磷脂表面修饰以降低干扰素α2b粉雾剂的引湿性

采用混悬．旋转蒸发包衣法对供吸入干扰素α2b粉末进行表面修饰，并用扫描电镜和化学分析电子能谱分析颗粒表面，考察了修饰前后粉末的引湿性及溶解性，测试了不同湿度条件对粉雾剂有效药物体外沉积的影响。结果表明，经修饰的载药颗粒表面更光滑，覆盖了一层磷脂膜；引湿性降低，溶解性提高，粉雾剂的体外沉积性能对湿度的耐受性明显提高。     

乳糖载体表面形态对吸入粉雾剂处方混合及分散性能的影响

乳糖的表面形态会对混合过程和吸入粉雾剂(DPI)处方的分散性能产生影响.本研究通过将乳糖(InhaLac230?)在高湿环境中放置72 h,得到了与未处理乳糖粒径相似、晶型相同,但表面较光滑的另一种载体颗粒.将2种乳糖颗粒与微粉化马来酸氯苯那敏分别进行混合,得到DPI粉末研究模型.测定了混合过程中不同混合时间点的粉末静...     

可溶性载体对左旋硫酸沙丁胺醇胶囊型粉雾剂的体外影响

目的：通过对左旋硫酸沙丁胺醇胶囊型粉雾剂可溶性载体的考察,筛选出最佳的载体材料及制备工艺。方法：对于可溶性载体辅料,采用纳米磨与喷雾干燥仪分别制备药物、辅料的颗粒物,测定颗粒的理化性质及肺部有效沉积率。结果：喷雾干燥仪制备后,载体粒径在25.35~52.94 μm之间,其中乳糖外观圆整,粒径为25.35 μm,乳糖的休止角为33.20°,乳糖的含水量最低为0.99%,压缩度为17.68%,有效沉积率为14.21%,符合药典对粉雾剂的要求。结论：喷雾制备的乳糖,其粉体性能良好,是适合左旋沙丁胺醇粉雾剂的载体材料。     

吸入粉雾剂的喷雾工艺及表征研究进展

吸入粉雾剂是改善肺部疾病治疗的研究热点,具有上市产品多、生产工艺成熟、颗粒影响因素多、晶型转化因素多、颗粒表面物性变化等特点。目前,吸入粉雾剂存在产品效用、贮藏及生产工艺因素的关联研究不系统等问题,本文对近年来肺部吸入粉雾剂制备新技术（喷雾冷冻干燥技术、微流控-喷雾技术、模板打印技术）及粉体颗粒物理化学表征新技术（反向气相色谱、原子力显微镜测定技术、能量色散X射线光谱技术、飞行时间-离子质谱法等）进行综述,以期对该剂型的研发提供新的借鉴。     

吸入粉雾剂工程颗粒技术研究

对于吸入粉雾剂来说,由于活性药物成分（API）较小的粒径和较高的表面能,导致微粉易于团聚,难以分散。微粒间的内聚力和微粒与乳糖间的粘附力导致粉雾剂产品较低的微细粒子比例（FPF）。通过工程颗粒可以改善API微粒的物化性质,进而显著提高DPI产品的递送效率。概述通过工程颗粒的制备API微粉的方法,包括反溶剂结晶、湿法粉碎/研磨、喷雾/冷冻干燥、超临界流体等方法,可以显著提高粉雾剂的雾化性能。     

L-亮氨酸对干扰素粉雾剂性能的影响

考察了L-亮氨酸含量对以甘露醇或乳糖为主要赋形剂的载干扰素喷雾干燥颗粒的粒径、形态、吸湿性、流动性、分散性和胶囊中颗粒残留量等粉体学性质的影响,并进行了粉雾剂的体外沉积试验.结果表明,加入L-亮氨酸后,以甘露醇为赋形剂的颗粒压缩度大于乳糖颗粒,吸湿性和胶囊中颗粒残留量均小于乳糖颗粒.L-亮氨酸可提高两种粉雾剂的体外沉积量.     

