Candesartan Cilexetil (CC) is a prodrug widely used in the treatment of hypertension and heart failure, but it has some limitations, such as very poor aqueous solubility, high affinity to P-glycoprotein efflux mechanism, and hepatic first-pass metabolism. Therefore, it has very low oral bioavailability. In this study, glyceryl monostearate (GMS) and Capryol™ 90 were selected as solid and liquid lipids, respectively, to develop CC-NLC (nanostructured lipid carrier). CC was successfully encapsulated into NLP (CC-NLC) to enhance its oral bioavailability. CC-NLC was formulated using a hot homogenization-ultrasonication technique, and the physicochemical properties were characterized. The developed CC-NLC formulation was showed in nanometric size (121.6 ± 6.2 nm) with high encapsulation efficiency (96.23 ± 3.14%). Furthermore, it appeared almost spherical in morphology under a transmission electron microscope. The surgical experiment of the designed CC-NLC for absorption from the gastrointestinal tract revealed that CC-NLC absorption in the stomach was only 15.26% of that in the intestine. Otherwise, cellular uptake study exhibit that CC-NLCs should be internalized through the enterocytes after that transported through the systemic circulation. The pharmacokinetic results indicated that the oral bioavailability of CC was remarkably improved above 2-fold after encapsulation into nanostructured lipid carriers. These results ensured that nanostructured lipid carriers have a highly beneficial effect on improving the oral bioavailability of poorly water-soluble drugs, such as CC.

The current study inspects the screening of the formulation components further, evaluates the physicochemical properties of the nanostructured lipid carriers (NLCs) for the antihypertensive drug as Candesartan Cilexetil (CC). The sequence screening of all excipients required for the preparation of NLCs should be performed. Firstly, the solubility of CC in different solid and liquid lipids is the major parameter for the selection of the best one. Precirol® ATO 5, Compritol ® 888 ATO and Glyceryl Monostearate (GMS) were showed the maximum solubility of the CC (1000±4.12 mg, 1500±4.15 mg and 1750±3.16 mg), respectively. Hence, they were selected as the solid lipids for the development of NLCs. Liquid lipids Transcutol® HP (30±2.21 mg/ml), Labrasol® ALF (25±1.32 mg/ml) and CapryolTM 90 (18±1.34 mg/ml) were observed to have good affinity for the drug on systematic screening of different liquid lipids. However, Precirol® ATO 5 was found to has good physical compatibility with Transcutol® HP, Compritol ATO 888 was found to has high physical miscibility with Labrasol® ALF and last GMS was appeared in good affinity and compatibly with CapryolTM 90. Hence, the following binary lipid mixtures (Precirol® ATO 5 - Labrasol® ALF), (Compritol® 888 ATO-Transcutol® HP) and (GMS - CapryolTM 90) were selected for the preparation of NLCs. The liquid–solid lipid mixture in the ratio up to 30:70 was observed to have sufficient melting point (55-59 0C). Lutrol F-68, Lutrol F-127, Cremophore EL and Cremophore® RH. In addition to, the combination of (Lutrol® F68:Cremophore® EL) and (Lutrol® F127: Cremophore® RH) were selected as the main surfactants for the preparation of NLCs formulations because of its good emulsification efficacy and homogeneity for the solid-liquid lipid mix. The prepared formulations were investigated for the different quality issues. All designed formulations observed in nanometer size of particles ranged from (408.9±11.5 to 114.6±8.3 nm) with high encapsulation efficiency around 99%. Also, the obtained results revealed that the ZP of the various formulations was consistently negative surface charge in between ((-13 ±2.3 to27.3±3.7 mV). Finally, formula number nine of CC (CC-NLC9) which composed of GMS (solid lipid), CapryolTM 90 (liquid lipid) and Lutrol® F127: Cremophore® RH (surfactants combination) was selected as the best formulation after the rank order for further investigations in the next work.  Peer Review History: UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file Average Peer review marks at initial stage: 5.0/10 Average Peer review marks at publication stage: 7.5/10 Reviewer(s) detail: Name: Dr. Mohammed Abdel-Wahab Sayed Abourehab Affiliation: Umm Al-Qura University;  Makkah Al-Mukarramah, Saudi Arabia E-mail: maabourehab@uqu.edu.sa   Name: Dr.  Maha Khalifa Ahmed Khalifa    Affiliation: Al-Azhar Universit - Cairo, Egypt E-mail: mahakhalifa.ahmed@hotmail.com   Name: Dr. Evren Alğin Yapar Affiliation: Turkish Medicines and Medical Devices Agency, Turkiye E-mail: evren.yapar@yahoo.com Comments of reviewer(s): Similar Articles: FORMULATION AND CHARACTERIZATION OF TOPICAL NANO EMULGEL OF TERBINAFINE A REVIEW ON GOLD NANOPRTICLES SYNTHESIS AND CHARACTERIZATION FORMULATION AND EVALUATION OF ELASTIC LIPOSOMES OF DECITABINE PREPARED BY ROTARY EVAPORATION METHOD

Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the most important trends in overcoming such problems is the use of a vesicular system. Cubosomes are considered one of the most important vesicular systems used to improve solubility and oral bioavailability. In this study, GFT cubosomal nanoparticles (GFT-CNPs) were prepared by the emulsification method. The selected formulation variables were analyzed and optimized by full factorial design and response surface methodology. Drug entrapment efficiency (EE%), transmission electron microscopy, particle size, polydispersity index, in vitro release and its kinetics, and the effect of storage studies were estimated. The chosen GFT-CNPs were subjected to further investigations as gene expression levels of tissue inhibitors of metalloproteinases-1 (TIMP-1) and matrix metalloproteinases-7 (MMP-7), colon biomarkers, and histopathological examination of colon tissues. The prepared GFT-CNPs were semi-cubic in shape, with high EE%, smaller vesicle size, and higher zeta potential values. The in vivo data showed a significant decrease in the serum level of embryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and gene expression level of TIMP-1 and MMP-7. Histopathological examination showed enhancement in cancer tissue and highly decreased focal infiltration in the lamina propria after treatment with GFT-CNPs.