FORMULATION AND EVALUATION OF POLYMERIC NANOSUSPENSION OF NARINGENIN


R. Sumathi, S. Tamizharasi, T. Sivakumar

Abstract


Objective: The objective of this study was to formulate and evaluate the poorly soluble drug, naringenin (NAR) into nanosuspension to increase the solubility and enhance the dissolution rate and then improve its bioavailability.

Methods: Nanosuspenion of naringenin (NARNS) was prepared using high-pressure homogenization method using Soya lecithin, Polaxamer-407, Polaxamer-188, Hydroxypropyl methyl cellulose (HPMC) and Tween-80. Ten formulations were prepared to show the effect of stabilizer and its ratio. D-α-Tocopheryl polyethene glycol succinate 1000 (TPGS) was added as a co-stabilizer. All these formulations were evaluated for their particle size, PDI, zeta potential, FT-IR study, drug content, saturation solubility studies, entrapment efficiency, in vitro permeability and in vitro drug release. The formulation was further evaluated for scanning electron microscope (SEM), differential scanning calorimetry (DSC) and Powder X-ray diffraction (P-XRD) and hemocompatibility assessment.

Results: All the prepared formulations were in the nano size. The optimum concentration of the stabilizer was in the formulation was found 1:1.5:1 (drug: stabilizer: co-stabilizer ratio). Dramatic effect of the particle size reduction was found by the addition of the co-stabilizer (TPGS) in formulation N2 that has P. S 80.52±0.13 nm. The solubility and dissolution of NAR in the form of NARNS were significantly higher than those of pure NAR. SEM report shows that naringenin nanosuspension revealed a smooth texture. P-XRD crystallography diffraction and DSC studies indicated that the crystalline state of NAR was converted into amorphous nature. The safety evaluation showed that NARNS provided a lower rate of erythrocyte hemolysis. 

Conclusion: In this study, (NARNS) was successfully carried out by high-pressure homogenization technique and characterized. The physio-chemical characterization shown that crystalline naringenin was converted to a polymorphic form (DSC and P-XRD Study) which evidenced by enhanced dissolution rate in comparisons of the formulation with (NAR) pure drug. The NARNS has shown 7.5±0.4 fold increased relative bioavailability when compared to the NAR. The increased drug dissolution rate may have a significant impact in absorption which in turn the improved oral bioavailability of naringenin. Thus, this delivery system may prefer to improve the dissolution of poorly soluble drugs like NAR and thus enhanced oral bioavailability. The safety evaluation showed that nanoformulation (NF2) shows a lower rate of erythrocyte hemolysis. These findings suggest that the selected formulation may represent a promising new drug formulation for intravenous administration in the treatment of certain cancers.


Keywords


Naringenin, High-Pressure Homogenization, Nanosuspenion, Solubility, Bioavailability

| PDF | HTML |

References


Assi M, Usta J, Mounimne Y, Aboul-Ela M, EL Lakany A. Phytochemical study and the antiproliferative activity of inula vulgaris species grown in lebanon. Int J Pharm Pharm Sci 2017;9:75-83.

Narain JP, Garg R, Fric A. Non-communicable diseases in the south-east Asia region: burden, strategies and opportunities. Natl Med J India 2011;24:280-7.

Thun MJ, DeLancey JO, Center MM, Jemal A, Ward EM. The global burden of cancer: priorities for prevention. Carcinogenesis 2010;31:100-10.

Moorthi C, Manavalan R, Kathiresan K. Nanotherapeutics to overcome conventional cancer chemotherapy limitations. J Pharm Pharm Sci 2011;14:67-77.

Brewer E, Coleman J, Lowman A. Emerging technologies of polymeric nanoparticles in cancer drug delivery. J Nanomater 2011;1-10. http://dx.doi.org/10.1155/2011/408675

Hollman PCH, Katan MB. Dietary flavonoids: intake, health effects and bioavailability. Food Chem Toxicol 1999;37:937–42.

Cohen J, Kristal A, Stanford J. Fruit and vegetable intakes and prostate cancer risk. J Natl Cancer Inst 2000;92:61–8.

Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther 2001;90:157–77.

Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, Griel AE, et al. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med 2001;113:71–88.

Verhoeyen ME, Bovy A, Collins G, Muir S, Robinson S, Colliver S, et al. Increasing antioxidant levels in tomatoes through modification of the flavonoids biosynthetic pathway. J Exp Bot 2002;53:2099–106.

Bugianesi R, Salucci M, Leonardi C, Ferracane R, Catasta G, Azzini E, et al. Effect of domestic cooking on human bioavailability of naringenin, chlorogenic acid, lycopene and beta-carotene in cherry tomatoes. Eur J Nutr 2004;43:360-6.

Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M. Quantitation of flavonoids constituents in citrus fruits. J Agric Food Chem 1999;47:3565–71.

Frydoonfar HR, McGrath DR, Spiegelman AD. The variable effect on proliferation of a colon cancer cell line by citrus fruit flavonoid naringenin. Colorectal Disease 2002;5:149–52.

Virgili F, Acconcia F, Ambra R, Rinna A, Totta P, Marino M. Nutritional flavonoids modulate estrogen receptor a signaling. IUBMB Life 2004;56:145–51.

Monica Kristiani, Sismindari, Ronny Martien, Hilda Ismail, Agustinus Yuswanto. Cytotoxic activity of acidic ribosome inactivating proteins mirabilis Jalapa L. (Rip Mj-C) nanoparticle formulated with low-chain chitosan and low-methylated pectin. Int J Pharm Pharm Sci 2017;9:69-74.

Mustafa R, Abdulbaqi. Evaluation the effect of nanotechnology on pharmaceutical and biological properties of metronidazole. Int J Pharm Pharm Sci 2017;9:139-45.

Kunal S, Ravindra B. UV spectrophotometric method for the estimation of azilsartan medoxomil in bulk and pharmaceutical formulations. World J Pharm Res 2015;4:1667-72.

Gandhi S, Mittal P, Pahade A, Rege S. Development and validation of stability indicating HPTLC method for estimation of azilsartan medoxomil. Pharm Sci Monitor 2015;6:224-32.

Lina Winarti, Lusia Oktora Ruma Kumala Sari, Agung Endro Nugroho. Naringenin-loaded chitosan nanoparticles formulation and its in vitro evaluation against t47d breast cancer cell line. Indonesia J Pharm 2015;26:145-57.

Sun M, Gao Y, Pei Y, Guo C, Li H. Development of nanosuspension formulation for oral delivery of quercetin. J Biomed Nanotechnol 2010;6:325-32.

Kidambi S, Yarmush RS, Novik E, Chao P, Yarmush ML, et al. Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance. Proc Natl Acad Sci USA 2009;106:15714–9.

Huong DT, Takahashi Y, Ide T. Activity and mRNA levels of enzymes involved in hepatic fatty acid oxidation in mice fed citrus flavonoids. Nutrition 2006;22:546–52.

Rajalakshmi R, Venkataramudu T, Kumar R, Divya K, Kiranmayi M. Design and characterization of valsartan nanosuspension. Int J Pharmacother 2012;2:70-81.

Kroyer G. The antioxidant activity of citrus fruit peels. Z. Ernahrungswiss 1986;25:63−9.

Prakash S, Vidyadhara S, Sasidhar RLC, Abhijit D, Akhilesh D. Development and characterization of Ritonavir nanosuspension for oral use. Pharm Lett 2013;5:48-55.

Sahu BP, Das MK. Nanosuspension for enhancement of oral bioavailability of felodipine. Appl Nanosci 2013;4:1-9.

Kanaze FI, Bounartzi MI, Georgarakis M, Niopas I. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur J Clin Nutr 2007;61:472-7.

Kunal S, Ravindra B. UV spectrophotometric method for the estimation of azilsartan medoxomil in bulk and pharmaceutical formulations. World J Pharm Res 2015;4:1667-72.

Yuancai D, Wai KN, Jun H, Shoucang S, Reginald BHT. A continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs. Int J Pharm 2010;386:256–61.

Dubhi M, Ghodasara U, Mori D, Patel K, Manek R, Sheth NR. Formulation, optimization and characterization of candesartan cilexetil nanosuspension for in vitro dissolution enhancement. Afr J Pharm Pharmacol 2015;9:102-13.

Ige PP, Baria RK, Gattani SG. Fabrication of fenofibrate nanocrystals by probe sonication method for enhancement of dissolution rate and oral bioavailability. Colloids Surf B 2013;108:366–73.

Natarajan Jawahar, Subramanya Nainar Meyyanathan, Venkatachalam Senthil, Kuppusamy Gowthamarajan, Kannan Elango. Studies on physicochemical and pharmacokinetic properties of olanzapine through nanosuspension. J Pharm Sci Res 2013;5:196–202.

Mahendra Nakarani, Priyal Patel, Jayvadan Patel, Pankaj Patel, Rayasa S, R Murthy, et al. Cyclosporine a–nanosuspension: formulation, characterization and in vivo comparision with a marketed formulation. Sci Pharm 2010;78:345-61.

Liqin Zhang, Li Song, Peipei Zhang, Tingting Liu, Li Zhou, Guangde Yang, et al. Solubilities of naringin and naringenin in different solvents and dissociation constants of naringenin. J Chem Eng Data 2015;60:932–40.

