Lactose Carrier Particles Research Articles

Novel inhalable powder formulation of pirfenidone with sustained release properties to improve pulmonary deposition

The aim of this study was to develop a new respirable powder (RP) formulation of pirfenidone (PFD) with sustained release properties to ameliorate the pharmacokinetic drawbacks of the previously-developed PFD-RP on rapid elimination from the lung after insufflation. Based on screenings using several polymers, Kollidon® SR was chosen to produce a solid dispersion of PFD with sustained release properties (SRSD/PFD), and an RP formulation of SRSD/PFD (SRSD/PFD-RP) was prepared. Characteristics of SRSD/PFD-RP were examined in terms of biopharmaceutical, pharmacological, and phototoxic properties. In laser diffraction analysis, SRSD/PFD-RP could be dispersed to SRSD/PFD and lactose carrier particles, and SRSD/PFD in SRSD/PFD-RP had suitable particle sizes for inhalation. Insufflated SRSD/PFD-RP (0.03 mg-PFD/rat) showed a prolonged elimination half-life and mean residence time of PFD since these values were approximately 3.7-fold higher than those of insufflated PFD-RP (0.3 mg-PFD/rat: a pharmacologically-effective dose). Insufflated SRSD/PFD-RP (0.03 mg-PFD/rat) showed a similar anti-inflammatory potential in the lung of antigen-evoked lung inflammatory models compared with insufflated PFD-RP (0.3 mg-PFD/rat). Obvious skin phototoxicity was negligible after insufflation of SRSD/PFD-RP (0.03 mg-PFD/rat). In conclusion, SRSD/PFD-RP would be an attractive dosage form for an inhalation system of PFD and contribute to PFD medication for idiopathic pulmonary fibrosis with high efficacy and safety.

Surface Modification of lactose carrier particles using a fluid bed coater to improve fine particle fraction for dry powder inhalers

Surface roughness of carrier particles can impact dry powder inhaler (DPI) performance. There are opposing views on the effect of roughness on DPI performance. Hence, a systematic approach is needed to modify carrier surfaces and evaluate the impact on drug delivery. Carrier particle surfaces were modified by fluid bed coating with saturated lactose containing micronized lactose of different sizes (2, 5 and 8 μm) and coated to different levels (20, 40, 60 and 80%). Their drug delivery performance was assessed by the fine particle fraction (FPF). Roughness parameters, mean arithmetic roughness (Ra) and arithmetic mean height (Sa), of the carrier particles, were also evaluated using optical profilometry and scanning laser microscopy. Generally, particles of higher Ra had higher FPF. Higher Sa resulted in higher FPF only for particles with 60 and 80% coat levels. Reduced contact surface area between the drug particle and rougher carrier particle resulted in easier drug detachment during aerosolization. The 5 µm micronized lactose produced optimal carrier particles with respect to FPF and surface roughness. The study highlighted that with the ideal particles for surface roughening and coating level, surface roughening could be efficiently achieved by fluid bed coating for superior DPI performance.

The influence of relative humidity on the carrier particle surface characteristics used in dry powder inhalation formulation

Purpose: Investigation of the effect of carrier storage at elevated relative humidities on the carrier surface fines. The resulted effects of this storage conditions on the carrier surface characteristics when mixed with micronized salbutamol sulphate and the subsequent in vitro deposition were investigated. Methods: Lactose (InhaLac120) and mannitol (Pearlitol160) carrier particles (112 µm – 140 µm) were subjected to different relative humidities for 6 weeks period of time in order to get a smoother surface. In vitro deposition carried out for those modified carriers after mixing with salbutamol sulphate using a Next Generation Impactor (NGI). The modified carriers were characterized by scanning electron microscope, Brunauer Emmet and Teller specific surface area determination, differential scanning calorimetry, X-ray powder diffraction and water vapour sorption in comparison with the treated carrier without added fines. Results: The modified lactose and mannitol carriers stored at different relative humidities starting from 35% RH-75% RH show no change in fine particle fraction (FPFs). Subsequently, the carrier storage at 95% RH shows a significant decrease in the in vitro drug release. This probably by increasing drug-carrier adhesion and show a difficult detachment of the drug particles from the carrier surface smoothed at 95% RH. Conclusions: Storage of lactose and mannitol carriers at different relative humidities up to 75% result in un-significant change in drug fine particle fraction using the NGI. Additionally, storage of those carriers at high relative humidity up to 95% RH found to decrease significantly the dispersion of the drug and subsequently the FPF in the in vitro deposition test.

