Objective: To enhance the pharmaceutical potential and oral bioavailability of quercetin contents of Allium cepa peel extract by novel nanosuspension technology. Methods: Nanoprecipitation approach was successfully used for the formulation of nanosuspension. To obtain pharmaceutical-grade nanosuspension with minimum particle size and polydispersity index, sodium lauryl sulphate was selected as a stabilizer. Important formulation parameters were statistically optimized by the response surface methodology approach. The optimized nanosuspension was subjected to stability and in vitro dissolution testing and characterized by scanning electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy, and zeta sizer. To evaluate the preeminence of nanosuspension over coarse suspension, comparative bioavailability studies were carried out in male albino rats. The pharmaceutical potential of developed nanosuspension was evaluated by antioxidant, antimicrobial, and toxicity studies. Results: The optimized nanosuspension showed an average particle size of 275.5 nm with a polydispersity index and zeta potential value of 0.415 and -48.8 mV, respectively. Atomic force microscopy revealed that the average particle size of nanosuspension was below 100 nm. The formulated nanosuspension showed better stability under refrigerated conditions. Nanosuspension showed an improved dissolution rate and a 2.14-fold greater plasma concentration of quercetin than coarse suspension. Moreover, the formulated nanosuspension exhibited enhanced antioxidant and antimicrobial potential and was non-toxic. Conclusions: Optimization of nanosuspension effectively improves the pharmaceutical potential and oral bioavailability of Allium cepa extract.

Objective: To enhance the dissolution rate and oral bioavailability of Terminalia arjuna bark extract by formulating its nanosuspension. Methods: Nanoprecipitation approach was used for the formulation of nanosuspension using polysorbate-80 as a stabilizer. The formulated nanosuspension was assessed for particle size, polydispersity index, zeta potential value and for in vitro dissolution study. Oral bioavailability studies were carried out in Wistar male albino rats by administering a single dose (50 mg/kg. b. wt) of the formulated nanosuspension and coarse suspension. The storage stability of the formulated nanosuspension was determined after three months of storage at room temperature and under the refrigerated condition. Mutagenicity assay was carried out to evaluate the toxicity of the formulated nanosuspension using two mutant strains (Salmonella typhimurium TA100 and Salmonella typhimurium TA98). Results: The mean particle size of the formulated nanosuspension was 90.53 nm with polydispersity index and zeta potential values of 0.175 and-15.7 mV, respectively. Terminalia arjuna nanosuspension showed improved dissolution rate and 1.33 fold higher oral bioavailability than its coarse suspension. The formulated nanosuspension also showed better stability under the refrigerated condition and was non-mutagenic against both strains. Conclusions: Our study demonstrates that nanosuspension technology can effectively enhance the dissolution rate and oral bioavailability of Terminalia arjuna bark extract. Zafar Fatiqa 1 Department of Chemistry, University of Okara, Okara Jahan Nazish 2 Department of Chemistry, University of Agriculture, Faisalabad Khalil-Ur-Rahman 3 Department of Biochemistry, University of Agriculture, Faisalabad Asi Muhammad 4 Food Toxicology Lab, Plant Protection Division, Nuclear Institute for Agriculture and Biology, Faisalabad Zafar Waseeq-Ul-Islam 5 Department of Computer Science, COMSATS University of Information and Technology, Islamabad Pawar SS, Dahifale BR, Nagargoje SP, Shendge RS. Nanosuspension technologies for delivery of drugs. Nanosci Nanotech Res 2017; 4(2): 5966. Kilor V, Sapkal N, Daud A, Humne S, Gupta T. Development of stable nanosuspension loaded oral films of glimepiride with improved bioavailability. Int J Appl Pharm 2017; 9(2): 28-33. He J, Han Y, Xu G, Yin L, Neubi MN, Zhou J, et al. Preparation and evaluation of celecoxib nanosuspensions for bioavailability enhancement. RSC Adv 2017; 7: 13053-13064. Wang Y, Zheng Y, Zhang L, Wang Q, Zhang D. Stability of nanosuspensions in drug delivery. J Control Release 2013; 172(3): 11261141. ElShagea HN, ElKasabgy NA, Fahmy RH, Basalious EB. Freeze-dried self-nanoemulsifying self-nanosuspension (snesns): A new approach for the preparation of a highly drug-loaded dosage form. AAPS Pharm Sci Tech 2019; 20: 1-14. Gao L, Zhang D, Chen M, Duan C, Dai W, Jia L, et al. Studies on pharmacokinetics and tissue distribution of oridonin nanosuspensions. Int J Pharm 2008; 355(1-2): 321-327. Srivalli KMR, Mishra B. Drug nanocrystals: A way toward scale-up. Saudi Pharm J 2016; 24(4): 386-404. Geng T, Banerjee P, Lu Z, Zoghbi A, Li T, Wang B. Comparative study on stabilizing ability of food protein, non-ionic surfactant and anionic surfactant on BCS type Π drug carvedilol loaded nanosuspension: Physicochemical and pharmacokinetic investigation. Eur J Pharm Sci 2017; 109: 200-208. Jahan N, Rehman KU, Ali S, Bhatti IA. Antioxidant