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      Formulation development for the orexin receptor antagonist almorexant: assessment in two clinical studies

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          Almorexant, a dual orexin receptor antagonist, was investigated for the treatment of insomnia. The following observations initiated further formulation development: the active pharmaceutical ingredient (API) was sticking to the apparatus used during tablet compression; almorexant has an absolute bioavailability of 11.2%; and almorexant modestly decreased the latency to persistent sleep by 10.4 minutes in patients. Two randomized crossover studies were performed to investigate the pharmacokinetics of several new formulations in healthy subjects. In study I, the old “sticky” tablet was compared to two new formulations developed to prevent sticking: a qualitatively similar tablet but with a larger API crystal size and a tablet with 30% more excipients as well as a larger API crystal size. This latter formulation was available in two strengths. The geometric mean ratios and 90% confidence interval of the area under the curve (AUC) were within the bioequivalence range of 0.80–1.25 for the different comparisons between formulations. In study II, 100 mg of the reference tablet was compared to 25 and 50 mg of a liquid-filled hard gelatin capsule developed to increase the bioavailability of almorexant. The geometric mean ratios of the maximum concentration and AUC comparing the new 25 and 50 mg capsule formulations to the reference tablet did not exceed 0.25 and 0.50, respectively, indicating that the new capsule formulation did not increase the maximum concentration of or the total exposure to almorexant. In conclusion, a new tablet was developed but formulation development aimed at increasing the bioavailability of almorexant failed.

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          Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.

          The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.
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            The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.

            We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.
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              Lipid-based formulations for intestinal lymphatic delivery.

              The current state of the art of intestinal lymphatic transport is given by reviewing the more recent publications, which have utilized lipid-based vehicles. The results published often show variable trends depending on, the design of the vehicle, the components used, the physicochemical properties of the drug, the animal model and experimental techniques, these variables often make direct comparisons difficult. Traditionally intestinal lymphatic delivery has been expressed as a percentage of the dose transported in the lymph. Using this parameter results obtained to date, with lipid-based vehicles, are somewhat disappointing maximising at approximately 20-30%, for highly lipophilic compounds including DDT and halofantrine (Hf). Recent data, monitoring Hf, in a fed versus fasted dog study, have shown that a higher degree of lymphatic transport is possible (>50% dose) in the postprandial state, this study should result in stimulating renewed interest in the potential of achieving significant levels of lymphatic targeting. Although some relevant features controlling lymphatic transport have been identified over the years a deeper appreciation of all the mechanisms, which is vital for therapeutic exploitation of lymphatic transport, is still unrealized. This review analyses the success and limitations of a formulation approach using lipid-based vehicles and highlights potential areas for further research.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                28 April 2014
                : 8
                : 397-403
                Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
                Author notes
                Correspondence: Jasper Dingemanse, Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Gewerbestrasse 16, Allschwil, Switzerland, Tel +41 61 565 6463, Fax +41 61 565 6200, Email jasper.dingemanse@ 123456actelion.com
                © 2014 Dingemanse et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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