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Background: Although a variety of drug delivery devices have been launched in recent years, few studies have comprehensively investigated the market trends of combination drugs and medical devices approved or certified in Japan and the regulatory challenges related to their approval. Among the drug delivery devices, autoinjectors are more convenient than traditional prefilled syringes and are designed with safety features to prevent needlestick accidents, allowing self-injection by patients. Therefore, autoinjectors have been incorporated into the treatment of various diseases and have shown significant growth among drug delivery devices. Aim: This study aimed to investigate the market trends of combination drugs approved in Japan, especially those with autoinjector formulations, and to explore the challenges in the regulatory aspects of combination drugs. Methods: Information on the number of marketed drugs and medical devices was obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) database using specific definitions. We looked at the annual changes in the number of drug delivery devices approved and certified as combination drugs or medical devices and the number of canceled certifications. We also examined the classification and main certification criteria for Japanese medical device nomenclature. Results: The study suggested that the number of combination drugs with autoinjector formulations is increasing, replacing previously approved or certified pen-type medication injectors. Moreover, 53% of all drug products were approved for autoinjector formulations after the initial authorization approval in Japan, and more than half of them obtained approval for additional formulations for autoinjectors within five years of the initial authorization approval, with the largest number of cases obtaining approval for additional formulations two years later. Conclusion: The lack of clear regulatory requirements for autoinjectors may lead to confusion among applicants. Furthermore, there are challenges in filing regulatory applications, thus hindering the rapid launch of combination drugutilizing devices with superior usability. [ABSTRACT FROM AUTHOR]

Objectives: This research aims to present and assess the Primary Functions of autoinjectors introduced in ISO 11608-1:2022. Investigate the risks in current autoinjector technology, identify and assess risks and benefits associated with Artificial Intelligence (AI) powered autoinjectors, and propose a framework for mitigating these risks. ISO 11608-1:2022 is a standard that specifies requirements and test methods for needle-based injection systems intended to deliver drugs, focusing on design and function to ensure patient safety and product effectiveness. 'KZH' is an FDA product code used to classify autoinjectors, for regulatory purposes, ensuring they meet defined safety and efficacy standards before being marketed. Method: A comprehensive analysis of autoinjectors problems is conducted using data from the United States Food and Drug Administration (FDA) database. This database records medical device reporting events, including those related to autoinjectors, reported by various sources. The analysis focuses on events associated with the product code KZH, covering data from January 1, 2008, to September 30, 2023. This research employs statistical frequency analysis and incorporates pertinent the FDA, United Kingdom, European Commission regulations, and ISO standards. Results: 500 medical device reporting events are assessed for autoinjectors under the KZH code. Ultimately, 188 of these events are confirmed to be associated with autoinjectors, all 500 medical devices were seen to lack AI capabilities. An analysis of these events for traditional mechanical autoinjectors revealed a predominant occurrence of malfunctions (72%) and injuries (26%) among event types. Device problems, such as breakage, defects, jams, and others, accounted for 45% of incidents, while 10% are attributed to patient problems, particularly missed and underdoses. Conclusion: Traditional autoinjectors are designed to assist patients in medication administration, underscoring the need for quality control, reliability, and design enhancements. AI autoinjectors, sharing this goal, bring additional cybersecurity and software risks, requiring a comprehensive risk management framework that includes standards, tools, training, and ongoing monitoring. The integration of AI promises to improve functionality, enable real-time monitoring, and facilitate remote clinical trials, timely interventions, and tailored medical treatments. [ABSTRACT FROM AUTHOR]