Novel spherical lactose produced by solid state crystallisation as a carrier for aerosolised salbutamol sulphate, beclomethasone dipropionate and fluticasone propionate

The purpose of the present work was to engineer lactose carrier particles for inhalation using a solid-state crystallisation of amorphous spray dried lactose approach. A suspension of spray dried lactose was contacted with hot ethanol for 10 and 30 s to produce spherical particles (ESDL10) and (ESDL30) with different degrees of crystallinity, particle size, and controlled surface rugosity. Lactohale® (control) and engineered spray dried lactose (ESDL) particles were characterised by Scanning Electron Microscopy, X-ray Powder Diffraction and Tribo-electrification. Lactohale® and engineered lactose particles were mixed separately with salbutamol sulphate (SS), beclomethasone dipropionate (BDP) and fluticasone propionate (FP) and each formulation was assessed for drug content uniformity, drug segregation after tribo-electrification and drug deposition using Andersen Cascade Impactor (ACI). Lactohale® showed the highest but opposite affinity for electrical surface charges compared to engineered lactose. Lactohale® showed the greatest variation in drug content uniformity with SS but to a lesser extent with BDP and FP, whereas the ESDL carriers produced an acceptable uniform mix with all drugs. SS-Lactohale® formulation showed the highest segregation after tribo-electrification up to 119-fold in comparison to that observed with SS-engineered lactose. ESDL10 carrier promoted a better drug deposition for both BDP and FP and showed the least variation in both content uniformity and FPD with all three drugs. Therefore, production of crystalline spherical lactose carrier with controlled surface texture, size and crystallinity is achievable using solid state crystallisation for DPIs, whilst providing less variation in drug content uniformity and consistent fine particle dose to the lungs in-vitro for both hydrophilic and hydrophobic drugs.

Prediction of the carrier shape effect on particle transport, interaction and deposition in two dry powder inhalers and a mouth-to-G13 human respiratory system: A CFD-DEM study

Documentation of comparability between generic inhaler designs and the reference listed drug (RLD) inhalers is essential for regulatory approval of the products. Such assessments need high-fidelity numerical methods to accurately predict the transport, interactions, and deposition of orally inhaled drug products (OIDPs) in the human respiratory systems delivered via inhalers such as dry powder inhalers (DPIs). To explicitly model the particle-particle and particle-wall interactions for OIDPs, this study developed a computational fluid dynamics (CFD) and discrete element method (DEM) to examine drug delivery efficiency, determine emitted aerodynamic particle size distributions (APSDs), and quantify the resultant lung depositions of both lactose carriers and active pharmaceutical ingredient (API) particles. Numerical parametric studies were also performed with multiple actuation flow rates, carrier shapes, and DPI designs. Spiriva™ Handihaler™ (SH) and a generic DPI were selected in this study. The comparability assessment between the generic DPI and SH has been numerically performed. Specifically, CFD-DEM simulations were run at actuation flow rates of 30, 39, 60, and 90 L/min. Simulations were performed for both spherical and elongated lactose carrier particles with aspect ratios of 1, 5, and 10. Using the emitted APSDs as the mouth inlet conditions, the transport and deposition of API and lactose carriers from mouth to the tracheobronchial tree were also simulated. Numerical results indicate that with the same particle volume, the shape of lactose carriers can significantly influence the DPI delivery efficiency without a monotonic trend, due to the complex resuspension effect after deposition. However, the shape effect of lactose carriers is not significant on the lung deposition patterns of the API. Low actuation flow rates could potentially enhance the overall DPI-airway drug delivery efficiency. Using spherical lactose carriers, the comparability between the generic DPI and SH is demonstrated at all four actuation flow rates. The CFD-DEM model provides a feasible pathway on how to use CFD and DEM to evaluate the comparability between inhalers. The modeling framework also can help obtain new insights on transport dynamics of actines in DPIs to lung, thereby reducing the cost of generic product innovations and accelerating product review and approval.

