Development of a drug delivering round window niche implant for cochlear pharmacotherapy.

BACKGROUND: There exists an unfulfilled requirement for effective cochlear pharmacotherapy. Controlled local drug delivery could lead to effective bioavailability. The round window niche (RWN), a cavity in the middle ear, is connected to the cochlea via a membrane through which drug can diffuse. We are developing individualized drug-eluting RWN implants (RNIs). To test their effectiveness in guinea pigs, a commonly used model in cochlear pharmacology studies, it is first necessary to develop guinea pig RNIs (GP-RNI). METHODS: Since guinea pigs do not have a RWN such as it is present in humans and to reduce the variables in in vivo studies, a one-size-fits-all GP-RNI model was designed using 12 data sets of Dunkin-Hartley guinea pigs. The model was 3D-printed using silicone. The accuracy and precision of printing, distribution of the sample ingredient dexamethasone (DEX), biocompatibility, bio-efficacy, implantability and drug release were tested in vitro. The GP-RNI efficacy was validated in cochlear implant-traumatized guinea pigs in vivo. RESULTS: The 3D-printed GP-RNI was precise, accurate and fitted in all tested guinea pig RWNs. DEX was homogeneously included in the silicone. The GP-RNI containing 1% DEX was biocompatible, bio-effective and showed a two-phase and sustained DEX release in vitro, while it reduced fibrous tissue growth around the cochlear implant in vivo. CONCLUSIONS: We developed a GP-RNI that can be used for precise inner ear drug delivery in guinea pigs, providing a reliable platform for testing the RNI's safety and efficacy, with potential implications for future clinical translation.

Stability of Dexamethasone during Hot-Melt Extrusion of Filaments based on Eudragit® RS, Ethyl Cellulose and Polyethylene Oxide.

Hot-melt extrusion (HME) potentially coupled with 3D printing is a promising technique for the manufacturing of dosage forms such as drug-eluting implants which might even be individually adapted to patient-specific anatomy. However, these manufacturing methods involve the risk of thermal degradation of incorporated drugs during processing. In this work, the stability of the anti-inflammatory drug dexamethasone (DEX) was studied during HME using the polymers Eudragit® RS, ethyl cellulose and polyethylene oxide. The extrusion process was performed at different temperatures. Furthermore, the influence of accelerated screw speed, the addition of the plasticizers triethyl citrate and polyethylene glycol 6000 or the addition of the antioxidants butylated hydroxytoluene and tocopherol in two concentrations were studied. The DEX recovery was analyzed by a high performance liquid chromatography method suitable for the detection of thermal degradation products. The strongest impact on the drug stability was found for the processing temperature, which was found to reduce the DEX recovery to <20% for certain processing conditions. In addition, differences between tested polymers were observed, whereas the use of additives did not result in remarkable changes in drug stability. In conclusion, suitable extrusion parameters were identified for the processing of DEX with high drug recovery rates for the tested polymers. Moreover, the importance of a suitable analysis method for drug stability during HME that is influenced by several parameters was highlighted.

Open forum conference on the ICH M13A bioequivalence guideline.

The Network on Bioavailability and Biopharmaceutics of EUFEPS (European Federation for Pharmaceutical Sciences) had organised an Open Discussion Forum on the ICH M13A draft "Guideline on bioequivalence for immediate-release solid oral dosage forms". This conference was cosponsored by the Arbeitsgemeinschaft Pharmazeutische Verfahrenstechnik (APV) and the Frankfurt Foundation Quality of Medicines. Scientists from academia and industry attended this workshop on May 15, 2023, in Frankfurt/Germany, to discuss the suggested regulations with the European members of the ICH drafting group. The aim of this report is to summarise and highlight the main discussion points such as choice of study population (females and/or males), request for fasted and/or fed studies, consequences of differences in drug product content, handling of aberrant plasma profiles and additional requirements in case of pH-dependant solubility. During the discussion important arguments were presented for a revision of certain requirements suggested in the draft guideline.

