Clinical Investigation of Large Volume Subcutaneous Delivery up to 25 mL for Lean and Non-Lean Subjects.

PURPOSE: To evaluate the clinical feasibility and tolerability of large volume subcutaneous delivery at different injection depths for lean and non-lean subjects. METHODS: A single-center, randomized, subject-blinded, crossover study in 62 healthy subjects was conducted to evaluate delivery of a 10-cP solution containing hyaluronic acid. Subjects were separated into lean and non-lean cohort by SC thickness. A syringe pump was used to study the effect of different volumes (5, 12, 25 mL) of a viscous placebo solution and needle lengths (6, 9 and 12 mm) delivered at 0.5 mL/min. RESULTS: Across all treatments, injection sites were observed to have negligible leakage, ~34 kPa of back pressure, and VAS of mild pain with higher pain from needle insertion than during injection. While mild to moderate erythema was the most frequently reported ISR and edema was most prominent for 25 mL injections, all ISRs were resolved within 4 hours post injection. Subjects were unbothered by ISRs across all treatments and rated them as low distress scores (average 1.0-1.5 out of 6). CONCLUSION: SC injection of 25 mL is feasible and tolerable using a low-pain formulation for abdomen injection irrespective of subcutaneous thickness and injection depths at a delivery rate of 0.5 mL/min.

Assessment of Cavitation Intensity in Accelerating Syringes of Spring-Driven Autoinjectors.

PURPOSE: Cavitation is an undesired phenomenon that may occur in certain types of autoinjectors (AIs). Cavitation happens because of rapid changes of pressure in a liquid, leading to the formation of small vapor-filled cavities, which upon collapsing, can generate an intense shock wave that may damage the device container and the protein drug molecules. Cavitation occurs in the AI because of the syringe-drug relative displacement as a result of the syringe's sudden acceleration during needle insertion and the ensuing pressure drop at the bottom of the container. Therefore, it's crucial to analyze the potential effect of cavitation on AI. The goal of the current study is to investigate the effects of syringe and AI design parameters such as air gap size, syringe filling volume, fluid viscosity, and drive spring force (syringe acceleration) on the risk and severity of cavitation. METHODS: A model autoinjector platform is built to record the syringe and cavitation dynamics which we use to estimate the cavitation intensity in terms of extension rate and to study the effects of design parameters on the severity of cavitation. RESULTS: Our results show the generation of an intense shock wave and a high extension rate upon cavitation collapse. The induced extension rate increases with syringe acceleration and filling volume and decreases with viscosity and air gap size. CONCLUSION: The most severe cavitation occurred in an AI device with the larger drive spring force and the syringe of a smaller air gap size filled with a less viscous fluid and a larger filling volume.

Social media impact on qualitative performance metrics: Analysis and trends of top revenue grossing U.S. Hospitals.

Social media is a common, multi-purpose tool used by most hospitals to engage a broad audience. The relationship between hospital social media activity and performance on influential reputation and patient experience ratings is not well described. The aim of this study was to characterize social media activity across the top 100 revenue grossing U.S. hospitals and its impact on key patient experience and hospital rankings. While nearly all top 100 revenue grossing U.S. hospitals have a presence on social media, usage and following significantly varied. Social media activity metrics collected showed some limited association with reputation and patient experience-influenced rankings.

The Interface Motion and Hydrodynamic Shear of the Liquid Slosh in Syringes.