Preparation and Characterization of Spray-Dried Inhalable Powders Containing Polymeric Micelles for Pulmonary Delivery of Paclitaxel in Lung Cancer

Local delivery of chemotherapeutic drugs to the lungs offers many advantages for lung cancer treatment compared to conventional systemic chemotherapy. In the present study, novel mixed polymeric micelles based on tocopheryl succinate-polyethylene glycol 1000 and 5000 Da (TPGS1K and TPGS5K) were synthesized and loaded with paclitaxel (PTX). Then, the optimized micelles were incorporated as colloidal drug delivery system into lactose carrier particles using a spray drying technique. The mixed micelles of TPGS5K and TPGS1K in different molar ratios (10:0, 7:3, 5:5, 3:7, 0:10) were prepared and physicochemical properties including: particle size, zeta potential, critical micelle concentration (CMC), drug loading, drug release rate, and in vitro cytotoxicitywere investigated in details. The optimized nanoparticles were co-spray dried with lactose carriers to produce the spherical particle morphology of the inhalable particles. Particle sizes and zeta potentials of the different formulations varied in the range of 102 to 196 nm and -9.4 to -13.8 mV, respectively. The lowest CMC values were calculated for 5:5 and 7:3 combinations (16.33 and 17.89 µM, respectively). The drug release rate from different formulations were very slow and only 30% of the drug was released during 72 h. Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded mixed micelles compared to the free drug. The in vitro deposition data indicated that spray drying of PTX-loaded micelles with lactose resulted in the production of inhalable powders with the high fine particle fraction (60%). These results demonstrate that this novel PTX-loaded micelles embedded in dry powder inhalation aerosol platform has a great potential to be used in lung cancer treatment.

Characterizing the Surface Roughness Length Scales of Lactose Carrier Particles in Dry Powder Inhalers.

Surface roughness is well recognized as a critical physical property of particulate systems, particularly in relation to adhesion, friction, and flow. An example is the surface property of carrier particles in carrier-based dry powder inhaler (DPI) formulations. The numerical characterization of roughness remains rather unsatisfactory due to the lack of spatial (or length scale) information about surface features when a common amplitude parameter such as average roughness ( Ra) is used. An analysis of the roughness of lactose carrier particles at three different length scales, designed for specificity to the study of interactive mixtures in DPI, was explored in this study. Three Ra parameters were used to represent the microscale, intermediate scale, and macroscale roughness of six types of surface-modified carriers. Coating of micronized lactose fines on coarse carrier particles increased their microroughness from 389 to 639 nm while the macroroughness was not affected. Roller compaction at higher roll forces led to very effective surface roughening, particularly at longer length scales. Changes in Ra parameters corroborated the visual observations of particles under the scanning electron microscope. Roughness at the intermediate scale showed the best correlation with the fine particle fraction (FPF) of DPI formulations. From the range of 250 to 650 nm, every 100 nm increase in the intermediate roughness led to ∼8% increase in the FPF. However, the effect of surface roughness was greatly diminished when fine lactose (median size, 9 μm) of comparable amounts to the micronized drug were added to the formulation. The combination of roughness parameters at various length scales provided much discriminatory surface information, which then revealed the "quality" of roughness necessary for improving DPI performance.

PEGylated composite nanoparticles of PLGA and polyethylenimine for safe and efficient delivery of pDNA to lungs

Achieving stable, efficient and non-toxic pulmonary gene delivery is most challenging requirement for successful gene therapy to lung. Composite nanoparticles (NPs) of the poly(lactic-co-glycolic acid) (PLGA) and cationic polymer polyethyleneimine (PEI) is an efficient alternative to viral and liposomal vectors for the pulmonary delivery of pDNA. NPs with different weight ratios (0–12.5%w/w) of PLGA/PEI were prepared and characterized for size, morphology, surface charge, pDNA loading and in vitro release. The in vitro cell uptake and transfection studies in the CFBE41o–cell line revealed that NPs with 10% w/w PEI were more efficient but they exhibited significant cytotoxicity in MTT assays, challenging the safety of this formulation. Surface modifications of these composite NPs through PEGylation reduced toxicity and enhanced cellular uptake and pDNA expression. PEGylation improved diffusion of NPs through the mucus barrier and prevented uptake by pulmonary macrophages. Finally, PEGylated composite NPs were converted to DPI by lyophilization and combined with lactose carrier particles, which resulted in improved aerosolization properties and lung deposition, without affecting pDNA bioactivity. This study demonstrates that a multidisciplinary approach may enable the local delivery of pDNA to lung tissue for effective treatment of deadly lung diseases.