The Influence of Shape Parameters on Unidirectional Drug Release from 3D Printed Implants and Prediction of Release from Implants with Individualized Shapes.

The local treatment of diseases by drug-eluting implants is a promising tool to enable successful therapy under potentially reduced systemic side effects. Especially, the highly flexible manufacturing technique of 3D printing provides the opportunity for the individualization of implant shapes adapted to the patient-specific anatomy. It can be assumed that variations in shape can strongly affect the released amounts of drug per time. This influence was investigated by performing drug release studies with model implants of different dimensions. For this purpose, bilayered model implants in a simplified geometrical shape in form of bilayered hollow cylinders were developed. The drug-loaded abluminal part consisted of a suitable polymer ratio of Eudragit® RS and RL, while the drug-free luminal part composed of polylactic acid served as a diffusion barrier. Implants with different heights and wall thicknesses were produced using an optimized 3D printing process, and drug release was determined in vitro. The area-to-volume ratio was identified as an important parameter influencing the fractional drug release from the implants. Based on the obtained results drug release from 3D printed implants with individual shapes exemplarily adapted to the frontal neo-ostial anatomy of three different patients was predicted and also tested in an independent set of experiments. The similarity of predicted and tested release profiles indicates the predictability of drug release from individualized implants for this particular drug-eluting system and could possibly facilitate the estimation of the performance of customized implants independent of individual in vitro testing of each implant geometry.

Ex Vivo Visualization of Distribution of Intravitreal Injections in the Porcine Vitreous and Hydrogels Simulating the Vitreous.

The characterization of intravitreal dosage forms with regard to their behavior in vivo is usually explored in preclinical development through animal studies. In vitro vitreous substitutes (VS) to simulate the vitreous body for preclinical investigations have so far been insufficiently studied. To determine a distribution or concentration in the mostly gel-like VS, extraction of the gels is required in many cases. This destroys the gels, which makes a continuous investigation of the distribution impossible. In this work, the distribution of a contrast agent in hyaluronic acid agar gels and polyacrylamide gels was studied by magnetic resonance imaging and compared with the distribution in ex vivo porcine vitreous. The porcine vitreous served as a surrogate for human vitreous since both are similar in their physicochemical properties. It was shown that both gels do not completely represent the porcine vitreous body, but the distribution in the polyacrylamide gel is similar to that in the porcine vitreous body. In contrast, the distribution throughout the hyaluronic acid agar gel is much faster. It was also shown that anatomical features such as the lens and the interfacial tension to the anterior eye chamber could have an influence on the distribution that is difficult to reproduce using in vitro VS. However, with the presented method, new in vitro VS can be investigated continuously without destruction in the future, and thus their suitability as a substitute for the human vitreous can be verified.

3D Printing of Paracetamol Suppositories: An Automated Manufacturing Technique for Individualized Therapy.

Pharmaceutical compounding using the molding technique is the currently applied method for the on-demand manufacturing of suppositories and pessaries. Potential errors of this method are difficult to detect, and the possibilities of individualization of size and shape of the suppositories are limited. In this study, a syringe-based semi-solid 3D printing technique was developed for the manufacturing of suppositories in three different printing designs with the suppository bases polyethylene glycol (PEG) and hard fat (HF). The 3D printed suppositories were analyzed for their visual appearance, uniformity of mass and content, diametrical dimension, breaking force and release behavior and compared to suppositories of the same composition prepared by a commonly used molding technique. The results showed no adverse properties for the 3D printed suppositories compared to the molded ones. Moreover, the easy adaptation of shape using the 3D printing technique was demonstrated by the printing of different sizes and infill structures. Thus, 3D printing has great potential to complement the available manufacturing methods for compounded suppositories, as it represents an automated system for the individualized manufacturing of suppositories that meet patients' needs.

Individualized, Additively Manufactured Drug-Releasing External Ear Canal Implant for Prevention of Postoperative Restenosis: Development, In Vitro Testing, and Proof of Concept in an Individual Curative Trial.

