Recent advances in transdermal insulin delivery technology: A review.

Transdermal drug delivery refers to the administration of drugs through the skin, after which the drugs can directly act on or circulate through the body to the target organs or cells and avoid the first-pass metabolism in the liver and kidneys experienced by oral drugs, reducing the risk of drug poisoning. From the initial singular approach to transdermal drug delivery, there has been a shift toward combining multiple methods to enhance drug permeation efficiency and address the limitations of individual approaches. Technological advancements have also improved the accuracy of drug delivery. Optimizing insulin itself also enables its long-term release via needle-free injectors. In this review, the diverse transdermal delivery methods employed in insulin therapy and their respective advantages and limitations are discussed. By considering factors such as the principles of transdermal penetration, drug delivery efficiency, research progress, synergistic innovations among different methods, patient compliance, skin damage, and posttreatment skin recovery, a comprehensive evaluation is presented, along with prospects for potential novel combinatorial approaches. Furthermore, as insulin is a macromolecular drug, insights gained from its transdermal delivery may also serve as a valuable reference for the use of other macromolecular drugs for treatment.

Microfluidic Delivery of High Viscosity Liquids Using Piezoelectric Micropumps for Subcutaneous Drug Infusion Applications.

Goal: Auto-injectors for self-administration of drugs are usually refrigerated. If not warmed up prior to the injection, ejection of the total drug volume is not guaranteed, as their spring and plunger mechanism cannot adjust for a change in viscosity of the drug. Here, we develop piezoelectric micro diaphragm pump that allows these modifications possible while investigating the effectiveness of this alternative dosing method. Methods: The dosing of highly viscous liquid of 25 mPa·s is made possible using application-specific micropump design. By comparing the analytical with experimental results, the practicality of the concept is verified. Results: Using a powerful piezoelectric stack actuator, the micropump achieves high fluid pressures of up to (368 ± 17) kPa. In order to assess the influence of viscosity, we characterize the fluidic performance of the designed micropump through 27G gauge needle for various water-glycerin mixtures. We find maximum flow rates of 2 mL/min for viscosities of up to 25 mPa·s. Conclusions: The developed micro diaphragm pump enables the development of smart auto-injectors with flow rate regulation to achieve drug delivery for high viscosity drugs through 27G needles.

Needle-Free Jet Injection of Poly-(Lactic Acid) for Atrophic Acne Scars: Literature Review and Report of Clinical Cases.

Acne scars, particularly atrophic ones, present a persistent challenge in cosmetic medicine and surgery, requiring extended and multifaceted treatment approaches. Poly-(lactic acid) injectable fillers show promise in managing atrophic acne scars by stimulating collagen synthesis. However, the utilization of needle-free injectors for delivering poly-(lactic acid) into scars remains an area requiring further exploration. In this article, a summary of the latest advancements in needle-free jet injectors is provided, specifically highlighting the variations in jet-producing mechanisms. This summary emphasizes the differences in how these mechanisms operate, offering insights into the evolving technology behind needle-free injection systems. The literature review revealed documented cases focusing on treating atrophic acne scars using intralesional poly-(lactic acid) injections. The results of these clinical studies could be supported by separate in vitro and animal studies, elucidating the feasible pathways through which this treatment operates. However, there is limited information on the use of needle-free jet injectors for the intradermal delivery of poly-(lactic acid). Clinical cases of atrophic acne scar treatment are presented to explore this novel treatment concept, the needle-free delivery of poly-(lactic acid) using a jet pressure-based injector. The treatment demonstrated efficacy with minimal adverse effects, suggesting its potential for scar treatment. The clinical efficacy was supported by histological evidence obtained from cadaver skin, demonstrating an even distribution of injected particles in all layers of the dermis. In conclusion, we suggest that novel needle-free injectors offer advantages in precision and reduce patient discomfort, contributing to scar improvement and skin rejuvenation. Further comprehensive studies are warranted to substantiate these findings and ascertain the efficacy of this approach in scar treatment on a larger scale.

Analysis of Changes in the Opening Pressure of Marine Engine Injectors Based on Vibration Parameters Recorded at a Constant Torque Load.

