A simple and low-cost environmental enrichment program improves the welfare of Calomys callosus, a species that adapts to animal facilities.

An environmental enrichment protocol is essential for testing experimental models because it upholds animal welfare, aligns with ethical principles in animal experimentation, and reduces the number of animals needed. Calomys callosus, a South American rodent from the Cricetidae family, is bred in rodent animal facilities for its ease of handling, longevity, prolificacy, and effectively mimicking diseases like Toxoplasmosis, Leishmaniasis, Chagas, and Schistosomiasis. There are no reports on environmental enrichments for this species or their impact on reproductive parameters. This study aimed to analyze the influence of the Environmental Enrichment Program (EEP) on the reproductive and zootechnical performance of C. callosus kept in the Rodents Animal Facilities Complex of Universidade Federal de Uberlândia (UFU). Two experimental groups were established: with environmental enrichment EE+ and without environmental enrichment EE-. The materials used in the experimental design were changed weekly and alternated between dietary, occupational, physical/cognitive, and non-enrichment items. After the inclusion of the EEP, an improvement in the reproductive indices of C. callosus was identified in the EE+ group. These improvements included increased female precocity, a decreased interbirth interval, and a higher number of pairs producing more offspring. The postpartum zootechnical indices were also better, such as the number of animals born alive, improved weaning rates, and a reduced average number of deaths from birth to weaning. After the inclusion of the EEP, the general health status of C. callosus improved, reducing cases of non-infectious lumbar alopecia. Therefore, EEP allows C. callosus to express natural reproductive behaviors and improves parental care.

Drug administration via feeding tubes-a procedure that carries risks: systematic identification of critical factors based on commonly administered drugs in a cohort of stroke patients.

PURPOSE: Drug administration via feeding tubes is considered a process with many uncertainties. This review aimed to give a comprehensive overview of data available on feeding tube application and to carry out risk assessments for drug substances commonly administered to stroke patients. METHODS: Drugs frequently administered via feeding tubes were identified through a retrospective analysis of discharge letters from a stroke unit. Physicochemical, pharmacokinetic, and stability properties of these drugs and data on drug-enteral nutrition interactions were systematically searched for in the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, and the Martindale Complete Drug Reference, as well as from databases including DrugBank, DrugDex, PubChem, Google Scholar, and PubMed. RESULTS: Of the drugs most commonly administered via feeding tubes in the present stroke patient cohort, bisoprolol, candesartan, and ramipril could be considered the least critical due to their overall favourable properties. Acetylsalicylic acid, amlodipine, hydrochlorothiazide, omeprazole and esomeprazole, simvastatin, and torasemide pose risks based on pH or light-dependent instability or proposed food effects. The most critical drugs to be administered via feeding tubes are considered to be furosemide, levodopa, and levothyroxine as they show relevant instabilities under administration conditions and substantial food effects; the latter two even possess a narrow therapeutic index. However, little information is available on drug-tube and drug-formula interactions. CONCLUSION: Feeding tube administration of medications turned out to be a highly complex process with several unmet risks. Therefore, investigations that systematically assess these risk factors using clinically relevant model systems are urgently needed.

Impact of quality and transparency in scientific writing on the reduction of animal usage in experimental protocols: a review based in pertinent literature.

The irreproducibility in scientific research has become a critical issue. Despite the essential role of rigorous methodology in constructing a scientific article, more than half of publications, on average, are considered non-reproducible. The implications of this irreproducibility extend to reliability problems, hindering progress in technological production and resulting in substantial financial losses. In the context of laboratory animal research, this work emphasizes the importance of choosing an appropriate experimental model within the 3R's principle (Refine, Reduce, Replace). This study specifically addresses a deficiency in data specification in scientific articles, revealing inadequacies in the description of crucial details, such as environmental conditions, diet, and experimental procedures. For this purpose, 124 articles from journals with relevant impact factors were analyzed, conducting a survey of data considered important for the reproducibility of studies. Important flaws in the presentation of data were identified in most of the articles evaluated. The results of this study highlight the need to improve the description of essential information, standardizing studies, and ensuring the reproducibility of experiments in areas such as metabolism, immunity, hormones, stress, among others, to enhance the reliability and reproduction of experimental results, aligning with international guidelines such as ARRIVE and PREPARE.