ObjectivesThis research aims to present and assess the Primary Functions of autoinjectors introduced in ISO 11608-1:2022. Investigate the risks in current autoinjector technology, identify and assess risks and benefits associated with Artificial Intelligence (AI) powered autoinjectors, and propose a framework for mitigating these risks. ISO 11608-1:2022 is a standard that specifies requirements and test methods for needle-based injection systems intended to deliver drugs, focusing on design and function to ensure patient safety and product effectiveness. ‘KZH’ is an FDA product code used to classify autoinjectors, for regulatory purposes, ensuring they meet defined safety and efficacy standards before being marketed.MethodA comprehensive analysis of autoinjectors problems is conducted using data from the United States Food and Drug Administration (FDA) database. This database records medical device reporting events, including those related to autoinjectors, reported by various sources. The analysis focuses on events associated with the product code KZH, covering data from January 1, 2008, to September 30, 2023. This research employs statistical frequency analysis and incorporates pertinent the FDA, United Kingdom, European Commission regulations, and ISO standards.Results500 medical device reporting events are assessed for autoinjectors under the KZH code. Ultimately, 188 of these events are confirmed to be associated with autoinjectors, all 500 medical devices were seen to lack AI capabilities. An analysis of these events for traditional mechanical autoinjectors revealed a predominant occurrence of malfunctions (72%) and injuries (26%) among event types. Device problems, such as breakage, defects, jams, and others, accounted for 45% of incidents, while 10% are attributed to patient problems, particularly missed and underdoses.ConclusionTraditional autoinjectors are designed to assist patients in medication administration, underscoring the need for quality control, reliability, and design enhancements. AI autoinjectors, sharing this goal, bring additional cybersecurity and software risks, requiring a comprehensive risk management framework that includes standards, tools, training, and ongoing monitoring. The integration of AI promises to improve functionality, enable real-time monitoring, and facilitate remote clinical trials, timely interventions, and tailored medical treatments.

Healthcare trends continue to move from hospital to home and many targeted therapies and precision medicines are now being designed to be self-administered by patients or delivered in a home setting. In the case of long acting injectables and bio-therapeutics, the importance of optimal drug/biologic-device combination in terms of user needs becomes critical for successful clinical outcomes. The risk especially increases for novel therapies due to unknowns and uncertainties surrounding new formulation flow behavior, delivery methods, new injection sites and therapeutic optimization. Other risk factors include patient tolerability and acceptability. The success of the clinical outcome is now dependent on the optimal delivery in these situations for a consistent pharmacokinetics (PK) response. In addition, the complexity of formulations and challenging delivery needs have brought to light some of the limitations of existing legacy device technology, which may not be suited for these novel applications. The formulation itself may not be an exact fit to deliver with existing standard device technologies and may need to be designed to deliver the specific formulation appropriately. Formulations may have to be optimized both for delivery and for the therapeutic outcome creating many iterative development cycles. Rapid development of the therapies requires simultaneous development of drug and device and thus the importance of early-stage characterization. We present a novel integrated approach that includes drug delivery optimization via an autoinjector simulator in pre-clinical and clinical studies to assess the PK performance and potential to establish path to device early on and reduce time to the clinic. [ABSTRACT FROM AUTHOR]

ObjectivesAutoinjectors are pivotal for precise self-administration of medications across a wide range of medical conditions. Nevertheless, the absence of a dedicated Medical Device Development Tool (MDDT) for autoinjectors represents a gap that may result in variations in the quality and regulatory compliance of autoinjectors as components of combination products. This research aim is to utilize the recently introduced Primary Functions outlined in ISO 11608-1:2022 with the title “Needle-based injection systems for medical use. Requirements and test methods. Part 1: Needle-based injection systems” to create a comprehensive MDDT framework tailored specifically for autoinjectors.MethodsTo support the creation of the framework, the analysis of the FDA MDDTs that were already approved, FDA's design controls regulations, FDA's guidance related to autoinjectors, and the Primary functions outlined in ISO 11608-1:2022 were utilized.ResultsThe research identifies the Primary Functions in autoinjector to be Holding Force, Cap Removal Force, Activation Force, Extended Needle Length, Injection Time, Dose Accuracy and Needle Guard Lockout. Leveraging these Primary Functions and the FDA's MDDT approach, the research aims to bridge the gap by proposing a structured framework for the development of a specific MDDT tailored to autoinjectors.ConclusionThis study presents a MDDT framework tailored to the development of autoinjectors for drug delivery. This framework provides a structured methodology to support predictability and effectiveness of the autoinjector development and support regulatory review process, thereby expediting FDA approval for autoinjectors as part of combination product.