This article deals with the problems related to the difficulties in the vibration diagnostics of modern marine engines. The focus was on the injection system, with a particular emphasis on injectors. An unusual approach to the implementation of research enabling the smooth regulation of the opening pressure of the mechanical injector during engine operation at a constant load was presented. This approach obtained repeatability of conditions for subsequent measurements, which is very difficult to achieve when using the classic approach that forces the injector to be disassembled after each test.

3D-printed sheet jet for stable megahertz liquid sample delivery at X-ray free-electron lasers.

X-ray free-electron lasers (XFELs) can probe chemical and biological reactions as they unfold with unprecedented spatial and temporal resolution. A principal challenge in this pursuit involves the delivery of samples to the X-ray interaction point in such a way that produces data of the highest possible quality and with maximal efficiency. This is hampered by intrinsic constraints posed by the light source and operation within a beamline environment. For liquid samples, the solution typically involves some form of high-speed liquid jet, capable of keeping up with the rate of X-ray pulses. However, conventional jets are not ideal because of radiation-induced explosions of the jet, as well as their cylindrical geometry combined with the X-ray pointing instability of many beamlines which causes the interaction volume to differ for every pulse. This complicates data analysis and contributes to measurement errors. An alternative geometry is a liquid sheet jet which, with its constant thickness over large areas, eliminates the problems related to X-ray pointing. Since liquid sheets can be made very thin, the radiation-induced explosion is reduced, boosting their stability. These are especially attractive for experiments which benefit from small interaction volumes such as fluctuation X-ray scattering and several types of spectroscopy. Although their use has increased for soft X-ray applications in recent years, there has not yet been wide-scale adoption at XFELs. Here, gas-accelerated liquid sheet jet sample injection is demonstrated at the European XFEL SPB/SFX nano focus beamline. Its performance relative to a conventional liquid jet is evaluated and superior performance across several key factors has been found. This includes a thickness profile ranging from hundreds of nanometres to 60 nm, a fourfold increase in background stability and favorable radiation-induced explosion dynamics at high repetition rates up to 1.13 MHz. Its minute thickness also suggests that ultrafast single-particle solution scattering is a possibility.

Knowledge, attitudes and practice of infection prevention and control in the CT suite.

BACKGROUND: Infection, prevention, and control (IPC) practices are essential to protect patients and staff within healthcare facilities. Radiology departments cater to both inpatients and outpatients, and breaches of IPC practice have led to outbreaks of disease within healthcare facilities. This study aims to examine the knowledge, attitudes and practice (KAP) of computed tomography (CT) radiographers and nurses in their infection, prevention, and control (IPC) practice. The KAP components focuses on the CT environment, contrast injector use, and workplace factors that impact IPC practice. METHODS: A cross-sectional KAP survey was distributed online to Australian CT radiographers and radiology nurses across different institutions. The survey covered demographics, each KAP component, and workplace culture. Spearman's correlation was used to compare KAP scores. Kruskal-Wallis test was used to compare the KAP scores between demographic categories, and Chi Square was used to compare demographic data with workplace culture. RESULTS: There were 147 respondents, 127 of which were radiographers and 20 were nurses. There was a moderate positive correlation between knowledge and attitude for radiographers (rho = 0.394, p < 0.001). Radiographers also had a moderate positive relationship between attitudes and practice (rho = 0.466, p < 0.001). Both radiographers and nurses scored high in the knowledge section of the survey, but nurses had statistically significant higher practice scores than radiographers (p = 0.014). CT radiographers who had an IPC team in their workplace or worked in public hospitals, had statistically significant higher attitudes and practice scores. Age, education, and years of experience did not impact on KAP scores. CONCLUSION: The study found that radiographers and nurses had a good baseline knowledge of standard precautions. IPC teams and continued training is important to positively influence knowledge and attitudes of health professionals towards IPC practice. The KAP survey was a useful tool to assess the knowledge, attitudes, and practice on IPC of CT radiographers and nurses and identified areas for education, interventions, and leadership.

Stenotrophomonas maltophilia outbreak with a commercial blood gas injector as the culprit and interventions for source and prevention: A possible passage between patient and ECMO water heater device.