Postoperative restenosis in patients with external ear canal (EEC) atresia or stenosis is a common complication following canaloplasty. Our aim in this study was to explore the feasibility of using a three dimensionally (3D)-printed, patient-individualized, drug ((dexamethasone (DEX)), and ciprofloxacin (cipro))-releasing external ear canal implant (EECI) as a postoperative stent after canaloplasty. We designed and pre-clinically tested this novel implant for drug release (by high-performance liquid chromatography), biocompatibility (by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay), bio-efficacy (by the TNF-α (tumor necrosis factor-alpha)-reduction test (DEX) and inhibition zone test (for cipro)), and microbial contamination (formation of turbidity or sediments in culture medium). The EECI was implanted for the first time to one patient with a history of congenital EEC atresia and state after three canaloplasties due to EEC restenosis. The preclinical tests revealed no cytotoxic effect of the used materials; an antibacterial effect was verified against the bacteria Staphylococcus aureus and Pseudomonas aeruginosa, and the tested UV-irradiated EECI showed no microbiological contamination. Based on the test results, the combination of silicone with 1% DEX and 0.3% cipro was chosen to treat the patient. The EECI was implantable into the EEC; the postoperative follow-up visits revealed no otogenic symptoms or infections and the EECI was explanted three months postoperatively. Even at 12 months postoperatively, the EEC showed good epithelialization and patency. Here, we report the first ever clinical application of an individualized, drug-releasing, mechanically flexible implant and suggest that our novel EECI represents a safe and effective method for postoperatively stenting the reconstructed EEC.

The EyeFlowCell: Development of a 3D-Printed Dissolution Test Setup for Intravitreal Dosage Forms.

An in vitro dissolution model, the so-called EyeFlowCell (EFC), was developed to test intravitreal dosage forms, simulating parameters such as the gel-like consistency of the vitreous body. The developed model consists of a stereolithography 3D-printed flow-through cell with a polyacrylamide (PAA) gel as its core. This gel needed to be coated with an agarose sheath because of its low viscosity. Drug release from hydroxypropyl methylcellulose-based implants containing either triamcinolone acetonide or fluorescein sodium was studied in the EFC using a schematic eye movement by the EyeMovementSystem (EyeMoS). For comparison, studies were performed in USP apparatus 4 and USP apparatus 7. Significantly slower drug release was observed in the PAA gel for both model drugs compared with the compendial methods. Drug release from fluorescein sodium-containing model implants was completed after 40 min in USP apparatus 4, whereas drug release in the gel-based EFC lasted 72 h. Drug release from triamcinolone acetonide-containing model implants was completed after 35 min in USP apparatus 4 and after 150 min in USP apparatus 7, whereas this was delayed until 96 h in the EFC. These results suggest that compendial release methods may overestimate the drug release rate in the human vitreous body. Using a gel-based in vitro release system such as the EFC may better predict drug release.

3D-Printing of Drug-Eluting Implants: An Overview of the Current Developments Described in the Literature.

The usage of 3D-printing for drug-eluting implants combines the advantages of a targeted local drug therapy over longer periods of time at the precise location of the disease with a manufacturing technique that easily allows modifications of the implant shape to comply with the individual needs of each patient. Research until now has been focused on several aspects of this topic such as 3D-printing with different materials or printing techniques to achieve implants with different shapes, mechanical properties or release profiles. This review is intended to provide an overview of the developments currently described in the literature. The topic is very multifaceted and several of the investigated aspects are not related to just one type of application. Consequently, this overview deals with the topic of 3D-printed drug-eluting implants in the application fields of stents and catheters, gynecological devices, devices for bone treatment and surgical screws, antitumoral devices and surgical meshes, as well as other devices with either simple or complex geometry. Overall, the current findings highlight the great potential of the manufacturing of drug-eluting implants via 3D-printing technology for advanced individualized medicine despite remaining challenges such as the regulatory approval of individualized implants.

