Drug losses during infusions can be caused by complex adsorption and absorption phenomena at the interface between aqueous formulations and polymer-based medical devices, most commonly made of plasticized poly(vinyl chloride) (PVC). Despite their success in describing adsorption phenomena, molecular simulation methods are inherently limited by their length and time scales, which precludes their application to the study of absorption processes. Here, we extended this molecular understanding using the Martini 3 coarse-grained framework to explore absorption within plasticized PVC matrices containing either DEHT or TOTM plasticizers. We used a top-down approach to refine intermolecular interactions. After optimizing the solute-water and solute-PVC nonbonded interactions to reproduce experimental partitioning data, we combined potential of mean force (PMF), free-energy perturbation (BAR), and long equilibrium simulations to map both the thermodynamic and kinetic aspects of sorption. This work establishes a transferable coarse-grained framework for modeling drug-polymer interactions over extended time scales, bridging atomistic insights with experimental observations and paving the way toward full infusion-system simulations including excipients and complex polymer formulations.

INTRODUCTION:Multi-dose ophthalmic devices equipped with complex dropper systems can release substances, such as 2,4-Di‑tert-butylphenol (2,4-DTBP), that could then contaminate the patients. The objectives of this study were to determine if and how much 2,4-DTBP migrates into eye drops and to assess its cytotoxicity threshold. MATERIALS AND METHODS:Tests simulating patient use of eye drops were carried out on 10 ophthalmic medications including ciclosporin = CsA at 1, 10 and 20 mg/mL, tacrolimus = TAC and voriconazole = VCZ. Drops were collected twice a day for one month and analyzed by liquid chromatography to detect and quantify 2,4-DTBP. Its in vitro cytotoxicity threshold was determined on L929 mouse fibroblasts, according to the MTT test of ISO 10,993-5. RESULTS:2,4-DTBP was only detected in TAC, CsA and VCZ eye drops. It was most extracted in the first drops of 20 mg/mL CSA, with an average of 0.8 µg/day on the 2nd day, then its amount decreased to 0.1 µg/day after one month, while in VCZ it was extracted at a stable amount of 0.4 µg/day throughout the study. The cytotoxicity threshold was determined at 1.2 µg/day. DISCUSSION AND CONCLUSION:The nature of the medication influenced the migration of 2,4-DTBP, as it was only found in eye drops composed of a hydrophobic active ingredient solubilized with amphiphilic excipients. Cytotoxicity tests performed on the L929 cell revealed no toxicity of 2,4-DTBP after 24 h at the quantities present in the drops, nor after 7 days of contact.

Safe and well-tolerated sedative formulations are essential in pediatric procedural care. Pentobarbital, a short-acting barbiturate, remains widely used for pediatric sedation. However, its oral administration is limited by poor palatability. Rectal administration therefore represents a relevant alternative, provided that formulation stability is ensured. This study evaluated the physicochemical and microbiological stability of fast-dissolving pentobarbital suppositories developed for pediatric use. Suppositories containing 30 or 60 mg of pentobarbital sodium were formulated with two sodium hydroxide (NaOH) concentrations and stored under refrigerated (5°C) or frozen (−20°C) conditions for up to 180 days. Stability was assessed by macroscopic examination, pH measurement, dissolution testing, mechanical strength, softening time, and microbiological quality. Solid-state changes were analyzed using Raman spectroscopy and X-ray diffraction, and precipitation kinetics were modeled. Refrigerated storage led to progressive precipitation from day 90, associated with pH decrease and conversion of pentobarbital sodium to its free acid, resulting in incomplete dissolution. In contrast, frozen storage preserved pH, physical integrity, and complete dissolution, even after 30 days at 5°C following thawing. Spectroscopic and diffraction analyses confirmed recrystallization under refrigeration, whereas frozen formulations retained an amorphous structure. Increased NaOH content delayed, but did not prevent, instability at 5°C. All formulations complied with pharmacopeial mechanical and microbiological requirements. Storage temperature was the main determinant of stability, with freezing ensuring long-term preservation. NaOH buffering mitigated gelatin acidity and delayed drug conversion, thereby extending shelf life. These findings support further biopharmaceutical and clinical evaluation of pentobarbital suppositories for pediatric sedation.

