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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 At fixed time intervals, samples were withdrawn, filtered and spectrophotometrically assayed at 243 nm with a Perkin Elmer Lambda 45 UV-vis in a 10 mm quartz cell.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.

BackgroundHuntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). Consequently, the mutant protein is ubiquitously expressed and drives HD pathogenesis via a toxic gain-of-function mechanism.1–3 HD animal models demonstrate that reducing huntingtin protein (HTT) levels alleviates motor and neuropathological abnormalities, supporting HTT lowering as a therapeutic approach2. Clinical and preclinical stage modalities including antisense oligonucleotides, virally delivered microRNAs, and zinc finger transcription factors, reduce HTT levels by repressing HTT transcription, stability and/or translation.1 2 Such modalities require invasive procedures to reach the central nervous system (CNS) and are not evenly distributed. These compounds act via a novel mechanism promoting the inclusion of a pseudoexon containing a premature termination codon, leading to HTT messenger RNA (mRNA) degradation and reduction of HTT levels.AimsWe aimed to develop a class of small molecule splicing modifiers specifically synthesised to promote selective splicing and ultimately reduction in huntingtin mRNA and protein levels.Methods/TechniquesHere, we describe the identification of small molecule splicing modifiers lowering HTT expression by selective modulation of the critical recognition step of pre-mRNA splicing.Results/OutcomeThese data demonstrate the potential of small molecules that effectively lower HTT consistently throughout the CNS and periphery to be a non-invasive effective treatment option for patients.ConclusionsThis work represents the first example of the identification and optimisation of orally bioavailable splicing modifiers that penetrate all tissues and lower HTT evenly throughout the body.ReferencesWild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in huntington’s disease. Lancet Neurol 2017;16:837–847.Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin lowering strategies for disease modification in huntington’s disease. Neuron 2019;101:801–819.Nopoulos PC. Huntington disease: a single-gene degenerative disorder of the striatum. Dialogues Clin Neurosci 2016;18:91–98.

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.

Abstract Introduction Sodium oxybate is an effective treatment for excessive daytime sleepiness and cataplexy in patients with narcolepsy. The FDA approved formulation requires twice-nightly dosing; at bedtime and 2.5 - 4 hours later. FT218 is a controlled-release formulation of sodium oxybate intended for once-nightly dosing, using Avadel’s proprietary Micropump™ technology. The objective of this study was to evaluate the relative bioavailability of investigational once-nightly sodium oxybate, FT218, 6 g, compared to commercially available twice-nightly sodium oxybate and the food effect of FT218. Methods Two crossover, single-dose pharmacokinetic studies were conducted in healthy volunteers. The first, a relative bioavailability study (n=28) was completed comparing FT218 6 g to twice-nightly sodium oxybate 6 g (in two divided doses of 3 g). The second, evaluated the food effect (n=16) of FT218 6g in the Fed vs. Fasted state. Results FT218 had a lower overall Cmax than twice-nightly sodium oxybate, while AUC was equivalent. C8h level and variability was comparable between FT218 and twice-nightly sodium oxybate. In the Fed, compared to the Fasted state, FT218 had a longer Tmax, lower Cmax and decreased AUC (Cmax 67%, AUC 86%, Tmax 1-hour slower than Fasted values). Adverse Events with FT218 were mostly mild or moderate in severity, non-serious and known AEs associated with sodium oxybate. The safety profiles of FT218 and twice-nightly sodium oxybate at 6 g appeared similar. Conclusion Once-nightly FT218 at 6 g demonstrated a lower overall Cmax and similar exposure to twice-nightly sodium oxybate, with similar C8h plasma levels and C8h variability. In the Fed state, AUC and Cmax of FT218 was lower than in the Fasted State. FT218 was generally safe and well tolerated and the safety profile appeared comparable to twice-nightly sodium oxybate. Support This work was supported by Avadel Pharmaceuticals.

Solubility is not to be confused with the ability to dissolve or liquefy a substance, since this process may occur not only because of dissolution but also because of a chemical reaction. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. Among all newly discovered chemical entities about 40% drugs are lipophilic and fail to reach therapeutic range due to their poor water solubility. Drug with poor water solubility cause slow dissolution rates, generally show erratic and incomplete absorption leading to low bioavailability when administered orally. This present review details about the different approaches used for the enhancement of the solubility of poorly water-soluble drugs include particle size reduction, nanonization, pH adjustment, solid dispersion, complexation, co-solvency, hydrotropy etc. The purpose of this article is to describe the techniques of solubilization for the attainment of effective absorption and improved bioavailability.

The concentrations of trace elements including As, Zn, Cu, Se, Pb, Hg and Cd, were determined in the blood of nesting Kemp's ridley turtles (Lepidochelys kempii) at Rancho Nuevo sanctuary, Tamaulipas, Mexico during 2018-2020. The sequential concentrations analyzed were Zn> Se> Cu> As> Pb; while Cd and Hg concentrations were below the limits of detection (0.01 [mu]g g.sup.-1). No significant differences were observed between the concentrations of trace elements (p> 0.05) by year, except Se levels, possibly resulting from recorded seasonal differences in turtle size. No relationships among turtle size vs elements concentration were observed. In conclusion, essential and toxic trace elements concentrations in the blood of nesting Kemp's ridley turtles may be a reflex of the ecosystem in which the turtles develop, that is, with low bioavailability of elements observed in the trophic webs in the Gulf of Mexico.

Phytic acid (PA) is the main source of phosphorus storage in plants. Since the molecule has a negative charge, it creates complexes with important minerals such as Cu, Zn, Co, Mn, Mg, Fe and Ca. It is therefore regarded as an antinutrient because monogastric animals do not have the necessary enzymes to break the bonds. This leads to major issues such as micronutrient deficiencies in the population, all the unused phosphorus is excreted and eventually reaches water bodies causing eutrophication. Up to 60-85 % of P from soil is stored as PA in grains, hence all this P is removed from the soil at harvest and this removed P has a cost, which has been estimated in billions. Hence, even small reductions in the PA concentrations could represent more efficient and nutritious crops as well as important money savings. In this study we analysed wheat samples grown in a hydroponic system and evaluated the effect of P and Zn treatments on its concentration in leaf and grain (Chapter 2). Treatments had significant effect over PA and other mineral concentrations in grain and leaf samples. We observed significant relationships between leaf and grain PA and mineral concentrations indicating that some predictions could be made from a single and simple analysis in leaves. In Chapters 3 and 4 we describe a huge variability in PA concentrations in diverse genotypes and environments. We found significant differences between the genotypes, environments and their interactions. Moreover, phytate to mineral molar ratios were calculated and the potential impact over the bioavailability of Ca, Fe and Zn is discussed. The results obtained here highlight the importance of PA determination as an important trait to be looked at when breeding or searching for mineral enhanced varieties. As we observed, some genotypes with high concentrations of Fe and Zn had also high concentrations of PA. High PA ratios will inevitably affect the bioavailability of Fe and Zn. A great amount of work has been done over the past years, but there are still gaps of knowledge to be filled, such as the transport and loading of P into seeds, the genetic control of P translocation from vegetative tissues to seed, the heritability of P and PA traits, among others. This work aims to set the basis for further and more specialized studies looking into developing new low phytate varieties.