BACKGROUND: Despite low virulence of Stenotrophomonas maltophilia, it represents one of the leading drug-resistant bacteria. We report a large outbreak of S. maltophilia infection associated with an unexpected source, which turned out to be a commercial needleless blood gas injector. METHODS: Over a period from January 1 to December10, 2021, 113 patients were identified to have S. maltophilia infection as documented by positive cultures from the clinical samples, extracorporeal membrane oxygenation (ECMO) water heater devices and commercial needleless blood gas injectors. RESULTS: Sixty-seven isolates (59 clinical, 4 ECMO, 4 blood gas injectors) were sent for molecular analysis. Both arbitrarily primed polymerase chain reaction and pulsed-field gel electrophoresis analyses showed 12 distinct genotypes. Of 67 isolates, 58 were clonally related (86.6%), with 52 indistinguishable strains from 4 blood gas needleless injectors, 46 patients' samples (78%), and 2 ECMO samples (50%). Two ECMO samples and 1 clinical sample were clonally identical. CONCLUSIONS: In the event that eradication of infections would not be possible despite taking all environmental disinfection measures including the ECMO devices, unexpected sources, such as a commercial needleless blood gas injector, should not be omitted from the list for surveillance. In addition, obtaining surveillance cultures of ECMO water reservoirs should be placed in the routine clinical practice.

A Look Into the Next Century After 100 Years of Insulin.

Being diagnosed with diabetes can be challenging, particularly if we do not know a similar individual with the same disease. A person's life may suddenly change and he/she may not be aware of the possibilities or treatment options available or the questions that need to be asked; hence, instead of looking for assistance, many people hide their diabetic condition from others. But due to innovative devices, individuals no longer need to be concerned. Various gadgets today help provision insulin via a subcutaneous route, for example, an insulin pen, pump, vial, or syringe. Despite being the most familiar way to provide insulin, subcutaneous insulin delivery is linked to needle pain, injection anxiety, lipodystrophy, compliance issues, and peripheral hyperinsulinemia; thus, there is a need for an insulin delivery system that is both less invasive and more biological. The discovery of insulin and its uses are linked to the beginning of diabetes treatment. Initially, the delivery of insulin was accomplished using giant, heavy, reusable syringes equipped with plungers, barrels, and wide-bore needles. To prepare these syringes and needles for reuse, these were boiled. The development of insulin syringes, which are presently in use and have revolutionized healthcare, resulted from manufacturers' continued efforts and technological innovations. Injections of insulin may become obsolete if research from the University of Alberta is successful. Researchers from the University of Alberta claim that insulin-producing cells developed from stem cells are secure for transplantation to wean diabetes patients from injectable insulin permanently. In a significant mice experiment, experts demonstrated the role of the inceptor (insulin inhibitory receptor), which protects the beta cells from insulin pathway activation. Insulin resistance in diabetes may be exacerbated by the inceptor's ability to block insulin signaling. Technologies known as "smart insulin" (glucose-responsive insulin) deliver insulin according to the patient's glycemic condition without needing additional monitoring by the patient or the physician in charge. The review of insulin administration devices and several cutting-edge insulin-related ideas are the main topics of this article.

Delivering Endothelial Keratoplasty Grafts: Modern Day Transplant Devices.

PURPOSE: To summarize the graft loading, transporting and delivery devices used for endothelial keratoplasty (EK). METHODS: A literature search of electronic databases was performed. RESULTS: New techniques and devices have been introduced and implemented to prepare, load, transport and transplant the grafts for EK. The advantages are not only limited to the surgical theatre but also widely spread across the eye banking field. Investigation of advanced materials and designs have been rapidly growing with continuous evolution in the field of eye banking and corneal transplantation. Innovative techniques and modern devices have been evaluated to reduce the endothelial cell loss and increase the precision of the transplant in order to benefit both surgeons and the patients. CONCLUSIONS: It is extremely important to reduce any potential wastage and optimize the use of every available donor cornea due to the limited availability of healthy cadaveric donor corneas required for transplants. As a result, the use of pre-cut and pre-loaded grafts supplied by the eye banks in calibrated devices have been gaining momentum. Innovation in the field of bioengineering for the development of new devices that facilitate excellent clinical outcomes along with reduction in learning curve has shown promising results.