BACKGROUND:The use of automated injectors for the administration of radiopharmaceuticals limits staff exposure and optimises the dose administered to patients, but many of these devices are only validated for a limited number of radiopharmaceuticals. The objectives of this study were to investigate the physicochemical phenomena occurring during the manipulation of fluorinated radiopharmaceuticals when in contact with injector tubings and to quantify and qualify the interactions between the radiopharmaceuticals and the tubing materials. RESULTS:For six of the radiopharmaceuticals tested, the measured doses reached 97.64 ± 0.24% of the programmed dose. These results indicate an absence of sorption phenomena and validate their use on the injector. In contrast, the three most lipophilic molecules caused the injector to malfunction, resulting in significant residual activity in the tubing of up to 67%. These results were confirmed by activimeter measurements and positron emission tomography images. RESULTS:from electronic microscopy results showed an alteration of the inner surface of the tubings that came into contact with lipophilic radiopharmaceuticals; however, this modification did not drastically alter the surface Zeta potential. Infrared spectroscopy confirmed the composition of the tubings as being plasticized polyvinyl chloride (PVCp), and plasticizer identification and quantification showed the presence of di-(2-ethylhexyl) adipate (reaching 37.5%) and di-(2-ethylhexyl) phthalate (more than 20%). A clear improvement was observed when co-extruded polyethylene / PVPp tubings were used. CONCLUSIONS:Unlike lipophilic radiopharmaceuticals, which exhibit sorption behaviour dependent on the presence of plasticizers, the tested hydrophilic radiopharmaceuticals demonstrated minimal interaction with PVCp tubing and can be reliably administered using the automated injector.

Neonates hospitalized in neonatal intensive care units (NICUs) are exposed to complex mixtures of plasticizers released from medical devices during critical developmental periods. While biomonitoring studies typically assess individual metabolites, such approaches provide limited insight into realistic multiexposure patterns that are relevant for mixture toxicity assessment. Using urinary biomonitoring data from the ARMED-NEO cohort, we applied non-negative matrix factorization (NMF) to identify data-driven exposure mixtures in NICU neonates. This approach enabled the decomposition of high-dimensional metabolite data into a limited number of representative mixtures defined by their composition and contribution patterns. Three distinct exposure mixtures were identified, corresponding to coherent and clinically plausible multiexposure profiles associated with medical device use and care practices. These mixtures capture dominant co-occurrence patterns of plasticizer metabolites and provide a more realistic representation of neonatal exposure than single compound analyses. By translation of complex biomonitoring data into interpretable exposure profiles, this study offers a pragmatic framework for mixture-oriented toxicological research. These results support the design of targeted in vitro bioassays and contribute to improving the assessment of endocrine-disrupting mixture effects in vulnerable neonatal populations.

The study of extractable chemicals is used to evaluate whether a medical device contains harmful substances susceptible to migrate and contaminate the patients they are used in. The analysis of the biomaterial itself after extraction is often left aside. The aim of this study is to characterise and investigate whether any changes occur during the extraction process. Two biomaterials (thermoplastic polyurethane (TPU) and silicone from intravenous catheters) were studied after extraction, using acetone and hexane. To study the surface, we used scanning electron microscopy (morphological aspect), energy dispersive spectroscopy and x-ray photoelectron spectroscopy (atomic composition), infrared spectroscopy (molecular composition). Thermogravimetric analysis and differential scanning calorimetry were used for in-depth characterisation. It was found that the extreme surface consisted of the polymer and external contaminants or organic products that had migrated from the core to the surface. Analysis of TPU showed that acetone was a suitable swelling agent. No significant change in the material was observed after hexane maceration. For silicone, the situation was reversed. We concluded that the solvents used were well suited for an extractables study of these two materials, and gained understanding of the phenomena that could lead to leaching during their medical use.

Implantable medical devices must meet biocompatibility requirements before clinical use, making the profiling of extractables and leachables crucial for assessing risks. Although guidelines outline methods for identifying extractables, they lack guidance on the monitoring of leachables. This study evaluates the stability of a brain phantom stored at 37 °C for 180 days for leachables monitoring. White matter (WM) and gray matter (GM) components, creating an emulsion‐gel with cholesterol, agar, and carboxymethylcellulose, are separated. Homogeneity is assessed using polydispersity index (PDI), and stability is investigated using Young's modulus (YM), rheological behavior, and apparent diffusion coefficient of water (ADCs) immediately after preparation and after 180 days of storage. PDI values are 0.258 ± 0.009 for WM and 0.362 ± 0.008 for GM. YM values are 2.32 ± 0.14 kPa for WM and 1.11 ± 0.11 kPa for GM. Dynamic viscosities are 16.62 ± 6.36 kPa s for WM and 5.99 ± 2.79 kPa s for GM at 0.1 rad s −1 . ADCs are 1130 ± 64 µm 2 s −1 for WM and 1449 ± 34 µm 2 s −1 for GM. All parameters remain within physiological range during 180 days at 37 °C. Comparison with clinical data is necessary to validate this medium for leachable studies.

