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The application of three-dimensional printing (3DP) in the pharmaceutical industry brings a broad spectrum of benefits to patients by addressing individual needs and improve treatment success. This study investigates the sustained release properties of 3DP tablets containing Theophylline (TPH), which is commonly used to treat respiratory diseases and recently having a comeback due to its potential in the treatment of conditions like Covid-19. Since TPH is a narrow therapeutic window (NTW) drug with serious side effects in the event of overdose, the release properties must be observed particularly closely. We employed a state-of-the-art single screw extrusion 3D printer, which is fed with granules containing the drug. By employing a Taguchi orthogonal array design of experiments (DOE), tablet design parameters and factor related process stability were sought to be evaluated fundamentally. Following this, examinations regarding tailored TPH dosages were undertaken and a relationship between the real printed dose of selected tablet designs and their sustained drug release was established. The release profiles were analyzed using different mathematical model fits and compared in terms of mean dissolution times (MDT). Finally, in-vivo/in-vitro correlation (IVIVC) and physiologically based pharmacokinetic (PBPK) modeling showed that a paradigm patient group could be covered with the dosage forms produced.

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In this study, a compartmental disintegration and dissolution model is proposed for the prediction and evaluation of the dissolution performance of directly compressed tablets. This dissolution model uses three compartments (Bound, Disintegrated, and Dissolved) to describe the state of each particle of active pharmaceutical ingredient. The disintegration of the tablet is captured by three fitting parameters. Two disintegration parameters, ß0 and ßt,0, describe the initial disintegration rate and the change in disintegration rate, respectively. A third parameter, α, describes the effect of the volume of dissolved drug on the disintegration process. As the tablet disintegrates, particles become available for dissolution. The dissolution rate is determined by the Nernst-Brunner equation, whilst taking into account the hydrodynamic effects within the vessel of a USP II (paddle) apparatus. This model uses the raw material properties of the active pharmaceutical ingredient (solubility, particle size distribution, true density), lending it towards early development activities during which time the amount of drug substance available may be limited. Additionally, the strong correlations between the fitting parameters and the tablet porosity indicate the potential to isolate the manufacturing effects and thus implement the model as part of a real-time release testing strategy for a continuous direct compression line.

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Three-dimensional printing (3DP) technology in pharmaceutical areas is leading to a significant change in controlled drug delivery and pharmaceutical product development. Pharmaceutical industries and academics are becoming increasingly interested in this innovative technology due to its inherent inexpensiveness and rapid prototyping. The 3DP process could be established in the pharmaceutical industry to replace conventional large-scale manufacturing processes, particularly useful for personalizing pediatric drugs. For instance, shape, size, dosage, drug release and multi-drug combinations can be tailored according to the patient's needs. Pediatric drug development has a significant global impact due to the growing needs for accessible age-appropriate pediatric medicines and for acceptable drug products to ensure adherence to the prescribed treatment. Three-dimensional printing offers several significant advantages for clinical pharmaceutical drug development, such as the ability to personalize medicines, speed up drug manufacturing timelines and provide on-demand drugs in hospitals and pharmacies. The aim of this article is to highlight the benefits of extrusion-based 3D printing technology. The future potential of 3DP in pharmaceuticals has been widely shown in the last few years. This article summarizes the discoveries about pediatric pharmaceutical formulations which have been developed with extrusion-based technologies.

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Oral dosage forms are the most widely and frequently used formulations to deliver active pharmaceutical ingredients (APIs), due to their ease of administration and noninvasiveness. Knowledge of intragastric release rates and gastric mixing is crucial for predicting the API release profile, especially for immediate release formulations. However, knowledge of the intragastric fate of oral dosage forms in vivo to date is limited, particularly for dosage forms administered when the stomach is in the fed state. An improved understanding of gastric food processing, dosage form location, disintegration times, and food effects is essential for greater understanding for effective API formulation design. In vitro standard and controlled modeling has played a significant role in predicting the behavior of dosage forms in vivo. However, discrepancies are reported between in vitro and in vivo disintegration times, with these discrepancies being greatest in the fed state. Studying the fate of a dosage form in vivo is a challenging process, usually requiring the use of invasive methods, such as intubation. Noninvasive, whole body imaging techniques can however provide unique insights into this process. A scoping review was performed systematically to identify and critically appraise published studies using MRI to visualize oral solid dosage forms in vivo in healthy human subjects. The review identifies that so far, an all-purpose robust contrast agent or dosage form type has not been established for dosage form visualization and disintegration studies in the gastrointestinal system. Opportunities have been identified for future studies, with particular focus on characterizing dosage form disintegration for development after the consumption food, as exemplified by the standard Food and Drug Administration (FDA) high fat meal.