Involvement of Inflammatory Cytokines, Renal NaPi-IIa Cotransporter, and TRAIL Induced-Apoptosis in Experimental Malaria-Associated Acute Kidney Injury.

The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA was used to investigate the relationship among pro-inflammatory cytokines, alterations in renal function biomarkers, and the induction of the TRAIL apoptosis pathway during malaria-associated acute kidney injury (AKI). Renal function was evaluated through the measurement of plasma creatinine and blood urea nitrogen (BUN). The mRNA expression of several cytokines and NaPi-IIa was quantified. Kidney sections were examined and cytokine levels were assessed using cytometric bead array (CBA) assays. The presence of glomerular IgG deposits and apoptosis-related proteins were investigated using in situ immunofluorescence assays and quantitative real-time PCR, respectively. NaPi-IIa downregulation in the kidneys provided novel insights into the pathogenesis of hypophosphatemia during CM. Histopathological analysis revealed characteristic features of severe malaria-associated nephritis, including glomerular collapse and tubular alterations. Pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, were upregulated. The TRAIL apoptosis pathway was significantly activated, implicating its role in renal apoptosis. The observed alterations in renal biomarkers and the downregulation of NaPi-IIa shed light on potential mechanisms contributing to renal dysfunction in ECM. The intricate balance between pro- and anti-inflammatory cytokines, along with the activation of the TRAIL apoptosis pathway, highlights the complexity of malaria-associated AKI and provides new therapeutic targets.

Prediction of subcutaneous drug absorption - Development of novel simulated interstitial fluid media for predictive subcutaneous in vitro assays.

Media that mimic physiological fluids at the site of administration have proven to be valuable in vitro tools for predicting in vivo drug release, particularly for routes of administration where animal studies cannot accurately predict human performance. The objective of the present study was to develop simulated interstitial fluids (SISFs) that mimic the major components and physicochemical properties of subcutaneous interstitial fluids (ISFs) from preclinical species and humans, but that can be easily prepared in the laboratory and used in in vitro experiments to estimate in vivo drug release and absorption of subcutaneously administered formulations. Based on data from a previous characterization study of ISFs from different species, two media were developed: a simulated mouse-rat ISF and a simulated human-monkey ISF. The novel SISFs were used in initial in vitro diffusion studies with a commercial injectable preparation of liraglutide. Although the in vitro model used for this purpose still requires significant refinement, these two new media will undoubtedly contribute to a better understanding of the in vivo performance of subcutaneous injectables in different species and will help to reduce the number of unnecessary in vivo experiments in preclinical species by implementation in predictive in vitro models.

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.

Do Women and Minority Orthopaedic Residents Report Experiencing Worse Well-being and More Mistreatment Than Their Peers?