Mcclements D. Crystals and crystallization in oil-in-water emulsions: implications for emulsion-based delivery systems. Adv Colloid Interface Sci 2012;174:1-30.

Ghosh I, Snyder J, Vippagunta R, Alvine M, Vakil R, Tong W. Comparison of HPMC based polymers performance as carriers for the manufacture of solid dispersions using the melt extruder. Int J Pharm 2011;419:12–9.

Rajebahadur M, Zia H, Nues A, Lee C. Mechanistic study of solubility enhancement of nifedipine using vitamin E TPGS or solutol HS-15. Drug Delivery 2006;13:201–6.

Helgason T, Awad TS, Kristbergsson K, McClements DJ, Weiss J. Effect of surfactant surface coverage on formation of solid lipid nanoparticles (SLN). J Colloid Interface Sci 2009;334:75-81.

Van Eerdenbrugh B, Vermant J, Martens JA, Froyen L, Van Humbeeck J, Augustijns P. A screening study of surface stabilization during the production of drug nanocrystals. J Pharm Sci 2009;98:2091-103.

Merisko-Liversidge E, Sarpotdar P, Bruno J, Hajj S, Wei L, Peltier N. Formulation and antitumor activity evaluation of nanocrystalline suspensions of poorly soluble anticancer drugs. Pharm Res 1996;13:272-8.

Müller RH, Jacobs C, Kayser O. Nanosuspension as particulate drug formulations in therapy rationale for development and what we can expect for the future. Adv Drug Delivery Rev 2001;47:3–19.

Sahu SK, Mallick SK, Santra S, Maiti TK, Ghosh SK, Pramanik P. In vitro evaluation of folic acid modified carboxymethyl chitosan nanoparticles loaded with doxorubicin for targeted delivery. J Mater Sci Mat Med 2010;21:1587-97.

Misra R, Sahoo SK. Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy. Eur J Pharm Sci 2010;39:152-63.

Patil P, Bhoskar M. Optimization and evaluation of spray dried chitosan nanoparticles containing doxorubicin. Int J Curr Pharm Res 2014;6:7-15.

Jose Raul Medina, Mariel Cortes, Erik Romo. Comparison of the USP apparatus 2 and 4 for testing the in vitro release performance of ibuprofen generic suspensions. Int J Appl Pharm 2017;9:90-5.

Dixit P, Jain DK, Dumbwani J. Standardization of an ex vivo method for determination of intestinal permeability of drugs using everted rat intestine apparatus. J Pharmacol Toxicol Methods 2012;65:13-7.

Mou D, Chen H, Wan J, Xu H, Yang X. Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with pH-dependent solubility. Int J Pharm 2011;413:237-44.

Mahapatra A, Murthy P. Solubility and dissolution rate enhancement of efavirenz by inclusion complexation and liquid anti-solvent precipitation technique. J Chem Pharm Res 2014;6:1099-106.

Naguib YW, Rodriguez BL, Li X, Hursting SD, Williams RO, Cui Z. Solid lipid nanoparticle formulations of docetaxel prepared with high melting point triglycerides: in vitro and in vivo evaluation. Mol Pharm 2014;11:1239–49.

Li J, Guo X, Liu Z. Preparation and evaluation of charged solid lipid nanoparticles of tetrandrine for ocular drug delivery system: pharmacokinetics, cytotoxicity and cellular uptake studies. Drug Dev Ind Pharm 2014;40:980–7.

Kim CK, Kim JH, Park KM, Oh KH, Oh U, Hwang SJ. Preparation and evaluation of a titrated extract of centella asiatica injection in the form of an extemporaneous micellar solution. Int J Pharm 1997;146:63–70.

Xiong R, Lu W, Li J, Wang P, Xu R, Chen T. Preparation and characterization of intravenously injectable nimodipine nanosuspension. Int J Pharm 2008;350:338–43.




About this article

Title

FORMULATION AND EVALUATION OF POLYMERIC NANOSUSPENSION OF NARINGENIN

Keywords

Naringenin, High-Pressure Homogenization, Nanosuspenion, Solubility, Bioavailability

DOI

10.22159/ijap.2017v9i6.21674

Date

08-11-2017

Additional Links

Manuscript Submission

Journal

International Journal of Applied Pharmaceutics
Vol 9, Issue 6 (Oct-Nov), 2017 Page: 60-70

Online ISSN

0975-7058

Statistics

30 Views | 9 Downloads

Authors & Affiliations

R. Sumathi
Nandha College of Pharmacy and Research Institute, Erode-630052, Tamilnadu, India
India

S. Tamizharasi
Nandha College of Pharmacy and Research Institute, Erode-630052, Tamilnadu, India

T. Sivakumar
Nandha College of Pharmacy and Research Institute, Erode-630052, Tamilnadu, India


Refbacks

  • There are currently no refbacks.