PURPOSE: Interface motion and hydrodynamic shear of the liquid slosh during the insertion of syringes upon autoinjector activation may damage the protein drug molecules. Experimentally validated computational fluid dynamics simulations are used in this study to investigate the interfacial motion and hydrodynamic shear due to acceleration and deceleration of syringes. The goal is to explore the role of fluid viscosity, air gap size, syringe acceleration, syringe tilt angle, liquid-wall contact angle, surface tension and fill volume on the interface dynamics caused by autoinjector activation. METHODS: A simplified autoinjector platform submerged in water is built to record the syringe and liquid motion without obstruction of view. The syringe kinematics is imported to the simulations based on OpenFOAM InterIsoFoam solver, which is used to study the effects of various physical parameters. RESULTS: The simulations agree with experiments on the air-liquid interface profile and interface area. The interfacial area and the volume of fluid subject to high strain rate decrease with the solution viscosity, increase with the air gap height, syringe velocity, tilt angle and syringe wall hydrophobicity, and hardly change with the surface tension and liquid column height. The hydrodynamic shear mainly occurs near the syringe wall and entrained bubbles. CONCLUSION: For a given dose of drug solution, the syringe with smaller radius and larger length will generate less liquid slosh. Reducing the air volume and syringe wall hydrophobicity are also helpful to reduce interface area and effective shear. The interface motion is reduced when the syringe axis is aligned with the gravitational direction.

Subcutaneous Injection Site Pain of Formulation Matrices.

PURPOSE: The objective of this work was to systematically evaluate the effects of formulation composition on subcutaneous injection site pain (ISP) using matrices comprising of common pharmaceutical excipients. METHODS: Two randomized, blinded, crossover studies in healthy subjects were conducted at a single site, where subjects received 1 mL SC injections of the buffer matrices. ISP intensity was measured using a 100 mm visual analogue scale (VAS), which was then analyzed via heatmap, categorical grouping, subgroup analysis, and paired delta analysis. RESULTS: Buffer type, buffer concentration and tonicity agent showed a substantial impact on ISP. Citrate buffer demonstrated a higher ISP than acetate buffer or saline). The 20 mM citrate buffer was more painful than 10 or 5 mM citrate buffers. NaCl and propylene glycol were significantly more painful than sugar alcohols (mannitol, sucrose, trehalose or glycerol). Histidine buffers exhibited ISP in the descending order of 150 mM > 75 mM > 25 mM > 0 mM NaCl, while histidine buffers containing Arginine-HCl at 0, 50, or 150 mM all showed very low ISP. Histidine buffer at pH 6.5 showed a lower ISP than pH 5.7. CONCLUSIONS: This systematic study via orthogonal analyses demonstrated that subcutaneous ISP is significantly influenced by solution composition.

Subcutaneous Injection Performance in Yucatan Miniature Pigs with and without Human Hyaluronidase and Auto-injector Tolerability in Humans.

Recombinant human hyaluronidase PH20 (rHuPH20) facilitates subcutaneous (SC) delivery of co-administered therapeutic agents by locally and transiently degrading hyaluronan in the SC space, and can be administered with therapeutics using a variety of devices. Two SC delivery studies were carried out to assess auto-injector (AI) performance, each in 18 Yucatan miniature pigs. Abdominal injections were administered using three auto-injectors of 1 mL (AI1) and 2 mL (AI2 and sAI2) with different injection speeds and depths (5.5-7.5 mm) and two pre-filled syringe (PFS) devices of 1 and 2 mL. The injection included a placebo buffer with and without rHuPH20 to evaluate the effect of rHuPH20 on SC injection performance. The feasibility of using similar devices to deliver a placebo buffer in humans was investigated. rHuPH20 was not studied in humans. In miniature pigs, postinjection swelling was evident for most PFS/AI injections, particularly 2 mL. Swelling heights and back leakage were typically lower with rHuPH20 co-administration versus placebo for most device configurations (1 or 2 mL PFS or AI). Auto-injections with versus without rHuPH20 also resulted in reduced swelling firmness and faster swelling resolution over time. Slow injections with rHuPH20 had shorter and more consistent injection time versus placebo. In humans, minimal injection site swelling and negligible back leakage were observed for 2-mL injections of placebo, while more erythema was observed in humans versus miniature pigs. Even at high delivery rates with PFS or AI, the addition of rHuPH20 resulted in improved SC injection performance versus placebo in miniature pigs.

Two Contrasting Failure Modes of Enteric Coated Beads.