Optimizing the geometry of aerodynamic lens injectors for single-particle coherent diffractive imaging of gold nanoparticles.

Single-particle X-ray diffractive imaging (SPI) of small (bio-)nanoparticles (NPs) requires optimized injectors to collect sufficient diffraction patterns to allow for the reconstruction of the NP structure with high resolution. Typically, aerodynamic lens-stack injectors are used for NP injection. However, current injectors were developed for larger NPs (>100 nm), and their ability to generate high-density NP beams suffers with decreasing NP size. Here, an aerodynamic lens-stack injector with variable geometry and a geometry-optimization procedure are presented. The optimization for 50 nm gold-NP (AuNP) injection using a numerical-simulation infrastructure capable of calculating the carrier-gas flow and the particle trajectories through the injector is also introduced. The simulations were experimentally validated using spherical AuNPs and sucrose NPs. In addition, the optimized injector was compared with the standard-installation 'Uppsala injector' for AuNPs. Results for these heavy particles showed a shift in the particle-beam focus position rather than a change in beam size, which results in a lower gas background for the optimized injector. Optimized aerodynamic lens-stack injectors will allow one to increase NP beam density, reduce the gas background, discover the limits of current injectors and contribute to structure determination of small NPs using SPI.

Elucidating Drivers for Variations in the Explosive Human Immunodeficiency Virus Epidemic Among People Who Inject Drugs in Pakistan.

BACKGROUND: Pakistan's explosive human immunodeficiency virus (HIV) epidemic among people who inject drugs (PWID) varies widely across cities. We evaluated possible drivers for these variations. METHODS: Multivariable regression analyses were undertaken using data from 5 national surveys among PWID (n = 18 467; 2005-2017) to determine risk factors associated with variations in city-level HIV prevalence. A dynamic HIV model was used to estimate the population-attributable fraction (PAF; proportion of HIV infections prevented over 10 years when that risk factor is removed) of these risk factors to HIV transmission and impact on HIV incidence of reducing their prevalence. RESULTS: Regression analyses suggested that city-level HIV prevalence is strongly associated with the prevalence of using professional injectors at last injection, heroin use in last month, and injecting ≥4 times per day. Through calibrating a model to these associations, we estimate that the 10-year PAFs of using professional injectors, heroin use, and frequent injecting are 45.3% (95% uncertainty interval [UI], 4.3%-79.7%), 45.9% (95% UI, 8.1%-78.4%), and 22.2% (95% UI, 2.0%-58.4%), respectively. Reducing to lowest city-level prevalences of using professional injectors (2.8%; median 89.9% reduction), heroin use (0.9%; median 91.2% reduction), and frequent injecting (0.1%; median 91.8% reduction) in 2020 reduces overall HIV incidence by 52.7% (95% UI, 6.1%-82.0%), 53.0% (95% UI, 11.3%-80.2%), and 28.1% (95% UI, 2.7%-66.6%), respectively, over 10 years. CONCLUSIONS: Interventions should focus on these risk factors to control Pakistan's explosive HIV epidemic among PWID, including a concomitant expansion of high-coverage needle/syringe provision, opioid substitution therapy, and antiretroviral therapy.

Healthcare workers` knowledge level regarding anaphylaxis and usage of epinephrine auto-injectors.