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A threat to human health in developed and, in particular, in developing countries, counterfeit medicines represent the largest identified fraud market worldwide. 3D screen printing (3DSP), an additive manufacturing technology that enables large-scale production, offers unique opportunities to combat counterfeit drugs. One such possibility is the generation of oral dosage forms with a distinct colored inner structure that becomes visible upon breakage and cannot be copied with conventional manufacturing methods. To illustrate this, we designed tablets containing a blue cross. Owing to paste properties and the limited dimensions of the cross, the production process was chosen to be continuous, involving two screen and paste changes. The two pastes (tablet body, cross) were identical except for the blue color of the latter. This ensured the build-up and mechanical stability of the resulting tablets in a mass production environment. The ensuing tablets were found to be uniform in weight and size and to comply with regulatory requirements for hardness, friability, and disintegration time (immediate release). Moreover, all tablets exhibited the covert anticounterfeit feature. The study delivers a proof-of-concept for incorporating complex structures into tablets using 3DSP and showcases the power of the technology offering new avenues for combating counterfeit drugs.

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PURPOSE: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. METHODS: Meloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles. RESULTS: The solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation. CONCLUSION: For drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction.

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Pharmaceutical three-dimensional printing (3DP) is now in its golden age. Recent years have seen a dramatic increase in the research in 3D printed pharmaceuticals due to their potential to deliver highly personalised medicines, thus revolutionising the way medicines are designed, manufactured, and dispensed. A particularly attractive 3DP technology used to manufacture medicines is stereolithography (SLA), which features key advantages in terms of printing resolution and compatibility with thermolabile drugs. Nevertheless, the enthusiasm for pharmaceutical SLA has not been followed by the introduction of novel excipients specifically designed for the fabrication of medicines; hence, the choice of biocompatible polymers and photoinitiators available is limited. This work provides an insight on how to maximise the usefulness of the limited materials available by evaluating how different formulation factors affect printability outcomes of SLA 3D printed medicines. 156 photopolymer formulations were systematically screened to evaluate the influence of factors including photoinitiator amount, photopolymer molecular size, and type and amount of liquid filler on the printability outcomes. Collectively, these factors were found highly influential in modulating the print quality of the final dosage forms. Findings provide enhanced understanding of formulation parameters informing the future of SLA 3D printed medicines and the personalised medicines revolution.

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Three-dimensional printing (3DP) is an emerging technology, offering the possibility for the development of dose-customized, effective, and safe solid oral dosage forms (SODFs). Although 3DP has great potential, it does come with certain limitations, and the traditional drug manufacturing platforms remain the industry standard. The consensus appears to be that 3DP technology is expected to benefit personalized medicine the most, but that it is unlikely to replace conventional manufacturing for mass production. The 3DP method, on the other hand, could prove well-suited for producing small batches as an adaptive manufacturing technique for enabling adaptive clinical trial design for early clinical studies. The purpose of this review is to discuss recent advancements in 3DP technologies for SODFs and to focus on the applications for SODFs in the early clinical development stages, including a discussion of current regulatory challenges and quality controls.

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PURPOSE: In Europe, most medicines are taken orally and primarily packaged as single solid oral dosage forms (SODF) in blister chambers (alveoli) arranged on blister cards. Blister cards are constructed as multilayer laminates of aluminum (Al) foils and/or various plastic polymers bonded together, forming the alveoli, which are separated by more or less large gaps. We calculated the amount of packaging material (and thus waste) generated annually for the packaging of the most commonly prescribed SODF in Germany and estimated how much waste could be saved by rearranging the alveoli. METHODS: For this purpose, we analysed the SODF of the 50 most frequently prescribed medicines that were packaged in alveoli (N = 45; 13 of aluminum-aluminum blisters, 32 of mixed materials), measured and weighed their packaging material and content, calculated the annual amount of waste produced from them, and estimated how much waste could be saved if the alveoli were optimally positioned on the blister cards. In addition, we examined the variability of the blister packaging of eight groups of commonly prescribed generics of the same strength. RESULTS: Detailed analysis of the blister cards revealed that most of the material (69%) was used for the space between blisters and that aluminum-aluminum alveoli were more than four times larger than the packaged SODF. The (conservatively) estimated annual amount of composite waste generated for the primary packaging of these SODF was 3868 t (and extrapolated to the entire German pharmaceutical market 8533 t), of which an optimized arrangement of the blister chambers, i.e., a 2-mm sealing area around each alveolus and the arrangement of the SODF in 2 rows, would save approximately 37%. CONCLUSION: Considering that other ecological strategies are not yet mature, the optimal arrangement of blister chambers would be a captivatingly simple and, above all, immediately implementable strategy to avoid large amounts of avoidable waste.