Abstract Background Sensoready® autoinjector pen facilitates self-administration of subcutaneous ofatumumab injections at home. We aim to investigate patient and nurse preference for using Sensoready® versus comparator autoinjectors in multiple sclerosis (MS). Methods A pilot survey was conducted in Germany followed by in-field interviews across United States, Germany, France, and Italy. The survey recruited 80 MS patients and 50 MS nurses. Respondents were interviewed for 45-min on qualitative open-ended and quantitative close-ended survey consisting of 31 questions for patients and 41 for nurses. Ratings were measured on Likert scale from 1 (not at all important) to 10 (extremely important). Results “Easy to perform self-injection with the pen” and “Patient able to use independently” (both, mean overall score 9.4) were the most important attributes for both patients and nurses. Sensoready® scored high across most important attributes for both patients and nurses (p

Background: Sensoready® autoinjector pen facilitates self-administration of subcutaneous ofatumumab injections at home. We aim to investigate patient and nurse preference for using Sensoready® versus comparator autoinjectors in multiple sclerosis (MS). Methods: A pilot survey was conducted in Germany followed by in-field interviews across United States, Germany, France, and Italy. The survey recruited 80 MS patients and 50 MS nurses. Respondents were interviewed for 45-min on qualitative open-ended and quantitative close-ended survey consisting of 31 questions for patients and 41 for nurses. Ratings were measured on Likert scale from 1 (not at all important) to 10 (extremely important). Results: "Easy to perform self-injection with the pen" and "Patient able to use independently" (both, mean overall score 9.4) were the most important attributes for both patients and nurses. Sensoready® scored high across most important attributes for both patients and nurses (p < 0.05). Sensoready® was preferred over comparator devices across majority of the important attributes (84%; p < 0.05), especially ease of use of the pen (mean overall score 9.4). Sensoready® was preferred over their current device by 9/10 nurses and 8/10 patients if they had to choose a treatment based on the device alone. Conclusion: Both MS patients and nurses preferred the Sensoready® (ofatumumab) over comparator autoinjectors for their treatment, mostly driven by ease of administration. [ABSTRACT FROM AUTHOR]

Objective: This noninvasive study aimed to understand the interaction between shield-triggered autoinjectors (AI) and skin at the point of activation, hypothesizing that the AI's housing absorbs a significant amount of the user-applied force depending on shield design and skin characteristics., Methods: Twenty-seven volunteers used a test device measuring applied force versus shield force and indentation depth relative to shield length (2,4,6,8 mm) in standing and sitting positions., Results: Significant differences were found between applied and shield force for the different shield lengths. Shorter shields resulted in significantly lower force transfer coefficients, with means ranging from 0.72 for the 2 mm shield to 0.94 for the 8 mm shield. ANOVA revealed statistically significant factors ( p  < .05), including position and gender, with females generally having lower coefficient values. Indentation depth increased with higher forces and varied significantly between positions without significant shield length impact., Conclusion: The findings confirm that an increase in shield length at the point of activation reduces skin friction with the housing, resulting in less force loss and a lower device activation force perceived by the user. Force loss can be further reduced by standing up. Understanding device-tissue interactions will support development of better AIs with fewer user failures.

Anaphylaxis is a medical emergency with adrenaline acknowledged as the first‐line therapy. It is therefore important that patients have access to self‐injectable adrenaline in the community. Manufacturers have been requested by European Medicine Regulators to generate pharmacokinetic data for these autoinjector devices. For the first time, these data provide an insight into how individual devices work in different populations, and how they compare. We undertook a thorough literature search and also accessed grey literature, using searches of medicine regulators' websites and freedom of information requests. The data demonstrate that it takes at least 5–10 min to achieve early peak plasma concentration for most devices. The specific autoinjector device seems to be the most important determinant of pharmacokinetics, with different devices giving rise to different plasma adrenaline profiles. Needle length does not seem to be the most important factor; rather, the force and speed of injection (which varies from one device to another) is likely to be of greater importance. In general, peak plasma adrenaline concentration is lower and time‐to‐peak concentration longer with increased skin‐to‐muscle depth. However, it is difficult to draw conclusions with the current available data, due to a lack of head‐to‐head comparisons, small numbers of study participants and the failure to acknowledge the biphasic nature of intramuscular adrenaline absorption for analysis purposes. [ABSTRACT FROM AUTHOR]