3D Printing of Mini Tablets for Pediatric Use.

In the treatment of pediatric diseases, suitable dosages and dosage forms are often not available for an adequate therapy. The use of innovative additive manufacturing techniques offers the possibility of producing pediatric dosage forms. In this study, the production of mini tablets using fused deposition modeling (FDM)-based 3D printing was investigated. Two pediatric drugs, caffeine and propranolol hydrochloride, were successfully processed into filaments using hyprolose and hypromellose as polymers. Subsequently, mini tablets with diameters between 1.5 and 4.0 mm were printed and characterized using optical and thermal analysis methods. By varying the number of mini tablets applied and by varying the diameter, we were able to achieve different release behaviors. This work highlights the potential value of FDM 3D printing for the on-demand production of patient individualized, small-scale batches of pediatric dosage forms.

Evaluation of the suitability of a fluidized bed process for the coating of drug-eluting stents.

Drug-eluting stents are often coated using single-stent coating techniques. In pharmaceutical industry, single-tablet coating is unthinkable. Instead large batches of tablets are coated in fluidized bed apparatuses or pan coaters. Therefore, it was the aim of this work to evaluate whether stents can be coated using a fluidized bed process. For this purpose stents were coated with the model fluorescent drug triamterene embedded in ammonium methacrylate copolymer. Different stent lengths as well as different coating yields were assessed and also a drug-free topcoat was evaluated. The coated stents were analysed regarded coating layer mass, drug content, surface structure, coating thickness and drug release. Furthermore, coating yield and stent defect rate were examined. Except for one stent configuration good results were obtained without optimization of process parameters which indicates the suitability of the method to coat large amounts of stents simultaneously in principle. Drug release was tuneable over a wide range of time spans and a wide range of drug loadings was produced. Further work will be necessary to transform the results of this study from a model stent to a clinically relevant product.

Influence of Dissolution Vessel Geometry and Dissolution Medium on In Vitro Dissolution Behaviour of Triamterene-Coated Model Stents in Different Test Setups.

The aim of this study was to investigate if the geometry of the dissolution vessel, the dissolution medium volume and composition might contribute to the variation in drug release from drug-eluting stents (DES) in different test setups, which has been observed in previous in vitro studies. Therefore, DES containing triamterene as model substance were produced via fluidised-bed technology. Dissolution testing was carried out using different incubation setups, the reciprocating holder (USP Apparatus 7) and two flow-through methods, a method similar to the USP Apparatus 4 (FTC) and the vessel-simulating flow-through cell (vFTC) equipped with a hydrogel as a second compartment simulating the blood vessel wall. The results indicate that dissolution vessel geometry and medium volume had no influence on the release behaviour and only the flow-through cell methods yielded a lower dissolution rate than the incubation setups (80.6 ± 2.0% released in the FTC after 14 days compared to > 90% for all incubation setups). The composition of the hydrogel used in the vFTC also affected the dissolution rate (53.9 ± 4.5% within 14 days with a hydrogel based on phosphate-buffered saline compared to 78.2 ± 1.2% obtained with a hydrogel based on water) possibly due to different solubility of triamterene in the release media as well as interactions between the coating polymer and the release medium. Hence, the introduction of a hydrogel as a second compartment might lead to a more biorelevant test setup.

Effects of 1-Methyltryptophan on Immune Responses and the Kynurenine Pathway after Lipopolysaccharide Challenge in Pigs.