This study aimed to elucidate the mechanisms and kinetics of coating failure for enteric coated beads exposed to high-humidity conditions at different storage temperatures. Enteric coated beads were placed on high-humidity conditions (75 to 98% relative humidity (RH)) in the temperature range of 5 to 40°C. These stability samples of beads were tested for acid dissolution and water activity and also analyzed with SEM, X-ray CT, and DMA. Exposure of enteric coated beads to high humidity led to increased gastric release of drug which eventually failed the dissolution specification. SEM showed visible cracks on the surface of beads exposed to 5°C/high humidity and fusion of enteric beads into agglomerates at 40°C/high humidity. In a non-destructive time elapse study, X-ray CT demonstrated swelling of microcrystalline cellulose cores, crack initiation, and propagation through the API layer within days under 5°C/98% RH storage conditions and ultimately fracture through the enteric coating. DMA data showed a marked reduction in Tg of the enteric coating materials after exposure to humidity. At 5°C/high humidity, the hygroscopic microcrystalline cellulose core absorbed moisture leading to core swelling and consequent fracture through the brittle API and enteric layers. At 40°C (high humidity) which is above the Tg of the enteric polymer, enteric coated beads coalesced into agglomerates due to melt flow of the enteric coating. We believe it is the first report on two distinct failure models of enteric coated dosage forms.

The role of initial lymphatics in the absorption of monoclonal antibodies after subcutaneous injection.

The subcutaneous injection is the most common method of administration of monoclonal antibodies (mAbs) due to the patient's comfort and cost-effectiveness. However, the available knowledge about the transport and absorption of this type of biotherapeutics after subcutaneous injection is limited. Here, a mathematical framework to study the subcutaneous drug delivery of mAbs from injection to lymphatic uptake is presented. A poro-hyperelastic model of the tissue is exploited to find the biomechanical response of the tissue together with a transport model based on an advection-diffusion equation in large-deformation poro-hyperelastic Media. The process of mAbs transport to the lymphatic system has two major parts. First is the initial phase, where mAbs are dispersed in the tissue due to momentum exerted by injection. This stage lasts for only a few minutes after the injection. Then there is the second stage, which can take tens of hours, and as a result, mAb molecules are transported from the subcutaneous layer towards initial lymphatics in the dermis to enter the lymphatic system. In this study, we investigate both stages. The process of plume formation, interstitial pressure, and velocity development is explored. Then, the effect of the injection delivery parameters, injection site, and sensitivity of long-term lymphatic uptake due to variability in permeability, diffusivity, viscosity, and binding of mAbs are investigated. Finally, we study two different injection scenarios with variable injection volume and drug concentration inside the syringe and evaluate them based on the rate of lymphatic uptake. We use our results to find an equivalent lymphatic uptake coefficient similar to the coefficient widely used in pharmacokinetic (PK) models to study the absorption of mAbs. Ultimately, we validate our computational model against available experiments in the literature.

A qualitative study of barriers and facilitators to pediatric early warning score (PEWS) implementation in a resource-limited setting.

Objectives: Globally, pediatric hospitals have implemented Pediatric Early Warning Scores (PEWS) to standardize escalation of care and improve detection of clinical deterioration in pediatric patients. This study aims to utilize qualitative methodology to understand barriers and facilitators of PEWS implementation at Philippine Children's Medical Center (PCMC), a tertiary care hospital in Manila, Philippines. Methods: Semi-structured interviews querying current processes for clinical monitoring, Pediatric Intensive Care Unit (PICU) transfer, and clinician attitudes towards PEWS implementation were audio recorded. In-person hospital observations served to triangulate interview findings. The Systems Engineering Initiative for Patient Safety (SEIPS) framework guided content coding of interviews to characterize work systems, processes, and outcomes related to patient monitoring and care escalation. Thematic coding was performed using Dedoose software. This model allowed identification of barriers and facilitators to PEWS implementation. Results: Barriers within PCMC workflow included: limited bed capacity, delay in referral, patient overflow, limited monitoring equipment, and high patient to staff ratio. Facilitators of PEWS implementation included support for PEWS adaptation and existence of systems for vital sign monitoring. Observations by study personnel confirmed validity of themes. Conclusion: Utilizing qualitative methodology to understand barriers and facilitators to PEWS in specific contexts can guide implementation at resource-limited hospitals.