activity of gemmo therapeutically treated indigenous medicinal plants. Asian J Chem 2011; 23: 3461-3470. Zafar F, Jahan N, Rahman KU, Khan A, Akram W. Cardioprotective potential of polyphenolic rich green combination in catecholamine induced myocardial necrosis in rabbits. Evid Based Complement Alternat Med 2015; 2015: 734903. Ramesh R, Dhanaraj T. GC-MS analysis of bioactive compounds in Terminalia arjuna root. Int J Multidiscip Res Dev 2015; 2: 460-462. Shanbhag D, Khandagale A. Screening and standardization of Terminalia arjuna used as medicine in homeopathy using hptlc method. Int J Ana Bioana Chem 2011; 1: 57-60. Pooja S. Production of flavonoids from Terminalia arjuna (ROXB.) in vivo and in vitro tissue cultures. Int J ChemTech Res 2014; 6: 881-885. Gao L, Liu G, Wang X, Liu F, Xu Y, Ma J. Preparation of a chemically stable quercetin formulation using nanosuspension technology. Int J Pharm 2011; 404(1-2): 231-237. Arshad MS, Sohaib M, Nadeem M, Saeed F, Imran A, Javed A, et al. Status and trends of nutraceuticals from onion and onion by-products: A critical review. Cogent Food Agric 2017; 3: 1-14. Penalva R, Gonzalez-Navarro CJ, Gamazo C, Esparza I, Irache JM. Zein nanoparticles for oral delivery of quercetin: Pharmacokinetic studies and preventive anti-inflammatory effects in a mouse model of endotoxemia. Nanomedicine 2017; 13(1): 103-110. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: An overview. Sci World J2013; 2013: 162750. Thadkala K, Nanam PK, Rambabu B, Sailu C, Aukunuru J. Preparation and characterization of amorphous ezetimibe nanosuspensions intended for enhancement of oral bioavailability. Int J Pharm Investig 2014; 4(3): 131-137. Khan S, Iqbal T, Ahmed N, Jamil A. Antioxidant, hemolytic and mutagenic potential of Psoralea corylifolia. J Animal Plant Sci 2015; 25(5): 1451-1456. Gera S, Talluri S, Rangaraj N. Formulation and evaluation of naringenin nanosuspensions for bioavailability enhancement. AAPS Pharm Sci Tech 2017; 18(8): 3151-3162. Sun W, Mao S, Shi Y, Li LC, Fang L. Nanonization of itraconazole by high pressure homogenization: Stabilizer optimization and effect of particle size on oral absorption. J Pharm Sci 2010; 100(8): 3365-3373. Jahan N, Rehman KU, Ali S, Asi MR, Akhtar A. Cardioprotective potential of gemmomodified extract of Terminalia arjuna against chemically induced myocardial injury in rabbits. Pak Vet J 2012; 32: 255-259. Huang S, Chang WH. Advantages of nanotechnology-based chinese herb drugs on biological activities. Curr Drug Metab 2009; 10(8): 905-913. Dizaj SM, Vazifehasl Z, Salatin S, Adibkia K, Javadzadeh Y. Nanosizing of drugs: Effect on dissolution rate. Res Pharm Sci 2015; 10(2): 95-108. Abd-Elsalam WH, ElKasabgy NA. Mucoadhesive olaminosomes: A novel prolonged release nanocarrier of agomelatine for the treatment of ocular hypertension. Int J Pharm 2019; 560: 235-245. Rachmawati H, Shaal LA, Muller RH, Keck CM. Development of curcumin nanocrystal: Physical aspects. J Pharm Sci 2013; 102(1): 204214. Hong C, Dang Y, Lin G, Yao Y, Li G, Ji G, et al. Effects of stabilizing agents on the development of myricetin nanosuspension and its characterization: An in vitro and in vivo evaluation. Int J Pharm 2014; 477(1-2): 251-260. Karadag A, Ozcelik B, Huang Q. Quercetin nanosuspensions produced by high-pressure homogenization. J Agric Food Chem 2014; 62(8): 18521859. Papdiwal A, Pande V, Sagar K. Design and characterization of zaltoprofen nanosuspension by precipitation method. Der Pharma Chemica 2014; 6(3): 161-168. Sumathi R, Tamizharasi S, Gopinath K, Sivakumar T. Formulation, characterization and in vitro release study of silymarin nanosuspension. Indo Am J Pharm Sci 2017; 4: 85-94. [31]Thakkar HP, Patel BV, Thakkar SP. Development and characterization of nanosuspensions of olmesartan medoxomil for bioavailability enhancement. J Pharm Bioall Sci 2011; 3(3): 426-434. Mohd-Fuat AR, Kofi EA, Allan GG. Mutagenic and cytotoxic properties of three herbal plants from Southeast Asia. Trop Biomed 2007; 24(2): 4959. Ravichandran R. Studies on dissolution behaviour of nanoparticulate curcumin formulation. Adv Nanoparticles 2013; 2(1): 51-59. Hussain N, Jaitley V, Florence AT. Recent Advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics. Adv Drug Deliv Rev 2001; 50(1-2): 107-142. Yuan H, Chen J, Du YZ, Hu FQ, Zeng S, Zhao HL. Studies on oral absorption of stearic acid sln by a novel fluorometric method. Colloids Surf B Biointerfaces 2007; 58(2): 157-164. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (sedds) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 2004; 58(3): 173-182. Liu D, Pan H, He F, Wang X, Li J, Yang X, et al. Effect of particle size on oral absorption of carvedilol nanosuspensions: In vitro and in vivo evaluation. Int J Nanomed 2015; 10: 6425-6434. Wang Y, Zhang D, Liu Z, Liu G, Duan C, Jia L, et al. In vitro and in vivo evaluation of silybin nanosuspensions for oral and intravenous delivery. Nanotechnology 2010; 21(15): 1-12. Hao J, Gao Y, Zhao J, Zhang J, Li Q, Zhao Z, et al. Preparation and optimization of resveratrol nanosuspensions by antisolvent precipitation using box-behnken design. AAPS Pharm Sci Tech 2015; 16(1): 118-128.