Background: Although a variety of drug delivery devices have been launched in recent years, few studies have comprehensively investigated the market trends of combination drugs and medical devices approved or certified in Japan and the regulatory challenges related to their approval. Among the drug delivery devices, autoinjectors are more convenient than traditional prefilled syringes and are designed with safety features to prevent needlestick accidents, allowing self-injection by patients. Therefore, autoinjectors have been incorporated into the treatment of various diseases and have shown significant growth among drug delivery devices., Aim: This study aimed to investigate the market trends of combination drugs approved in Japan, especially those with autoinjector formulations, and to explore the challenges in the regulatory aspects of combination drugs., Methods: Information on the number of marketed drugs and medical devices was obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) database using specific definitions. We looked at the annual changes in the number of drug delivery devices approved and certified as combination drugs or medical devices and the number of canceled certifications. We also examined the classification and main certification criteria for Japanese medical device nomenclature., Results: The study suggested that the number of combination drugs with autoinjector formulations is increasing, replacing previously approved or certified pen-type medication injectors. Moreover, 53% of all drug products were approved for autoinjector formulations after the initial authorization approval in Japan, and more than half of them obtained approval for additional formulations for autoinjectors within five years of the initial authorization approval, with the largest number of cases obtaining approval for additional formulations two years later., Conclusion: The lack of clear regulatory requirements for autoinjectors may lead to confusion among applicants. Furthermore, there are challenges in filing regulatory applications, thus hindering the rapid launch of combination drug-utilizing devices with superior usability., Competing Interests: MM was employed by MSD K.K. The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Mochizuki and Maeda.)

[Display omitted] Cavitation, the formation and collapse of vapor-filled bubbles, poses a problem in spring-driven autoinjectors (AIs). It occurs when the syringe accelerates abruptly during activation, causing pressure fluctuations within the liquid. These bubbles expand and then collapse, generating shock waves that can harm both the device and the drug molecules. This issue stems from the syringe's sudden acceleration when the driving rod hits the plunger. To better understand cavitation in AIs, we explore how design factors like drive spring force, air gap size, and fluid viscosity affect its likelihood and severity. We use a dynamic model for spring-driven autoinjectors to predict and analyze the factors contributing to cavitation initiation and severity. This model predicts the motion of AI components, such as the displacement and velocity of the syringe barrel, and allows us to investigate pressure wave propagation and the subsequent dynamics of cavitation under various operating conditions. We investigated different air gap heights (from 1 to 4 mm), drive spring forces (from 8 to 30 N), and drug solution viscosities (from 1 to 18 cp) to assess cavitation inception based on operational parameters. Results reveal that AI dynamics and cavitation onset and severity strongly depend upon AI operating parameters, namely drive spring force and air gap height. The maximum syringe acceleration increases with spring stiffness and decreases with air gap height; increases in air gap height prolong the time interval of syringe acceleration but diminish the maximum syringe acceleration. From actuation to injection, air gap pressure peaks twice, first due to impact with the rod/plunger and secondly due to the deacceleration event upon injection. The maximum air gap pressure increases with spring stiffness and decreases with air gap height. Results show that maximum cavitation bubble radii and collapse-driven extension rates occur with higher driver spring forces, smaller air gap heights, and less viscous solutions. A cavitation criterion is developed for cavitation in autoinjectors that concludes that cavitation in autoinjectors depends on the peak syringe acceleration. [ABSTRACT FROM AUTHOR]

