Effect of mixing of fine carrier particles on dry powder inhalation property of salbutamol sulfate (SS)

The most commonly used formulations for dry powder inhalations are binary ordered mixes composed of micronized drugs and coarse carriers. An optimal dry powder aerosol formulation should possess an optimal inhalation property and a good flow property. These characteristics are especially important for a multidose dry powder inheler (DPI). In the present study, model powder blend were prepared consisting of synthesized sugar (different particle sized isomalt; IM-PF, IM-FS, IM-F) as a carrier and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO DPI (SkyePharma AG) and in vitro deposition properties (fine particle fraction, FPF) were evaluated by a twin impinger (TI) at a flow rate of 60 l/min. The separation property between SS and carrier particles was investigated by the centrifuge method and air jet sieve (AJS) method. It was found that FPF decreased with increasing carrier particle size. However, a large carrier particle possesses a good flow property. Therefore, the effect of mixing of fine carrier particles (IM-PF) into the large carrier particles (IM-FS) on dry powder inhalation property was investigated. When the proportion of IM-PF (fine carrier) increase from 0% to 25% of the total carrier powder blend, the FPF also increases from 16.7% to 38.9%. It is concluded that the effect of mixing of fine carrier particles might be a suitable method for improving the dry powder inhalation properties.     

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。     

速克喘干粉吸入剂在慢性阻塞性肺疾病急性发作期的作用

目的：了解速克喘干粉吸入剂在慢性阻塞性肺疾病（ＣＯＰＤ）急性发作期的作用。方法：ＣＯＰＤ急性发作期３０例（男性２１例，女性９例，年龄６９±ｓ６ａ），用速克喘吸入４００μｇ。结果：临床总有效率为７５％，吸入后５ｍｉｎ肺功能即有明显改善，２ｈ后用力肺活量，１ｓ用力呼气量和最大呼气流速有明显增加（Ｐ＜０．０５，Ｐ＜０．０１），有效时间达４ｈ以上。无明显不良反应。结论：ＣＯＰＤ急性发作期病人用速克喘可缓解胸闷、气急等症状。     

Studies on the spray dried lactose as carrier for dry powder inhalation

The purpose of this study was to investigate the spray dried lactose as carrier for dry powder inhalation (DPI). The lactose particles were prepared by spray drying, then the particle size, shape and crystal form were characterized by laser diffraction, scanning electron microscopy (SEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The spray dried lactose particles were spherical and amorphous, but would transfer to crystal form when storage humidity was above 32%. Thus, the humidity of the storage environment should be controlled below 30% strictly in order to maintain the amorphous nature of spray dried lactose which is a great benefit to DPI development.     

Engineering drug ultrafine particles of beclomethasone dipropionate for dry powder inhalation

Sucrose esters (SEs) are widely used in the food and cosmetic industries and there has recently been great interest in their applicability in different pharmaceutical fields. They are natural and biodegradable excipients with well-known emulsifying and solubilizing behavior. Currently the most common pharmaceutical applications of SEs are for the enhancement of drug dissolution and drug absorption/permeation, and in controlled-release systems. Although the number of articles on SEs is continuously increasing, they have not yet been widely used in the pharmaceutical industry. The aim of this review is to discuss and summarize some of the findings and applications of SEs in different areas of drug delivery. The article highlights the main properties of SEs and focuses on their use in pharmaceutical technology and on their regulatory and toxicological status.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.     

影响干粉吸入剂肺沉积的制剂因素

干粉吸入剂的制剂因素包括药物粉末的处方组成、给药装置类型等,是影响药物肺沉积的主要因素。文中按照药物处方组成将干粉吸入剂分成无载体、药物-载体、药物-添加剂、药物-载体-添加剂4种类型,并分别对其影响肺沉积的制剂因素进行了分析。     

Particle engineering of materials for oral inhalation by dry powder inhalers. I-Particles of sugar excipients (trehalose and raffinose) for protein delivery

