小和形态的差别可能引起它们空气动力学行为的不同,从而导致两组分的递送剂量不均一。本试验采用喷雾冷冻干燥法制备了无载体的布地奈德和富马酸福莫特罗混合颗粒。考察制备过程中雾化压力、供液流速、药液浓度对最终样品的物理特性的影响。结果表明,复方粉末中药物均为无定形形态,扫描电镜下观察到颗粒呈多孔性球状,测得其比表面积为57 m~2/g,几何中值粒径为11μm,玻璃化转变温度为90℃。采用Aerolizer?装置在90 L/min流速下通过新一代撞击器测得2种组分空气动力学行为高度一致,细微颗粒分数(FPF)达到50%,中位空气动力学粒径(MMAD)约为3.3μm。雾化压力会影响颗粒的几何粒径从而影响其空气动力学行为,供液流速对几何粒径无显著影响,药液浓度对颗粒空气动力学行为的影响不显著。
Carrier-free budesonide and formoterol fumarate composite particles were prepared by spray freezedrying(SFD). The effects of atomization pressure, liquid supply flow rate and drug concentration of the solution on the physical properties of the composite particles were investigated. The higher atomization pressure was, the smaller geometric mean particle size of the particles got and the better their aerodynamic behavior became. The liquid supply flow rate had no significant influences on the geometric particle size and the drug concentration of the liquid solution had no significant effects on the porosity of the particles. Therefore, the two factors exerted little influence on aerodynamic performance of the final products. The results showed that the co-amorphous budesonide-formoterol fumarate was prepared by spray freeze-drying and its glass transition temperature was about 90 ℃. The particles were observed to be porous spherical under scan electron microscope. When the atomization pressure was 0.10 MPa, the geometric mean particle size was about 11 μm and the specific surface area was about 57 m~2/g. According to the determination results of a next generation impactor at a flow rate of 90 L/min with an Aerolizer? device, it was found that aerodynamic performance of the two components with fine particle fraction(FPF) of about 50% and mass median aerodynamic diameter(MMAD)of approximately 3.3 μm was highly consistent. And the two components had nearly the same deposition patterns. It indicated that SFD seemed to be a good method to prepare inhalable particles containing two APIs.
Carrier-free budesonide and formoterol fumarate composite particles were prepared by spray freezedrying(SFD). The effects of atomization pressure, liquid supply flow rate and drug concentration of the solution on the physical properties of the composite particles were investigated. The higher atomization pressure was, the smaller geometric mean particle size of the particles got and the better their aerodynamic behavior became. The liquid supply flow rate had no significant influences on the geometric particle size and the drug concentration of the liquid solution had no significant effects on the porosity of the particles. Therefore, the two factors exerted little influence on aerodynamic performance of the final products. The results showed that the co-amorphous budesonide-formoterol fumarate was prepared by spray freeze-drying and its glass transition temperature was about 90 ℃. The particles were observed to be porous spherical under scan electron microscope. When the atomization pressure was 0.10 MPa, the geometric mean particle size was about 11 μm and the specific surface area was about 57 m~2/g. According to the determination results of a next generation impactor at a flow rate of 90 L/min with an Aerolizer? device, it was found that aerodynamic performance of the two components with fine particle fraction(FPF) of about 50% and mass median aerodynamic diameter(MMAD)of approximately 3.3 μm was highly consistent. And the two components had nearly the same deposition patterns. It indicated that SFD seemed to be a good method to prepare inhalable particles containing two APIs.
引文
[1] RATTANUPATAM T, SRICHANA T. Budesonide dry powder for inhalation:effects of leucine and mannitol on the efficiency of delivery[J]. Drug Deliv, 2014, 21(6):397-405.
[2] HOPPENTOCHT M, HAGEDOORN P, FRIJLINK H W, et al. Technological and practical challenges of dry powder inhalers and formulations[J]. Adv Drug Deliv Rev, 2014,75:18-31.
[3] FRIJLINK H W, DE BOER A H. Dry powder inhalers for pulmonary drug delivery[J]. Expert Opin Drug Deliv,2004,1(1):67-86.
[4] KUMON M, KWOK P C, ADI H, et al. Can low-dose combination products for inhalation be formulated in single crystalline particles?[J]. Eur J Pharm Sci, 2010, 40(1):16-24.
[5] BUTTINI F, BRAMBILLA G, COPELLI D, et al.Effect of flow rate on in vitro aerodynamic performance of NEXThaler(?)in comparison with Diskus(?)and Turbohaler(?)dry powder inhalers[J]. J Aerosol Med Pulm Drug Deliv,2016,29(2):167-178.
[6] LIU S, WATTS A B, DU J, et al. Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery[J]. Eur J Pharm Biopharm, 2015, 96:132-142.
[7] SABOTI D, MAVER U, CHAN H K, et al. Novel budesonide particles for dry powder inhalation prepared using a microfluidic reactor coupled with ultrasonic spray freeze drying[J]. JPharm Sci,2017, 106(7):1881-1888.
