扫描电子显微镜-能谱仪在吸入式干粉制剂表征中的应用进展

目的 综述扫描电子显微镜-能谱仪在吸入式干粉制剂表征中的重要应用。方法 通过文献调研与归纳,扫描电子显微镜-能谱仪法表征吸入式干粉制剂,自动颗粒粒形粒径分析软件统计分析载体颗粒,对扫描电子显微镜在吸入式干粉制剂的研发过程中的4个广泛应用场景进行论证和总结。结果 吸入式干粉制剂学是高度依赖颗粒工程学的制剂类型,其性能和治疗功效很大程度上取决于原料药与辅料的微观特性。载体颗粒的尺寸、形状对高效肺部输送起决定性作用。而载体颗粒的表面粗糙度直接影响原料药与载体颗粒之间的黏附-脱附平衡,最终直接影响制剂雾化性能。扫描电子显微镜可以很直观地对颗粒的粒径、粒形以及表面粗糙情况进行快速评估。此外,也可通过扫描电子显微镜图像结合能谱分析判断原料药在载体颗粒上的负载情况,还可用来直接评估原料药颗粒的脱附能力。结论 扫描电子显微镜-能谱仪在吸入式干粉制剂的研发中具有广泛的应用意义,为该类型制剂的研发提供了先进的表征工具。     

Particle interactions involved in aerosol dispersion of ternary interactive mixtures

Purpose. To investigate the mechanism of action of ternary components within dry powder aerosols. Methods. Ternary interactive mixtures were prepared containing salbutamol sulphate (SS), coarse lactose carriers and either micronized lactose (ML) or micronized glucose (MG). In vitro drug and excipient aerosol deposition was performed using a twin-stage impinger (TSI) at 60 L/min with a Rotahaler device. Adhesional properties of the lactose carrier were examined using an atomic force microscope (AFM) colloidal probe technique. Result. The fine particle fraction (FPF) from ternary mixtures were dependent upon carrier type (p < 0.001), ternary concentration (p < 0.001) and ternary component type (p < 0.05). Ternary mixtures produced higher FPF than binary mixtures, except those containing Superfine (SF), which was attributed to the high proportion of intrinsic fine carrier particles. The higher FPF obtained from ternary mixtures was independent of the mixing order (p = 0.08). Increased adhesion force was observed on the carrier surface following the addition of ternary components (p < 0.001). Conclusion. The results confirm that ternary components increase aerosol deposition of powder mixtures. Some results were not entirely consistent with the saturation of active site theory and a hypothesis involving competitive and multilayer adhesion was proposed and requires further testing.     

Pulmonary Deposition and Clinical Response of99mTc-Labelled Salbutamol Delivered from a Novel Multiple Dose Powder Inhaler

Pulmonary deposition of ^99mTc-labelled sulbutamol was determined after delivery from a novel multiple dose powder inhaler (Easyhaler^®). The clinical efficacy of the inhalation powder, evaluated simultaneously with gamma camera detection, was compared with that obtained after drug delivery from a metered dose inhaler-spacer combination. The study was performed as an open, non-randomized cross-over trial. A single dose of radiolabelled inhalation powder was inhaled on the first and the inhalation aerosol, as control, on the second study day. Sulbutamol sulphate was labelled with ^99mtechnetium, and the inhalation powder was formulated by mixing radioactive drug particles with carrier material. Aerodynamic properties of the radiolabelled inhalation powder were similar to those of the unlabelled salbutamol powder. Delivered dose from the breath-actuated powder inhaler was adjusted to be equal to two puffs from a conventional aerosol actuator with a short plastic mouthpiece. Twelve non-smoking asthmatic patients participated in the trial. The mean pulmonary deposition of 24% was obtained after drug delivery from Easyhaler^® powder inhaler. Clinical efficacy of the medications was similar in terms of area under the FEV₁ curve, maximum FEV₁ and the improvement ratio. Thus it can be suggested that powder delivery from Easyhaler^® powder inhaler and the aerosol delivery through the spacer are equally effective.     

Dry powder aerosol delivery systems: current and future research directions.