BACKGROUND: Despite the increased risk of attrition for women and minority residents during orthopaedic residency, there is currently a paucity of research examining the training environment of these residents. To address this, we examined how well-being constructs may differ for women or minority residents compared with their peers, and whether these residents report experiencing more mistreatment during residency. QUESTIONS/PURPOSES: (1) How does the psychologic wellbeing of women and minority residents compare with that of their peers regarding the constructs of burnout, lifestyle satisfaction, social belonging, and stereotype threat? (2) Do reported mistreatment experiences during residency differ among women and minority residents compared with their peers? (3) Is there a difference in the proportion of women and minority orthopaedic residents with thoughts of leaving residency compared with their peers? METHODS: Seventeen orthopaedic residency programs in the 91 programs comprising the Collaborative Orthopaedic Educational Research Group agreed to participate in the study. Program directors sent an anonymous one-time survey with two reminders to all orthopaedic residents at their respective institutions. The survey instrument comprised validated and previously used instruments with face validity designed to measure burnout, satisfaction, duty-hour violations, belonging, stereotype threat, mistreatment, and thoughts of leaving residency, in addition to demographic information. Forty-three percent (211 of 491) of residents responded to the survey. Race or ethnicity data were combined into "White" and "underrepresented in orthopaedics" (URiO), which included residents who self-identified as Asian, African American, Hispanic or Latino, Native American, or other, given that these groups are all underrepresented racial and ethnic groups in orthopaedics. The demographic makeup of our study, 81% men and 75% White, is roughly comparable to the current demographic makeup of orthopaedic residency programs, which is 82% men and 74% White. Data were analyzed using chi-square tests, Fisher exact tests, and t-tests as appropriate. For comparisons of Likert scale measures, we used an anchor-based approach to determining the minimum detectable change (MDC) and set the MDC as a 1-point difference on a 5-point scale and a 1.5-point difference on a 7-point scale. Stereotype threat is reported as the mean ▵ from the neutral response, and ▵ of 1.5 or greater was considered significant. RESULTS: Women residents were more likely than men to report experiencing emotional exhaustion (odds ratio 2.18 [95% confidence interval 1.1 to 4.5]; p = 0.03). Women reported experiencing stereotype threat regarding their identity as women surgeons (mean ▵ 1.5 ± 1.0). We did not identify a difference in men's and women's overall burnout (OR 1.4 [95% CI 0.7 to 3.0]; p = 0.3), lifestyle satisfaction across multiple domains, or sense of social belonging (men: 4.3, women 3.6; mean difference 0.7 [95% CI 0.4 to 0.9]; p < 0.001). We did not identify differences in overall burnout (OR 1.5 [95% CI 0.8 to 3.0]; p = 0.2), lifestyle satisfaction across multiple domains, sense of social belonging (White: 4.2, URiO: 3.9; mean difference 0.3 [95% CI 0.17 to 0.61]; p < 0.001), or stereotype threat (mean ▵ 0.8 ± 0.9) between White and URiO surgeons. Women were more likely than men to report experiencing mistreatment, with 84% (32 of 38) of women and 43% (70 of 164) of men reporting mistreatment at least a few times per year (OR 7.2 [95% CI 2.8 to 18.1]; p < 0.001). URiO residents were more likely than White residents to report experiencing mistreatment overall, with 65% (32 of 49) of URiO residents and 45% (66 of 148) of White residents reporting occurrences at least a few times per year (OR 2.3 [95% CI 1.2 to 4.6]; p = 0.01). Women were more likely than men to report experiencing gender discrimination (OR 52.6 [95% CI 18.9 to 146.1]; p < 0.001), discrimination based on pregnancy or childcare status (OR 4.3 [95% CI 1.4 to 12.8]; p = 0.005), and sexual harassment (OR 11.8 [95% CI 4.1 to 34.3]; p < 0.001). URiO residents were more likely than White residents to report experiencing racial discrimination (OR 7.8 [95% CI 3.4 to 18.2]; p < 0.001). More women than men had thoughts of leaving residency (OR 4.5 [95% CI 1.5 to 13.5]; p = 0.003), whereas URiO residents were not more likely to have thoughts of leaving than White residents (OR 2.2 [95% CI 0.7 to 6.6]; p = 0.1). CONCLUSION: Although we did not detect meaningful differences in some measures of well-being, we identified that women report experiencing more emotional exhaustion and report stereotype threat regarding their identity as women surgeons. Women and URiO residents report more mistreatment than their peers, and women have more thoughts of leaving residency than men. These findings raise concern about some aspects of the training environment for women and URiO residents that could contribute to attrition during training. CLINICAL RELEVANCE: Understanding how well-being and mistreatment affect underrepresented residents helps in developing strategies to better support women and URiO residents during training. We recommend that orthopaedic governing bodies consider gathering national data on resident well-being and mistreatment to identify specific issues and track data over time. Additionally, departments should examine their internal practices and organizational culture to address specific gaps in inclusivity, well-being, and mechanisms for resident support.

What to consider for successful administration of oral liquids via enteral feeding tubes? a case study with paediatric ibuprofen suspensions.