Background: This study examines how shield-triggered autoinjectors (AIs), for subcutaneous drug delivery, affect injection depth. It focuses on shield size and applied force, parameters that could potentially lead to inadvertent intramuscular (IM) injections due to tissue compression., Method: A blinded ex-vivo study was performed to assess the impact of shield size and applied force on injection depth. Shields of 15, 20, and 30 mm diameters and forces from 2 to 10 N were investigated. The study involved 55 injections in three Landrace, Yorkshire, and Duroc (LYD) pigs, with injection depths measured with computed tomography (CT). An in-vivo study, involving 20 injections in three LYD pigs, controlled the findings, using fluoroscopy (FS) videos for depth measurement., Results: The CT study revealed that smaller shield sizes significantly increased injection depth. With a 15 mm diameter shield, 10 N applied force, and 5 mm needle protrusion, the injection depth exceeded the needle length by over 3 mm. Injection depth increased with higher applied forces until a plateau was reached around 8 N. Both applied force and size were significant factors for injection depth (analysis of variance [ANOVA], P < .05) in the CT study. The FS study confirmed the ex-vivo findings in an in-vivo setting., Conclusions: The study demonstrates that shield size has a greater impact on injection depth than the applied force. While conducted in porcine tissue, the study provides useful insights into the relative effects of shield size and applied force. Further investigations in humans are needed to confirm the predicted injection depths for AIs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Anne-Sofie Madsen Staples is employed as Industrial Ph.D. student at Novo Nordisk A/S. Mette Poulsen, Kezia Ann Friis Præstmark, and Thomas Sparre are full-time employees at Novo Nordisk A/S.

Objectives: Autoinjectors are pivotal for precise self-administration of medications across a wide range of medical conditions. Nevertheless, the absence of a dedicated Medical Device Development Tool (MDDT) for autoinjectors represents a gap that may result in variations in the quality and regulatory compliance of autoinjectors as components of combination products. This research aim is to utilize the recently introduced Primary Functions outlined in ISO 11608-1:2022 with the title "Needle-based injection systems for medical use. Requirements and test methods. Part 1: Needle-based injection systems" to create a comprehensive MDDT framework tailored specifically for autoinjectors., Methods: To support the creation of the framework, the analysis of the FDA MDDTs that were already approved, FDA's design controls regulations, FDA's guidance related to autoinjectors, and the Primary functions outlined in ISO 11608-1:2022 were utilized., Results: The research identifies the Primary Functions in autoinjector to be Holding Force, Cap Removal Force, Activation Force, Extended Needle Length, Injection Time, Dose Accuracy and Needle Guard Lockout. Leveraging these Primary Functions and the FDA's MDDT approach, the research aims to bridge the gap by proposing a structured framework for the development of a specific MDDT tailored to autoinjectors., Conclusion: This study presents a MDDT framework tailored to the development of autoinjectors for drug delivery. This framework provides a structured methodology to support predictability and effectiveness of the autoinjector development and support regulatory review process, thereby expediting FDA approval for autoinjectors as part of combination product., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Machal.)

Buprenorphine drug cartridge was made for autoinjector device for use in emergency and critical situations to reduce the morbidity and mortality. Water-filled cartridges were prepared and buprenorphine was injected aseptically in the cartridge, to make 0.05 and 0.10 mg/mL. Rats were injected intraperitoneally, buprenorphine (0.3 and 0.6 mg/kg), repeatedly with the autoinjector and compared with manual injection (7 days and 14 days) using various haematological and biochemical parameters. No significant change was observed in the body weight, organ to body weight ratio and haematological variables in any of the experimental groups compared with the control group. Except serum urea and aspartate aminotransferase, no significant change was observed in glucose, cholesterol, triglycerides, bilirubin, protein, albumin, creatinine, uric acid, alanine aminotransferase, gamma glutamyltransferase and alkaline phosphatase. The autoinjectors deliver the drugs with spray effect and force for faster absorption. In the present study, the autoinjector meant for intramuscular injection was injected intraperitoneally in rats, and the drug was delivered with force on the vital organs. No significant difference was observed in the autoinjector group compared to the manual group showing tolerability and safety of the buphrenorphine autoinjector. This study shows that buprenorphine autoinjector can be considered for further research work. [ABSTRACT FROM AUTHOR]