Development of dry powder aerosol delivery system involves powder production, formulation, dispersion, delivery, and deposition of the powder aerosol in the airways. Insufficiency of conventional powder production by crystallization and milling has led to development of alternative techniques. Over the last decade, performance of powder formulations has been improved significantly through the use of engineered drug particles and excipient systems which are (i) of low aerodynamic diameters (being porous or of low particle density), and/or (ii) less cohesive and adhesive (via corrugated surfaces, low bulk density, reduced surface energy and particle interaction, hydrophobic additives, and fine carrier particles). Early insights into particle forces and surface energy that help explain the improvement have been provided by analytical techniques such as the atomic force microscopy (AFM) and inverse gas chromatography (IGC). Relative humidity is critical to the performance of dry powder inhaler (DPI) products via capillary force and electrostatic interaction. Electrostatic charge of different particle size fractions of an aerosol can now be measured using a modified electrical low-pressure impactor (ELPI). Compared with powders, much less work has been done on the inhaler devices at the fundamental level. Most recently, computational fluid dynamics has been applied to understand how the inhaler design (such as mouthpiece, grid structure, air inlet) affects powder dispersion. The USP throat is known to under-represent the oropharyngeal deposition of DPI aerosols. Studies using magnetic resonance imaging (MRI) model casts have been undertaken to explain the inter- and intra- subject variation in oropharyngeal deposition. Most of the lung deposition studies performed on commercial products did not allow a thorough understanding of the determinants affecting in vivo lung deposition. A more systematic approach would be necessary to build a useful database on the dependence of lung deposition on the breathing parameters, inhaler design, and powder formulation properties.     

Influence of Air Flow on the Performance of a Dry Powder Inhaler Using Computational and Experimental Analyses

Purpose The aims of the study are to analyze the influence of air flow on the overall performance of a dry powder inhaler (Aerolizer^®) and to provide an initial quantification of the flow turbulence levels and particle impaction velocities that maximized the inhaler dispersion performance.Methods Computational fluid dynamics (CFD) analysis of the flowfield in the Aerolizer^®, in conjunction with experimental dispersions of mannitol powder using a multistage liquid impinger, was used to determine how the inhaler dispersion performance varied as the device flow rate was increased.Results Both the powder dispersion and throat deposition were increased with air flow. The capsule retention was decreased with flow, whereas the device retention first increased then decreased with flow. The optimal inhaler performance was found at 65 l min⁻¹ showing a high fine particle fraction (FPF) of 63 wt.% with low throat deposition (9.0 wt.%) and capsule retention (4.3 wt.%). Computational fluid dynamics analysis showed that at the critical flow rate of 65 l min⁻¹, the volume-averaged integral scale strain rate (ISSR) was 5,400 s⁻¹, and the average particle impaction velocities were 12.7 and 19.0 m s⁻¹ at the inhaler base and grid, respectively. Correlations between the device flow rate and (a) the amount of throat deposition and (b) the capsule emptying times were also developed.Conclusions The use of CFD has provided further insight into the effect of air flow on the performance of the Aerolizer^®. The approach of using CFD coupled with powder dispersion is readily applicable to other dry powder inhalers (DPIs) to help better understand their performance optimization.     

Carriers in drug powder delivery

The performance of dry powder inhaler (DPI) systems depends on the design of the powder formulation, the dose-metering system, and the device used to disperse the powder as an aerosol. Multiple factors associated with drug and carrier particles are known to influence dry powder performance. Elucidation of a mechanistic understanding of particulate system properties and how these relate to powder performance and the disruption of inter-particulate forces that cause aggregation has not yet been achieved. However, the complexity of interactions within dry powder formulations has not restricted research in this area. Various strategies of overcoming inter-particulate forces have been devised, ranging from active inhaler designs to powder engineering approaches. The influence of the interactive carrier system’s physicochemical properties (i.e. size, shape, chemical properties, surface roughness, electrostatics, humidity, and ternary excipients) on the performance of carrier-based systems has been examined extensively in the literature. In addition, matrix carriers, which contain drug and functional excipients for promotion of powder performance, control of pharmacokinetics, stability, controlled release of active drug and enhanced control of drug targeting, have also been investigated. Both the interactive carrier and matrix carrier approaches are attempts to develop DPI systems that perform as device-independent formulations and/or provide patient-independent delivery (controlled carrier systems). It seems likely that the future of DPI systems will combine both of these strategies with future developments in device design (formulation independency).     