Administration of medications via enteral feeding tubes (EFTs) is a common practice for children who cannot swallow properly. Although liquid formulations are the preferred dosage forms for this route of administration, little attention has been paid to the amount of drug that reaches the site of absorption after administration via an EFT. This systematic in vitro study aimed to identify formulation parameters and administration approaches that are critical for successful dose delivery via EFTs. For this purpose, drug recovery after administration of three different paediatric ibuprofen suspensions via different types of EFTs was studied using derivative UV spectrophotometry for quantification. Study results indicate that in addition to formulation parameters, feeding tube characteristics and the administration process can have a significant impact on the administered dose. The ratio between the total administered fluid volume (TAV), represented by the sum of dose- and flushing volume, and the feeding tube volume (FTV) proved to be a valuable indicator for assessing successful administration. Incorrect dosing and complications could be avoided if the TAV/FTV ratio was greater than 4. This and other knowledge gained in the study will help to make the administration of liquid paediatric medicines via EFTs both more effective and safer.

A toolbox for mimicking gastrointestinal conditions in children: Design and evaluation of biorelevant dissolution media for mimicking paediatric gastric- and small intestinal conditions.

The goal of the present work was to develop an in vitro toolbox to evaluate the oral administration of dosage forms to children of different age groups and under different administration conditions (fasted/fed). Based on current data on the gastrointestinal physiology of children, a set of new biorelevant media was designed to mimic the composition and physicochemical properties of resting gastric and resting small intestinal fluid in children of different age groups. In addition, guidelines were developed on how to generate fasted and fed state gastric and small intestinal fluids by combining these media with age-specific drinking volumes or portions of already established simulated paediatric breakfast meals, respectively. These fluids can simulate the conditions in the paediatric stomach and small intestine after administration of a dosage form in the fasting state or after a breakfast. The in vitro toolbox was evaluated using the example of pre-school children with a total of five paediatric medicines. Results from the corresponding set of in vitro studies highlight the importance of addressing patient-specific characteristics rather than downscaling existing adult in vitro models.

Republication of "Perspectives in Treatments of End-Stage Ankle Arthritis Among Orthopaedic Surgeons: Analysis of an American Orthopaedic Foot & Ankle Society (AOFAS) Member Survey".

Background: This study aimed to assess the preferred operative treatment for patients over the age of 60 with end-stage ankle arthritis and perspectives on total ankle replacement (TAR) among American Orthopaedic Foot & Ankle Society (AOFAS) members. Associated factors were analyzed for potential contraindications among members with different levels of experience. Method: A questionnaire containing 6 questions was designed and sent to 2056 members of the AOFAS. Responses were received from 467 orthopaedic surgeons practicing in the United States (76%), Canada (5%), and 26 other countries (20%). Participants were grouped for response comparisons according to country as well as experience level. Differences in contraindications were compared using χ2 tests or exact tests. Results: Respondents practicing in the United States and surgeons who perform 11 or more TARs per year tended to recommend operative treatments favoring TAR and displayed recognition of its increasing role (P < .05). Overall, respondents felt that 41% of typical patients over 60 years old with end-stage arthritis would be best treated with TAR. Talus avascular necrosis, morbid obesity (body mass index >40 kg/m2), and poorly controlled diabetes with neuropathy were most recognized as the absolute contraindications to TAR. Surgeon's experience affected the consideration of these clinical factors as contraindications. Conclusions: Total ankle replacement has a substantial and increasing role in the treatment of end-stage ankle arthritis in patients over the age of 60. Absolute and potential contraindications of the procedures were indicated from a cross-sectional survey of AOFAS members. Surgeons more experienced with total ankle replacement felt more comfortable employing it in a wider range of clinical settings. Level of Evidence: Level III, therapeutic.

Colour of Medicines and Children's Acceptability? A Systematic Literature Review of Children's Perceptions about Colours of Oral Dosage Forms.