An enhanced indoleamine 2,3-dioxygenase 1 (IDO1) activity is associated with an increased mortality risk in sepsis patients. Thus, the preventive inhibition of IDO1 activity may be a promising strategy to attenuate the severity of septic shock. 1-methyltryptophan (1-MT) is currently in the interest of research due to its potential inhibitory effects on IDO1 and immunomodulatory properties. The present study aims to investigate the protective and immunomodulatory effects of 1-methyltryptophan against endotoxin-induced shock in a porcine in vivo model. Effects of 1-MT were determined on lipopolysaccharide (LPS)-induced tryptophan (TRP) degradation, immune response and sickness behaviour. 1-MT increased TRP and its metabolite kynurenic acid (KYNA) in plasma and tissues, suppressed the LPS-induced maturation of neutrophils and increased inactivity of the animals. 1-MT did not inhibit the LPS-induced degradation of TRP to kynurenine (KYN)-a marker for IDO1 activity-although the increase in KYNA indicates that degradation to one branch of the KYN pathway is facilitated. In conclusion, our findings provide no evidence for IDO1 inhibition but reveal the side effects of 1-MT that may result from the proven interference of KYNA and 1-MT with aryl hydrocarbon receptor signalling. These effects should be considered for therapeutic applications of 1-MT.

7.1 T MRI and T2 mapping of the human and porcine vitreous body post mortem.

Numerous literature reports describe the liquefaction of the vitreous body with increasing age. It must be expected that this process also influences drug distribution and elimination following intravitreal application of active pharmaceutical ingredients (APIs). To better understand the impact and extent of the liquefaction a magnetic resonance imaging (MRI) study was performed examining human donor eyes post mortem. For comparison, eyes of juvenile pigs were also examined representing a fully gelled vitreous. 7.1Tesla ultra-high field MRI and T2 mapping of the vitreous body were used in this study since it must be expected that age-induced degradation processes and structural changes of the vitreous gel to a liquid state will result in changes of the T2 relaxation time of water proton spins. The vitreous bodies were imaged in 12 axial slices and within each image the T2 relaxation times of water proton spins were determined. It was found that T2 relaxation time increased with increasing age of the donor. Whilst the mean T2 relaxation time (±standard deviation) of water proton spins within the central vitreous body of a juvenile porcine eye was 210.1 ±â€¯31.1 ms, the mean T2 relaxation time within the central vitreous body of the 88-year-old and therefore oldest human donor was 528.0 ±â€¯79.3 ms. Within the vitreous body of a single donor, the T2 relaxation time increased from the anterior to the posterior segment, for example in the vitreous body of the oldest human donor from 388.0 ±â€¯31.1 ms on average in the anterior to 631.7 ±â€¯42.8 ms in the posterior segment, indicating an increase in intravitreal liquefaction respectively inhomogeneity from anterior to posterior regions. Additionally, physicochemical parameters were determined yielding averages of 7.54 ±â€¯0.34 for pH, 1.33629 ±â€¯0.00044 for refractive index, 368.99 ±â€¯26.87 mosmol/kg for osmolality, 97.56 ±â€¯0.43% for drying mass loss and 0.73 ±â€¯0.18 mg/mL for total protein content. The aging process and the liquefaction of the vitreous body are expected to affect the pharmacokinetic profile of intravitreally injected APIs, which is of high relevance to drug release from intravitreal drug delivery systems and the therapeutic concept in the treatment of posterior segment diseases. Our data indicate that such processes are not reflected in animal models. Since there is still a need for valid pharmacokinetic data, invitro test systems for the characterization of intraocular drug delivery systems have to be improved according to the current state of knowledge about the vitreous structure and intravitreal transport phenomena.

Development of a dual extrusion printing technique for an acid- and thermo-labile drug.

Over the last years fused deposition modeling has been increasingly considered as a game-changing technique for the preparation of individualized pharmaceutical products. Until now investigations have mainly focused on dosage forms loaded with very stable drugs or model substances. Going beyond this early stage of research, developers will also have to deal with more challenging active substances. In this work different printing designs for tablets containing the acid- and thermo-labile drug pantoprazole sodium were tested. Initial dual extrusion printing of a cellulose acetate phthalate coat and a tablet core of polyethylene glycol 6000 with 10% (m/m) pantoprazole sodium resulted in thermal degradation of pantoprazole at cellulose acetate phthalate printing temperatures of 141 °C. Therefore, different tablet designs were developed. The sectioning of the design of the tablet coat in a gastro-resistant cellulose acetate phthalate bottom part and an upper nearly insoluble polycaprolactone part printed at only 58 °C was suitable to prevent visible signs of thermal degradation. Dissolution testing indicated also no drug loss during dual extrusion printing. However, printed enteric tablets with shell thicknesses of 0.4 to 0.5 mm were not completely gastro-resistant. Drug release at intestinal pH values was delayed compared to uncoated cores. In conclusion, 3D-printing of gastro-resistant tablets containing thermo- and acid-labile drugs seems in principle possible. However, it remains an unsolved challenge to meet United States Pharmacopeia requirements.

