The Cohesive-Adhesive Balances in Dry Powder Inhaler Formulations I: Direct Quantification by Atomic Force Microscopy

PURPOSE: To obtain a quantitative assessment of the cohesive and adhesive force balance within dry powder inhaler formulations. METHODS: The atomic force microscope (AFM) colloid probe technique was used to measure the adhesive and cohesive force characteristics of dry powder systems containing an active component (budesonide, salbutamol sulphate) and alpha-lactose monohydrate. To minimize the variations in contact area between colloid probe and substrates, nanometer smooth crystal surfaces of the drugs and the excipient were prepared. RESULTS: The uniformity in contact area allowed accurate and reproducible force measurements. Cohesive-adhesive balance (CAB) graphs were developed to allow direct comparison of the interaction forces occurring in model carrier-based formulations. A salbutamol sulphate-lactose system revealed a significant tendency for the two materials to adhere, suggesting a propensity for the powder to form a homogenous blend. In contrast, the budesonide-lactose system exhibited strong cohesive properties suggesting that the formulation may exhibit poor blend homogeneity and potential for segregation upon processing and handling. CONCLUSIONS: The novel approach provides a fundamental insight into the cohesive-adhesive balances in dry powder formulations and further understanding of powder behavior.     

Influence of Mouthpiece Geometry on the Aerosol Delivery Performance of a Dry Powder Inhaler

Purpose

To investigate the influence of mouthpiece geometry on the amount of throat deposition and device retention produced using a dry powder inhaler (Aerolizer^®), along with the subsequent effect on the overall inhaler performance.

Materials and Methods

Computational Fluid Dynamics analysis of the flowfield generated in the Aerolizer^® with various modified mouthpiece geometries (including cylindrical, conical and oval designs) was used in conjunction with experimental dispersions of mannitol powder using a multi-stage liquid impinger to determine how the overall inhaler performance varied as the mouthpiece geometry was modified.

Results

Geometry of the inhaler mouthpiece had no effect on device retention or the inhaler dispersion performance. In contrast, the mouthpiece geometry strongly affected the amount of throat deposition by controlling the axial component of the exit air flow velocity. The radial motion of the emitted aerosol jet was found to have little effect on throat deposition in representative mouth–throat models. Despite the reduced throat deposition, there was no difference in the overall inhaler performance.

Conclusions

For cases where low throat deposition is a key design parameter, this study demonstrates that the amount of throat deposition can be reduced by making minor modifications to the inhaler mouthpiece design.

     

Influence of Realistic Inspiratory Flow Profiles on Fine Particle Fractions of Dry Powder Aerosol Formulations

Purpose The purpose of the study was to determine how air flow profiles affect fine particle fractions (FPF) (<5 μm) from dry powder aerosol formulations and whether laser diffraction (LD) could be used to measure FPF of aerosols generated by variable flows. Materials and Methods Carrier-based formulations containing 1.5% w/w micronized salbutamol base blended with the 63–90 μm fraction of alpha-lactose monohydrate or sorbitol or maltose were aerosolised from a model glass device using either a constant flow rate or a predetermined flow profile. The FPFs of the same aerosolised particles were first measured by LD and then by a liquid impinger. Volunteer inhalation airflow profiles and 3-phase (acceleration, constant flow rate and deceleration) square wave airflow profiles were generated using the Electronic Lung™ and an Inhalation Profile Recorder. Similar experiments were conducted for a carrier-free formulation from the Bricanyl Turbohaler™. Results Salbutamol FPFs of all carrier-based formulations were found to increase by increasing the initial flow increase rate (FIR) from 200 to 600 l min⁻¹ s⁻¹ although they could be placed in an increasing order of maltose blend < sorbitol blend < lactose blend. A significant linear correlation was found between FPFs measured by LD and by inertial impaction (R ² = 0.95, p < 0.01, ANOVA). For the Bricanyl Turbohaler™, increasing FIR from 120 to 600 l min⁻¹ s⁻¹ for a constant peak flow rate (PFR) of 60 l min⁻¹ increased the mean Terbutaline FPF from 18.2% to 45.5%. For the volunteer inhalation profiles, a higher FIR tended to be associated with higher PFR, leading to a marked increase in drug FPF due to the combined effect of FIR and PFR. Conclusion Drug FPF from either carrier-free or carrier-based formulations is determined by both FIR and PFR. LD is a viable technique to measure the performance of dry powder aerosol formulations at realistic inspiratory flow profiles.     

The Influence of Fine Excipient Particles on the Performance of Carrier-Based Dry Powder Inhalation Formulations

The inclusion of a small amount of fine particle excipient in a carrier-based dry powder inhalation system is a well researched technique to improve formulation performance and is employed in the pharmaceutical industry. The removal of intrinsic fines from a lactose carrier has been found to decrease formulation performance, whereas adding fines of many different materials into formulations increased performance. Changing the particle size of these fines, the amount added and the technique by which they were prepared also affected formulation behaviour. Despite this body of research, there is disagreement as to the mechanism by which fines improved formulation performance, with two main hypotheses presented in the literature. The first hypothesis suggested that fines prevent the drug from adhering to the strongest binding sites on the carrier, whilst the second proposed that fine particles of drug and excipient form mixed agglomerates that are more easily dispersed and deaggregated during aerosolisation. The evidence in support of each hypothesis is limited and it is clear that future research should aim to produce stronger mechanistic evidence. The investigation of interparticulate interactions using techniques such as atomic force microscopy and inverse gas chromatography may prove useful in achieving this aim.     