The colour of a product plays an important role in consumer experiences, and in the context of pharmaceutical products, this could potentially affect a patient's expectations, behaviours, and adherence. Several studies have been conducted on adults, but little is known about children's opinions on colours of medicines and to what extent medicines' colour affects their acceptability. To address this gap, a systematic search in PubMed, Scopus, MEDLINE, and Web of Science was conducted. Two authors independently screened the titles, abstracts, and references of all articles and selected studies conducted on children (0-18 years old), assessing children's preferences or opinions about colour of oral dosage forms as either a primary or secondary objective or as an anecdotal record. A total of 989 publications were identified and, after screening, 18 publications were included in the review. Red and pink were the most liked colours and there appeared to be a relationship between the colour of a medicine and expected taste/flavour. The review also highlighted a scarcity of information, usually collected as an anecdotal record. Several gaps in the current knowledge were underlined, emphasizing the need of patient-centred studies to understand if the use of certain colours can improve or worsen the acceptability of a paediatric medicine. This will help inform pharmaceutical manufacturers and regulators on the role and need of colours in children's medicines beyond quality purposes.

Semaglutide, delayed gastric emptying, and intraoperative pulmonary aspiration: a case report.

PURPOSE: We report a case in which the use of semaglutide for weight loss was associated with delayed gastric emptying and intraoperative pulmonary aspiration of gastric contents. CLINICAL FEATURES: A 42-yr-old patient with Barrett's esophagus underwent repeat upper gastrointestinal endoscopy and ablation of dysplastic mucosa. Two months earlier, the patient had started weekly injections of semaglutide for weight loss. Despite having fasted for 18 hr, and differing from the findings of prior procedures, endoscopy revealed substantial gastric content, which was suctioned before endotracheal intubation. Food remains were removed from the trachea and bronchi using bronchoscopy. The patient was extubated four hours later and remained asymptomatic. CONCLUSION: Patients using semaglutide and other glucagon-like peptide 1 agonists for weight management may require specific precautions during induction of anesthesia to prevent pulmonary aspiration of gastric contents.

RéSUMé: OBJECTIF: Nous rapportons un cas dans lequel l'utilisation de sémaglutide à des fins de perte de poids a été associée à un retard de vidange gastrique et à une aspiration pulmonaire peropératoire du contenu gastrique. CARACTéRISTIQUES CLINIQUES: Un patient de 42 ans souffrant d'un œsophage de Barrett a subi une cinquième endoscopie gastro-intestinale supérieure avec ablation de la muqueuse dysplasique. Deux mois plus tôt, le patient avait commencé à recevoir des injections hebdomadaires de sémaglutide pour perdre du poids. Bien qu'à jeun depuis 18 heures et à la différence des évaluations lors des interventions antérieures, l'endoscopie a révélé un contenu gastrique important, qui a été aspiré avant l'intubation endotrachéale. Les restes de nourriture ont été retirés de la trachée et des bronches par bronchoscopie. Le patient a été extubé quatre heures plus tard et est demeuré asymptomatique. CONCLUSION: Les patients utilisant du sémaglutide et d'autres agonistes du peptide analog au glucagon-1 pour la gestion du poids pourraient nécessiter des précautions spécifiques lors de l'induction de l'anesthésie pour empêcher l'aspiration pulmonaire du contenu gastrique.

Prediction of subcutaneous drug absorption - Characterization of subcutaneous interstitial fluids as a basis for developing biorelevant in vitro models.

Unlike orally administered drugs, the absorption profile of subcutaneously injectable drugs in humans is difficult to predict from preclinical studies. Since the subcutaneous interstitial fluid (ISF) is the first fluid interacting with the administered formulation before the respective drug is absorbed, it could critically affect bioavailability. The aim of the present study was to gain a better understanding of the similarities and differences of ISF of different species. For this purpose, ISF was isolated from subcutaneous tissues of five preclinical animal species, i.e., mice, rats, minipig, landrace pig, non-human primates, and humans, using a centrifugation method, and characterized with respect to its major constituents and physicochemical properties. The results show trends between animal species, with ISF from non-human primates differing significantly from that of the other preclinical species for most parameters analyzed and showing similarities to ISF of human origin. Although from a statistical point of view it will be necessary to further increase the existing data sets, the presented data provide valuable information for the development of biorelevant in vitro models to predict the in vivo performance of subcutaneously administered formulations, as they provide fundamental information for the design of biorelevant ISF media for both preclinical species and humans.

Effect of Postoperative Immobilization Time on PROMIS Scores and Clinical outcomes in Ankle Fracture Patients.