The pulmonary route of delivery offers a potential alternative to parenteral administration of peptides and proteins. Protection of protein structure is essential in both processing and storage of the final formulation. Sugars, such as trehalose and raffinose, have been employed to act as protein stabilisers. Optimisation of the aerodynamic characteristics of microparticles in dry powder inhaler formulations is critical to ensure optimum deposition of the formulation into the respiratory tract. In the present study we examine the adaptation to hydrophilic materials, specifically the disaccharide, trehalose and the trisaccharide, raffinose, of a previously reported spray drying process for producing nanoporous microparticles (NPMPs). We also investigate the feasibility of incorporating a model protein, lysozyme, into these sugar-based NPMPs. While spray drying raffinose or trehalose from aqueous solution or ethanol:water solutions resulted in non-porous microspheres, spray drying from a methanol:n-butyl acetate mixed solvent system resulted in microparticles which appeared to consist of an agglomeration of individual nanoparticles, i.e. nanoporous/nanoparticulate microparticles. NPMPs of trehalose and raffinose were amorphous, with glass transition temperatures (Tgs) that were sufficiently high (124°C and ～120°C for trehalose and raffinose, respectively) to suggest good physical stability at room temperature and good potential to act as protein carriers and/or stabilisers. NPMPs demonstrated improved aerosolisation properties compared to spray dried non-porous particles. The successful incorporation of lysozyme into these NPMPs at a sugar to protein weight ratio of 1:4 demonstrated the potential of these systems to act as carriers for peptide or protein drugs which could be delivered via the pulmonary route.     

Characterisation and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolised salbutamol sulfate from dry powder inhalers.

Lactose particles with different elongation ratio, roundness, polymorphic form and crystallinity were prepared by a one-step crystallisation process using varying ratios of acetone/water. The crystals were characterised using image analysis optical microscopy, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The elongation ratio was found to increase with increasing acetone ratio which therefore, appears to accelerate the growth in length rather than width and/or thickness. The crystallinity and polymorphic forms were also acetone-concentration dependent. For example, the crystals formed using 65-80% v/v acetone were almost all of the alpha-form whereas at 85% v/v a small amount of beta-form was precipitated, as detected by a peak at the reflection angle 2 theta=10.4 in the X-ray diffractogram. When 90% v/v acetone was incorporated a mixture of alpha- and beta-forms were produced in almost equal quantity, whereas, with 95% v/v acetone the beta-form predominated. At high acetone concentration (90 and 95% v/v), the crystallisation proceeded rapidly leading to the creation of some amorphous content. The 63-90-microm sieve cut of either commercial grade lactose (CL) or crystallised lactose was mixed with salbutamol sulfate and dispersibility was determined using the twin stage liquid impinger. All the formulations containing carrier particles generated by crystallization from solvent showed higher dispersibility and fine particle fraction (FPF) of the drug compared to the formulation made containing CL. The carrier that showed the highest elongation ratio (produced from an 85% acetone 15% water solution), when mixed with salbutamol sulfate produced the highest dispersibility (38.5%) and highest FPF (29.24%). These parameters were six times higher than the values obtained with the formulation containing CL.     

Effect of inhalation flow rate on the dosing characteristics of dry powder inhaler (DPI) and metered dose inhaler (MDI) products.

Both the dose delivered from the device and the particle size of the medication are important parameters for inhalation products because they influence the amount of drug that is delivered to the patient's lung. The inspiratory flow rate may vary from dose to dose in a given patient and between patients. The Marple-Miller Cascade Impactor, a new multistage inertial impactor that operates at two flow rates (30 and 60 liters/min) with comparable particle size cut-offs, provides a means to study the effect of inhalation flow rate on the particle size distributions of inhalation products. The medication delivery, mass median aerodynamic diameter (MMAD), and fine particle mass were determined, in a randomized fashion, for albuterol, beclomethasone, budesonide, and terbutaline in both metered dose inhaler (MDI) and dry powder inhaler (DPI) products as a function of flow rate. In all cases, independent of drug or device used, the MDI products had a more reproducible respirable dose than the breath-actuated DPI products tested as a function of inhalation flow rate.     