大黄素固体分散体制备、表征与释药机制研究

摘要：目的 制备大黄素固体分散体，提高其体外溶出度并探究其释药机制。方法 采用分子对接技术，辅助筛选聚合物载体。以大黄素为原料药，Kollidon VA64为聚合物载体，采用热熔挤出工艺制备大黄素固体分散体。通过溶出仪测定其体外溶出，利用SEM，DCS和PXRD对原料药和固体分散体的表面形态和晶型进行表征，最后采用FTIR，NMR和分子动力学模拟对固体分散体的释药机制进行探究。结果 相较于大黄素原料药，大黄素固体分散体在4种介质中的溶出被明显改善，大黄素由结晶态转化为无定形态，药物与聚合物载体间形成了氢键。结论 固体分散体中药物晶型的转变和氢键的产生是改善药物体外溶出的主要因素。     

Towards a More Desirable Dry Powder Inhaler Formulation: Large Spray-Dried Mannitol Microspheres Outperform Small Microspheres

Purpose

To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer^®) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid–state form but different sizes.

Methods

Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid–state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance.

Results

All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM.

Conclusion

Particle shape and solid–state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study.     

Protein Deposition from Dry Powder Inhalers: Fine Particle Multiplets as Performance Modifiers

Purpose. To evaluate the use of carrier-based dry powder aerosols for inhalation delivery of proteins and examine the effect of fine particle excipients as potential formulation performance modifiers. Methods. Bovine serum albumin (BSA) was co-processed with malto-dextrin by spray-drying to produce model protein particles. Aerosol formulations were prepared by tumble mixing protein powders with -lactose monohydrate (63–90 m) or modified lactoses containing between 2.5 and 10% w/w fine particle lactose (FPL) or micronised polyethylene glycol 6000. Powder blends were characterised in terms of particle size distribution, morphology and powder flow. Formulation performance in Diskhaler^® and Rotahaler^® devices was investigated using a twin stage impinger operating at 60 1 min^–1. Results. Inhalation performance of binary ordered mixes prepared using BSA-maltodextrin and lactose (63–90 m) was improved by addition of FPL and micronised PEG 6000. For the addition of 5% w/w FPL the protein fine particle fraction (0.5–6.4 m) using the Diskhaler^® was increased from 31.7 ± 2.4% to 47.4 ± 2.2%. Inclusion of FPL and micronised PEG 6000 changed the bulk properties of inhalation powders and reduced powder flow but did not affect device emptying. Unexpectedly, improvements in performance were found to be independent of the order of addition of FPL to the ternary powder formulations. SEM studies revealed that this was probably the result of a redistribution of protein particles between the coarse carrier lactose component and added FPL during mixing. Conclusions. Fine particle excipients can be used to improve the performance of carrier-based protein dry powder aerosols. Mechanistically, enhancement of performance is proposed to result from a redistribution of protein particles from coarse carrier particles to the fine particle component in the ternary mix.     

