Quantification and Evaluations of Catechin Hydrate Polymeric Nanoparticles Used in Brain Targeting for the Treatment of Epilepsy
Authors: Mohd Amir
Hassan Mohammed Ali Almatar
Niyaz Ahmad
Ridha Abdullah Alrasheed
Md Sarafroz
Rizwan Ahmad
Abdullah Sami Al-Ramadan
Journal: Pharmaceutics (2020)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: UHPLC-MS/MS; brain bioavailability and pharmacokinetic; catechin hydrate; chitosan-coated‚ÄìPLGA‚Äìnanoparticles; epilepsy.
Affiliations: Department of Pharmaceutics, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 314441, Saudi Arabia., Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 314441, Saudi Arabia., Department of Natural Products and Alternative Medicine, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 314441, Saudi Arabia.

Abstract:  To formulate novel chitosan (CS)-coated-PLGA-nanoparticles (NPs) using a central composite design approach and use them in order to improve brain bioavailability for catechin hydrate (CH) through direct nose-to-central nervous system (CNS) delivery for the evaluation of a comparative biodistribution study of CH by the newly developed ultra high performance liquid chromatography mass spectroscopy and mass spectroscopy (UHPLC-MS/MS) method in the treatment of epilepsy. For PLGA-NPs' preparation, a double emulsion-solvent evaporation method was used, where a four-factor, three-level central composite design was used to obtain the best nanoformulation. For the optimization, four independent variables were chosen, that is, PLGA, polyvinyl alcohol (PVA), sonication time, and temperature. The optimized PLGA-NPs were further coated with chitosan and assessed for drug release, nasal permeation study, as well as a comparative pharmacokinetic and pharmacodynamic study. Independent and dependent variables helped to optimize the best nanoformulation based on the composition of PLGA (50.0 mg), PVA (1.10%), sonication time (90.0 s), and temperature (25.0 ¬∞C). The values of dependent variables were observed, such as polydispersity index (PDI), particle size, and zeta potential (ZP)-that is, 0.106 ¬± 0.01, 93.46 ¬± 3.94 nm, and -12.63 ¬± 0.08 mV, respectively. The ZPs of CS-coated PLGA-NPs were changed from negative to positive value with some alteration in the distribution of particle size. Excellent mucoadhesive-nature of CS-CH-PLGA-NPs as compared with CH-S and CH-PLGA-NPs was seen, with a retention time of 0.856 min and m/z of 289.23/245.20 for CH, together with a retention time of 1.04 min and m/z of 301.21/151.21 for Quercetin as an internal standard (IS). For a linear range (1-1000 ng mL-1), % accuracy (93.07-99.41%) and inter- and intraday % precision (0.39-4.90%) were determined. The improved Cmax with area under curve (AUC)0-24 was found to be highly significant (p &lt; 0.001) in Wistar rats' brain as compared with the i.n. and i.v. treated group based on the pharmacokinetics (PK) results. Furthermore, CS-CH-PLGA-NPs were found to be more significant (p &lt; 0.001) for the treatment of seizure threshold rodent models, that is, increasing current electroshock and pentylenetetrazole-induced seizures. A significant role of CS-CH-PLGA-NPs was observed, that is, p &lt; 0.001, for the enhancement of brain bioavailability and the treatment of epilepsy. 