Impact of feed counterion addition and cyclone type on aerodynamic behavior of alginic-atenolol microparticles produced by spray drying

The inhalatory route has emerged as an interesting non-invasive alternative for drug delivery. This allows both pulmonary (local) and systemic treatments (via alveolar absorption). Further advantages in terms of stability, dose and patient preference have often lead researchers to focus on dry powder inhaler delivery systems. Atenolol is an antihypertensive drug with low oral bioavailability and gastrointestinal side effects. Because atenolol possesses adequate permeation across human epithelial membranes, it has been proposed as a good candidate for inhalatory administration. In a previous work, atenolol was combined with alginic acid (AA) and microparticles were developed using spray-drying (SD) technology. Different AA/atenolol ratios, total feed solid content and operative variables were previously explored. In order to improve particle quality for inhalatory administration and the SD yield, in this work the AA acid groups not neutralized by atenolol were kept either free or neutralized to pH∼7 and two different SD cyclones were used. Particle morphology, flow properties, moisture uptake and in vitro aerosolization behavior at different pressure drops were studied. When the AA acid groups were neutralized, particle size decreased as a consequence of the lower feed viscosity. The SD yield and in vitro particle deposition significantly increased when a high performance cyclone was employed, and even when lactose carrier particles were not used. Although the in vitro particle deposition decreased when the storage relative humidity increased, the developed SD powders showed adequate characteristics to be administered by inhalatory route up to storage relative humidities of about 60%.

Preparation of slab-shaped lactose carrier particles for dry powder inhalers by air jet milling

Dry powder inhalers are often formulated by attaching micronized drug particles onto carrier particles, which are generally lactose. In this study, commercially available lactose was air jet milled to produce unique slab-like coarse carrier particles, which have larger and rougher surfaces compared to other commercially available lactose. Two key processing factors, i.e., classifier speed and jet milling pressure, were systematically investigated. The largest fraction of slab-like particles in the resulting powder was obtained at a classifier speed of 3000 rpm. The slab-like coarse carrier particles are expected to exhibit superior performance than commercial lactose due to their unique surface properties.

Fast dissolution of poorly water soluble drugs from fluidized bed coated nanocomposites: Impact of carrier size

Formation of core-shell nanocomposites of Fenofibrate and Itraconazole, model poorly water soluble drugs, via fluidized bed (FB) coating of their well-stabilized high drug loaded nanosuspensions is investigated. Specifically, the extent of dissolution enhancement, when fine carrier particles (sub–50μm) as opposed to the traditional large carrier particles (>300μm) are used, is examined. This allows testing the hypothesis that greatly increased carrier surface area and more importantly, thinner shell for finer carriers at the same drug loading can significantly increase the dissolution rate when spray-coated nanosuspensions are well-stabilized. Fine sub–50μm lactose (GranuLac® 200) carrier particles were made fluidizable via dry coating with nano-silica, enabling decreased cohesion, fluidization and subsequent nanosuspension coating. For both drugs, 30% drug loaded suspensions were prepared via wet-stirred media milling using hydroxypropyl methyl cellulose and sodium dodecyl sulfate as stabilizers. The stabilizer concentrations were varied to affect the milled particle size and prepare a stable nanosuspension. The suspensions were FB coated onto hydrophilic nano-silica (M-5P) dry coated sub-50μm lactose (GranuLac® 200) carrier particles or larger carrier particles of median size >300μm (PrismaLac®40). The resulting finer composite powders (sub-100μm) based on GranuLac® 200 were freely flowing, had high bulk density, and had much faster, immediate dissolution of the poorly water-soluble drugs, in particular for Itraconazole. This is attributed to a much higher specific surface area of the carrier and corresponding thinner coating layer for fine carriers as opposed to those for large carrier particles.