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Abstract The last decade provided significant advances in the understanding of microbiota and its role in human health. Probiotics are live microorganisms with proven benefits for the host and were mostly studied in the context of gut health, but they can also confer significant benefits for oral health, mainly in the treatment of gingivitis. Postbiotics are cell-free extracts and metabolites of microorganisms which can provide additional preventive and therapeutic value for human health. This opens opportunities for new preventive or therapeutic formulations for oral administration. The microorganisms that colonize the oral cavity, their role in oral health and disease, as well as the probiotics and postbiotics which could have beneficial effects in this complex environment were discussed. The aim of this study was to review, analyse and discuss novel probiotic and postbiotic formulations intended for oral administration that could be of great preventive and therapeutic importance. A special attention has been put on the formulation of the pharmaceutical dosage forms that are expected to provide new benefits for the patients and technological advantages relevant for industry. An adequate dosage form could significantly enhance the efficiency of these products.

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Objective: To explore the extent of use and perceived effectiveness of using a medication lubricant that is specifically designed to help people who struggle to swallow their solid medications whole. Method: Health care workers of varying professional levels in aged care facilities (ACFs) across Australia who are involved in medication administration were invited to participate in a structured online survey. Results: Of the 355 health care workers who completed the survey, 48% had used the medication lubricant to aid administration of whole and/or crushed solid oral dosage forms, and of these 89% agreed with the statement that "it is effective method to facilitate medication swallowing in residents." The main benefits of using the medication lubricant were considered to be easier medication administration to residents (49%), reduction in need for crushing of medications (34%), and better adherence with medications (33%). Conclusions: This study showed that using a medication lubricant for aged care residents may facilitate the process of medication administration for health care workers, which they perceive to improve residents' adherence with medications. Serious complications associated with solid dosage form modification may also be decreased by using a medication lubricant, as the need for modifying medications is reduced. Therapeutic Goods Administration (TGA)-approved medication lubricants could therefore be a valuable tool to aid the medication administration for patients who have difficulties swallowing medications. Future research may consider the clinical efficacy and acceptability of medication lubricants specifically for people with swallowing difficulties.

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One of the major challenges in the development of effective pharmaceutical formulations for oral administration is the poor solubility of active pharmaceutical ingredients. For this reason, the dissolution process and drug release from solid oral dosage forms, such as tablets, is usually thoroughly studied in order to understand the dissolution behaviour under various conditions and optimize the formulation accordingly. Standard dissolution tests used in the pharmaceutical industry provide information on the amount of drug released over time; however, these do not allow for a detailed analysis of the underlying chemical and physical mechanisms of tablet dissolution. FTIR spectroscopic imaging, by contrast, does offer the ability to study these processes with high spatial and chemical specificity. As such, the method allows us to see the chemical and physical processes which occur inside the tablet as it dissolves. In this review, the power of ATR-FTIR spectroscopic imaging is demonstrated by presenting a number of successful applications of this chemical imaging technique to dissolution and drug release studies for a range of different pharmaceutical formulations and study conditions. Understanding these processes is essential for the development of effective oral dosage forms and optimization of pharmaceutical formulations.

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Quality issues related to compressed oral solid dosage (OSD) forms, such as tablets, arise during the design, development, and production stages, despite established processes and robust production tools. One of the primary quality concerns is the disintegration properties and drug release profile of immediate-release OSD products, which depend on their micro-texture and micro-viscoelastic properties at the grain level. These properties are influenced by the composition of the formulation, particularly the disintegrant level in the tablet matrix and the porosity of the matrix. In this study, a novel, rapid, non-destructive ultrasonic characterization technique was proposed to correlate the sensitivity of propagating elastic wave speeds, physical/mechanical properties, and the dispersion profile of the OSD material with the disintegrant level (% w/w) in the formulation and the compression force applied during tableting. The proposed characterization framework involves transmitting pressure (longitudinal) and shear (transverse) waves through the OSDs to calculate the speed of sound, which in turn provides information on the apparent Young's and shear moduli. In addition, the attenuation profile of the propagating wave is obtained through dispersion analysis. To investigate the impact of disintegrants and compression force on ultrasonic wave propagation in OSDs, we incorporated seven levels of a frequently used disintegrant. In each formulation, OSDs are compacted in five compaction forces. The sensitivity of wave speeds, physical/mechanical properties, and attenuation profile was observed with each disintegrant and compression force level. The utilization of ultrasonic techniques may present a viable solution for rapid, non-destructive, non-invasive, and cost-effective testing methods required in continuous manufacturing (CM) and real-time release testing (RTRT), and its practical utility in pharmaceutical manufacturing is also discussed.

