Tralokinumab pharmacokinetics and tolerability when administered by different subcutaneous injection methods and rates
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OBJECTIVE: Tralokinumab, administered as two 1-mL subcutaneous injections every 2 weeks, at the target dose 300 mg, has been shown to improve lung function in patients with asthma. This study evaluated the pharmacokinetic (PK) and tolerability profile of tralokinumab 300 mg when administered by different rates of subcutaneous injection, as part of a pilot investigation of new injection regimens. METHODS: This phase I study randomized 60 healthy adults to receive 300 mg tralokinumab, as two 1-mL subcutaneous injections, each delivered over 10 seconds, or one 2-mL injection delivered over 10 seconds (12 mL/min), 1 minute (2 mL/min), or 12 minutes (0.167 mL/min). RESULTS: No differences in the PK profile of tralokinumab were observed between cohorts. Immediately following injection, injection-site pain intensity (mean (SD)) was lowest following 0.167 mL/min injection (5.1 mm (8.0) via visual analog scale (VAS)) and greatest following 12 mL/min injection (41 mm (27.7) via VAS); with mean injection-site pruritus intensity low for all participants. Two types of local injection-site reactions were observed: erythema (58.3%) and hematoma/bleeding (18.3%). All treatment-emergent adverse events were mild. CONCLUSIONS: Tralokinumab 300 mg is well tolerated, with comparable PK, when administered by a single 2-mL injection at different rates of subcutaneous injection vs. two 1-mL injections.
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Understanding Subcutaneous Tissue Pressure for Engineering Injection Devices for Large-Volume Protein Delivery.

Subcutaneous injection allows for self-administration of monoclonal antibodies using prefilled syringes, autoinjectors, and on-body injector devices. However, subcutaneous injections are typically limited to 1 mL due to concerns of injection pain from volume, viscosity, and formulation characteristics. Back pressure can serve as an indicator for changes in subcutaneous mechanical properties leading to pain during injection. The purpose of this study was to investigate subcutaneous pressures and injection site reactions as a function of injection volume and flow rate. A pressure sensor in the fluid path recorded subcutaneous pressures in the abdomen of Yorkshire swine. The subcutaneous tissue accommodates large-volume injections and with little back pressure as long as low flow rates are used. A 1 mL injection in 10 seconds (360 mL/h flow rate) generated a pressure of 24.0 ± 3.4 kPa, whereas 10 mL delivered in 10 minutes (60 mL/h flow rate) generated a pressure of 7.4 ± 7.8 kPa. After the injection, the pressure decays to 0 over several seconds. The subcutaneous pressures and mechanical strain increased with increasing flow rate but not increasing dose volume. These data are useful for the design of injection devices to mitigate back pressure and pain during subcutaneous large-volume injection.

Automated actuation of nasal spray products: effect of hand-related variability on the in vitro performance of Flonase nasal spray.

OBJECTIVE: To determine if patient-related variability for adults and children recorded during hand spraying of Flonase with an instrumented nasal spray results in significant differences in spray weight, droplet size or spray pattern. METHODS: Settings derived from adult and pediatric participants hand-spraying nasal sprays were implemented into force and velocity-controlled automated actuators. Spray weight, droplet size distribution and spray pattern tests were performed using iterations of actuation force (AF) and force rise, hold and fall times. Travel, actuation velocity and release velocity settings were also investigated. RESULTS: The variability measured in adult-derived actuator settings did not result in any differences in spray weight, but pediatric participants spraying with low AF and/or compression velocity (CV) were predicted to receive a partial dose or no dose at all under some circumstances. Droplet size characteristics were sensitive to the hand-based variability, with actuation force, force rise time and CV hand-related settings all resulting in significant differences in the droplet size. CONCLUSIONS: This study demonstrated how variability in hand spraying by adults and pediatric patients could result in differences in nasal spray characteristics, thus demonstrating the importance of monitoring how the prospective patient groups are likely to use a nasal spray.

Automated actuation of nasal spray products: determination and comparison of adult and pediatric settings.

OBJECTIVE: To determine and compare patient-relevant settings for automated nasal spray actuation stations from adult and pediatric hand data. METHODS: Twenty adults and 20 pediatric participants were asked to spray Flonase(®) Nasal Spray six times in a Hand Actuation Monitor, which records force and displacement data in 5-ms increments. Settings for force- and velocity-controlled actuation stations were determined from the data using a predefined set of calculations. RESULTS: For force-controlled settings, hand spraying by children resulted in lower actuation forces, and longer force rise, hold and fall times. Pediatric velocity-controlled actuator settings were lower for travel, compression velocity, and release velocity compared with adults. The pediatric spray weight recorded during hand spraying was significantly lower than the spray weight generated by adult participants. Adult participants were able to generate full sprays with each attempt, whereas 11 out of 120 actuations performed by pediatric participants resulted in partial and 'no spray' events. No differences in spray weight were detected in participants who chose to actuate the nasal spray using both hands. CONCLUSIONS: A predefined set of calculations was used to determine patient-relevant settings from force and displacement hand data for force- and velocity-controlled automated actuation stations. This study determined and quantified, for the first time, the differences in hand spraying between adults and children.

Use of flexible weighted nasal spray dip tubes to improve product performance.

BACKGROUND: Nasal spray performance attributes are related to the formulation, device, and patient, with the delivery of precise doses with minimal waste being key goals during product development, especially for potent and high cost drugs. METHODS: We investigated the influence of replacing the traditional rigid dip tube with a weighted, flexible dip tube on spray weight and tail-off characteristics in five over-the-counter nasal sprays representing varying viscosities, metering chamber volumes, formulation volumes, and active ingredients. Nasal sprays were actuated in ways representative of patient use. RESULTS: Compared to inherently curved, rigid dip tubes that were actuated in their worst case orientation, we found that weighted, flexible dip tubes (that seek the lowest point in the bottle irrespective of orientation) significantly increase the number of full sprays (in four out of five products) and reduce the duration of the tail-off period (in three out of five products). Shaking significantly decreased the spray weight in Afrin, Rite Aid, and Zicam nasal sprays using the original rigid dip tubes, and Afrin, Nostrilla, and Rite Aid when flexible dip tubes were used. CONCLUSIONS: This study demonstrated that flexible dip tubes can improve the performance of many nasal sprays, and that shaking may have negative effects on spray weight uniformity.