Investigations on the Mechanism of Magnesium Stearate to Modify Aerosol Performance in Dry Powder Inhaled Formulations

The potential of the force control agent magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient-blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry and single particle aerosol mass spectrometry (SPAMS), and particle size, morphology, and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0% to 10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model active pharmaceutical ingredients were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor and also with SPAMS using a Breezhaler^® inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared with blends without force control agent, low-shear blending of MgSt increases the FPF of the model drug SX, whereas high-shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt, and additional information in terms of dispersibility of fine particles could be generated.     

The Role of Fines in the Modification of the Fluidization and Dispersion Mechanism Within Dry Powder Inhaler Formulations

PURPOSE: To investigate the role of in situ generated fine excipient particles on the fluidization and aerosolization properties of dry powder inhaler (DPI) formulations. MATERIALS AND METHODS: Carrier based DPI formulations were prepared under low and high shear blending. Powder rheometery was utilized to measure bulk powder properties in a consolidated and aerated state. Powder fluidization and aerosolization characteristics were related to bulk powder properties using high speed imaging and inertial impaction measurements. RESULTS: High shear blending of formulations resulted in the in situ generation of excipient fines, which corresponded to an increase in aerosolization efficiency. The generation of fines were shown to increase the tensile strength and free volume of the carrier, which resulted in a characteristic change in the fluidization properties, as observed by high speed imaging. The increase in minimum fluidization velocity and aerodynamic drag forces required to aerate the powder may provide the source of energy for the increase in fine particle re-suspension. CONCLUSIONS: The in situ generation of excipient fines affect bulk powder properties of DPI formulations, which directly affects fluidization and aerosolization behaviour of DPI formulations. The study suggests an alternative mode of action by which fines increase DPI formulation performance.     

Fundamental Effects of Particle Morphology on Lung Delivery: Predictions of Stokes' Law and the Particular Relevance to Dry Powder Inhaler Formulation and Development

Key factors that contribute to the aerodynamic properties of aerosol particles are found in Stokes' law. These factors may be monitored or controlled to optimize drug delivery to the lungs. Predictions of the aerodynamic behavior of therapeutic aerosols can be derived in terms of the physical implications of particle slip, shape and density. The manner in which each of these properties have been used or studied by pharmaceutical scientists to improve lung delivery of drugs is readily understood in the context of aerosol physics. Additional improvement upon current aerosol delivery of particulates may be predicted by further theoretical scrutiny.     

Drug Delivery to the Skin From Sub-micron Polymeric Particle Formulations: Influence of Particle Size and Polymer Hydrophobicity

Purpose  To investigate the influence of particle size and polymer properties on the topical delivery of a lipophilic “active” species (Nile Red (NR)) from sub-micron polymeric particles. Methods  Three poly-(ε-caprolactone) (CAPA) formulations were examined to assess the impact of particle size. Three other formulations, based on cellulose acetate butyrate (CAB), CAPA and polystyrene were studied to address the role of polymer hydrophobicity. In vitro skin permeation, and confocal microscopy and stratum corneum (SC) tape-stripping were used to evaluate the cutaneous disposition of NR. Results  NR delivery into the SC was greater from the larger particles, the overall smaller surface area of which enhanced the “leaving tendency” of the lipophilic “active”. Skin uptake of NR (measured as “%payload released”) from polystyrene, CAPA and CAB particles increased with decreasing polymer hydrophobicity (polystyrene > CAPA > CAB) as expected. Confocal microscopy revealed that NR released from the particles accumulated in, and penetrated via, lipid domains between the SC corneocytes. The particles showed affinity for hairs, and concentrated on the skin surface at the follicular openings. Conclusions  Delivery of a model drug to the skin from sub-micron polymeric particle formulations is sensitive to the particle size and the relative hydrophobicity of the carrier.     

Study of a pingyangmycin delivery system: Zein/Zein-SAIB in situ gels

Venous malformations (VM) are common vascular abnormality, and their management remains difficult. Pingyangmycin hydrochloride (PYM) is a useful sclerosant to treat venous malformations. This study was aimed to evaluate the effect of a new drug delivery system, PYM-loaded Zein/Zein-sucrose acetate isobutyrate (SAIB) in situ gels, in gelling and extending the local release of PYM. It was demonstrated that in vitro and in vivo release of PYM from the in situ gels could be extended up to 7 and 4 days, respectively. SAIB could significantly cut down the initial burst of PYM from the in situ gels (P<0.05). The possible gel forming and drug release mechanisms were described according to the morphology analysis by atomic force microscopy (AFM), optical microscopy and SEM. The gel forming efficacy and the viscosity of in situ gel solutions were satisfying.     

The Preparation of Dextran Microspheres in an All-Aqueous System: Effect of the Formulation Parameters on Particle Characteristics

Purpose. The purpose of this study was to investigate the effect of the formulation parameters on the characteristics of dextran-based microspheres, prepared in an all-aqueous system. Methods. Dextran microspheres were formed by polymerization of methacryloyl groups attached to dextran (dexMA), emulsified in an aqueous poly(ethylene glycol) (PEG) solution. DexMA/PEG/water phase diagrams were established. Results. The binodals in the phase diagrams shifted to higher concentrations of dextran and PEG with decreasing molecular weight of both polymers, and with increasing degree of MA substitution. The volume-number mean diameter of the microspheres, varied between 2.5 and 20 m. For a given formulation, the particle size was independent of the PEG/dexMA volume ratio > 40 and increased for volume ratios < 40. Furthermore, larger particles were obtained with decreasing viscosity of the continuous phase and increasing viscosity of the discontinuous phase. Conclusions. Particle characteristics of dextran microspheres prepared in an all-aqueous system, among which the size and initial water content, can be tailored by adjusting the formulation parameters.participant in the Groningen-Utrecht Institute for Drug Exploration (GUIDE)