Improving Dry Powder Inhaler Performance by Surface Roughening of Lactose Carrier Particles.

This study investigated the impact of macro-scale carrier surface roughness on the performance of dry powder inhaler (DPI) formulations. Fluid-bed processing and roller compaction were explored as processing methods to increase the surface roughness (Ra) of lactose carrier particles. DPI formulations containing either (a) different concentrations of fine lactose at a fixed concentration of micronized drug (isoniazid) or (b) various concentrations of drug in the absence of fine lactose were prepared. The fine particle fraction (FPF) and aerodynamic particle size of micronized drug of all formulations were determined using the Next Generation Impactor. Fluid-bed processing resulted in a modest increase in the Ra from 562 to 907nm while roller compaction led to significant increases in Ra > 1300nm. The roller compacted carriers exhibited FPF > 35%, which were twice that of the smoothest carriers. The addition of up to 5%, w/w of fine lactose improved the FPF of smoother carriers by 60-200% whereas only < 30% increase was observed in the rough carriers. Analysis of the FPF in tandem with shifts in the mass median aerodynamic diameter of dispersed drug suggested that the finest drug particles were entrapped on rougher surfaces while larger drug particles were dispersed in the air. The results showed that the processing of lactose carrier particles by roller compaction was immensely beneficial to improving DPI performance, primarily due to increased surface roughness at the macro-scale.

Sub-100 micron fast dissolving nanocomposite drug powders

This study focuses on the preparation of sub-100μm freely flowing yet fast dissolving core–shell nanocomposite powders via fluidized bed (FB) coating of poorly water-soluble drug nanosuspensions onto fine carrier particles (sub-50μm). This is in contrast to conventional FB coating processes that utilize carrier particles as large as 850μm resulting in much larger final nanocomposites. Fluidization and subsequent FB processing of sub-50μm, Geldart group C powders, is a major technological barrier, which can be overcome by either increasing the body weight of the powders, or decreasing their cohesion. Here, the latter is considered as a practical way to enhance fluidization, accomplished through applying a discrete, fairly uniform layer of nano-sized silica particles onto the surface of the cohesive host particles dry coating. Fenofibrate was considered as a model poorly water-soluble drug, and was wet-milled in a stirred media mill and stabilized via an optimized polymer and surfactant combination. The nanoparticle suspensions were then coated onto hydrophilic nano-silica (M5P) coated sub-50 micron lactose (Granulac® 200) or potato starch carrier particles in a FB process. Their coating with drug particle nanosuspensions was achieved without appreciable agglomeration, which is a major novelty of this work. In spite of having a median particle size well under 100μm, the resulting final composite powders were freely flowing, had high bulk density, and allowed for fast dissolution of a poorly water-soluble drug in comparison to either micronized or nano-milled drug along with the same excipients in physical mixtures.

CARS microscopy as a tool for studying the distribution of micronised drugs in adhesive mixtures for inhalation

Drug particles can be produced in the proper aerodynamic particle size distribution (PSD) for inhalation by techniques such as micronisation or spray drying (1–5 µm). However, mixing with coarse carrier particles may change the PSD by agglomeration. Furthermore, the spatial distribution of the drug particles on the carrier particles in adhesive mixtures is highly relevant to the dispersion performance of inhalation powders. Coherent anti‐Stokes Raman scattering (CARS) microscopy is capable of chemically selective imaging, allowing the distribution of drug particles on the surface of carrier particles to be visualised. We used CARS microscopy to image the drug distribution for budesonide and salmeterol on the surface of lactose carrier particles. Image analysis was performed to determine the drug PSD that was then compared with the PSD obtained from laser diffraction. Additionally, comparative CARS and scanning electron microscopy (SEM) images were recorded to allow a direct comparison of the images obtained from CARS microscopy and from SEM. CARS microscopy revealed the drug to be in clusters on the surface of the carrier particles, while the image analysis identified 68% of the particles to have a median area of 0.4 µm2. Image analysis resulted in measurement of larger particles than laser diffraction, which may be caused by agglomeration during mixing. The combined chemical and morphological information from comparative CARS and SEM analysis resulted in unambiguous identification of the spatial drug distribution over the carrier surface. Our results indicate that CARS microscopy is a useful tool to study adhesive mixtures for inhalation. Copyright © 2014 John Wiley &amp; Sons, Ltd.

