Följande examensarbete är skrivet på Kungliga Tekniska Högskolan inom maskinteknik med inriktningen industriell ekonomi och produktion och utförd i ett ingenjörsföretag. ISO standarden 11608–1:2014 listar olika tester som måste genomföras för att få en autoinjektor godkänd för användning. Ett utav testerna är att man släpper autoinjektorn från en bestämd höjd och riktning i fritt fall. Det testet kallas för droptest. Minimikraven för ISO 11608–1 för droptest kan potentiellt ha begränsningar då de inte representerar verkligheten, som exempelvis att en autoinjektor kan falla från höjder och riktningar som inte tillhör minimikraven. Detta kan skapa osäkerheter hur en autoinjektor kan prestera under nödsituationer. Syftet med arbetet är att undersöka ifall man kan öka säkerheten vid användning av autoinjektorer vid nödsituationer, och då har man satt som mål att undersöka ifall det krävs att droptesta mer än minimikravet i ISO-standarden. Detta utförs genom att genomföra olika experiment för att avgöra om ISO-standarden räcker till. Där man experimenterar med att släppa autoinjektorer från högre höjder och fler riktningar samt utför hur detta har påverkat funktionen på apparaterna. Metoden genomförs i företaget, kommer ge data hur funktionen har påverkats. Mer specifikt data på om det krävs mer eller mindre kraft för att dra bort locket. Och data på hur aktiveringen av sprutan har påverkats. Med hjälp av lådagram så analyseras värdena då man skapar grafer för att hitta olika trender som kan uppstå. Resultatet efter genomföranden och analysen blev det att inga tydliga trender uppstod och inga tydliga indikationer att det krävs att drop testa över minimikravet. Däremot kan analysen från detta examensarbete användas som underlag vid diskussioner och planering av droptest på företaget / The following thesis will give the reader a better understanding about autoinjectors and drop tests. ISO standard 11608-1:2014 lists various tests that must be carried out to get an autoinjector approved for use. One of the tests is to drop the autoinjector from a certain height and direction in free fall. That test is called a drop test. The minimum requirements of ISO 11608-1 for drop testing can potentially have limitations as they do not represent reality, such as an autoinjector falling from heights and directions outside the minimum requirements. This can create uncertainties in how an autoinjector can perform during emergency situations. The purpose of this thesis is to investigate whether it is possible to increase safety when using autoinjectors in emergency situations, where the goal is to investigate whether droptests from higher heights and different directions are required. This is done by conducting various experiments to determine if the ISO standard is sufficient. Where one first performs dropstests from higher heights and more directions and secondly performs functional testing on the devices to see how they have been affected. The method is carried out in the company and will provide data on how the function has been affected. More specifically, data on whether force is required to pull the lid off. And data on how the activation of the syringe has been affected. Through using boxplots, the values are analysed when creating graphs to find different trends that may occur. The result after implementation and analysis was that no clear trends emerged and there were no clear indications that it is required to drop test above the minimum requirement. However, the analysis from this thesis can be used as a basis for discussions and planning of drop tests for others.

<div><br></div><div> Today, autoinjectors are developed for more viscous drug solutions, which require larger forces for actuating the syringe and impose larger stresses on the drug solution during the administration of autoinjectors. We developed experimentally validated high-fidelity simulations to investigate the liquid jet formation, liquid slosh and cavitation during the insertion process of an autoinjector. </div><div> </div><div> The jet formed due to an acceleration-deceleration motion of syringe is found to be governed by the interplay between inertial, viscous, surface tension and gravitational forces. A scaling for the jet velocity and a criterion for the jet breakup in a simplified geometry are proposed.</div><div> </div><div> When the syringe accelerates and decelerates during the insertion, liquid slosh occurs and there is a vehement motion of the air-liquid interface. Here, we quantified the area of air-liquid interface and hydrodynamic strain rate, which increase with the air gap size, syringe velocity, tilt angle and inner wall hydrophobicity, and decrease with the solution viscosity and hardly change with the liquid column height and surface tension. The strain rate is not sufficient to unfold the protein and the air-liquid interface is more likely to cause protein aggregation.</div><div> </div><div> In a spring-driven autoinjector, the plunger is actuated by the impact of a driving rod, which generates a strong pressure wave and can cause cavitation inception. The cavtiation bubbles can be impeded by the syringe walls and form a re-entrant jet shooting toward the syringe wall. During the process, the protein molecules are focused in the jet, pushed toward the syringe wall and spread across the wall, which can be the reason for the protein aggregation and adsorption on the syringe walls. The impedance effects of the wall decreases with the wall distance and increases with the maximum bubble size. The maximum bubble radius also increases with the liquid column size and nucleus size and decreases with the air gap pressure. Since inertia effects dominate in the cavitation process, the liquid viscosity and surface tension hardly changes the cavitation bubble dynamics. Small bubbles can also form in the bulk, which may generate aggregates in the bulk solution. Bubbles in the cavitation bubble cloud may coalesce with nearby bubbles and induce a higher pressure at the collapse (up to 1000 bar). This high pressure can potentially generate hydroxyl radicals that oxidize the protein molecules.</div><div> </div><div> The current study presents a detailed picture of fluid flows in autoinjectors and provide recommendations for mitigating the liquid slosh and cavitation generated in syringes. The results can be combined with future experiments to understand the implications of fluid flows on protein drugs and the performance of autoinjectors.</div>