Background: Pen needles and autoinjectors are necessary for millions of patients needing injectable drug treatment but pose economic and environmental burdens. A durable device with a multiuse needle could reduce cost and improve user experience. This study explores a novel robust needle tip (EXP) designed for multiple uses and durability against hooking., Method: Needle robustness was investigated through a structural analysis. Furthermore, EXP and control needles (NF30, NF28) were evaluated in an in-vivo porcine model as pen needles or embedded in autoinjectors to study the resulting increase in skin blood perfusion (SBP). The SBP was assessed by laser speckle contrast analysis (LASCA) of 192 randomized and blinded needle insertions., Results: Forming a 33 µm hook against a hard surface requires 0.92 N for the NF30 control needle and 5.38 N for EXP. The EXP did not induce more tissue trauma than the NF30. There was a positive relation between needle diameter and SBP ( P < .05). Furthermore, the presence of an autoinjector shield and applied force of 10 N was found to significantly reduce SBP for worn EXP needles ( P < .05) compared to insertions without autoinjector shield., Conclusions: The investigated robust needle EXP is on par with the single-use needle NF30 in terms of tissue trauma, which is further reduced by combining the needle with a needle shield. These results should encourage the innovation and development of durable, reusable injection systems with pharmacoeconomic and environmental value and a simplified and enhanced user experience for patients., Competing Interests: Declaration of Conflicting InterestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A-SMS is employed as Industrial PhD student at Novo Nordisk A/S. JS and KAFP are full-time employees at Novo Nordisk A/S.

Introduction: The growing interest in subcutaneous delivery of larger single-dose volumes using handheld autoinjectors raises questions about the feasible upper limits for injection volume and rate. This review critically evaluates the literature on subcutaneous administration with dose volumes greater than 1.0 mL. In so doing, it examines how previous work has addressed limitations and considerations for designing and developing large-volume autoinjectors., Areas Covered: This article synthesizes 31 studies on large-volume subcutaneous delivery through a systematic review process and structures their findings based on three themes critical to developing large-volume autoinjectors: injection tolerability, suitability for self-administration, and pharmacokinetic equivalence with existing dosing options. This review highlights the answers provided by previous studies and identifies promising avenues for future research., Expert Opinion: This review finds that the literature supports the feasibility of delivering single large-dose subcutaneous volumes, providing a foundation for large-volume autoinjectors. Moreover, the review guides future research to address questions within and across themes critical to large-volume autoinjector development, helping to provide health-care professionals and patients with more effective and convenient dosing options.

Current parenteral administration of drugs suffers from several drawbacks including the requirement of healthcare personnel to administer the drug, the risk of needle stick injuries that may result in the transmission of blood borne pathogens, and patient discomfort. Prefilled devices have emerged as powerful tools to improve parenteral administration of drugs. There are a number of clinical conditions including treatment of endocrine diseases, neurological disorders, autoimmune diseases and emergency medicine where prefilled devices have made major improvements to patient care. Prefilled devices have become an important set of tools for the medical practitioner due to their ease of use and safety, cost effectiveness and patient convenience. This review provides a comprehensive summary of existing prefilled devices, their current clinical uses and corresponding regulatory processes. [ABSTRACT FROM AUTHOR]

[Display omitted] • An accurate deep neural network surrogate greatly reduces computational cost. • Sensitivity analysis helps us focus on key factors. • Pymoo can effectively determine the Pareto front in multi-objective optimization. • Proposed framework enables decision-makers to incorporate design constraints. The major challenges in the optimization of autoinjectors lie in developing an accurate model and meeting competing requirements. We have developed a computational model for spring-driven autoinjectors, which can accurately predict the kinematics of the syringe barrel, needle displacement (travel distance) at the start of drug delivery, and injection time. This paper focuses on proposing a framework to optimize the single-design of autoinjectors, which deliver multiple drugs with different viscosity. We replace the computational model for spring-driven autoinjectors with a surrogate model, i.e., a deep neural network, which improves computational efficiency 1,000 times. Using this surrogate, we perform Sobol sensitivity analysis to understand the effect of each model input on the quantities of interest. Additionally, we pose the design problem within a multi-objective optimization framework. We use our surrogate to discover the corresponding Pareto optimal designs via Pymoo, an open source library for multi-objective optimization. After these steps, we evaluate the robustness of these solutions and finally identify two promising candidates. This framework can be effectively used for device design optimization as the computation is not demanding, and decision-makers can easily incorporate their preferences into this framework. [ABSTRACT FROM AUTHOR]