Immediate Release 3D-Printed Tablets Produced Via Fused Deposition Modeling of a Thermo-Sensitive Drug.

PURPOSE: Dissolution speeds of tablets printed via Fused Deposition Modeling (FDM) so far are significantly lower compared to powder or granule pressed immediate release tablets. The aim of this work was to print an actual immediate release tablet by choosing suitable polymers and printing designs, also taking into account lower processing temperatures (below 100°C) owing to the used model drug pantoprazole sodium. METHODS: Five different pharmaceutical grade polymers polyvinylpyrrolidone (PVP K12), polyethylene glycol 6000 (PEG 6000), Kollidon® VA64, polyethylene glycol 20,000 (PEG 20,000) and poloxamer 407 were successfully hot-melt-extruded to drug loaded filaments and printed to tablets at the required low temperatures. RESULTS: Tablets with the polymers PEG 6000 and PVP K12 and with a proportion of 10% pantoprazole sodium (w/w) demonstrated a fast drug release that was completed within 29 min or 10 min, respectively. By reducing the infill rate of PVP tablets to 50% and thereby increase the tablet porosity it was even possible to reduce the mean time for total drug release to only 3 min. CONCLUSIONS: The knowledge acquired through this work might be very beneficial for future FDM applications in the field of immediate release tablets especially with respect to thermo-sensitive drugs.

Influence of the test method on in vitro drug release from intravitreal model implants containing dexamethasone or fluorescein sodium in poly (d,l-lactide-co-glycolide) or polycaprolactone.

Sustained intravitreal dexamethasone (DX) administration with the FDA and EMA approved Ozurdex® implant is indicated for the treatment of macular edema and non-infectious uveitis. Since drug release after intravitreal application cannot be determined in vivo in human eyes, the characterization of drug release in vitro in addition to animal models is of great importance. The aim of this study was to provide information about the influence of the test method on the in vitro drug release from intravitreal model implants. The following test methods were used: a shaking incubator experiment in reagent tubes, the small volume USP apparatus 7, the Vitreous Model (VM) and a system simulating the impact of movement on the VM (Eye Movement System, EyeMoS). Cylindrical model implants composed of DX and PLGA (poly (d,l-lactide-co-glycolide)) and additional polycaprolactone (PCL) implants containing fluorescein sodium (FS) as a model substance were produced by hot melt extrusion and were cut to a length of approximately 6 mm. Drug release was studied in ringer buffer pH 7.4 and in a modified polyacrylamide gel (PAAG) as vitreous substitute. In combination with the VM, the shape, the gel structure and a partial liquefaction (50%) were simulated in vitro. Swelling, disintegration, fragmentation, surface enlargement and changes in shape of the PLGA model implants were observed during the drug release study. We experienced that not each of the test methods and media were suitable for drug release studies of the PLGA implants. Marked differences in the release profiles were observed depending on the employed test method. These results emphasize the necessity to understand the underlying in vivo processes and to transfer the knowledge about the release determining factors into reliable in vitro test systems.

In vitro dissolution testing of parenteral aqueous solutions and oily suspensions of paracetamol and prednisolone.