粉雾剂中乳糖对药物在模拟呼吸道沉降部位的影响

以硫酸沙丁胺醇为模型药物,以休止角为流动性指标。选用双冲程碰撞试验仪,评价乳糖的类型、大小对粉雾剂流动性以及对药物在呼吸道沉降的影响。结果显示,重结晶乳糖休止角较市售乳糖小,并优选其粒径54-100μm的为粉雾剂载体,呼吸道沉降研究结果显示,在各粒径区域,以粒径54-100μm重结晶乳糖为载体的物理混合型粉雾剂在模拟肺部沉降量最大。     

载体对微粉型粉雾剂呼吸道沉降的影响

目的：研究载体对微粉型粉雾剂呼吸道沉降的影响，筛选适合的载体组成和制备工艺。方法：以硫酸沙丁胺醇为模型药物，选用双冲程碰撞试验仪，评价以乳糖、甘露醇为载体的微粉型粉雾剂对药物在呼吸道沉降的影响。结果：含药甘露醇溶液喷雾干燥微粉，在模拟肺部药和沉降量最大（30．2％），明显高于两者分别喷雾干燥微粉的物理混合物（4．9％），处方中加入2％泊洛沙姆，并不显著增加药物沉降量；而以乳糖为载体时，呼吸道沉降量并不受乳糖介入方式的影响，但处方加入2％洛沙姆有助于提高药物在模拟肺部沉降。结论：选用甘露醇为载体以喷雾干燥法可制得较理想的微粉型粉雾剂。     

气流速度对粉雾剂在呼吸道沉降的影响

目的 :研究吸入速度对不同粒径粉雾剂在呼吸道沉降的影响。方法 :以硫酸沙丁胺醇为模型药物 ,用双冲程试验仪评价不同的气流速度对吸入型粉雾剂在模拟肺部的沉降量。结果 :粒径为 5 4～ 10 0μm的重结晶乳糖为载体的硫酸沙丁胺醇混合型粉雾剂 ,增加吸入速度 ,提高药物在肺部的沉积量 ;而乳糖、甘露醇为载体 ,喷雾干燥法制备的粒径为 0 .5～ 6.5 μm粉雾剂 ,增加吸入速度 ,药物在肺部沉积量基本不变直至下降。结论 :物理混合型吸入剂随气流速度的增加 ,药物在肺部的沉降量增加。含载体喷干型吸入剂 (0 .5～ 6.5 μm)中的药物在肺部的沉降量取决于载体 (如甘露醇 )和吸入速度 (如 3 0 L· min-1 )。     

布地奈德粉雾剂的制备及质量控制

目的将布地奈德制备成胶囊型吸入粉雾剂,并对其进行初步质量研究,为同类制剂提供质量研究参考。方法采用SCF技术进行原料药微粉化,选用乳糖作载体,以处方量制备粉雾剂,并以粉体的休止角、排空率,胶囊药物含量及均匀度为指标对6批样品测定其质量性能。结果微粉粒径均在0.5～5μm,以每粒胶囊含主药0.2mg,含载体25mg的处方量,采用等量倍增稀释法混合制成粉雾剂,测得6批样品的休止角Ф<40°,排空率均在95%以上。结论按选定的制备方法和处方制得的粉雾剂粒子细小且分布均匀,流动性更好,分散性更强,含量及均匀度合格,有利于生产和使用。     

Use of recrystallized lactose as carrier for inhalation powder of interferon a2b

The aim of the present investigation was to evaluate the effects of physical properties of the carrier on the in vitro deposition performance of dry powder inhalations (DPIs) of recombination human interferon a2b (IFN a2b). Recrystallized lactose was used as the carrier. Inverse gas chromatography (IGC) was used to assess the surface energy, and atomic force microscopy (AFM) was used to assess the roughness and topography of the carrier. In vitro performance of the powder blends was strongly correlated to the physical properties of the carrier. Plotting emitted dose (%) vs. flow rate and fine particle fraction vs. surface energy, yielded an R2 value of 0.9621 and 0.9146, respectively.     

