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Modulation of the S1P1 receptor has been described to be an effective treatment of autoimmune diseases (eg, multiple sclerosis).

BackgroundRepaglinide is an oral hypoglycemic drug especially useful for the treatment of type 2 diabetes. This molecule has poor aqueous solubility, which is the rate-limiting step for absorption of the drug. Solubility can be increased by forming a complex with b-cyclodextrin because this molecule enhances the aqueous solubility of the drug through inclusion.PurposeThe aim of this work was to formulate a mouth-dissolving tablet of repaglinide-b-cyclodextrin complex, enhancing the bioavailability of the drug.Material and methodsRepaglinide and b-cyclodextrin were purchased from Sigma. Repaglinide and b-cyclodextrin were weighed accurately at 1:1, 2:1 and 3:1 molar ratios, mixed by trituration and sieved through a 0.25 micron sieve. A minimum volume of ethanol and water (1:1) was added. The tablets were prepared by the direct compression method using mycrocristalline cellulose, lactose and magnesium stearate. In vitro dissolution studies were performed using an apparatus with a rotating paddle (50 rpm) at 37°±0.2°C in a phosphate buffer (pH 6.8). At fixed time intervals, samples were withdrawn, filtered and spectrophotometrically assayed at 243 nm with a Perkin Elmer Lambda 45 UV-vis in a 10 mm quartz cell. Data was subjected to ANOVA followed by studentized range test using the software Statistica. A confidence limit of p<0.5 was fixed for the interpretation of results.ResultsThe inclusion efficency of different ratios of drug and b-cyclodextrin (1:1, 2:1 and 3:1) were calculated and results showed that the inclusion efficiency of 1:1 molar ratio complex was the highest. A dissolution study showed that the complex is more soluble than the drug.ConclusionThe main problem with repaglinide is poor bioavailability and its limited aqueous solubility. Results show that it is possible to enhance the dissolution rate and the bioavailability by preparing a complex with b-cyclodextrin and direct compression.References and/or acknowledgementsNo conflict of interest.

Phosphate (Pi) deficiency triggers the differential expression of a large set of genes, which communally adapt the plant to low Pi bioavailability. To infer functional modules in early transcriptional responses to Pi deficiency, we conducted time-course microarray experiments and subsequent coexpression-based clustering of Pi-responsive genes by pairwise comparison of genes against a customized database. Three major clusters, enriched in genes putatively functioning in transcriptional regulation, root hair formation, and developmental adaptations, were predicted from this analysis. Validation of gene expression by quantitative reverse transcription-PCR revealed that transcripts from randomly selected genes were robustly induced within the first hour after transfer to Pi-deplete medium. Pectin-related processes were among the earliest and most robust responses to Pi deficiency, indicating that cell wall alterations are critical in the early transcriptional response to Pi deficiency. Phenotypical analysis of homozygous mutants defective in the expression of genes from the root hair cluster revealed eight novel genes involved in Pi deficiency-induced root hair elongation. The plants responded rapidly to Pi deficiency by the induction of a subset of transcription factors, followed by a repression of genes involved in cell wall alterations. The combined results provide a novel, integrated view at a systems level of the root responses that acclimate Arabidopsis (Arabidopsis thaliana) to suboptimal Pi levels.

Abstract Disclosure: P.D. Susilo: None. M. Kanelli: None. O. Petropulos: None. C. Dial: None. K. Kadasia: None. M. Buzo Mena: None. J. Liang: None. A. Hayward: None. K.A. Gaspie: None. S.M. Barron: None. R.R. Basani: None. A. Lopes: None. A. Yu: None. Introduction: Incretin peptide therapies have revolutionized obesity and diabetes treatment, yet overcoming oral delivery challenges—such as rapid gastrointestinal transit and limited intestinal absorption—is crucial to improving patient adherence, accessibility, and real-world effectiveness. To address these barriers, we developed the Peroral Mucosal Epithelium Absorption Enhancer (PERMEATE) method, which integrates synthetic tissue lining (SYNT) platform with proprietary permeation enhancers (PEs) to improve intestinal residence time and drive higher absorption. This proof-of-concept study demonstrates PERMEATE's ability to both create and significantly enhance the oral bioavailability of semaglutide (SEMA) in pig and rat models. Methods: A high-throughput ex vivo screen identified single and combination PEs with synergistic effects on SEMA permeation across porcine intestinal tissue. Ex vivo Franz experiments optimized formulation components and ratios to maximize colocalization of SEMA and PEs onto the intestinal tissue. Saline buffer washes were implemented to mimic a dynamic environment physiologically relevant to digestion. Lead formulations were tested in vivo in anesthetized Yorkshire pigs, a physiologically relevant gastrointestinal model, with plasma SEMA concentrations measured via LC-MS/MS over 168 hours. The area under the curve (AUC) was normalized by dose and compared to intravenous SEMA administration (n=4) to determine absolute bioavailability. To enhance replicates and rigor, formulations were also delivered via oral gavage to male rats (650-750 g, n=5-6 per group), with bioavailability assessed over 24 hours using the same methods. Results: Glycocholic acid (GCA) and ammonium carbonate (NHCO) were identified as the most effective PE combination with SEMA and SYNT, achieving a 15.5-fold increase in permeation compared to SEMA control in ex vivo tests. Optimized PERMEATE formulations improved colocalization of SEMA by 71.5-fold compared to a SEMA+PE control, after two washes, highlighting the ability of PERMEATE to create a localized depot and achieve prolonged residence time. In vivo, PERMEATE demonstrated a SEMA bioavailability of 2.4±1.6% in Yorkshire pigs (n=4), representing a significant 6-fold increase over the SEMA+PE control (0.4±0.3%, n=5; p=0.0316) and SEMA-Only control (0%, n=1). Improved bioavailability compared to controls was also observed in rats, highlighting translatability across multiple mammalian models. Conclusions: The PERMEATE platform, powered by SYNT™, significantly enhances the bioavailability of semaglutide (SEMA) in preclinical models, demonstrating up to a 6-fold improvement compared to controls. These findings underscore the potential of PERMEATE as a transformative platform for optimizing the oral delivery of macromolecule therapeutics. Presentation: Sunday, July 13, 2025

The term solid dispersion refers to a group of the solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug and matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or in crystalline particles. Solid dispersion technologies are particularly promising for improving the aqueous solubility, dissolution rate and bioavailability of BCS Class II drugs as bioavailability of drugs depends on their solubility and permeability. The main objective of the present work was to evaluate the feasibility of the melt granulation technique to improve the dissolution characteristics of a poorly water soluble drug, Glibenclamide. Glibenclamide was chosen as a water-insoluble model drug. Conjugation of Glibenclamide with the different types of carriers was used to increase its Solubility and dissolution rate. Formulation of granules was done by physical mixture and melt granulation technique. The drug carrier interactions were studied by IR spectral analysis. Granules were evaluated by Bulk density, Tapped density, Carr’s index, Hausner ratio and Angle of repose. In-vitro dissolution studies were done on solid dispersion formulations.