Effect of carrier particle shape on dry powder inhaler performance

The aim of this study was to characterise the aerosolisation properties of salbutamol sulphate (SS) from dry powder inhaler (DPI) formulations containing different carrier products. The difference in the elongation ratio (ER) of the different carriers was highlighted. Different set of carriers, namely commercial mannitol (CM), commercial lactose (CL), cooling crystallised mannitol (CCM), acetone crystallised mannitol (ACM) and ethanol crystallised mannitol (ECM) were used and inspected in terms of size, shape, density, crystal form, flowability, and in vitro aerosolisation performance using Multi Stage Liquid Impinger (MSLI) and Aerolizer^® inhaler device. Solid-state and morphological characterization showed that CM product was in pure β-form having particles with smaller ER (CM: ER = 1.62 ± 0.04) whereas ACM and ECM mannitol particles were in pure α form with higher ER (ACM: ER = 4.83 ± 0.18, ECM: ER = 5.89 ± 0.19). CCM product crystallised as mixtures of β-form and δ-form and showed the largest variability in terms of particle shape, size, and DPI performance. Linear relationships were established showing that carrier products with higher ER have smaller bulk density (D_b), smaller tap density (D_t), higher porosity (P), and poorer flow properties. In vitro aerosolisation assessments showed that the higher the ER of the carrier particles the greater the amounts of SS delivered to lower airway regions indicating enhanced DPI performance. Yet, DPI performance enhancement by increasing carrier ER reached a “limit” as increasing carrier ER from 4.83 ± 0.18 (ACM) to 5.89 ± 0.19 (ECM) did not significantly alter fine particle fraction (FPF) of SS. Also, carrier particles with higher ER were disadvantageous in terms of higher amounts of SS remained in inhaler device (drug loss) and deposited on throat. Linear relationship was established (r² = 0.87) showing that the higher the carrier ER the lower the drug emission (EM) upon inhalation. Moreover, poorer flowability for carrier products with higher ER is disadvantageous in terms of DPI formulation dose metering and processing on handling scale. In conclusion, despite that using carrier particles with higher ER can considerably increase the amounts of drug delivered to lower airway regions; this enhancement is restricted to certain point. Also, other limitations should be taken into account including higher drug loss and poorer flowability.     

A New Powder Design Method to Improve Inhalation Efficiency of Pranlukast Hydrate Dry Powder Aerosols by Surface Modification with Hydroxypropylmethylcellulose Phthalate Nanospheres

Purpose. A new particle design method to improve the aerosolization properties of a dry powder inhalation system was developed using surface modification of hydrophobic drug powders (pranlukast hydrate) with ultrafine hydrophilic particles, hydroxypropylmethylcellulose phthalate (HPMCP) nanospheres. The mechanism of the improved inhalation properties of the surface-modified particles and their deposits on carrier particles (lactose) was clarified in vitro. Methods. Drug particles were introduced to aqueous colloidal HPMCP dispersions prepared by emulsion-solvent diffusion techniques followed by freeze- or spray-drying of the resultant aqueous dispersions. The surface-modified powders obtained with HPMCP nanospheres and their mixture with lactose powders were aerosolized by Spinhaler and their mode of deposition in lung was evaluated in vitro using a twin impinger. To elucidate the inhalation mechanism of these surface modified particles, we measured their modified micromeritic properties, such as surface topography, specific surface area, dissolution rate, and dispersibility in air. Results. Dramatically improved inhalation properties of the surface modified powder, i.e. a two-fold increase in emission and a three-fold increase in delivery to deep lung, were found in vitro compared with the original unmodified powder. Improved inhalation was also found with the surf ace-modified drug deposited on lactose particles. Those improvements were attributed to the increased surface roughness and hydrophilicity of the surface-modified particles, and the resultant increased dispersibility in air. Conclusions. Surface modification of hydrophobic drug particles with HPMCP nanospheres to improve hydrophilicity was extremely useful in increasing the inhalation efficiency of the drug itself and the drug deposited on carrier; this was attributed to increased dispersibility in air and emission from the device, for spray- and freeze-dried particles, respectively.     

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.     

Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder

Purpose. To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere® powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs). Methods. Budesonide PulmoSphere (PS_bud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 g budesonide PulmoSphere inhaled from Eclipse® DPI at target PIF of 25 L·min^-1 (PS_bud25), and 50 L·min^-1 (PS_bud50), and 800 g of pelletized budesonide from Pulmicort® Turbuhaler® at 60 L·min^-1(TH_bud60). PS_bud powder was radiolabeled with ^99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation. Results. Pulmonary deposition (mean ± sd) of PS_bud was 57 ± 7% and 58 ± 8% of the nominal dose at 25 and 50 L·min^-1, respectively. Mean peak plasma budesonide levels were 4.7 (PS_bud25), 4.0 (PS_bud50), and 2.2 ng·ml^-1 (TH_bud60). Median t_max was 5 min after both PS_bud inhalations compared to 20 min for Turbuhaler (P < 0.05). Mean AUCs were comparable after all inhalations, 5.1 (PS_bud25), 5.9 (PS_bud50), and 6.0 (TH_bud60) ng·h·ml^-1. The engineered PS_bud powder delivered at both flow rates from the Eclipse® DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L·min^-1 from the Turbuhaler. Intersubject variability was also dramatically decreased for PS_bud relative to TH_bud. Conclusion. Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.     