[8] WANNING S, SUVERKRUP R, LAMPRECHT A.Pharmaceutical spray freeze drying[J]. Int J Pharm, 2015,488(1/2):136-153.
[9] ISHWARYA S P,ANANDHARAMAKRISHNAN C,STAPLEY A G F. Spray-freeze-drying:A novel process for the drying of foods and bioproducts[J]. Trends Food Sci Tech, 2015, 41(2):161-181.
[10] MUEANNOOM W, SRISONGPHAN A, TAYLOR K M, et al. Thermal ink-jet spray freeze-drying for preparation of excipient-free salbutamol sulphate for inhalation[J]. Eur J Pharm Biopharm, 2012, 80(1):149-155.
[11] SHARMA G, MUEANNOOM W, BUANZ A B, et al.In vitro characterisation of terbutaline sulphate particlesprepared by thermal ink-jet spray freeze drying[J]. Int J Pharm, 2013,447(1/2):165-170.
[12] JARRING K, LARSSON T, STENSLAND B, et al.Thermodynamic stability and crystal structures for polymorphs and solvates of formoterol fumarate[J]. J Pharm Sci, 2006, 95(5):1144-1161.
[13] TAJBER L, CORRIGAN D O, CORRIGAN O I, et al.Spray drying of budesonide, formoterol fumarate and their composites--I. Physicochemical characterisation[J]. Int J Pharm, 2009, 367(1/2):79-85.
[14] SALUJA V, AMORIJ J P, KAPTEYN J C, et al. A comparison between spray drying and spray freeze drying to produce an influenza subunit vaccine powder for inhalation[J]. J Controlled Release, 2010, 144(2):127-133.
[15] D'ADDIO S M, CHAN J G, KWOK P C, et al. Constant size,variable density aerosol particles by ultrasonic spray freeze drying[J]. Int J Pharm, 2012, 427(2):185-191.
[2] HOPPENTOCHT M, HAGEDOORN P, FRIJLINK H W, et al. Technological and practical challenges of dry powder inhalers and formulations[J]. Adv Drug Deliv Rev, 2014,75:18-31.
[3] FRIJLINK H W, DE BOER A H. Dry powder inhalers for pulmonary drug delivery[J]. Expert Opin Drug Deliv,2004,1(1):67-86.
[4] KUMON M, KWOK P C, ADI H, et al. Can low-dose combination products for inhalation be formulated in single crystalline particles?[J]. Eur J Pharm Sci, 2010, 40(1):16-24.
[5] BUTTINI F, BRAMBILLA G, COPELLI D, et al.Effect of flow rate on in vitro aerodynamic performance of NEXThaler(?)in comparison with Diskus(?)and Turbohaler(?)dry powder inhalers[J]. J Aerosol Med Pulm Drug Deliv,2016,29(2):167-178.
[6] LIU S, WATTS A B, DU J, et al. Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery[J]. Eur J Pharm Biopharm, 2015, 96:132-142.
[7] SABOTI D, MAVER U, CHAN H K, et al. Novel budesonide particles for dry powder inhalation prepared using a microfluidic reactor coupled with ultrasonic spray freeze drying[J]. JPharm Sci,2017, 106(7):1881-1888.
[8] WANNING S, SUVERKRUP R, LAMPRECHT A.Pharmaceutical spray freeze drying[J]. Int J Pharm, 2015,488(1/2):136-153.
[9] ISHWARYA S P,ANANDHARAMAKRISHNAN C,STAPLEY A G F. Spray-freeze-drying:A novel process for the drying of foods and bioproducts[J]. Trends Food Sci Tech, 2015, 41(2):161-181.
[10] MUEANNOOM W, SRISONGPHAN A, TAYLOR K M, et al. Thermal ink-jet spray freeze-drying for preparation of excipient-free salbutamol sulphate for inhalation[J]. Eur J Pharm Biopharm, 2012, 80(1):149-155.
[11] SHARMA G, MUEANNOOM W, BUANZ A B, et al.In vitro characterisation of terbutaline sulphate particlesprepared by thermal ink-jet spray freeze drying[J]. Int J Pharm, 2013,447(1/2):165-170.
[12] JARRING K, LARSSON T, STENSLAND B, et al.Thermodynamic stability and crystal structures for polymorphs and solvates of formoterol fumarate[J]. J Pharm Sci, 2006, 95(5):1144-1161.
[13] TAJBER L, CORRIGAN D O, CORRIGAN O I, et al.Spray drying of budesonide, formoterol fumarate and their composites--I. Physicochemical characterisation[J]. Int J Pharm, 2009, 367(1/2):79-85.
[14] SALUJA V, AMORIJ J P, KAPTEYN J C, et al. A comparison between spray drying and spray freeze drying to produce an influenza subunit vaccine powder for inhalation[J]. J Controlled Release, 2010, 144(2):127-133.
[15] D'ADDIO S M, CHAN J G, KWOK P C, et al. Constant size,variable density aerosol particles by ultrasonic spray freeze drying[J]. Int J Pharm, 2012, 427(2):185-191.