Atropine sulphate and pralidoxime chloride are considered as essential antidotes in the treatment of nerve agent poisoning. Now in India these antidotes are available in the form of self injectable autoinjectors. This study is designed with aim to replace two individual autoinjectors with single one. Stability of the components plays a vital role in the development of any dosage form, in this study we investigated the stability of the antidotes in combination (atropine sulphate+2 PAMCl) in single drug cartridges. In the present work shelf life of pralidoxime chloride (300 mg/ml) and atropine sulphate (1 mg/ml) solution in combination was evaluated by accelerated studies. The derived model is based on the rate equation and Arrhenius equation was used for extrapolation. Further, antidotal efficacy of atropine sulphate in vitro, using rat's isolated ileum and pralidoxime chloride by survival studies in vivo against dichlorvas in mice were evaluated, for further confirmation of analytical findings. The constituted formulation was found to be stable for 24 months. [ABSTRACT FROM AUTHOR]

To cope with the rapid onset of the life-threatening cholinergic crisis after poisoning with organophosphorus compounds, atropine-oxime preparations should be available in autoinjectors allowing i.m. administration also in the absence of a physician. Such a scenario is conceivable in the battlefield, when nerve agents are disseminated, and can no longer be excluded in civilian areas, as demonstrated most recently in Tokyo. In addition, autoinjectors may be of value in agriculture when medical care is remote. The use of second generation oximes with broad antidotal spectrum, e.g., HI 6 (1-(((4-(aminocarbonyl)pyridinio)- methoxy)methyl)-2-((hydroxyimino)methyl) pyridinium dichloride monohydrate; CAS 34433-31-3) and HLö 7(1-(((4-(aminocarbonyl)pyridinio)methoxy)methyl) 2,4-bis((hydroxyimino)methyl) pyridinium dimethanesulfonate; CAS 145613-73-6) is only possible in dry/wet autoinjectors because their stability is limited in concentrated solution. To detect a possible delay in atropine absorption by the two oximes, the pharmacokinetics of atropine after 'autoinjection' in beagle dogs were determined. Commercially available autoinjectors from two manufacturers [STI International Ltd (BJ) and Astra Tech (AT)] were filled with atropine sulfate, either alone (2 mg) or in combination with HI 6 (500 mg) and HLö 7 (200 mg), respectively, and injected according to a complete cross-over design. Atropine concentration was determined as l-hyoscyamine equivalents in a radioreceptor assay (RRA). In the range of 0.1-6.9 ng/ml, atropine sulfate displaced [ N-methyl-H]-scopolamine methyl chloride ([H]NMS) competitively from rat cerebral cortex membranes. At 200 pmol/l [H]NMS, IC was 1.4±0.1×10 M atropine (CV=8.1%). The intra-assay deviation was about 6%; day-to-day deviation in determination of 1 nM (0.695 ng/ml) atropine was 2.6%(CV=5.2%). AT autoinjectors containing HI 6 delivered only 1.81 mg atropine sulfate while 2.14 mg was released by the other injectors. According to the manufacturer, the reduced delivery was caused by a defective Teflon-coated O-ring as detected later on in the batch used. To allow comparison of the bioavailability of atropine from various autoinjectors, the AUCs were normalized to a constant dose. The atropine absorption half-time (7 min) was not affected either by the autoinjector type or by the combination with oximes. The other pharmacokinetic data likewise did not reveal any differences between the groups. Maximal plasma concentration was 33 ng ml, elimination half-life 52 min, V 3.2 l kg and Cl 44 ml min kg. The relatively high clearance of l-hyoscyamine is discussed. [ABSTRACT FROM AUTHOR]