An Investigation into the Dispersion Mechanisms of Ternary Dry Powder Inhaler Formulations by the Quantification of Interparticulate Forces

Purpose To investigate the dispersion mechanism(s) of ternary dry powder inhaler (DPI) formulations by comparison of the interparticulate adhesions and in vitro performance of a number of carrier–drug–fines combinations. Materials and Methods The relative levels of adhesion and cohesion between a lactose carrier and a number of drugs and fine excipients were quantified using the cohesion–adhesion balance (CAB) approach to atomic force microscopy. The in vitro performance of formulations produced using these materials was quantified and the particle size distribution of the aerosol clouds produced from these formulations determined by laser diffraction. Results Comparison between CAB ratios and formulation performance suggested that the improvement in performance brought about by the addition of fines to which the drug was more adhesive than cohesive might have been due to the formation of agglomerates of drug and fines particles. This was supported by aerosol cloud particle size data. The mechanism(s) underlying the improved performance of ternary formulations where the drug was more cohesive than adhesive to the fines was unclear. Conclusions The performance of ternary DPI formulations might be increased by the preferential formation of drug–fines agglomerates, which might be subject to greater deagglomeration forces during aerosolisation than smaller agglomerates, thus producing better formulation performance.     

Use of Solid Corrugated Particles to Enhance Powder Aerosol Performance

Purpose. To study the dispersion performance of non-porous corrugated particles, with a focus on the effect of particle surface morphology on aerosolization of bovine serum albumin (BSA) powders. Methods. The solid-state characteristics of the spray-dried BSA powders, one consisting of smooth spherical particles and another corrugated particles, were characterized by laser diffraction, X-ray powder diffraction, scanning electron microscopy, confocal microscopy, thermogravimetric analysis, surface area analyzer, and buoyancy method. The powders were dispersed using the Rotahaler® and the Dinkihaler® coupled to a four-stage liquid impinger operating at 30 to 120 L/min. Fine particle fraction (FPF) was expressed as the wt. % of BSA particles of size 5 m collected from the liquid impinger. Results. Apart from the morphology and morphology-related properties (specific surface area, envelope density), the corrugated particles and spherical particles of BSA had very similar solid-state characteristics (particle size distribution, water content, true density, amorphous nature). Using the Dinkihaler®, the FPFs of the corrugated particles were 10-20 wt. % higher than those of the smooth particles. Similar FPF differences were found for the powders dispersed by the Rotahaler®, but the relative changes were larger. In addition, the differences were inversely proportional to the air flows (17.3% at 30 L/min, 25.2% at 60 L/min, 13.8% at 90, 8.5% at 120 L/min). Depending on the inhaler, capsule and device retention and impaction loss at the impinger throat were lower for the corrugated particles. Conclusions. Enhanced aerosol performance of powders can be obtained by surface modification of the particles. The surface asperities of the corrugated particles could lower the true area of contact between the particles, and thus reduce the powder cohesiveness. A distinct advantage of using corrugated particles is that the inhaler choice and air flow become less critical for these particles.     

载体颗粒表面修饰对其表面能及粉雾剂性能的影响

目的研究载体的表面修饰对粉雾剂性能的影响。方法用不同的润滑剂对乳糖颗粒进行了表面修饰,并利用反向气相法测定了乳糖修饰前后的表面能,考察了表面能对干扰素α-2b粉雾剂沉积性能的影响。结果表面修饰后乳糖颗粒的流动性、表面光滑度都得到较大程度的改善,表面能也相应降低,而粉雾剂的性能得以提高。结论利用反向气相色谱法测定载体的表面能来预测粉雾剂的性能,可以为粉雾剂的处方设计和筛选提供一种快速有力的工具。     