Polycaprolactone microspheres as carriers for dry powder inhalers: effect of surface coating on aerosolization of salbutamol sulfate

This study reports the factors controlling aerosolization of salbutamol sulfate (SS) from mixtures with polycaprolactone (PCL) microspheres fabricated using an emulsion technique with polyvinyl alcohol (PVA) as stabilizer. The fine particle fraction (FPF) of SS from PCL measured by a twin-stage impinger was unexpectedly found to be zero, although scanning electron microscopy showed that the drug coated the entire microsphere. Precoating the microspheres with magnesium stearate (MgSt) excipient solutions (1%-2%) significantly increased (p < 0.05, n = 5) the FPF of SS (11.4%-15.4%), whereas precoating with leucine had a similar effect (FPF = 11.3 ± 1.1%), but was independent of the solution concentration. The force of adhesion (by atomic force microscopy) between the PCL microspheres and SS was reduced from 301.4 ± 21.7?nN to 110.9 ± 30.5 nN and 121.8 ± 24.6 nN, (p < 0.05, n = 5) for 1% and 2% MgSt solutions, respectively, and to 148.1 ± 21.0 nN when coated with leucine. The presence of PVA on the PCL microspheres (detected by X-ray photoelectron spectroscopy) affected the detachment of SS due to strong adhesion between the two, presumably due to capillary forces acting between them. Precoating the microspheres with excipients increased the FPF significantly by reducing the drug-carrier adhesion.     

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.     

Effect of milling and sieving on functionality of dry powder inhalation products

Alpha-lactose monohydrate is the standard excipient used as diluent or carrier in dry powder inhaler (DPI) formulations. Earlier studies have already revealed that raw materials for the production of inhalation grade lactose have to be carefully selected in order to avoid batch-to-batch variability. In the present study, the effect of milling and milling intensity on the flow properties and the physico-chemical characteristics of lactose crystals has been determined. The milled lactoses were then further processed by sieving to give lactose qualities with identical size distribution data, but different batch history (non-milled and milled at different conditions). These were then used to manufacture low concentration (0.25%) drug blends with the model drugs salbutamol sulphate (SBS) and beclometasonedipropionate (BDP); the blends were analysed with a Multistage Liquid Impinger (MLI) after delivery from an Easyhaler and an Aerolizer device. It could be shown that gentle milling already results in surface defects on the lactose crystal which are further enhanced by using a higher milling intensity. Produced fine lactose particles during the milling process strongly adhere to the lactose surface and cannot be removed by compressed air which is used for the particle sizing. By trend, a higher milling intensity resulted in higher fine particle fractions (FPF) with both devices. Also, SBS was found to generally give higher fine particle fractions than BDP, independent from the device used. In conclusion, lactose pre-treatment by gentle or strong milling affects the carrier surface and thereby the aerosolization properties of drug/lactose blends produced.     

Effects of formulation and operating variables on Zanamivir dry powder inhalation characteristics and aerosolization performance

Abstract

The objective of this study was to investigate the influence of formulation and operating variables on the physical characteristics and aerosolization performance of zanamivir spary-dried powders for inhalation. Spray-dried samples of zanamivir, zanamivir/mannitol and zanamivir/mannitol/leucine were prepared from their corresponding aqueous solutions under the same conditions to study the influence of the composition, and zanamivir/mannitol/leucine (1/1/3 by weight) formulation was used for investigation of the effect of the preparation process. Dry powders were characterized afterwards for different physical properties, including morphology, particle size, flowability, density and moisture absorption. The in vitro deposition was also evaluated after the aerosolization of powders at 100?L?min^?1 via the Aerolizer® into a Next Generation Impactor (NGI). The highest FPF of 41.40?±?1.1% was obtained with a zanamivir/mannitol/leucine ratio of 1/1/3, which had an average D_g of 3.11?±?0.13?μm and an angle of repose of 36°^?±?1. It was found that the influence of the preparation process on zanamivir spary-dried powders characteristics and aerosolization properties was relatively small, but the influence of the composition was relatively large. Optimization of DPI can be achieved by selecting the most appropriate formulation and preparation process.     