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Powder flow is a critical attribute of pharmaceutical blends to ensure tablet weight uniformity and production of tablets with consistent and reproducible properties. This study aims at characterizing different powder blends with a number of different rheologic techniques, in order to understand how particles' attributes and interaction between components within the formulation generate different responses when analysed by different rheological tests. Furthermore, this study intends on reducing the number of tests in early development phases, by selecting the ones that provide the best information about the flowability attributes of the pharmaceutical blends. This work considered two cohesive powders - spray-dried hydroxypropyl cellulose (SD HPMC) and micronized indomethacin (IND) - formulated with other four commonly used excipients [(lactose monohydrated (LAC), microcrystalline cellulose (MCC), magnesium stearate (MgSt) and colloidal silica (CS)]. The experimental results showed that powder flowability may be affected by materials particles' size, bulk density, morphology, and interactions with lubricant. In detail, parameters, such as angle of repose (AoR), compressibility percentage (CPS), and flow function coefficient (ffc) have shown to be highly affected by the particle size of the materials present in the blends. On the other hand, the Specific Energy (SE) and the effective angle of internal friction (φe) showed to be more related with particle morphology and materials interaction with the lubricant. Since both ffc and φe parameters are generated from the yield locus test, data suggest that a number of different powder flow features may be understood only by applying this test, avoiding redundant powder flow characterization, as well as extensive time and material spent in early development formulation stages.

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Older adults represent the major target population for oral medications, due to the high prevalence of multimorbidity. To allow for successful pharmacological treatments, patients need to adhere to their medication and, thus, patient-centric drug products with a high level of acceptability by the end users are needed. However, knowledge on the appropriate size and shape of solid oral dosage forms, as the most commonly used dosage forms in older adults, is still scarce. A randomized intervention study was performed including 52 older adults (65 to 94 years) and 52 young adults (19 to 36 years). Each participant swallowed four coated placebo tablets differing in weight (250 to 1000 mg) and shape (oval, round, oblong) in a blinded manner on three study days. The choice of tablet dimensions allowed for a systematic comparison between different tablet sizes of the same shape, as well as between different tablet shapes. Swallowability was assessed using a questionnaire-based method. All tested tablets were swallowed by ≥80% of adults, independent of age. However, only the 250 mg oval tablet was classified as well swallowable by ≥80% of old participants. The same was true for young participants; however, they also considered the 250 mg round and the 500 mg oval tablet as well swallowable. Furthermore, swallowability was seen to influence the willingness to take a tablet on a daily basis, especially for an intake over longer time periods.

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Swallowability, visual perception, and any handling to be conducted prior to use are all influence factors on the acceptability of an oral dosage form by the patient. Knowing the dosage form preferences of older adults, as the major group of medication end users, is needed for patient-centric drug development. This study aimed at evaluating the ability of older adults to handle tablets as well as to assess the anticipated swallowability of tablets, capsules, and mini tablets based on visual perception. The randomized intervention study included 52 older adults (65 to 94 years) and 52 younger adults (19 to 36 years). Within the tested tablets, ranging from 125 mg up to 1000 mg in weight and being of different shapes, handling was not seen as the limiting factor for the decision on appropriate tablet size. However, the smallest sized tablets were rated worst. According to visual perception, the limit of acceptable tablet size was reached at around 250 mg for older adults. For younger adults, this limit was shifted to higher weights and was dependent on the tablet shape. Differences in anticipated swallowability with respect to tablet shapes were most pronounced for tablets of 500 mg and 750 mg in weight, independent of the age category. Capsules performed worse compared to tablets, while mini tablets appeared as a possible alternative dosage form to tablets of higher weight. Within the deglutition part of this study, swallowability capabilities of the same populations were assessed and have been reported previously. Comparing the present results with the swallowing capabilities of the same populations with respect to tablets, it shows adults' clear self-underestimation of their ability to swallow tablets independent of their age.