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PubPeer comments:
 Fig 5A.  Scanning electron microscopy (SEM) (A)... images of CS-coatedu2013CH-loadedu2013PLGAu2013NPs.  Fig 3A from [Ahmad et al (2020)] .  Scanning electron microscopy (SEM) [A] ... images of CS-coated-CH-loaded-PLGA-NPs. :  Scale bars are not compatible. , 
 Figure 8.  (A) In vitro release profile of CSu2013S, CH-loadedu2013PLGAu2013NPs, and chitosan-coatedu2013CHloadedu2013PLGAu2013NPs performed using the dialysis bag method, revealing the sustained release pattern of CH-loadedu2013PLGAu2013NPs and Chitosan-coatedu2013CH-loadedu2013PLGAu2013NPs (mean u00b1 SD, n = 3). (B) Ex vivo permeation profiles of developed chitosan-coatedu2013CH-loadedu2013PLGAu2013NPs as compared with CH-loadedu2013PLGAu2013NPs and pure CHu2013S through goat nasal mucosa.  These seem to be a duplicate publication of Figs 5A and 6A from [Ahmad et al (2020)] .  In vitro release profile of CTH-S, CTHu2013loadedu2013PLGAu2013NPs and Chitosan-coated-CTHu2013loadedu2013PLGAu2013NPs performed by using dialysis bag method, revealing sustained release pattern of CTHu2013loadedu2013PLGAu2013NPs and Chitosan-coated- CTHu2013loadedu2013PLGAu2013NPs (Temp was set at 37u202fu00b0C, meanu202fu00b1u202fSD, nu202f=u202f3) at pH 7.4 [A] ;  Ex vivo permeation profiles of developed Chitosan-coated-CHu2013loadedu2013PLGAu2013NPs as compared to CTHu2013loadedu2013PLGAu2013NPs and pure CTH-S through goat nasal mucosa.  , 
 Clockwise here from upper left: - Fig 7A from [Ahmad et al (2018)] .  The cumulative percentage release of Eugenol from EUG-NE as compared to pure Eugenol (reproduced as Fig. 5 in [Ahmad et al (2019)] ,  The cumulative percentage release of Eugenol from EUG ). - Fig. 2a from [Ahmad et al (2018b)] .  In vitro release profile of EUG-solution, EUG-loaded-PCL-NPs and CS-coated-EUG-loaded-PCL-NPs performed by using dialysis bag method, revealing sustained release pattern of EUG-loaded-PCL-NPs and CS-coated-EUG-loaded-PCL-NPs . - Fig. 5A from [Ahmad et al (2019a)] .  In vitro release profile of DAUNu2013S, DAUNu2013loadedu2013PLGAu2013NPs and CSu2013DAUNu2013PLGAu2013NPs performed by using dialysis bag method, revealing sustained release pattern of DAUNu2013PLGAu2013NPs, and CSu2013DAUNu2013PLGAu2013NPs . - Fig. (5)A from [Ahmad et al (2019b)] .  In vitro release profile of GRA-solution, GRA-loaded-PCL-NPs and CS-coated-GRA-loaded-PCL-NPs performed by using dialysis bag method, revealing sustained release pattern of GRA-loaded-PCL-NPs and CS-coated-GRA-loaded-PCL-NPs . - Fig 6a from [Ahmad et al (2019c)] .  The cumulative percentage release of curcumin from Cur-SNEDDS as compared to pure curcumin. - Fig 5A from [Ahmad et al (2020)] .  In vitro release profile of CTH-S, CTHu2013loadedu2013PLGAu2013NPs and Chitosan-coated-CTHu2013loadedu2013PLGAu2013NPs performed by using dialysis bag method, revealing sustained release pattern of CTHu2013loadedu2013PLGAu2013NPs and Chitosan-coated- CTHu2013loadedu2013PLGAu2013NPs (Temp was set at 37u202fu00b0C, meanu202fu00b1u202fSD, nu202f=u202f3) at pH 7.4 (reproduced as **Fig 8A in [Ahmad et al (2020a)] **). - Fig 6 from [Ahmad et al (2020b)] ,  the %age-cumulative-release of 5-FU from 5-FU-NE and 5-FU-NE-Gel when it compared with pure 5-FU-S . - Fig. 5a from [Ahmad et al (2020c)] .  In vitro release profile of THQ-S, and THQ-loaded-PLGA-NPs performed by using dialysis bag method, revealing sustained release pattern of THQ-PLGA-NPs .  All 8 superimposed:  Are there any nanopreparations with **different** pharmacokinetics? I am also impressed by the similarity of the release profiles of pure Eugenol, Daunorubicin, Glycyrrhizic Acid, curcumin, catechin, 5-FU and Thymoquinone, despite their different solubilities, etc.. ,