Introduction De nombreux médicaments intraveineux peuvent être administrés sur cathéter veineux central (CVC) courte durée en réanimation. Les mélanges dans les volumes communs des montages exposent à des risques d’incompatibilité physicochimique (IPC) ou perturbations dans la dynamique des flux et débits (PDFD). Dans notre établissement, cinq services de réanimations adultes disposent d’une base commune de montage. Suite à deux évènements indésirables (EI) (PDFD avec bolus de chlorure de potassium), un travail pluridisciplinaire a été réalisé pour optimiser le montage des lignes et sites de branchement des thérapeutiques. Matériel & méthode Après identification d’objectifs prioritaires, une enquête sur les pratiques de branchement des médicaments sur le montage a été conduite afin d’évaluer les divergences de pratique et proposer une voie préférentielle par médicament. En parallèle, le groupe a travaillé sur l’optimisation du montage de perfusion et améliorer la procédure institutionnelle sur ces problématiques. Résultats & discussion Six objectifs ont été identifiés : actions correctives en regard des EI, harmonisation des pratiques avec messages clés sur le branchement des thérapeutiques, gestion des IPC et PDFD, et mise à jour du protocole institutionnel. 69 % de divergences de pratique sur les 219 médicaments analysés ont été constatées. Une harmonisation sur une voie préférentielle a pu être faite. Plusieurs phases de communication et d’informations ont été déployées. Une majorité des objectifs a été atteinte avec succès, bien qu’il ait été impossible de produire une solution clés en main pour les IDE. In fine, cette procédure constitue un socle plus robuste pour améliorer la sécurité des soins en perfusion sur CVC courte durée.

Molecular simulations were carried out to investigate the mechanisms of drug delivery from poly(glycerol sebacate) (PGS). We simulated a number of key stages, from the encapsulation of the active pharmaceutical ingredients (API) in bulk PGS to their release into the water phase through the adsorption processes on the PGS surface. Caffeine, paracetamol, and ibuprofen were the studied APIs. Each stage of the API release was characterized by the calculation of a free energy property related to absorption, adsorption, or association. The free energy of absorption showed that the PGS material is able to accommodate APIs of different polarities and hydration properties due to the presence of hydrophobic and hydrophilic regions in the material. The free energy values of adsorption of the APIs on the PGS surface remain favorable, whereas the free energies of binding between APIs and glycerol, sebacic acid, and prepolymer molecules are weaker, thus indicating a possible release of the APIs into water from an energy viewpoint.

Insulin aspart, a biomacromolecule essential for diabetes treatment, is known to interact with polymer-based drug delivery systems. Plasticized poly(vinyl chloride) (PVC) materials, widely used in medical infusion tubing, contribute significantly to insulin aspart loss due to adsorption. However, experimental studies alone cannot distinguish the individual contributions of plasticizers and the PVC matrix in this process. To address this, we employed coarse-grained molecular dynamics (Martini 3) simulations to investigate protein-surface interactions over extended time scales, providing deeper insights into adsorption mechanisms. Our results revealed a strong preference for insulin aspart adsorption onto PVC regions rather than plasticizers, explaining the experimentally observed lack of adsorption differences between plasticized and nonplasticized PVC surfaces. Additionally, we explored the formation of the insulin aspart adsorption layer for both monomeric and hexameric forms, further characterizing the thermodynamics of the adsorption process.