BACKGROUND: Inadequate practices in diagnosis and management of anaphylaxis in parallel with an increase in its prevalence may cause serious public health problems today. This is the first study aiming to assess the theoretical knowledge of professional and non-professional healthcare workers from different lines of the healthcare service chain about anaphylaxis management, and their practice approaches for epinephrine autoinjectors (EAIs) together. METHODS: The study included 697 participants comprising physicians, dentists, pharmacists, and school staff. In face-to-face interviews, each participant was asked to fill out the questionnaire forms prepared for assessing their demographic characteristics, experience with a case of anaphylaxis and EAI and theoretical knowledge about the diagnosis and treatment of anaphylaxis, and to demonstrate how to use EAI in practice with trainer device. RESULTS: The rates of 391 physicians, 98 dentists, 102 pharmacists and 105 school staff of knowing the diagnosis criteria of anaphylaxis were 47.6%, 31.6%, 31.1%, 19%, and knowing the first and life-saving treatment of anaphylaxis were 87.2%, 79.6%, 47.6%, 15.2%, respectively. Predictors that affected physicians in knowing the first and life-saving treatment of anaphylaxis were having experience with EAIs [OR:5.5, (%95CI:1.330-23.351, p=0.015)] and a case of anaphylaxis [OR:2.4, (%95CI:1.442-4.020, p=0.001)], and knowing the administration route of epinephrine correctly [OR:1.9, (%95CI:1.191-3.314, p=0.008)]. 31.1% of the participants demonstrated the EAI usage correctly. The EAI usage steps with the most errors were `Place the appropriate injection tip into outer thigh/Press the trigger so it `clicks`` and `Turn the trigger to arrow direction` (60.3% and 34.9%, respectively). CONCLUSIONS: Healthcare workers` knowledge level regarding anaphylaxis management and ability to use EAIs correctly are not adequate. That most errors were made in the same steps of EAI usage indicates that the industry should continue to strive for developing the ideal life-saving device.

Setting up a successful nurse-led intravitreal injections service: pearls from Swindon.

The demand for performing intravitreal injections has increased in recent years, prompting the need for more nurse training in their administration. The Great Western Hospitals NHS Trust in Swindon has developed a structured nurse training programme and now has 8 independent nurse injectors trained to undertake injections independently; nurse practitioners now contribute upwards of 85% of the total number of injections. The authors have also demonstrated the financial benefits of using injection assistant devices and shown the positive impact such devices have on training. In September 2019, the authors organised the first course to offer nurses and doctors hands-on experience in administering injections, using the Swindon training model to provide participants with a structured approach to learn how to perform intravitreal injections safely. Nurses made up 96% of participants; the remainder were doctors and managers; 6% had never performed an intravitreal injection; of units where they had, disposable drapes and a speculum were used in 71% of these. The number of injections performed per session at participants' units at the time they attended the course was: 17 or more injections=46%, 13-14=39%, and 11-12=15%. The course was rated 8.9/10 overall for content, with 85% very likely to recommend it to colleagues. All participants indicated that using the Swindon model made them feel confident to deliver injections safely. The authors demonstrated that using a structured training protocol and intravitreal assistant device improves the quality of nurse training and increases confidence in administering intravitreal injections.

World allergy organization anaphylaxis guidance 2020.

Anaphylaxis is the most severe clinical presentation of acute systemic allergic reactions. The occurrence of anaphylaxis has increased in recent years, and subsequently, there is a need to continue disseminating knowledge on the diagnosis and management, so every healthcare professional is prepared to deal with such emergencies. The rationale of this updated position document is the need to keep guidance aligned with the current state of the art of knowledge in anaphylaxis management. The World Allergy Organization (WAO) anaphylaxis guidelines were published in 2011, and the current guidance adopts their major indications, incorporating some novel changes. Intramuscular epinephrine (adrenaline) continues to be the first-line treatment for anaphylaxis. Nevertheless, its use remains suboptimal. After an anaphylaxis occurrence, patients should be referred to a specialist to assess the potential cause and to be educated on prevention of recurrences and self-management. The limited availability of epinephrine auto-injectors remains a major problem in many countries, as well as their affordability for some patients.

Anaphylaxis in children.

Anaphylaxis in children is a potential acute life-threatening systemic hypersensitivity reaction. Anaphylaxis fatality rate is estimated to be 0.65% to 2%. Food is the main anaphylaxis trigger in children, notably cow's milk, peanuts, and tree nuts. Mucocutaneous manifestations are observed in more than 90% of cases, but it is not essential for diagnosis. Deaths are rather secondary to the laryngeal edema, observed in 40%-50% of cases. Personal history of asthma, allergy to particular foods such as peanuts and tree nuts, and adolescence are known risk factors for anaphylaxis and more severe reactions. Epinephrine (adrenaline) is the medication of choice for the first-aid treatment of anaphylaxis. However, adrenaline auto-injectors (AAIs) are commercially available in only 32% of world countries. There are still considerable unmet needs in the field of anaphylaxis in children. Therefore, the Montpellier WHO Collaborating Centre aims to start the global action plan applied to anaphylaxis.