The rapid onset of cholinergic crisis after intoxication with highly toxic organophosphorus compounds calls for pre-clinical administration of effective antidotes as early as possible. For this purpose, i.m. administration of the antidotes by autoinjectors is desired to allow early treatment also in the absence of a physician. Besides atropine, oximes with broad antidotal spectrum are considered valuable adjuncts that should be included in antidotal mixtures. To circumvent the problem of limited stability of the new-generation oximes, dry/wet autoinjectors were developed in which the unstable solid is dissolved by a diluent in an adjacent chamber upon activation of the device. In this study the tolerance, bioavailability and pharmacokinetics of 500 mg HI 6 [1-(((4-(aminocarbonyl) pyridinio)methoxy) methyl)-2-((hydroxyimino)methyl) pyridinium dichloride monohydrate] or 200 mg HLö 7 [1-(((4-(aminocarbonyl) pyridinio)methoxy)methyl)-2,4-bis ((hydroxyimino)methyl)pyridinium dimethanesulfonate] in combination with 2 mg atropine sulfate versus atropine alone, delivered by two dry/wet autoinjector types, were investigated in eight male beagle dogs (16 kg) in a complete cross-over design. The dogs tolerated the six injections with 3-week intervals without any symptoms of discomfort. Nonetheless, CPK activity increased, peaking at 6 h after injection. In contrast to atropine which merely led to a marginal increase, HI 6 plus atropine increased the baseline CPK activity about 10-fold, and HLö 7 plus atropine about 20-fold, regardless of the injector type. The HI 6 autoinjectors from Astra Tech were from an irregular production batch which did not deliver the declared HI 6 dose. The HLö 7 autoinjectors from Astra Tech and both Binjaect autoinjectors from STI functioned well: the bioavailability was complete with t values of about 25 min as observed after conventional i.m. injection. The absorption half-time was about 8 min, elimination t about 50 min, and V 0.26 l/kg. The urinary recovery of unchanged oximes was 70-80%, the renal clearance being the same as for inulin. Unexpectedly, hematocrit and hemoglobin content of blood decreased by about 15% within 2 h and reached pre-treatment values after 6-24 h. This decrease was observed with all three drug treatments and could not be accounted for by blood loss (<4%), thus pointing to an atropine effect. In conclusion, the newly developed dry/wet autoinjectors appear suitable for the administration of atropine and an oxime stored in solid form. [ABSTRACT FROM AUTHOR]

Background: The administration of adrenaline is a life-saving intervention for anaphylactic reactions. However, it has been questioned whether the needle length of the autoinjectors is sufficient to achieve genuine intramuscular delivery and optimal bioavailability., Objective: To assess the adequacy of Anapen, which has a relatively short needle length (10.5 mm), through a comparison of the depot localization, plasma pharmacokinetics, and cardiovascular responses of adrenaline delivered via Anapen versus a prefilled syringe with a 25.4-mm needle, which is generally used for intramuscular injections., Methods: This randomized, open-label, crossover study compared the impact of adrenaline administration at 2 sites in the thigh of 18 normal weight male volunteers, using either Anapen or the prefilled syringe; in addition, we studied the treatment of 12 overweight women with Anapen. The depot depth was measured by ultrasonography, plasma adrenaline level was evaluated by ultra performance liquid chromatography-mass spectrometry (UPLC-MS), and heart rates were measured using a Holter monitor., Results: Intramuscular injections were given with both devices at both thigh sites in nonobese men, but not in overweight women. Adrenaline levels showed a double peak, with parallel changes in the heart rate. The first peak, of potential vital importance in anaphylaxis treatment, occurred at approximately 10 minutes postinjection, with maximum concentration and area under the curve significantly higher with Anapen than with prefilled syringes; the magnitude of the second peak did not differ among the various conditions. Unexpectedly, in overweight women treated with Anapen, the magnitude of the first peak was similar to that observed in men, despite the injection being subcutaneous, and the overall bioavailability was enhanced., Conclusions: Needle length and intramuscular injection are not absolute requirements for autoinjector efficacy, but the monitoring of injection location, biphasic adrenaline levels, and cardiovascular responses is important for the assessment of their therapeutic relevance in anaphylaxis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)