The treatment of numerous retinal pathologies requires the use of intravitreal medications administered and compounded in medical 3-piece syringes. Particle formation influenced by storage conditions is a source of concern as it can have clinical impacts such as endophtalmitis or reduced visual acuity. The aim of this work was therefore to investigate and compare the physical stability of bevacizumab stored in syringes made of polypropylene lubricated with silicone oil (PP-SOL) or Cyclic Olefin Copolymer with crosslinked silicone at the surface of the barrel (COC-CLS). 0.2 mL of bevacizumab solutions were conditioned in both syringes types and the physical stability and particles or aggregate generation was followed after 3 days, 1 month and 3 months of storage, under three different storage conditions: refrigerated temperature (5 ± 3 °C), with or without mechanical stress after the storage period to simulate user manipulations before patient administration, and heat stress temperature (35 ± 2 °C). Particle counting, dynamic light scattering, size exclusion chromatography, size diffusion by taylor dispersion analysis, Fourier transform infrared spectroscopy, scanning electron microscopy and microanalysis X and calculated aggregation index via UV visible absorption were performed on the samples. Overall, the COC-CLS syringes generated less particles than the PP-SOL ones, in particular when submitted to a mechanical stress. The physical stability of the bevacizumab solutions was superior in COC-CLS syringes than in PP-SOL syringes.

Ocular surface diseases (OSDs) are characterised by an instability of the tear film. In severe cases, these disorders have been improved by using human serum or plasma formulated into eye drops. These blood-derived-products present a biological composition similar to that of tears and contain beneficial factors that modulate inflammation and tissue regeneration. However, the supply of blood derivatives remains a challenge due to the potential microbiological risk, the quality and inter-individual heterogeneity of the biological samples used, and logistical difficulties. Thus, the idea behind this work was to use a standardised blood-derived product produced and checked industrially from a pool of donors, and to combine it with protective excipients known for their lubricating, anti-inflammatory, and regenerative properties offering new treatment opportunities for OSDs. Attention was also given to the non-bioaccumulative nature of the excipients. In order to select the concentrations of different compounds of interest in the ophthalmic solution, a design of experiment was used to establish a formulation with physicochemical properties (pH, osmolality, turbidity, viscosity) compatible with good ocular tolerance. Once defined, a physicochemical stability study testing pH, osmolality and dosage of biological factors, was carried out using the storage conditions usually used in clinical practice. A comparator without the additional compounds was also tested. The final formulation consisted of 20 % allogenic plasma, 0.5 % sodium hyaluronate (HS), 3 % trehalose (TH), 0.2 % chondroitin sulfate (CS) and 0.5 % sodium chloride (NaCl) (m/v). Its physicochemical properties should allow for good ocular tolerance. The data from the preliminary stability study favours storage at -20 °C for some of the biological factors measured.

Bone infections are common and difficult to treat, and secondary bone defects, which are often observed, may require a bone allograft. In this case, the surgeon will add antibiotics (usually vancomycin) in direct contact with the bone graft during the procedure, in order to allow in-situ release after implantation in the operating site. Dalbavancin is a novel antibiotic indicated for treating acute bacterial infections resistant to vancomycin. Its modified chemical structure grants it an increased half-life that could modify its release kinetics from the bone allograft. The aim of this study was to determine the release kinetics of dalbavancin from bone grafts after they were immersed in a dalbavancin solution. The study was conducted using a Design of Experiments (DoE) protocol. Decellularized and delipidated allograft bone cubes were preliminarily characterized and put into contact with dalbavancin solutions. The parameters that were studied where the allograft mass, initial dalbavancin concentration and contact time. The samples were then transferred into the release media, which was sampled over time and dalbavancin was quantified using a high pressure liquid chromatography with diode array detector method that was developed for the occasion. Our results showed that on average, dalbavancin was fully released after 5 min for the lower mass bone grafts, but after 60 min for the high mass and high concentration conditions. Contact time had no impact, thus indicating a fast loading process of dalbavancin into the allograft. Although our study revealed the possible benefits of using dalbavancin in bone grafting, an in-vivo study is required to confirm our hypotheses.

Insulin aspart is a major therapeutic biomacromolecule used worldwide for the treatment of diabetes mellitus. It is administered either subcutaneously or intravenously, using infusion lines made most often from plasticized polyvinyl chloride (PVC). Unfortunately, its very nature makes it at high risk of surface interactions with the materials it can come into contact with, leading notably to greatly decreased concentrations and patient underdosing. In order to prevent this phenomenon, for which no adequate solution yet exists, in-depth knowledge of the behavior of insulin aspart at the water-solid interface is needed. The aim of this work was to shed new light on this highly problematic interaction and explain the adsorption phenomenon of insulin aspart and its phenolic excipients (phenol and metacresol) to plasticized PVC tubings from a thermodynamic point of view by combining experimental and molecular dynamics simulations. Our results proved that the hexameric form of insulin aspart possesses an important affinity for the PVC surface, to which it adsorbs nearly instantaneously to, whilst phenol and metacresol interacts with the PVC/plasticizer interface of the material. The molecular simulations of these surface interactions correlate well with the sorption processes that can be assumed to happen with the negatively charged PVC surfaces. Thermodynamic values obtained via the molecular simulation process were used to model successfully the experimental data. This combination of theoretical approaches could help us in predicting the risk of interfacial interactions in biomacromolecular systems.

