Fine excipient materials in carrier-based dry powder inhalation formulations: The interplay of particle size and concentration effects.

The contributions of fine excipient materials to drug dispersibility from carrier-based dry powder inhalation (DPI) formulations are well recognized, although they are not completely understood. To improve the understanding of these contributions, we investigated the influences of the particle size of the fine excipient materials on characteristics of carrier-based DPI formulations. We studied two particle size grades of silica microspheres, with volume median diameters of 3.31 µm and 8.14 µm, as fine excipient materials. Inhalation formulations, each composed of a lactose carrier material, one of the fine excipient materials (2.5% or 15.0% w/w), and a drug (fluticasone propionate) material (1.5% w/w) were prepared. The physical microstructure, the rheological properties, the aerosolization pattern, and the aerodynamic performance of the formulations were studied. At low concentration, the large silica microspheres had a more beneficial influence on the drug dispersibility than the small silica microspheres. At high concentration, only the small silica microspheres had a beneficial influence on the drug dispersibility. The results reveal influences of fine excipient materials on mixing mechanics. At low concentration, the fine particles improved deaggregation and distribution of the drug particles over the surfaces of the carrier particles. The large silica microspheres were associated with a greater mixing energy and a greater improvement in the drug dispersibility than the small silica microspheres. At high concentration, the large silica microspheres kneaded the drug particles onto the surfaces of the carrier particles and thus impaired the drug dispersibility. As a critical attribute of fine excipient materials in carrier-based dry powder inhalation formulations, the particle size demands robust specification setting.

Critical attributes of fine excipient materials in carrier-based dry powder inhalation formulations: The particle shape and surface properties.

The potential of fine excipient materials to improve the aerodynamic performance of carrier-based dry powder inhalation (DPI) formulations is well acknowledged but not fully elucidated. To improve the understanding of this potential, we studied two fine excipient materials: micronized lactose particles and silica microspheres. Inhalation formulations, each composed of a coarse lactose carrier, one of the two fine excipient materials (0.0-15.0 % w/w), and a spray-dried drug (fluticasone propionate) material (1.5 % w/w) were prepared. The physical structure, the flow behavior, the aerosolization behavior, and the aerodynamic performance of the formulations were studied. The two fine excipient materials similarly occupied carrier surface macropores. However, only the micronized lactose particles formed agglomerates and appeared to increase the tensile strength of the formulations. At 2.5 % w/w, the two fine excipient materials similarly improved drug dispersibility, whereas at higher concentrations, the micronized lactose material was more beneficial than the silica microspheres. The findings suggest that fine excipient materials improve drug dispersibility from carrier-based DPI formulations at low concentrations by filling carrier surface macropores and at high concentrations by forming agglomerates and/or enforcing fluidization. The study emphasizes critical attributes of fine excipient materials in carrier-based DPI formulations.

Insights into the potential of rheological measurements in development of dry powder inhalation formulations.

Study of flow is a key to development of dry powder inhalation formulations. Various static (bulk) and dynamic rheological measurements are used to study different aspects of powder flow and packing. Among rheological measurements, the permeability and the fluidization energy are, conceptually, most relevant to dispersion of dry powder inhalation formulations. The aim of the current study was to test the robustness and the range of applications of the two measurements, among other rheological measurements. To this end, we prepared and studied a series of ternary, carrier-based dry powder inhalation formulations. The formulations were mixtures of coarse-fine excipient (α-lactose monohydrate) blends, with different fine excipient concentrations (0.0-15.0 % w/w), and a spray-dried drug (fluticasone propionate) material. The excipient blends were characterized in terms of morphology, size, crystallinity, and rheological properties. The formulations were evaluated in vitro using a low resistance inhalation device, the Cyclohaler®, and a high resistance inhalation device, the Handihaler®. The study design aimed to complement literature data. Bulk rheological measurements, specifically the bulk density, the compressibility, and the permeability, exhibited satisfactory precision and could demonstrate changes in powder composition and structure. They hold a potential for use as critical material attributes to aid monitoring and optimization of carrier-based dry powder inhalation formulations in quality-by-design systems. On the other hand, dynamic rheological measurements, specifically the basic flowability energy, the specific energy, and the fluidization energy, generally exhibited high variability, which obscured interpretation of the measurements and implied heterogeneous powder structures. The fluidization energy could, nevertheless, convey structural changes taking place during powder fluidization.

The Application of Modern Powder Characterisation Methods in Product and Process Development of Solid Dosage Forms.

The pharmaceutical industry still produces the vast majority of their products, from powdered ingredients, in the form of solid doses. Despite their ubiquity, powders are difficult materials to characterise and understand, as evidenced by the frequent problems encountered during manufacture. The reason for this is their complex rheological behaviour coupled with numerous environmental variations, such as humidity. Equally, the range of processes used to manipulate powders subject them to extremes of stress from high compaction loads seen in compactors to the dispersed state seen in fluidised bed dryers. Thus, it is evident that ensuring that the powders characteristics are compatible with the way they are to be processed is a clear prerequisite for today's Quality by Design driven manufacturing. Modern, computer controlled instrumental techniques, including the dynamic, bulk and shear property measurements have enabled direct measurements of a powders response to aeration, consolidation and flow rate - all at low stresses - as well as quantifying shear and bulk properties (such as density, compressibility and permeability). In order to demonstrate how fully characterising a powder can be used in the design, operation and troubleshooting of processes, this paper will present examples of common pharmaceutical unit operations and the different powder characteristics that most influence the performance of each.

Patterns and frequency of anxiety in women undergoing gynaecological surgery.

AIMS: Within a gynaecological surgical setting to identify the patterns and frequency of anxiety pre- and postoperatively; to identify any correlation between raised anxiety levels and postoperative pain; to identify events, from the patients' perspective, that may increase or decrease anxiety in the pre- and postoperative periods. BACKGROUND: It is well documented that surgery is associated with increased anxiety, which has an adverse impact on patient outcomes. Few studies have been conducted to obtain the patient's perspective on the experience of anxiety and the events and situations that aggravate and ameliorate it. METHOD: The study used a mixed method approach. The sample consisted of women undergoing planned gynaecological surgery. Anxiety was assessed using the State Trait Anxiety Inventory. Trait anxiety was measured at the time of recruitment. State anxiety was then assessed at six time points during the pre- and postoperative periods. Postoperative pain was also measured using a 10 cm visual analogue scale. Taped semi-structured telephone interviews were conducted approximately a week after discharge. RESULTS: State anxiety rose steadily from the night before surgery to the point of leaving the ward to go to theatre. Anxiety then increased sharply prior to the anaesthetic decreasing sharply afterwards. Patients with higher levels of trait anxiety were more likely to experience higher levels of anxiety throughout their admission. Elevated levels of pre- and postoperative anxiety were associated with increased levels of postoperative pain. Telephone interviews revealed a range of events/situations that patients recalled distressing them and many were related to inadequate information. CONCLUSION: This study found higher rates of anxiety than previously reported and anxiety levels appeared raised before admission to hospital. This has important clinical and research implications. RELEVANCE TO CLINICAL PRACTICE: Patients with high levels of anxiety may be identified preoperatively and interventions designed to reduce anxiety could be targeted to this vulnerable group. Patient experiences can inform the delivery of services to meet their health needs better.