In Vivo and In Vitro Diclofenac Sodium Evaluation After Rectal Application of Soft Gelatine Capsules Enabling Application Induced Transformation (AIT) into a Semisolid System of Liquid Crystals (SSLC) for Controlled Release

Purpose. Reverse micellar solutions of diclofenac sodium were encapsulated in soft gelatine capsules. On contact with aqueous media they exhibited an application induced transformation (AIT) into a semisolid system of liquid crystals (SSLC) which slows down drug release. The aim of the present paper was to study in vitro and in vivo drug release from these systems after rectal application. Methods. In vitro drug release was determined in a self-constructed dissolution apparatus to simulate rectal application. For in vivo bioavailability studies rabbits were used as animal models. In vitro release and in vivobioavailability of the capsules was compared to Voltaren^® suppositories. Results. The release profiles of the in vitro experiments show zero-order kinetics. The in vivo bioavailability studies show bioequivalence in terms of AUC for both formulations (capsules and Voltaren^® suppositories). The mean residence time (parameter of sustained release) of the capsules is three time longer in comparison to Voltaren^® suppositories. Conclusions. Rectal administration of capsules provides an appropiate route for controlled release via AIT-SSLC which could be clearly verified in rabbits.     

Recent advances in liposomal dry powder formulations: preparation and evaluation

Liposomal drug dry powder formulations have shown many promising features for pulmonary drug administration, such as selective localization of drug within the lung, controlled drug release, reduced local and systemic toxicities, propellant-free nature, patient compliance, high dose carrying capacity, stability and patent protection. Critical review of the recent developments will provide a balanced view on benefits of liposomal encapsulation while developing dry powder formulations and will help researchers to update themselves and focus their research in more relevant areas. In liposomal dry powder formulations (LDPF), drug encapsulated liposomes are homogenized, dispersed into the carrier and converted into dry powder form by using freeze drying, spray drying and spray freeze drying. Alternatively, LDPF can also be formulated by supercritical fluid technologies. On inhalation with a suitable inhalation device, drug encapsulated liposomes get rehydrated in the lung and release the drug over a period of time. The prepared LDPF are evaluated in vitro and in vivo for lung deposition behavior and drug disposition in the lung using a suitable inhaler device. The most commonly used liposomes are composed of lung surfactants and synthetic lipids. Delivery of anticancer agents for lung cancer, corticosteroids for asthma, immunosuppressants for avoiding lung transplantation rejection, antifungal drugs for lung fungal infections, antibiotics for local pulmonary infections and cystic fibrosis and opioid analgesics for pain management using liposome technology are a few examples. Many liposomal formulations have reached the stage of clinical trials for the treatment of pulmonary distress, cystic fibrosis, lung fungal infection and lung cancer. These formulations have given very promising results in both in vitro and in vivo studies. However, modifications to new therapies for respiratory diseases and systemic delivery will provide new challenges in conducting well-designed inhalation toxicology studies to support these products, especially for chronic diseases.     

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.     

Heterogeneous Particle Deaggregation and Its Implication for Therapeutic Aerosol Performance

Aerosolization performance of dry powder blends of drugs for the treatment of asthma or chronic obstructive pulmonary diseases have been reported in three previous articles. In vitro aerosolization was performed at defined shear stresses (0.624–13.143 N/m²). Formulations were characterized aerodynamically and powder aerosol deaggregation equations (PADE) and corresponding linear regression analyses for pharmaceutical aerosolization were applied. Particle deaggregation is the result of overcoming fundamental forces acting at the particle interface. A new method, PADE, describing dry powder formulation performance in a shear stress range has been developed which may allow a fundamental understanding of interparticulate and surface forces. The application of PADE predicts performance efficiency and reproducibility and supports rational design of dry powder formulations. The analogy of aerosol performance with surface molecular adsorption has important implications. Expressions describing surface adsorption were intended to allow elucidation of mechanisms involving surface heterogeneity, lateral interaction, and multilayer adsorption of a variety of materials. By using a similar expression for drug aerosolization performance, it is conceivable that an analogous mechanistic approach to the evaluation of particulate systems would be possible.