Hydrodynamic considerations for spring-driven autoinjector design.

In recent years, significant progress has been made in the studies of the spring-driven autoinjector, leading to an improved understanding of this device and its interactions with tissue and therapeutic proteins. The development of simulation tools that have been validated against experiments has also enhanced the prediction of the performance of spring-driven autoinjectors. This paper aims to address critical hydrodynamic considerations that impact the design of spring-driven autoinjectors, with a specific emphasis on sloshing and cavitation. Additionally, we present a framework that integrates simulation tools to predict the performance of spring-driven autoinjectors and optimize their design. This work is valuable to the pharmaceutic industry, as it provides crucial insights into the development of spring-driven autoinjectors and therapeutic proteins. This work can also enhance the efficacy and safety of the delivery of therapeutic proteins, ultimately improving patient outcomes.

Computational modeling of the effect of skin pinch and stretch on subcutaneous injection of monoclonal antibodies using autoinjector devices.

Subcutaneous injection of monoclonal antibodies (mAbs) has experienced unprecedented growth in the pharmaceutical industry due to its benefits in patient compliance and cost-effectiveness. However, the impact of different injection techniques and autoinjector devices on the drug's transport and uptake is poorly understood. Here, we develop a biphasic large-deformation chemomechanical model that accounts for the components of the extracellular matrix that govern solid deformation and fluid flow within the subcutaneous tissue: interstitial fluid, collagen fibers and negatively charged proteoglycan aggregates. We use this model to build a high-fidelity representation of a virtual patient performing a subcutaneous injection of mAbs. We analyze the impact of the pinch and stretch methods on the injection dynamics and the use of different handheld autoinjector devices. The results suggest that autoinjector base plates with a larger device-skin contact area cause significantly lower tissue mechanical stress, fluid pressure and fluid velocity during the injection process. Our simulations indicate that the stretch technique presents a higher risk of intramuscular injection for autoinjectors with a relatively long needle insertion depth.

The role of liquid rheological properties on the injection process of a spring-driven autoinjector.

Accurate injection time prediction is essential in developing spring-driven autoinjector devices since the drug delivery is expected to finish within seconds to bring convenience, reduce the risk for early lift-off, and provide a consistent experience to users. The Carreau model captures the liquid's shear-dependent viscosity measured in our experiments. Thus, a quasi-steady model, which uses the Carreau model to describe the liquid's viscosity, is developed to predict the injection time of spring-driven autoinjectors. Analytical relations between the flow rate and the pressure drop in the needle are also obtained. The Carreau number in the spring-driven autoinjector is greater than one and smaller than a critical value; in this region, using the power-law model to describe the liquid viscosity accurately predicts the injection time, which agrees with the current literature findings. Additionally, a force threshold is identified for the friction force between the plunger and the syringe barrel, beyond which the injection time is infinite. Appreciation of this force threshold can help avoid device stalling and reduce the risk of underdosing. Moreover, the role of liquid's shear-thinning index on the injection time of spring-driven autoinjectors is quantified. Understanding the shear-thinning index allows formulators to experiment with excipients and pH to enhance confidence in drug/device combination product design and integration. Our experimental and theoretical results can help drug product and device developers with integrated product design and improve the patient experience.

The air entrainment and hydrodynamic shear of the liquid slosh in syringes.

Understanding the interface motion and hydrodynamic shear induced by the liquid sloshing during the insertion stage of an autoinjector can help improve drug product administration. We perform experiments to investigate the interfacial motion and hydrodynamic shear due to the acceleration and deceleration of syringes. The goal is to explore the role of fluid properties, air gap size, and syringe acceleration on the interface dynamics caused by autoinjector activation. We used a simplified autoinjector platform to record the syringe and liquid motion without any view obstruction. Water and silicone oil with the same viscosity are used as the model fluids. Particle Image Velocimetry (PIV) is employed to measure the velocity field. Simultaneous shadowgraph visualization captures the air entrainment. Our in-house PIV and image processing algorithms are used to quantify the hydrodynamic stress and interfacial area to investigate the effects of various autoinjector design parameters and fluid types on liquid sloshing. The results indicate that reducing the air gap volume and syringe acceleration/deceleration mitigate the interface area and effective shear. Moreover, the interfacial area and induced hydrodynamic stress decrease with the Fr=U/aD, where U is the interface velocity, a is the maximum syringe acceleration, and D is the syringe diameter.