Chemical synthesis and formulation design of a PEGylated vasoactive intestinal peptide derivative with improved metabolic stability

The present study aimed to design a PEGylated VIP derivative, [Arg15, 20, 21, Leu17]-VIP-GRR (IK312532), with improved metabolic stability, and develop its respirable powder (RP) formulation for inhalation therapy. IK312532 was chemically conjugated with PEG (5kDa, P5K), the physicochemical and biochemical properties of which were characterized by CD spectral analysis, binding assays, and metabolic stability. CD spectral analysis demonstrated that PEG conjugation had no impact on the conformational structure of IK312532. Although the receptor-binding activity of IK312532/P5K (IC50: 82nM) was estimated to be ca. 30-fold less than that of IK312532 (IC50: 2.8nM), the metabolic stability of IK312532/P5K was highly improved. The IK312532/P5K was jet-milled and blended with lactose carrier particles to provide RP formulation of IK312532/P5K (IK312532/P5K-RP). In vitro inhalation performance and in vivo pharmacological effects of the IK312532/P5K-RP in antigen-sensitized rats were also evaluated. In cascade impactor analyses, fine particle fraction of IK312532/P5K-RP was calculated to be ca. 37%. Insufflation of IK312532/P5K-RP (150μg of IK312532/P5K) in antigen-sensitized rats resulted in marked attenuation of inflammatory events, as evidenced by significant decreases in inflammatory biomarkers and granulocyte recruitment in pulmonary tissue 24h after the antigen challenge. From these findings, PEGylation of a VIP derivative, as well as its strategic application to the RP formulation, may be a viable approach to improve its therapeutic potential for the treatment of airway inflammatory diseases.

Dry powder inhaler delivery of amorphous drug nanoparticles: Effects of the lactose carrier particle shape and size

Abstract Stable amorphous drug nanoparticles represent a new bioavailability enhancement strategy of poorly soluble drugs. Herein we present dry powder inhaler (DPI) formulations of amorphous drug nanoparticles, where the effects of the lactose carrier particle shape (i.e. tomahawk, needle, and pollen) in two size ranges (i.e. ≈ 50–70 μm and 14–20 μm) on the aerosolization efficiency of the drug-carrier particle blends are investigated. Spherical ciprofloxacin nanoparticles (≈ 300 nm) prepared by drug-polyelectrolyte complexation are used as the amorphous nanoparticle model. The aerosolization efficiency is characterized by the emitted dose (ED), dispersibility, fine particle fraction (FPF), and mass median aerodynamic diameter (MMAD). Contrary to the findings in DPI delivery of drug microparticles, where the needle (NL) and pollen (PL) shaped lactose particles are often reported to exhibit superior aerosolization efficiency than the commercial tomahawk (CL) lactose particles, our results at two theoretical drug loadings (i.e. 10 and 20%) indicate that the CL particles yield equivalent aerosolization efficiencies as the NL and PL particles for the large and small carrier particle size ranges, respectively. The ED, dispersibility, FPF, and MMAD of the better drug-carrier particle blends (i.e. large/small CL, small PL, and large NL) are ≈ 70–80%, 20–30%, 16–18%, and 5.7–6.2 μm, respectively.

Influence of lactose carrier particle size on the aerosol performance of budesonide from a dry powder inhaler

