Enabling faster subcutaneous delivery of larger volume, high viscosity fluids.

OBJECTIVES: Many current subcutaneous (SC) biologic therapies may require >1 mL volume or have increased viscosity, necessitating new delivery system approaches. This study evaluated 2-mL large-volume autoinjector (LVAI) delivery performance across varying solution viscosities and design inputs to assess the design space and identify configurations that produce practical injection times. METHODS: Investigational LVAI delivery duration and volume, depot location, and tissue effects were examined in both air and in vivo models across various pre-filled syringe (PFS) cannula types (27 G Ultra-thin wall [UTW], 27 G special thin wall [STW], or 29 G thin-wall [TW]), drive spring forces (SFLOW or SFHIGH), and Newtonian solutions (2.3-50 centipoise [cP]). RESULTS: Within each design configuration, increasing PFS internal diameters and spring forces reduced delivery times, while increasing viscosity increased times. The 27 G UTW PFS/SFHIGH combination achieved shorter delivery times across all injection conditions, with 2 mL in vivo durations <15 seconds at ≤31 cP and routinely <20 seconds at 39 and 51 cP, with nominal and transitory tissue effects. CONCLUSION: PFS cannula and spring force combinations can be tailored to achieve various injection durations across viscosities, while UTW PFS enables faster rates to potentially better accommodate human factors during LVAI injection, especially at high viscosity.

Novel cannula design improves large volume auto-injection rates for high viscosity solutions.

A prototype reusable large-volume (2 mL) autoinjector (LVAI) was designed to compare injection performance of a novel 27 gauge ultra-thin wall (UTW) pre-filled syringe (PFS) cannula (8 mm external cannula length, 14.4 mm total needle length) against an existing 27 gauge special thin wall (STW) PFS cannula (12.7 mm external cannula length, 19 mm total needle length) across a range of injectate viscosities (2.3-30 cP) in a series of in vivo feasibility studies in swine. The UTW cannula had an approximately 30% greater cross-sectional lumen area than the STW cannula. The target exposed needle length was adjusted to ensure appropriate needle penetration depth and achieve injectate deposition in the subcutaneous (SC) tissue. Delivery time and volume, injection site leakage, injectate depot location, and local tissue effects were examined. The STW and UTW cannulae both provided effective SC delivery of contrast placebo solutions, and were able to accommodate injectate viscosity up to 30 cP without quantifiable leakage from the tissue and with minor tissue effects which resolved within 1-2 hours. Delivery times at each viscosity were significantly different between PFS types with the UTW PFS producing faster delivery times. In a histological substudy of the UTW cannula using injectate viscosities up to 50 cP, injection site reactions were rare and, when present, were of minimal severity. This series of studies demonstrates the feasibility of LVAI SC injection and informs autoinjector and PFS design considerations. Use of a UTW cannula may enable more rapid LVAI injections with minimal tissue effects, especially for higher viscosity formulations.

Evaluating the Impact of Human Factors and Pen Needle Design on Insulin Pen Injection.

BACKGROUND: Limited published data exists quantifying the influence of human factors (HF) and pen needle (PN) design on delivery outcomes of pen injection systems. This preclinical in vivo study examines the impact of PN hub design and applied force against the skin during injection on needle penetration depth (NPD). METHOD: To precisely locate injection depth, PN injections (20 µl; 2 IU, U-100 volume equivalent) of iodinated contrast agent were administered to the flank of Yorkshire swine across a range of clinically relevant application forces against the skin (0.25, 0.75, 1.25, and 2.0 lbf). The NPD, representing in vivo needle tip depth in SC tissue, from four 32 G × 4 mm PN devices (BD Nano™ 2nd Gen and three commercial posted-hub PN devices; n = 75/device/force, 1200 total) was measured by fluoroscopic imaging of the resulting depot. RESULTS: The reengineered hub design more closely achieved the 4 mm target NPD with significantly less variability ( P = .006) than commercial posted-hub PN devices across the range of applied injection forces. Calculations of IM (intramuscular) injection risk completed through in silico probability model, using NPD and average human tissue thickness measurements, displayed a commensurate reduction (~2-8x) compared to conventional PN hub designs. CONCLUSIONS: Quantifiable differences in injection depth were observed between identical labeled length PN devices indicating that hub design features, coupled with aspects of variable injection technique, may influence injection depth accuracy and consistency. The reengineered hub design may reduce the impact of unintended individual technique differences by improving target injection depth consistency and reducing IM injection potential.

Basal-like cells constitute the proliferating cell population in cystic fibrosis airways.

RATIONALE: Cystic fibrosis airways are recurrently exposed to noxious stimuli, leading to epithelial injury. Previous reports suggest that cystic fibrosis airway epithelia may respond to injury by increasing proliferation. OBJECTIVES: We sought to determine the characteristics of the proliferating cell population in cystic fibrosis airways. METHODS: Six cystic fibrosis and six normal lung sections from lung transplant recipients or lung surgery were obtained from the Duke Hospital pathology archives. Sections containing bronchi were evaluated for epithelial cell proliferation using immunohistochemistry for a nuclear proliferation antigen, Ki-67, and image analysis; immunohistochemistry for basal cells using a cytokeratin 5/14 antibody; and immunohistochemistry for the epidermal growth factor receptor and ErbB2, two receptor tyrosine kinases implicated in epithelial proliferation and differentiation. RESULTS: Overall, cystic fibrosis sections had a greater proliferation index than control sections with 25.1 +/- 2.1% positively staining nuclei/total nuclei compared with control sections, 4.6 +/- 0.9% (p = 0.002). In cystic fibrosis sections only, there were areas of hyperplastic cuboidal cells adjacent to normal pseudostratified columnar epithelial sections; in these areas of epithelial hyperplasia, there was uniform Ki-67 staining, indicating a zone of proliferating cells. The proliferating cell population also expressed the basal cell cytokeratins 5/14 and epidermal growth factor receptor. Expression of ErbB2 was diminished in the proliferating cells. CONCLUSIONS: Our results suggest that basal-like cells, expressing the epidermal growth factor receptor, constitute the proliferating cell population in cystic fibrosis airways.