Plasma Polymerized HMDSO Coatings For Syringes To Minimize Protein Adsorption.

Current parenteral containers used for the storage and delivery of protein-based drugs, contain silicone oil which may seep into the protein solution and can result in adsorption, aggregation and denaturation of the protein. Tightly adherent surface coatings prepared by radio frequency glow-discharge (RFGD) plasma polymerization are described in this paper. Using this robust technique, methacrylic acid (MA) (hydrophilic), hexamethyldisiloxane (HMDSO) (hydrophobic), tetraglyme (TG) (hydrophilic) were plasma polymerized onto glass. In addition, HMDSO and MA were copolymerized to create a plasma polymerized HMDSO-MA (hydrophobic) surface. Untreated glass and glass dip-coated in PDMS were used as controls. TG and MA plasma coatings adsorbed the least amount of protein in all pH conditions. Interestingly HMDSO-MA retained significantly lesser protein compared to HMDSO and dip-coated PDMS samples. In the presence of Polysorbate 80 (PS80) all plasma polymerized coatings adsorbed and retained negligible amounts of protein, compared to controls. Furthermore, the peak glide force of plasma coated syringes did not significantly increase compared to syringes without plasma coating. Due to the versatility of RFGD plasma, this process is scalable and could potentially be used for the treatment of hypodermic syringes used for the storage and delivery of protein-based therapeutics.

Physicochemical Excipient-Container Interactions in Prefilled Syringes and Their Impact on Syringe Functionality.

Previous studies have shown that parenteral formulation excipients can interact with the silicone oil in prefilled syringes, thereby causing variations in glide force that affect the performance of autoinjectors. Thus, it is crucial to control the glide force of the prefilled syringes to mitigate the potential risk of dose inaccuracies. This study provided a systematic understanding of the chemical interactions between the excipients, physical interactions between the excipients and the container, as well as their impact on the functional performance of prefilled syringes. The design of experiment approach used in this study generated statistically meaningful data, which confirmed that different excipients caused varying increase in glide force in siliconized prefilled syringes. The data indicated that poloxamer 188 can more effectively maintain stable glide forces during accelerated storage conditions compared with polysorbate 80. This finding was further enhanced using Hansen solubility parameters theory, which provided a fundamental understanding of the mechanisms behind the physical interactions. Chemical stability analysis of the surfactants suggested that degradation of excipients also impacts syringe functionality. In summary, the results revealed the unique interactions between parenteral pharmaceutical excipients and primary packaging systems and the physicochemical foundation behind them.

Modeling cavitation bubble dynamics in an autoinjector and its implications on drug molecules.

The collapse of cavitation bubbles induced by abrupt acceleration of the syringe in an autoinjector device can lead to protein aggregation. The details of bubble dynamics are investigated using an axisymmetric, three-dimensional simulation with passive tracers to illustrate the transport of protein molecules. When a bubble near the syringe wall collapses, protein molecules are concentrated in the re-entrant jet, pushed towards the syringe wall, and then spread across the wall, potentially leading to protein adsorption on the syringe wall and aggregation. This phenomenon is more prominent for bubbles positioned closer to the bottom wall, growing to a larger maximum radius. The bubble's maximum radius decreases with the bubble's distance from the syringe wall and air gap pressure, and increases with an increase in liquid column height and nucleus size. The strain rate induced by the bubble collapse is not large enough to unfold the proteins. When the re-entrant jet impacts the bubble surface or syringe wall, the bubble breaks up, generating smaller bubbles with high surface concentration of protein molecules, potentially inducing aggregation in the bulk. The bubble dynamics are influenced by dimensionless distance of the nucleus from the wall, normalized by maximum bubble radius (γ). The re-entrant jet velocity increases with γ, while the maximum liquid pressure, typically 100∼1000 bar, first decreases and then increases with γ. For a cloud of cavitation bubbles, i.e., closely clustered bubbles, coalescence of bubbles can occur, leading to a higher peak pressure at collapse.