Air classifier technology (ACT) in dry powder inhalation. Part 2. The effect of lactose carrier surface properties on the drug-to-carrier interaction in adhesive mixtures for inhalation

The effect of carrier surface properties on drug particle detachment from carrier crystals during inhalation with a special test inhaler with basic air classifier has been studied for mixtures containing 0.4% budesonide. Carrier crystals were retained in the classifier during inhalation and subsequently examined for the amount of residual drug (carrier residue: CR). Carrier surface roughness and impurity were varied within the range of their appearance in standard grades of lactose (Pharmatose 80, 100, 110, 150 and 200 M) by making special sieve fractions. It was found that roughness and impurity, both per unit calculated surface area (CSA), tend to increase with increasing mean fraction diameter for the carrier. Drug re-distribution experiments with two different carrier sieve fractions with distinct mean diameters showed that the amount of drug per CSA (drug load) in the state of equilibrium is highest for the coarsest fraction. This seems to confirm that surface carrier irregularities are places where drug particles preferentially accumulate. However, a substantial increase in surface roughness and impurity appears to be necessary to cause only a minor increase in CR at an inspiratory flow rate of 30 l/min through a classifier. At 60 l/min, CR is practically independent of the carrier surface properties. From the difference in CR between 30 and 60 l/min, it has been concluded that particularly the highest adhesive forces (for the largest drug particles) in the mixture are increased when coarser carrier fractions (with higher rugosity) are used. Not only increased surface roughness and impurities may be responsible for an increase in the adhesive forces between drug and carrier particles when coarser carrier fractions are used, but also bulk properties may play a role. With increasing mean carrier diameter, inertial and frictional forces during mixing are increased too, resulting in higher press-on forces with which the drug particles are attached to carrier crystals and to each other.     

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.     

Force control and powder dispersibility of spray dried particles for inhalation

This study aims towards a deeper understanding of the correlation between particle morphology, cohesion forces, and aerosol performance of spray dried powders for inhalation. Therefore, forces affecting cohesion and dispersion are considered and some novel contact models are introduced to explain the improved powder dispersibility of corrugated particles. Particles with different degrees of corrugation are prepared by spray drying and characterized. Powder dispersibility is measured by positioning a dry powder inhaler in front of the laser diffraction device. The particle sizes of all powders are in the range of x₅₀ = 2.11 ± 0.15 µm. The ratio of mass specific surface area S_m to volume specific surface area S_V rises from 0.54 cm³/g (spherical particles) to 0.83 cm³/g (most corrugation). The fine particle fraction (FPF) rises significantly with increasing corrugation at 24 L/min which can be explained by a distinct difference in powder dispersibility. From theoretical models a reduction in cohesion up to 90% can be estimated for corrugated particles compared to spherical particles. Advantages in powder dispersibility can be expected for particles having a lower density and smaller radius of curvature in the contact zone. Both characteristics are given in case of corrugated particles and can be optimized to a certain degree of corrugation. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:303–316, 2010     

Physicochemical characterization and stability of rifampicin liposome dry powder formulations for inhalation

Liposomes were used to encapsulate rifampicin (RIF) as an alternative formulation for delivery to the respiratory tract. Factors affecting the stability of liposomes containing RIF were determined. Four liposome suspensions were prepared, containing different millimole ratios of cholesterol (CH) and soybean L-infinity-phosphatidylcholine (SPC) by the chloroform film method, followed by freeze-drying. Cryo-transmission electron microscopy, photon correlation spectroscopy, (2)H and (31)P solid-state nuclear magnetic resonance were used to characterize the liposome suspensions. Differential scanning calorimetry and X-ray diffraction were used to examine the properties of the powder formulations. The powder was dispersed through an Andersen cascade impactor to evaluate the performance of the aerosolized powder. The liposomes were a mixture of 200-300 nm unilamellar and multilamellar vesicles. Higher CH content in the liposome formulation resulted in a smaller change in size distribution with time, and higher CH content was associated with an increase in the (2)H NMR splitting, indicative of an increase in order of the lipid acyl chains. Furthermore, the SS-NMR results indicated that RIF was located between the acyl chains of the phospholipid bilayer and associated with CH molecules. Fifty percent encapsulation of RIF was obtained when the lipid content was high (SPC 10 mM: CH 10 mM). Mannitol was found to be a suitable cryoprotectant, which is attributed to its crystallinity, and use of mannitol gave particles with a mass median aerodynamic diameter of less than 5 microm. In terms of chemical stability, RIF in dry powder formulations was considerably more stable when compared to RIF aqueous solutions and RIF liposomal suspensions.