Characterization of a surface modified dry powder inhalation carrier prepared by "particle smoothing"

Atomic force microscopy (AFM) was used to investigate drug-carrier interactions between beclometasone dipropionate (BDP) and a series of untreated and modified lactose surfaces. This quantitative information was correlated with bulk characterization methods and an in-vitro study. Modified lactose surfaces were prepared using a proprietary process referred to as "particle smoothing" to obtain smooth carrier surfaces with or without the presence of magnesium stearate. The engineering of lactose carrier surfaces using the particle smoothing process resulted in significant differences in surface morphology when compared with the "as supplied" starting material. The energy of separation, between BDP and lactose samples, determined by AFM suggested similar lognormal distributions with a rank decrease in median separation energy (e(0.5)) (26.7, 20.6 and 7.7 microJ for untreated, particle-smoothed and particle-smoothed with magnesium stearate, respectively). A series of in-vitro twin stage impinger studies showed good correlation with the AFM separation energy measurements. The mean fine particle dose increased for the two processed lactose samples, with a significant increase for the lactose processed with magnesium stearate, 102.0+/-16 microg compared with 24.2+/-10.7 microg for the untreated lactose. Thus, the AFM presents as a possible pre-formulation tool for rapid characterization of particle interactions.     

Predicting the quality of powders for inhalation from surface energy and area

Purpose. To correlate the surface energy of active and carrier components in an aerosol powder to in vitro performance of a passive dry powder inhaler. Methods. Inverse gas chromatography (IGC) was used to assess the surface energy of active (albuterol and ipratropium bromide) and carrier (lactose monohydrate, trehalose dihydrate and mannitol) components of a dry powder inhaler formulation. Blends (1%w/w) of drug and carrier were prepared and evaluated for dry powder inhaler performance by cascade impaction. The formulations were tested with either of two passive dry powder inhalers, Rotahaler^® (GlaxoSmithKline) or Handihaler^® (Boehringer Ingelheim). Results. In vitro performance of the powder blends was strongly correlated to surface energy interaction between active and carrier components. Plotting fine particle fraction vs. surface energy interaction yielded an R² value of 0.9283. Increasing surface energy interaction between drug and carrier resulted in greater fine particle fraction of drug. Conclusions. A convincing relationship, potentially useful for rapid formulation design and screening, was found between the surface energy and area parameters derived from IGC and dry powder inhaler performance.     

Inverse Gas Chromatography: Investigating Whether the Technique Preferentially Probes High Energy Sites for Mixtures of Crystalline and Amorphous Lactose

PURPOSE: Inverse gas chromatography (IGC) is rapidly gaining popularity as a method for assessing powder surface energy. It is vital to understand what IGC measures if results are to be useful. This work examines the view that IGC preferentially measures high-energy sites on a powder surface. METHODS: Mixtures of amorphous (high-energy) and crystalline (lower energy) lactose particles were prepared and tested using IGC with nonpolar probes. The surface area of the particles was measured in situ in the inverse gas chromatograph. RESULTS: The results were weighted averages of the surface energy for amorphous and crystalline material until the amorphous content exceeded 15% w/w of the sample, after which the surface energy become equivalent to that of the amorphous form. The amorphous content dominated when the surface area was 40% of the total area. Given that the amorphous particles were much smaller and adhered to the crystalline ones, it is reasonable to conclude that many (most) of the binding sites on the surface of the crystalline particles were masked by the amorphous particles by the time that the amorphous content dominated the surface energy measurements. CONCLUSIONS: IGC does not simply measure the high-energy sites in the packed column, but equally there is a complex process that results in measured data on mixtures not being a weighted mean of the surface energy of the two components.     

Influence of inverse gas chromatography measurement conditions on surface energy parameters of lactose monohydrate

Surface energy of any powder determined by inverse gas chromatography (IGC) should be independent of the measurement conditions or type of column used. In this study stainless steel and glass columns were filled with lactose powder. Dispersive and polar components of surface free energy were determined at different flow rates of carrier gas using lactose alone or diluted with calcinated diatomite (Chromosorb W). It was found that measurement conditions did not influence the value of the dispersive parameter of surface energy. On the contrary, K(a) and K(d) values were found to be dependent on dilution of lactose with Chromosorb W. The influence of other parameters on the results was found to be much smaller.     