Background: In patients with multiple sclerosis (MS), non-adherence to disease-modifying drug therapy is associated with an increased rate of MS relapses. Early identification of patients at risk of non-adherence would allow provision of timely and individualized support. The aim of the BETAPREDICT study was to investigate potential predictors of adherence in patients with MS in Germany treated with interferon β-1b (IFNβ-1b) using the BETACONNECT® autoinjector. Methods: BETAPREDICT was a national, multi-center, prospective, non-interventional, single-arm, 24-month cohort study of patients with relapsing–remitting MS or clinically isolated syndrome receiving IFNβ-1b via the BETACONNECT® autoinjector (ClinicalTrials.gov: NCT02486640). Injection data were captured by the autoinjector. The primary objective was to determine baseline predictors of compliance, persistence, and adherence to IFNβ-1b treatment after 12- and 24 months using multivariable-adjusted regression. Secondary objectives included evaluation of satisfaction with the autoinjector, injection site pain, vitamin and nutrient supplementation, clinical course, and patient-related outcome measures. Results: Of 165 patients enrolled, 153 were available for analysis (120 with autoinjector data). Seventy-two patients left the study prematurely. Compliance (N = 120), persistence (N = 153), and adherence (N = 120) at 24 months were 89.1, 53.6, and 41.7%, respectively. Compliance at 12- and 24 months was predicted by intake of vitamin D supplements and absence of specific injection site reactions. Positive predictors of persistence included age (at 12- and 24 months) and previous duration of treatment (at 12 months), while intake of vitamins/nutrients other than vitamin D was a negative predictor (at 12 months). Positive predictors of adherence at 24 months were age and being experienced with IFNβ-1b. Higher scores in specific SF-36 subscales were positive predictors of medication-taking behavior at 24 months. Satisfaction with the autoinjector was high at baseline and 24 months (median score: 9 out of 10). Conclusions: Compliance with IFNβ-1b treatment among participants still under observation remained high over a 24-month period, while persistence and adherence continuously declined. Multiple factors affected medication-taking behavior, including patient characteristics, treatment history, injection site reactions, patients’ perception of their health and support programs. The importance of these factors may differ among patients according to their individual situation.

This thesis is dedicated to the topic of the nerve agents with special emphasis on antidotal treatment utilizing application of the auto-injectors. Two methods were used ? literature research and quantitative research. Since this topic covers plenty of information as regards chemical warfare agents and in particular nerve agents these issues were addressed in the theoretical part of the thesis. In the chapter on current status based on literature resources a summary of evolution of the auto-injector is presented; from firsts notes until the situation today. Practical part of the thesis is concentrated on University of Southern Bohemia in ČeskéBudějovice, Faculty of Health and Social Studies students' knowledge in the area of nerve agents. The results of the research were acquired by the method of quantitative research ? questionnaires with 18 questions. With respect to each of the questions a selection of the 2 to 7 answers was offered to the students, whereas in every case only 1 answer was correct. The results were analyzed both with reference to each of the questions and with reference to each of the students. By this method it has been discovered that the respondents have a good knowledge in the area of nerve agents. Furthermore, the practical part of the thesis included an experiment concerning speed with which the respondents were able to apply antidotum with a training auto-injector by themselves with no prior instructions in comparison to how quickly they were able to do the same after being instructed. By this method were tested the quality of the instructions provided to the auto-injectors and its ergonomic qualities (intuitiveness of its application). Recorded times were statistically analyzed and the results, although materially different, were assessed as satisfactory.