The purpose of this study was to evaluate the effect of carrier particle size on properties of dry powder and its effect on dry powder inhaler (DPI) performance. Commercial α-lactose-monohydrate, a commonly used carrier in DPI formulations, was carefully sieved to obtain different lactose size fractions, namely Lac A (90–125μm), Lac B (63–90μm), Lac C (45–63μm), Lac D (20–45μm), and Lac E (<20μm). The lactose samples were analysed in terms of size, shape, solid state, density, and flowability. Lactose particles were blended with budesonide (<5μm) powder to generate five different formulations. These formulations were then evaluated in terms of budesonide–lactose adhesion properties, drug content homogeneity, and in vitro aerosolisation performance. The results demonstrated that lactose samples with smaller particle volume mean diameter have higher amorphous lactose content, higher true density (linear, r2=0.9932), higher surface smoothness (linear, r2=0.8752), smaller angularity (linear, r2=0.921), smaller bulk density, higher porosity (linear, r2=0.914), poorer flowability, and higher specific surface area. In general, the smaller the lactose particles the smaller are the budesonide–lactose adhesion properties. Budesonide formulated with smaller lactose particles exhibited smaller aerodynamic diameter and higher amounts of budesonide were delivered to lower stages of the impactor indicating improved DPI aerosolisation performance. However, the use of lactose particles with smaller volume mean diameter had a detrimental effect on budesonide content homogeneity and caused an increase in the amounts of budesonide deposited on oropharyngeal region. Therefore, particle size of the lactose within dry powder inhaler formulations should be selected carefully. Accordingly, higher drug aerosolisation efficiency of lactose particles with smaller size may have to be balanced due to considerations of other disadvantages including poorer flowability, reduced formulation stability, higher potential side effects, and higher dose variability.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 21Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9–11, 2010

Background: Various lactose carrier particle properties arerecognised as being relevant to the fine particle dose (FPD)from dry powder inhalers (DPIs). Particularly the presence ofa certain amount of lactose fines and smooth, clean carriersurfaces are believed to have a positive effect on drug redispersionduring inhalation.Methods: Adhesive mixtures were prepared with budesonideand different marketed carrier products from differentmanufacturers, having different particle size distributions,and tested upon FPD from two different DPI concepts, havingdifferent de-agglomeration principles, at 4 kPa. FPDs wererelated to different carrier properties to investigate whetherthe claims and suppositions made in literature regarding theeffects of these properties are irrefutably true.Results: The effects of carrier size distribution, carriersurface payload, the amount of lactose fines and surfacerugosity on FPD in this study appeared to depend on thetype of DPI concept used. In a number of examples the effectswere even opposite for the two different DPIs used.Conclusions: The findings underline the hypothesis that parametersand variables relevant to drug re-dispersion from adhesivemixtures during inhalation interact with each other. Theeffect of any of these parameters on FPD may depend on thechoicesmade for the others, as for the choice of DPI in this study.It can be shown that the effect of variations in carrier propertieson FPD may widely be eliminated by using an effective (e.g.classifier based) de-agglomeration principle, as in the Novolizer.

Relationship between sine random vibrations, resonance and drug content uniformity.

The effect of sine random vibrations on the segregation tendency of 3 ordered power mixes was studied. Ordered mixes containing either Emdex, Dipac or recrystallized lactose carrier particles mixed with 0.5% fine-particle potassium chloride were prepared. It was found that the coefficients of variation of drug content in samples removed from the ordered mixes following random vibration were, in general, lower than those derived from vibration at equivalent single frequencies. Ordered mixes vibrated at low centre-frequencies were found to be most prone to slight demixing and under these conditions, a vibration bandwidth of 30 Hz produced more de-mixing than a 10 Hz bandwidth. Most ordered mixes were considered to be segregation free following random vibration.

Effect of vibration time, frequency and acceleration on drug content uniformity.

The effect of different vibration conditions on the segregation tendency of three ordered powder mixes was studied. Segregation of the powders was measured using a cylinder, composed of interlocking units for sampling purposes, mounted on a vibration rig. Ordered mixes containing either Emdex or recrystallized lactose carrier particles mixed with 0.5% fine-particle potassium chloride were stable, except for slight segregation that occurred under severe vibration conditions at frequencies below 50 Hz and accelerations above 22 m s-2. Powder mixes of Dipac with potassium chloride were unstable at most vibration conditions from 20 to 1000 Hz and 7.4 to 29.4 m s-2. The intensity of segregation in vibrated mixes of Dipac with potassium chloride was most marked at frequencies below 50 Hz and accelerations above 22 m s-2. These vibration conditions were found to occur in several commonly-used types of tableting presses. When vibration was prolonged, for periods of 30 to 60 min, there was increased segregation found in ordered mixes.