Short contacts between medical devices and medications that they contain can cause drug sorption or leaching of unwanted compounds which can have clinical consequences. However, the parameters that govern these interactions are still incompletely understood. The objectives of this study were to evaluate the impact of the formulation parameters on migration of 2,4 Di-tert-butylphenol (2,4 DTBP) and sorption of tacrolimus (TAC) in a model micellar ophthalmic drug formulation which is known to interact with silicone elastomers. A design of experiments was established to evaluate the impact of the formulation parameters on 2,4 DTBP leaching and tacrolimus sorption by varying the initial concentrations of TAC (0.04; 0.2 and 1 mg/mL), polyoxyethylenated castor oil (KEL) (32; 80 and 200 mg/mL) and ethanol absolute (EtOH) (10 and 100 mg/mL), at 5°C and 25°C, during static contact between various formulations and silicone valves obtained from an ophthalmic multidose delivery device. Concentrations of 2,4 DTBP and TAC were monitored by liquid chromatography coupled with an UV–visible detector. Under the conditions studied, the amount of 2,4 DTBP leaching out increased during contact with the silicone valve, with increasing TAC concentration being quite interestingly the main factor decreasing its ability to leach out, whilst ethanol increased its leachability. The silicone valve did not cause any significant decrease of TAC concentrations over the duration of the study, regardless of the concentrations of KEL, EtOH, or temperature. This study showed the impact of formulation on the leaching of 2,4 DTBP from a silicone component.

Training and certification of personnel in capsule preparation are essential procedures, overseen by the pharmacist who delegates these tasks. These procedures aim not only to ensure the efficacy and safety of operations but also to establish a clear chain of responsibility. They align with established best practices. Certification grants formal authorization to qualified individuals to perform specific tasks. For new hires, a comprehensive training program is designed to facilitate their integration and empower them from the onset. We propose training objectives structured around a competency-based approach, highlighting objective evaluation criteria applicable in real-world practical settings. These training objectives address critical aspects such as the handling of hazardous substances, weighing and mixing of powders, and capsule filling. They also emphasize the importance of documentation and traceability. Specialized preparations and tools are offered to facilitate the assessment of learning outcomes.

High pressure liquid chromatography (HPLC) experiments and molecular simulations were combined to investigate the leaching process of DINCH, DEHT and TOTM plasticizers from PVC materials. Methodologies based on statistical thermodynamics were used to rationalize the migration of the different plasticizers in water and ethanolic solutions from different free energy contributions. We extended this combined approach to the study of the adsorption of a model drug (diazepam) on different plasticized-PVC materials. The drug loss by sorption was investigated in different solutions and rationalized at an energy level. The combination of experiments and theoretical approaches proved to be effective for these sophisticated systems and processes for which various energy contributions are involved.

Objectives. - To assess the impact of disparities in production and analytical control processes on the quality of parenteral nutrition (PN) preparations produced in the Auvergne -Rhone-Alpes region. Methods. - This study was carried out in four hospital pharmacies of the Auvergne -Rhone-Alpes region. To assess the impact of production processes, each centre produced ten PN preparations from the same prescription. Analytical controls (sodium, potassium and calcium dosage) were carried out on all the preparations. To assess the impact of the control processes, a batch of ten preparations was produced from the same prescription. Samples were sent to the four hospital pharmacies for analytical control (sodium, potassium and calcium dosage). Results. - Measurements of relative production bias show that there is a significant difference between the preparations from the four centres in terms of sodium and potassium content. Each centre had at least one production bias for one of the three electrolytes measured. Concerning analytical controls, there was a significant difference between the four centres in the sodium and potassium levels measured. With the exception of calcium, all the centres reported measurements within the usual specifications of f 10% of the target value. The results obtained have no clinically significant impact. Conclusion. - The diversity of NP practices has a real impact on the quality of the preparations made. A regional collaboration should be envisaged to standardise patient care.