<p>  </p> <p>Cavitation, liquid slosh, and splashes are ubiquitous in science and engineering. However, these phenomena are not fully understood. Yet to date, we do not understand when or why sometimes the splash seals, and other times does not. Regarding cavitation, a high temporal resolution method is needed to characterize this phenomenon. The low temporal resolution of experimental data suggests a model-based analysis of this problem. However, high-fidelity models are not always available, and even for these models, the sensitivity of the model outputs to the initial input parameters makes this method less reliable since some initial inputs are not experimentally measurable. As for sloshing, the air-liquid interface area and hydrodynamic stress for the liquid slosh inside a confined accelerating cylinder have not been experimentally measured due to the challenges for direct measurement.</p>

<p>Autoinjectors are pen-like devices that typically deliver drug products of 2 mL or less. They shield the needle before and after use, reducing patient anxiety from needle phobia and mitigating the risk of needlestick injuries and accidental contamination. Additionally, automatic delivery ensures more consistent needle penetration depth and injection force than manual injection methods. </p> <p><br></p> <p>To optimize autoinjector design, this thesis presents experimentally validated computational models that describe the processes of needle insertion, drug delivery, and transport of subcutaneously administered therapeutic proteins in the body. A multi-objective optimization framework is also proposed to guide the design of autoinjectors.</p> <p><br></p> <p>This thesis focuses on spring-driven autoinjectors, the most common type of autoinjector. It begins with an overview of the interactions between the spring-driven autoinjector, tissue, and therapeutic proteins. Moving on to Chapter 2, a computational model is presented to accurately predict the kinematics of the syringe barrel and plunger during the needle insertion process.</p> <p><br></p> <p>In Chapter 3, we present a quasi-steady model for the drug delivery process, which considers the rheology of therapeutic proteins. The Carreau model is adopted to describe protein viscosity, and explicit relationships between flow rate and pressure drop in the needle are derived. Furthermore, the applicable regime for the power-law model for protein viscosity is identified.</p> <p><br></p> <p>Chapter 4 quantifies the impact of sloshing and cavitation on therapeutic proteins in the syringe. Additionally, a workflow is presented to integrate available simulation tools to predict the performance of spring-driven autoinjectors. The influence of each design parameter of spring-driven autoinjectors on their performance is also discussed. </p> <p><br></p> <p>The spring-driven autoinjector delivers therapeutic proteins through subcutaneous administration. To gain insights into the transport process of therapeutic proteins, Chapter 5 presents a physiologically-based pharmacokinetic model that has been validated against experimental data for humans and rats. The lymph flow rate significantly affects the bioavailability of therapeutic proteins. This finding highlights the importance of studying the transport of therapeutic proteins in the lymphatic system in future research.</p> <p><br></p> <p>Chapter 6 provides a multi-objective design optimization framework for the spring-driven autoinjector. The computational model is replaced with an accurate deep neural network surrogate to improve the computational efficiency.  Using this surrogate model, we conduct a sensitivity analysis to identify essential design parameters. After that, we perform multi-objective optimization to find promising design candidates.</p> <p><br></p> <p>Chapter 7 presents a model for bubble dynamics in a protein solution. An explicit expression for the bubble dissolution rate is derived, enabling extraction of the interfacial properties of the protein-coated interface from the measured bubble radii. Moreover, analytical solutions for the response of a protein-coated bubble to an imposed acoustic pressure are derived. This work provides insight into protein-coated bubbles, which are used as vehicles to deliver drugs, as active miniature tracers to probe the rheology of soft and biological materials, or as contrast agents to enhance the ultrasound backscatter in ultrasonic imaging.</p> <p><br></p> <p>At last, in Chapter 8, we introduce a model for laser-induced cavitation that considers several key factors, such as liquid compressibility, heat transfer, and non-equilibrium evaporation and condensation. Our model's predictions for the time-course of bubble radii have been validated with experimental data. Moreover, our model reveals that the reduction of the bubble's oscillation amplitude is primarily due to a decrease in the number of vapor molecules inside the bubble, highlighting the crucial role of phase change in laser-induced cavitation bubbles.</p> <p><br></p> <p>The developed computational models and framework provide crucial insights into the development of spring-driven autoinjectors and cavitation bubbles. These studies can also enhance the efficacy and safety of the delivery of therapeutic proteins, ultimately improving patient outcomes.</p>