Prevalence, Characteristics, and Management of Chronic Noncancer Pain Among People Who Use Drugs: A Cross-Sectional Study.

INTRODUCTION: Most studies on chronic noncancer pain (CNCP) in people who use drugs (PWUD) are restricted to people attending substance use disorder treatment programs. This study assessed the prevalence of CNCP in a community-based sample of PWUD, identified factors associated with pain, and documented strategies used for pain relief. METHODS: This was a cross-sectional study nested in an ongoing cohort of PWUD in Montreal, Canada. Questionnaires were administered to PWUD seen between February 2017 and January 2018. CNCP was defined as pain lasting three or more months and not associated with cancer. RESULTS: A total of 417 PWUD were included (mean age = 44.6 ± 10.6 years, 84% men). The prevalence of CNCP was 44.8%, and the median pain duration (interquartile range) was 12 (5-18) years. The presence of CNCP was associated with older age (>45 years old; odds ratio [OR] = 1.8, 95% CI = 1.2-2.7), male sex (OR = 2.3, 95% CI = 1.2-4.2), poor health condition (OR = 1.9, 95% CI = 1.3-3.0), moderate to severe psychological distress (OR = 2.9, 95% CI = 1.8-4.7), and less frequent cocaine use (OR = 0.5, 95% CI = 0.3-0.9). Among CNCP participants, 20.3% used pain medication from other people, whereas 22.5% used alcohol, cannabis, or illicit drugs to relieve pain. Among those who asked for pain medication (N = 24), 29.2% faced a refusal from the doctor. CONCLUSIONS: CNCP was common among PWUD, and a good proportion of them used substances other than prescribed pain medication to relieve pain. Close collaboration of pain and addiction specialists as well as better pain assessment and access to nonpharmacological treatments could improve pain management in PWUD.

Current status and future opportunities for serial crystallography at MAX IV Laboratory.

Over the last decade, serial crystallography, a method to collect complete diffraction datasets from a large number of microcrystals delivered and exposed to an X-ray beam in random orientations at room temperature, has been successfully implemented at X-ray free-electron lasers and synchrotron radiation facility beamlines. This development relies on a growing variety of sample presentation methods, including different fixed target supports, injection methods using gas-dynamic virtual-nozzle injectors and high-viscosity extrusion injectors, and acoustic levitation of droplets, each with unique requirements. In comparison with X-ray free-electron lasers, increased beam time availability makes synchrotron facilities very attractive to perform serial synchrotron X-ray crystallography (SSX) experiments. Within this work, the possibilities to perform SSX at BioMAX, the first macromolecular crystallography beamline at  MAX IV Laboratory in Lund, Sweden, are described, together with case studies from the SSX user program: an implementation of a high-viscosity extrusion injector to perform room temperature serial crystallography at BioMAX using two solid supports - silicon nitride membranes (Silson, UK) and XtalTool (Jena Bioscience, Germany). Future perspectives for the dedicated serial crystallography beamline MicroMAX at MAX IV Laboratory, which will provide parallel and intense micrometre-sized X-ray beams, are discussed.

Epinephrine delivery via EpiPen® Auto-Injector or manual syringe across participants with a wide range of skin-to-muscle distances.