Background: Ankle fractures are among the most common injuries treated by orthopaedic surgeons, yet little guidance exists in postoperative protocols for ankle fractures concerning time of immobilization. Here, we aim to investigate the association between early mobilization and patient-reported outcomes. Our null hypothesis was that no difference in Patient-Reported Outcomes Measurement Information System (PROMIS) scores would be identified in patients when comparing the effect of time of immobilization. Methods: A retrospective review identified ankle fractures that underwent surgical fixation between 2015 and 2020 at a level 1 trauma center and its associated facilities. One hundred nineteen patients from 9 providers met inclusion criteria for our final analysis. Forty-seven patients were immobilized for <6 weeks (early) and 68 patients were immobilized for ≥6 weeks (late). Our primary outcome measures included the PROMIS questionnaire, time of immobilization, and time to full weightbearing. Our secondary outcome measures included time to return to work, wound complications (infection, delayed healing), and complications associated with fracture fixation (loss of reduction, delayed union, reoperation, hardware failure). Repeated measures analysis of variance as well as linear mixed outcome regression were used to predict each of the PROMIS outcomes of anxiety, depression, physical function, and pain interference. Each model included the predictors of age, sex, race, body mass index (BMI), diabetes, rheumatoid arthritis, smoking status, payor, provider, time to radiographic union, time to return to work, time to full weightbearing, and early vs late immobilized groups. Results: We found no differences in PROMIS scores between mobilization groups even when controlling for possible confounders such as age, BMI, rheumatoid arthritis, smoking status, and diabetes mellitus (P > .05). Furthermore, we found no differences in complications associated with fracture fixation (P > .05). Across our cohort, lower physical function scores were associated with higher BMI, increasing age, and longer time to return to work/play (P < .05). Our analysis further showed that depression, anxiety, pain interference, and physical function levels improve as a function of time (P < .05). Higher BMI was also noted to have a significant impact on PROMIS depression and anxiety when controlling for other variables. African Americans had greater pain interference scores (P < .05). Conclusion: Our study suggests that early mobilization in a walker boot after operative treatment of ankle fractures is a safe alternative to casting in non-neuropathic patients. When considering operative treatment of ankle fractures, factors such as increasing age and BMI are likely to negatively affect postoperative anxiety, physical function, and depression PROMIS scores regardless of immobilization time. Level of Evidence: Level III, retrospective cohort study.

Preparation of Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDS) by Co-Extrusion of Liquid SNEDDS and Polymeric Carriers-A New and Promising Formulation Approach to Improve the Solubility of Poorly Water-Soluble Drugs.

The present study focused on a new formulation approach to improving the solubility of drugs with poor aqueous solubility. A hot melt extrusion (HME) process was applied to prepare drug-loaded solid self-nanoemulsifying drug delivery systems (S-SNEDDS) by co-extrusion of liquid SNEDDS (L-SNEDDS) and different polymeric carriers. Experiments were performed with L-SNEDDS formulations containing celecoxib, efavirenz or fenofibrate as model drugs. A major objective was to identify a polymeric carrier and process parameters that would enable the preparation of stable S-SNEDDS without impairing the release behavior and storage stability of the L-SNEDDS used and, if possible, even improving them further. In addition to commercially available (co)polymers already used in the field of HME, a particular focus was on the evaluation of different variants of a recently developed aminomethacrylate-based copolymer (ModE) that differed in Mw. Immediately after preparation, the L-SNEDDS and S-SNEDDS formulations were tested for amorphicity by differential scanning calorimetry. Furthermore, solubility and dissolution tests were performed. In addition, the storage stability was investigated at 30 °C/65% RH over a period of three and six months, respectively. In all cases, amorphous formulations were obtained and, especially for the model drug celecoxib, S-SNEDDS were developed that maintained the rapid and complete drug release of the underlying L-SNEDDS even over an extended storage period. Overall, the data obtained in this study suggest that the presented S-SNEDDS approach is very promising, provided that drug-loaded L-SNEDDS are co-processed with a suitable polymeric carrier. In the case of celecoxib, the E-173 variant of the novel ModE copolymer proved to be a novel polymeric carrier with great potential for application in S-SNEDDS. The presented approach will, therefore, be pursued in future studies to establish S-SNEDDS as an alternative formulation to other amorphous systems.

