The Effect of Placement and Group Size on the Use of an Automated Brush by Groups of Lactating Dairy Cattle.

Mechanical brushes are often provided on dairy farms to facilitate grooming. However, current brush designs do not provide data on their use, and thus little is known about the effects of group size and placement of brushes within the pen. The objectives of this study were to automatically detect brush use in cow groups and to investigate the influence of (1) group size and the corresponding cow-to-brush ratio and (2) brush placement in relation to the lying stalls and the feeding and drinking areas. We measured brush use in groups of 60, 48, 36, and 24 cows, with the brush placed either in the alley adjacent to the feed bunk and water trough or in the back alley. Cows used the brush for longer when it was placed in the feed/water alley compared to when placed in the back alley. Average brush use per cow increased when cows were housed in smaller groups, but the brush was never in use more than 50% of the day, regardless of group size. We conclude that brush use increases when availability is increased and when the brush is placed closer to the feed and water.

Solid-state stability of spray-dried insulin powder for inhalation: chemical kinetics and structural relaxation modeling of Exubera above and below the glass transition temperature.

The effect of temperature on the chemical stability of an amorphous spray-dried insulin powder formulation (Exubera) was evaluated in the solid state at constant moisture content. The chemical stability of the powder was assessed using reversed-phase high-performance liquid chromatography (RP-HPLC) and high-performance-size exclusion chromatography (HP-SEC). The major degradants in spray-dried insulin produced during heat stressing were identified as A21-desamidoinsulin (A21) and high molecular weight protein (HMWP). As expected, the rates of formation of A21 and HMWP were observed to increase with temperature. A stretched-time kinetic model (degradation rate is proportional to the square root of time) was applied to the degradant profiles above and below the glass transition temperature (T(g)) and apparent reaction rate constants were determined. Below T(g), isothermal enthalpy of relaxation measurements were used to assess the effect of temperature on molecular mobility. The formation of A21 and HMWP was found to follow an Arrhenius temperature dependence above and below the T(g). Comparison of reaction rate constants to those estimated from structural relaxation experiments suggests that the reaction pathways to form A21 and HMWP below the T(g) may be coupled with the molecular motions involved in structural relaxation.

The design and performance of the exubera pulmonary insulin delivery system.

The Exubera system (Pfizer, New York, NY/Nektar Therapeutics, San Carlos, CA) is an integration of five major new technologies: protein formulation, powder processing, powder filling, drug packaging, and delivery device. The product provides a simple interface, where the patient interacts only with the delivery device and powder packaging. These components were designed together to assure repeatable dosing when used by a wide range of patients under real-world life-style and handling conditions. The device design is purely mechanical, using patient-generated compressed air as the energy source. Upon actuation, a sonic discharge of air through the novel release unit reproducibly extracts, de-agglomerates, and disperses the inhalation powder into a respirable aerosol. A clear holding chamber allows for patient feedback via dose visualization and separates aerosol cloud generation from the inspiratory effort. The Exubera product was tested under a wide range of typical use conditions and potential misuse scenarios and following long-term usage in clinical trials. These comprehensive characterization programs demonstrated robust aerosol and mechanical performance, confirming the design intent of the inhaler. These studies provide assurance of consistent and reliable dose delivery in a real-world use of the product.

Peptide drug delivery strategies for the treatment of diabetes.

Drug delivery strategies for diabetes have included a wide range of scientific and engineering approaches, including molecular design, formulation and device design. Molecular engineering has resulted in modified pharmacokinetics, such as rapid-acting or slow-release analogs of insulin. Long-acting insulin formulations are designed to meet the body's basal needs, whereas rapid-acting insulin formulations are designed to cover mealtime glucose spikes. Furthermore, the discovery of new therapeutic biomolecules, which like insulin need to be injected, will drive the need for more flexible and universally applicable delivery systems. Formulation design, such as particle engineering, can be used to modify pharmacokinetic profiles. In general, suspension formulations of insulin commonly demonstrate reduced solubility and result in sustained release. Similarly, depot injections can result in precipitation of insulin at the site of injection, again resulting in lower solubility and sustained release. Particle engineering also has been applied to pulmonary formulations for delivery to the deep lung. The creation of novel drug delivery methods for the treatment of diabetes should remove barriers to insulin therapy and increase patient acceptance and compliance. Eliminating routine injections with needle-free injectors, insulin pumps, inhalation, buccal sprays, intra-nasal delivery, and transdermal patches may offer increasingly attractive alternatives.

EXUBERA: pharmaceutical development of a novel product for pulmonary delivery of insulin.

Development of a product for pulmonary delivery of insulin presented significant technology challenges for this first-in-class pharmaceutical product. These included developing (a) a chemically stabilized protein, (b) a dry powder formulation exhibiting required aerosol physical characteristics, (c) low-dose powder filling and packaging technology, and (d) a mechanical device for powder dispersal and reliable dosing to the patient. The insulin drug is formulated using a novel excipient combination to create a powder with a high glass transition temperature (Tg). The high Tg minimizes insulin mobility (thus reactivity), enabling ambient storage conditions. The formulation composition results in minimal hygroscopicity, where customized packaging produced product ruggedness to humidity. The formulated insulin powder is manufactured by spray-drying. This technology was further engineered to produce the desired reproducible powder characteristics with tight control over particle size and moisture content. A solution step prior to drying assures homogeneity and minimizes dependence on the physical form of the components. Novel low-dose filling and packaging technology reproducibly meters milligram quantities of microfine powder to meet stringent quality requirements for dose control. The technology for accurate, uniform, high-throughput metering of drug powders allows for automation and is scaleable for commercial operations. Finally, the mechanical device design provides powder deagglomeration and dispersion processes in a reusable dry powder inhaler with unique characteristics. The device was designed to rely on patient-generated compressed air as the energy source. A sonic discharge of air through the novel TransJector reproducibly extracts, deagglomerates, and disperses the inhalation powder. A clear holding (spacer-type) chamber allows for patient feedback via dose visualization, and separates powder dispersal from the inspiratory effort. The EXUBERA [Pfizer (New York, NY) and sanofi-aventis (Paris, France)] product provides insulin into the bloodstream with similar reproducibly and effectiveness as subcutaneous injections.