BACKGROUND: Intramuscular (IM) injection of epinephrine (adrenaline) at the mid-anterolateral (AL) thigh is the international standard therapy for acute anaphylaxis. Concerns exist regarding implications of epinephrine auto-injector needles not penetrating the muscle in patients with greater skin-to-muscle-distances (STMD). METHODS: This open-label, randomized, crossover study investigated pharmacokinetics and pharmacodynamics following injection of epinephrine in healthy volunteers. Individuals were stratified by maximally compressed STMD (low, < 15 mm; moderate, 15-20 mm; high, > 20 mm). Participants received epinephrine injections via EpiPen® Auto-Injector (EpiPen; 0.3 mg/0.3 mL) or IM syringe (0.3 mg/0.3 mL) at mid-AL thigh or received saline by IM syringe in a randomized order. Eligible participants received a fourth treatment (EpiPen [0.3 mg/0.3 mL] at distal-AL thigh). Model-independent pharmacokinetic parameters and pharmacodynamics were assessed. RESULTS: There were numerical trends toward higher peak epinephrine concentrations (0.52 vs 0.35 ng/mL; geometric mean ratio, 1.40; 90% CI 117.6-164.6%) and more rapid exposure (time to peak concentration, 20 vs 50 min) for EpiPen vs IM syringe at mid-AL thigh across STMD groups. Absorption was faster over the first 30 min for EpiPen vs IM syringe (partial area under curve [AUC] over first 30 min: geometric mean ratio, 2.13; 90% CI 159.0-285.0%). Overall exposure based on AUC to the last measurable concentration was similar for EpiPen vs IM syringe (geometric mean ratio, 1.13; 90% CI 98.8-129.8%). Epinephrine pharmacokinetics after EpiPen injection were similar across STMD groups. Treatments were well tolerated. CONCLUSIONS: Epinephrine delivery via EpiPen resulted in greater early systemic exposure to epinephrine vs IM syringe as assessed by epinephrine plasma levels. Delivery via EpiPen was consistent across participants with a wide range of STMD, even when the needle may not have penetrated the muscle.Trial registrationsThis trial was registered with the German Clinical Trials Register (DRKS-ID: DRKS00011263; secondary ID, EudraCT 2016-000104-29) on 23 March 2017.

Injectable Combination Product Development: Facilitating Risk-Based Assessments for Efficiency and Patient Centric Outcomes.

Combination products (CPs), designated by the US Food and Drug Administration, continue to be on the rise, from the innovation of novel medicines and greater demand for injectable home and self-administration. CP qualification, its constituent parts or intended use, will depend upon the regulatory jurisdiction with reference to the product's primary mode of action. In the case of a drug product combined with a device, a consult or collaborative review process involving different Centers within the US Food and Drug Administration may be necessary. Policies and practices from different legislative branches of government will need to be merged for a single application. This presents a challenge for aligning information for the application dossier as it relates to a drug master file or drug-device CP design history file. A common objective for both pharmaceuticals and devices is to identify and evaluate patient risks to be mitigated, controlled, and managed across the drug product lifecycle. These concepts are reflected in the regulatory practices of pharmaceutical quality by design and device design controls. Early stakeholder engagement with this dynamic process between different regulatory paradigms becomes an advantage. This manuscript describes aspects for early planning for injectable drug-device development to facilitate time to market with patient centric solutions.

Hooked epinephrine auto-injector devices in children: four case reports with three different proposed mechanisms.

BACKGROUND: The prevalence of epinephrine auto-injectors (EAI) use is on the rise. Our objective was to describes children with hooked EAI needles that were embedded in soft tissues. CASE PRESENTATION: Results: Two children self-injected in their shins. The embedded EAIs required removal in the Emergency Department. Both needles were hooked and splayed at the tip. A boy in anaphylaxis kicked his leg during EAI injection and the hooked needle embedded under his skin and was difficult to dislodge. The exposed needle was curved. A girl had an EAI administered for anaphylaxis, which was also difficult to dislodge. On removal, the distal needle tip was hooked approximately 160 degrees. Images of the device revealed that the needle fired off-center from the device and the device components were cracked. We propose three different explanations for these hooked EAI needles. The first is that the needle could hit bone during injection and curve rather than penetrates further. Secondly, the needle could bend when the patient moves during injection. Thirdly, if a needle fires sufficiently off-center to hit the cartridge carrier, this could hook the needle prior to injection. CONCLUSIONS: Awareness of the reasons for needle hooking, damage observed, and challenges and successful approaches to their removal, can better prepare the provider for these uncommon events. Teaching parents, children and educators about safe EAI storage and appropriate restraint during use may prevent some of these accidental injuries. Reporting device failures may lead to improvements in device performance and design.