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    A novel delivery system for enhancing bioavailability of S-adenosyl-L-methionine: Pectin nanoparticles-in-microparticles and their in vitro - in vivo evaluation'
    (Elsevier, 2021) Ergin, Ahmet Dogan; Bayindir, Zerrin Sezgin; Ozcelikay, Arif Tanju; Yuksel, Nilufer
    Nanoparticles-in-microparticles (NIMs) are novel drug delivery systems, which combine the benefits of nano-, and micro-sized drug carriers within one system to improve the bioavailability of drugs or provide site specific drug delivery. The goal of this work was to study the in vitro and in vivo characteristics of a new pectin nanoparticle based NIM formulation for colon targeted delivery of S-adenosyl-L-methionine (SAMe). The effects of different formulation parameters on physicochemical characteristics of pectin nanoparticles prepared by ionicgelation method were estimated by a factorial design. The studied formulation variables were different amounts of drug, pectin and crosslinking agent. NIMs were prepared using fluidized bed technology by coating the optimum nanoparticle formulation (particle size 301.5 +/- 20.3 nm, zeta potential: -16.3 +/- 1.7 mV, entrapment efficiency: 74.80 +/- 3.75%, product yield: 69.61%) on inert pellets via subcoating and pH- sensitive functional coating materials. NIMs were characterized by particle size, surface charge, morphology, entrapment efficiency, DSC, XRPD, in vitro drug release in the presence and absence of enzymes (pepsin and pectinase) in simulated gastric and colonic fluids. The in vitro drug release studies suggested retarded drug release, which was interpreted as an advantage for improving oral bioavailability of SAMe via colonic absorption. Comparative bioavailability of SAMe was determined after oral administration of pure SAMe solution, SAMe loaded pectin nanoparticles and NIMs to Wistar rats. Although inter-subject variability was observed, the relative bioavailability of SAMe (260%) increased via oral NIMs administration. This outcome should be supported with further bioavailability studies in larger groups. Overall, this study suggests that developed fluidized bed coating technique can be used to construct solid microparticular systems for colonic delivery of nanoparticles and overcome the difficulties in processing nanoparticles.
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    A study to enhance the oral bioavailability of s-adenosyl-L-methionine (SAMe): SLN and SLN nanocomposite particles
    (Elsevier Ireland Ltd, 2021) Amasya, Gulin; Ergin, Ahmet Dogan; Cakirci, Ozge Erkan; Ozcelikay, Arif Tanju; Bayindir, Zerrin Sezgin; Yuksel, Nilufer
    The endogenous molecule, S-adenosyl-L-methionine (SAMe) is a key factor due to its role in the methylation cycle and modulation of monoaminergic neurotransmission. Since many mental disorders have linked to the monoaminergic system, the level of SAMe in blood and cerebrospinal fluid is important in the treatment of major depression. In this study, solid lipid nanoparticles (SLN) were prepared in order to increase the limited oral bioavailability of SAMe, and SLN based nanocomposite particles (SAMe-SLN-NC) were further developed using an enteric polymer for passive targeting of intestinal lymphatic system. In this manner, it was also aimed to protect SAMe loaded SLN from harsh gastric environment as well as hepatic first-pass metabolism. Dynamic light scattering (DLS) analysis of SLN was performed, drug content was measured, SAMe release patterns were examined and the permeation ability of SAMe was investigated by the Parallel Artificial Membrane Permeability Assay (PAMPA) to characterize SAMe loaded SLN formulation. According to the PAMPA results, SAMe-SLN with the average particle size of 242 nm showed enhanced SAMe permeability in comparison to pure drug. Delayed drug release obtained by SLN nanocomposite particles indicated the protection of drug-loaded SLN in the acidic gastric medium and their intact presence in the intestine. SAMe solution or particle suspensions were prepared using 0.45 (w/v) hydroxypropyl methylcellulose aqueous solution to be applied to groups of animals for pharmacokinetic studies. In vivo pharmacokinetic parameters revealed enhancement in relative bioavailability of SAMe upon oral administration of SLN based formulations. This was attributed to intact absorption of lipid matrix through lymphatic path. A statistically significant increase in SAMe plasma levels was obtained at 15th and 30th minutes with SAMe-SLN and at 2nd and 4th hours with SAMe-SLN-NC. Overall results suggest that SLN is a promising carrier to passive lymphatic targeting of SAMe and novel SLN nanocomposite particles which presented efficient oral bioavailability is a potential way for oral delivery of SAMe and treatment of major depression.