Oral drug delivery strategies for development of poorly water soluble drugs in paediatric patient population.

Selecting the appropriate formulation and solubility-enabling technology for poorly water soluble drugs is an essential element in the development of formulations for paediatric patients. Different methodologies and structured strategies are available to select a suitable approach and guide formulation scientists for development of adult formulations. However, there is paucity of available literature for selection of technology and overcoming the challenges in paediatric formulation development. The need for flexible dosing, and the limited knowledge of the safety of many formulation excipients in paediatric subjects, impose significant constraints and in some instances require adaptation of the approaches taken to formulating these drugs for the adult population. Selection of the best drug delivery system for paediatrics requires an efficient, systematic approach that considers a drug's physical and chemical properties and the targeted patient population's requirements. This review is a step towards development of a strategy for the design of solubility enhancing paediatric formulations of highly insoluble drugs. The aim of this review is to provide an overview of different approaches and strategies to consider in order to assist development of paediatric formulation for poorly water-soluble drugs with the provision of examples of some marketed products. In addition, it provides recommendations to overcome the range of challenges posed by these strategies and adaptations of the adult approach/product presentation required to enable paediatric drug development and administration.

Patient-specific in vitro drug release testing coupled with in silico PBPK modeling to forecast the in vivo performance of oral extended-release levodopa formulations in Parkinson's disease patients.

Biorelevant in vitro release models are valuable analytical tools for oral drug development but often tailored to gastrointestinal conditions in 'average' healthy adults. However, predicting in vivo performance in individual patients whose gastrointestinal conditions do not match those of healthy adults would be of great value for optimizing oral drug therapy for such patients. This study focused on establishing patient-specific in vitro and in silico models to predict the in vivo performance of levodopa extended-release products in Parkinson's disease patients. Current knowledge on gastrointestinal conditions in these patients was incorporated into model development. Relevant in vivo pharmacokinetic data and patient-specific in vitro release data from a novel in vitro test setup were integrated into patient-specific physiologically-based pharmacokinetic models. AUC, cmax and tmax of the computed plasma profiles were calculated using PK-Sim®. For the products studied, levodopa plasma concentration-time profiles modeled using this novel approach compared far better with published average plasma profiles in Parkinson's disease patients than those derived from in vitro release data obtained from the 'average' healthy adult setup. Although further work is needed, results of this study highlight the importance of addressing patient-specific gastrointestinal conditions when aiming to predict drug release in such specific patient groups.

Development and Characterization of Celecoxib Solid Self-nanoemulsifying Drug Delivery Systems (S-SNEDDS) Prepared Using Novel Cellulose-Based Microparticles as Adsorptive Carriers.

Self-nanoemulsifying drug delivery systems (SNEDDS) represent an interesting platform for improving the oral bioavailability of poorly soluble lipophilic drugs. While Liquid-SNEDDS (L-SNEDDS) effectively solubilize the drug in vivo, they have several drawbacks, including poor storage stability. Solid-SNEDDS (S-SNEDDS) combine the advantages of L-SNEDDS with those of solid dosage forms, particularly stability. The aim of the present study was to convert celecoxib L-SNEDDS into S-SNEDDS without altering their release behavior. Various commercially available adsorptive carrier materials were investigated, as well as novel cellulose-based microparticles prepared by spray drying from an aqueous dispersion containing Diacel® 10 and methyl cellulose or gum arabic as a binder prior to their use. Particle size and morphology of the carrier materials were screened by scanning electron microscopy and their effects on the loading capacity for L-SNEDDS were investigated, and comparative in vitro dissolution studies of celecoxib L-SNEDDS and the different S-SNEDDS were performed immediately after preparation and after 3 months of storage. Among the adsorptive carrier materials, the novel cellulose-based microparticles were found to be the most suitable for the preparation of celecoxib S-SNEDDS from L-SNEDDS, enabling the preparation of a solid, stable formulation while preserving the in vitro release performance of the L-SNEDDS formulation.