The number of intramuscularly applied dosage forms has been continuously increasing during the last decades. However, up to date no in vitro dissolution test method for parenteral dosage forms has been described in the Ph. Eur. or USP. It was the aim of this study to investigate dissolution test setups based on the compendial flow-through cell and the reciprocating holder for this purpose. Both apparatuses were equipped with dialysis membranes to accommodate the drug formulation. The suitability of the dissolution method was evaluated by comparing release profiles with blood level curves that were obtained previously in an in vivo study in rats by our group. Aqueous solutions and oily suspensions of paracetamol and prednisolone were tested in vitro that were also applied in the in vivo study. In the case of the aqueous solutions in which no formal dissolution occurs, transport from the applied depot across a dialysis membrane was investigated. While the drug transport across the dialysis membrane of both drugs in aqueous solution was similar in all applied test methods, differences in the release behavior of paracetamol and prednisolone as an oily suspension were observed. This was mainly due to sedimentation of the particles within the oily depot.

Distribution of fluorescein sodium and triamcinolone acetonide in the simulated liquefied and vitrectomized Vitreous Model with simulated eye movements.

Intravitreal administration is the method of choice for drug delivery to the posterior segment of the eye with special emphasis on the vitreous body and its surrounding retinal vasculature. In order to gain a better understanding of the underlying distribution processes, an in vitro model simulating the vitreous body (Vitreous Model, VM) and a system simulating the impact of movement on the VM (Eye Movement System, EyeMoS) was previously developed. In the study reported here, these systems were modified in regard to a standardized injection procedure, the diversity of simulated eye movements, extended periods of investigation, the opportunity to simulate the state after vitrectomy and in considering the physiological temperature. Fluorescein sodium (FS) and triamcinolone acetonide (TA) were used as (model) drugs to examine the drug distribution within the VM. Vitrectomy was simulated by replacing half the volume of the polyacrylamide gel that was used as vitreous substitute with the clinically used Siluron® 5000 whereas for a simulated liquefaction half the volume of the gel was replaced by buffer. A simulated liquefaction caused a 12-fold faster distribution of FS compared to the simulated juvenile VM, which was most likely caused by convective forces and mass transfer. Also, the injection technique (injection into the gel or into the buffer compartment) influenced the resulting distribution pattern. Without any liquefaction, the previously described initial injection channel occurred with both (model) drugs and, in the case of TA, remained almost unchanged during the investigation period of 72h. Simulating vitrectomized eyes, TA did not spread uniformly, but either remained in the depot or strongly sedimented within the VM suggesting that a homogenous distribution of a TA suspension is highly unlikely in vitrectomized eyes. High variabilities were observed with ex vivo animal eyes, demonstrating the limited benefit of explanted tissues for such distribution studies. The combination of the modified VM and EyeMoS seems a valuable tool for characterizing intravitreal dosage forms in a reproducible simulation of diversified eye movements and a partially liquefied or vitrectomized vitreous body.

Muscle Injury After Intramuscular Administration of Diclofenac: A Case Report Supported by Magnetic Resonance Imaging.

Intramuscular injection of diclofenac is still frequently practiced, although there is ample evidence that the risk of local tissue intolerability is highly underestimated. The aim of this study was to evaluate local toxicity in a patient using magnetic resonance imaging. A patient who gave written informed consent received a medically indicated intramuscular administration of diclofenac 75 mg/2 mL. Simultaneously with magnetic resonance imaging of the depot, a clinical-chemical evaluation and quantification of diclofenac in plasma was performed. A manifold enhancement of the T2-weighted magnetic resonance signal was observed in a muscle area of approximately 60 mL volume, with maximum signal intensity 30 min after injection, the time of maximum diclofenac plasma exposure. Plasma creatine kinase activity was elevated approximately sixfold within 8 h and normalized within 1 week, whereas the magnetic resonance enhancement disappeared within 5 weeks. Interestingly, the patient did not complain about any clinical symptoms at the injection site. Asymptomatic tissue injury after intramuscular injection of diclofenac, caused by intramuscular dosing, can be reliably evaluated by magnetic resonance imaging and should be applied early during the development of parenteral dosage forms. Clinical Trials Registration Number: BB130/16 (Ethics Committee of the University Medicine Greifswald).