An experimentally validated dynamic model for spring-driven autoinjectors.

This study focuses on developing a predictive dynamic model for spring-driven autoinjectors. The values of unknown physical parameters, such as the heat convection coefficient and the friction force between the plunger and the syringe barrel, are obtained by fitting the experimentally measured displacements of the plunger and the syringe barrel. The predicted kinematics of the components, such as the displacement and velocity of the syringe barrel, agree well with the experiments with a l2-norm error smaller than 10%. The predictions of the needle displacement at the start of drug delivery agree with the experimental measurements with a l2-norm error of 20%. The maximum air gap pressure and temperature decrease with the initial air gap height but increase with the elasticity and viscosity of the plunger and the mechanical stop. The proposed experimentally validated dynamic model can be effectively used for device design optimization as it is not computationally demanding.

Impact of Surfactants on the Functionality of Prefilled Syringes.

Previous studies revealed the impact of formulation factors (excipients and pH) on the functionality of prefilled syringes. Surfactant, a critical formulation component for therapeutic proteins and antibodies, aids in minimizing protein adsorption onto interfaces and reduces protein aggregation or particulate formation. This study evaluated the impact of different surfactants and protein concentration on the functionality of prefilled syringes. Syringes filled with solution formulations with different surfactants were stored at various temperatures and evaluated at selected time points. Upon thermal stress, polysorbate 80 and dodecyl-ß-d-maltoside containing formulations showed significantly greater increase in glide force when compared with poloxamer 407 containing formulations. In contrast, syringes filled with poloxamer 188 containing formulations did not show any increase in glide force under the same conditions. Based on the results from this study, the increase in syringe glide force was inversely correlated with hydrophobic-lipophilic balance values and surface tension of different surfactants. The mechanism of increase in glide force was primarily the change of silicone oil coverage and lubricity in the barrel of syringes.

Educational achievement and youth homicide mortality: a City-wide, neighborhood-based analysis.

BACKGROUND AND OBJECTIVE: Educational achievement, particularly among youth, may mitigate risk of exposure to violence and negative related health outcomes such as crime and gang activity. Few studies to date have examined relationships between education and youth homicide. The authors hypothesized association between educational achievement in grades 3 and 8 and youth homicide mortality. METHODS: Neighborhood-based, city-wide analysis was conducted of cross-sectional data regarding N = 55 neighborhoods in Baltimore, MD, extracted from Baltimore 2017 Neighborhood Health Profiles. RESULTS: Higher educational achievement (operationalized by reading proficiency) in third, but not eighth, grade was associated with reduced neighborhood youth homicide mortality rates in hierarchical linear regression, controlling for demographic and socioeconomic factors (ß = - 0.5082, p = 0.03), such that each 1.97% increase in proportion of students reading at an acceptable level was associated with one fewer neighborhood youth homicide per 100,000. Neighborhoods within the highest tertile of youth homicide mortality differed from those in the lowest tertile with fewer males (45% vs. 48%, p = 0.002), greater unemployment (17% vs. 8%, p < 0.001), familial poverty (35% vs. 16%, p < 0.001), and residents identifying as black or African-American (88% vs. 25%, p < 0.001). Causal mediation analysis demonstrated mediation effects of familial poverty and eighth grade educational achievement through third grade educational achievement (ACME = 0.151, p = 0.04; ACME = - 0.300, p = 0.03, respectively) with no significant direct effects. CONCLUSIONS: Higher educational achievement (operationalized by reading proficiency) predicts reduced homicide mortality among Baltimore youth and appears to mediate effects of familial poverty on homicide mortality as well. This converges with literature highlighting the importance of education as a determinant of social capital and violence. Future policy-based interventions should target inequalities in educational achievement to mitigate homicide risk among youth in communities facing disparities in violent crime.