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In the past few decades, texture analysis (TA) has gained importance as a valuable method for the characterization of solid oral dosage forms. As a result, an increasing number of scientific publications describe the textural methods that evaluate the extremely diverse category of solid pharmaceutical products. Within the current work, the use of texture analysis in the characterization of solid oral dosage forms is summarised with a focus on the evaluation of intermediate and finished oral pharmaceutical products. Several texture methods are reviewed regarding the applications in mechanical characterization, and mucoadhesion testing, but also in estimating the disintegration time and in vivo specific features of oral dosage forms. As there are no pharmacopoeial standards for pharmaceutical products tested through texture analysis, and there are important differences between reported results due to different experimental conditions, the choice of testing protocol and parameters is challenging. Thereby, this work aims to guide the research scientists and quality assurance professionals involved in different stages of drug development into the selection of optimal texture methodologies depending on the product characteristics and quality control needs.

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During drug product development, stability studies are used to ensure that the safety and efficacy of a product are not affected during storage. Any change in the dissolution performance of a product must be investigated, as this may indicate a change in the bioavailability. In this study, three different griseofulvin formulations were prepared containing microcrystalline cellulose (MCC) with either mannitol, lactose monohydrate, or dibasic calcium phosphate anhydrous (DCPA). The tensile strength, porosity, contact angle, disintegration time, and dissolution rate were measured after storage under five different accelerated temperature and humidity conditions for 1, 2, and 4 weeks. The dissolution rate was found to decrease after storage for all three batches, with the change in dissolution rate strongly correlating with the storage humidity. The changes in physical properties of each formulation were found to relate to either the premature swelling (MCC/DCPA, MCC/lactose) or dissolution (MCC/mannitol) of particles during storage. These results are also discussed with consideration of the performance- and stability-controlling mechanisms of placebo tablets of the same formulations (Maclean et al., 2021; Maclean et al., 2022).

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El consumo de analgésicos opioides ha experimentado un vertiginoso ascenso en las últimas décadas a nivel mundial. Este elevado consumo está relacionado con el aumento del número de prescripciones de opioides para el tratamiento del dolor crónico y por el aumento de la dependencia a opioides. Los analgésicos opioides tienen una corta duración de acción, siendo necesarias múltiples administraciones para obtener analgesia prolongada. El empleo de formulaciones de liberación prolongada permite espaciar los intervalos posológicos y estabilizar las concentraciones máximas de fármaco en sangre, favoreciendo el cumplimiento terapéutico y reduciendo el riesgo de desarrollar adicción. Sin embargo, estas formulaciones llevan dosis más altas de analgésicos opioides que las hacen más susceptibles de ser alteradas. Así, los avances en tecnología farmacéutica más recientes se han orientado hacia la aplicación de recursos tecnológicos disuasorios de su utilización por vías de administración alternativas con fines no terapéuticos. A su vez, los sistemas de liberación modificada también juegan un papel esencial en el tratamiento de la adicción a opioides: con el desarrollo de sistemas de administración parenteral capaces de prolongar la liberación de opioides durante meses se consigue superar una de las mayores dificultades para alcanzar el éxito del tratamiento en este tipo de pacientes como es el cumplimiento terapéutico. En este artículo se realiza una revisión bibliográfica de los diferentes sistemas de liberación prolongada de opioides que se encuentran actualmente autorizados en Europa y/o en Estados Unidos para el tratamiento del dolor y de la dependencia a opioides. (AU)

The consumption of opioid analgesics has increased drastically in the last decades worldwide. This high consumption is linked with a surge in the number of opioid prescriptions for the treatment of chronic pain and a surge in opioid misuse and addiction. Opioid analgesics have a short duration of action, making necessary frequent administrations to provide extended analgesia. The use of prolonged-release formulations enables dosing intervals to be spaced out and drug blood levels to be stabilized, improving therapeutic compliance, and reducing the likelihood of developing addiction. However, these formulations contain higher doses of opioid analgesics which make them more susceptible to be manipulated. Hence, the most recent advances in pharmaceutical technology have been oriented towards the application of abuse deterrent technologies aiming to prevent their administration through alternative routes. Moreover, prolonged- release systems also play an essential role in the treatment of opioid addictions with the development of parenteral dosage forms capable of prolonging opioid release for months that help overcome one of the most important drawbacks in achieving treatment success, namely, patient compliance. We review herein the different prolonged-release opioid dosage forms currently approved in Europe and/or the United States for the treatment of pain and opioid dependence. (AU)

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