Predicting the aerosol performance of dry powder inhalation formulations by interparticulate interaction analysis using inverse gas chromatography

Previous studies have demonstrated the utility of inverse gas chromatography (IGC) in discriminating the differences in surface energy between salmeterol xinafoate (SX) powders prepared by conventional sequential batch crystallization and micronization and by supercritical fluid crystallization. In the present study, solubility parameters derived from IGC analysis at infinite dilution (zero coverage) were further utilized to evaluate the influence of solid-solid interactions on the in vitro aerosol performance of these SX samples, with or without the inclusion of a lactose carrier. To this end, the strength of cohesive SX-SX interactions and that of adhesive SX-lactose interactions were computed for the samples from the corresponding solubility parameters, and their fine particle fractions determined using a multi-stage liquid impinger. It was found that the aerosol performance of SX could be substantially improved by the addition of lactose carrier only if the adhesive SX-lactose interactions were stronger than the cohesive SX-SX interactions. The difference in strength between these two forms of interactions also displayed a significant correlation with the increase in fine particle fraction after the addition of lactose carrier. These results suggest that IGC-based interparticulate interaction measurements may serve as a useful means for predicting the aerosol performance of dry powder inhalation formulations.     

The use of inverse gas chromatography for the study of lactose and pharmaceutical materials used in dry powder inhalers

Inverse gas chromatography (IGC) is a sensitive technique for the measurement of powder surface properties, especially surface energetics. Given the importance of these characteristics to the performance of dry powder inhaler formulations (DPIs), it is unsurprising that IGC has been applied to the study of these systems. Monitoring batch-to-batch variation and the effects of processing steps are established uses of IGC in this field and the relevant studies are discussed. A less established use of IGC is for the prediction of DPI performance. Although some groups have found a negative relationship between the dispersive surface energy of one formulation component and fine particle delivery, such studies often have a number of limitations. More complex approaches have failed to produce consistent results. Further, more carefully designed, studies are required in this area. In the final section of this article, some areas for on-going research are discussed, including the need to critically assess the best method for the calculation of the specific free energy of adsorption with pharmaceutical materials.     

Comparison of surface roughness parameters obtained by scanning probe microscopy for carrier particles of dry powder inhalers

Surface 3-D profiles of carrier particles for dry powder inhalers (DPIs) were obtained by scanning probe microscopy (SPM) and analyzed using various roughness parameters. Different roughness parameters were compared and evaluated for their suitability for distinctively quantifying the surface roughness of the lactose carrier particles. Arithmetic mean roughness (Ra) was found to be the most sensitive for differentiating the surface roughness of various lactose carriers while fractal dimension (FD) and surface ratio (SR) were less sensitive. On the other hand, maximum height (Ry) and 10-point mean roughness (Rz) were less representative of the roughness of the whole surface due to the methods of calculation involved. Scan area was found to be an important factor affecting the roughness results obtained and should be seriously considered in the measurement of surface roughness.     

Dry powder inhaler device influence on carrier particle performance

Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 μm were dispersed from both an Aerolizer? and Handihaler? through a cascade impactor at 60 L min(-1). For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 μm), medium (108 μm), and large (275 μm) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer?, reflecting the improved performance observed in vitro. Collisions within the Handihaler?, in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation.     

The influence of carrier roughness on adhesion, content uniformity and the in vitro deposition of terbutaline sulphate from dry powder inhalers

The aim of this study was to establish a correlation between carrier characteristics and the dispersibility of drug from the blend. The influence of the roughness of a commonly used carrier material, lactose monohydrate, on the adhesion, dose uniformity, and aerodynamic properties of a model drug, terbutaline sulphate was investigated. Evaluation of adhesion was carried out with a mechanical sieve and an Alpine air-jet sieve. For the characterisation of lactose roughness, we used image analysis software. Aerodynamic evaluation of fine particle dose and emitted dose was obtained using a twin stage impinger. The study with the mechanical sieve demonstrated that at least 60% of drug adheres to lactose. The Alpine air-jet sieve assays showed there was a correlation between drug separation from a carrier by sieving and that obtained from longer in vitro deposition studies. Adhesion, blend homogeneity and stability are related to the surface roughness of the lactose used as carrier. There is a linear relationship between the parameters "fine particle fraction" and "roughness". A compromise between homogeneity and drug liberation must be found: a certain roughness is necessary to allow for drug adhesion and blend homogeneity, but if too high it will prevent drug liberation after inhalation.