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Planta Med 2022; 88(01): 79-90
DOI: 10.1055/a-1332-2037
Formulation and Delivery Systems of Natural Products
Original Papers

Optimization and Evaluation of Self-nanoemulsifying Drug Delivery System for Enhanced Bioavailability of Plumbagin

Pavan Ram Kamble
Progressive Education Societyʼs Modern College of Pharmacy, Yamunanagar, Nigdi, Pune, Maharashtra, India (Affiliated with Savitribai Phule Pune University)
,
Karimunnisa Sameer Shaikh 
Progressive Education Societyʼs Modern College of Pharmacy, Yamunanagar, Nigdi, Pune, Maharashtra, India (Affiliated with Savitribai Phule Pune University)
› Author AffiliationsSupported by: Babasaheb Ambedkar Research Training Institute (BARTI) Pune Junior Research Fellowship
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Abstract

Plumbagin, a potential bioactive lipophilic molecule, possesses limited solubility and low oral bioavailability. The purpose of the present study was to examine the potential of the self-nanoemulsifying drug delivery system for improving solubility and oral bioavailability of plumbagin. The self-nanoemulsifying drug delivery system was formulated from Capmul MCM (oil), Tween 20 (surfactant), and propylene glycol (cosurfactant). Central composite design was employed as statistical tool to optimize the formulation variables, X1 (oil) and X2 (surfactant: co-surfactant mixture ratio), of the self-nanoemulsifying drug delivery system. The responses studied were droplet size, self-emulsification time, % of drug release in 15 min, and equilibrium solubility. The optimized liquid self-nanoemulsifying drug delivery system was adsorbed on Neusilin US2 and characterized for flow properties, X-ray diffractometry, differential scanning calorimetry, in vitro dissolution, in vivo anti-inflammatory activity, and bioavailability study in Wistar rats, as well as ex vivo permeation study. The droplet size, polydispersity index, self-emulsification time, and equilibrium solubility of the optimized formulation were 58.500 ± 1.170 nm, 0.228 ± 0.012, 17.660 ± 1.520 s, and 34.180 ± 1.380 mg/mL, respectively. Its zeta potential, transmittance value, and cloud point were − 28.200 ± 1.200 mV, 99.200% ± 0.600, and 90 °C, respectively. Drug release was found to be 93.320% ± 1.090. In vivo anti-inflammatory study confirmed more enhanced activity from the self-nanoemulsifying drug delivery system than with pure plumbagin. Pharmacokinetic study in rats revealed that solid self-nanoemulsifying drug delivery system had 4.49-fold higher bioavailability than pure plumbagin. Ex vivo permeation study demonstrated 1.75-fold increased intestinal permeability of the self-nanoemulsifying drug delivery system than pure plumbagin. The developed self-nanoemulsifying drug delivery system is a useful solid platform for improving solubility and oral bioavailability of plumbagin.

Key words

Plumbago zeylanica - Plumbaginaceae - solubility - SNEDDS - bioavailability - plumbagin

Supporting Information

    The overlay plot with design space and optimized P-L-SNEDDS composition is shown in Supporting Information. The results of the optimized SNEDDS stability studies are also shown in Supporting Information (Table 1S).

  • Supporting Information


Publication History

Received: 31 March 2020

Accepted after revision: 04 December 2020

Article published online:
15 January 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Alpana R. Effect of Plumbago zeylanica in hyperlipidaemic rabbits and its modification by vitamin E. Indian J Pharmacology 1996; 28: 161-166
    PubMedGoogle Scholar
  • 2 Kodati DR, Burra S, Goud PK. Evaluation of wound healing activity of methanolic root extract of Plumbago zeylanica L. in wistar albino rats. Asian J Plant Sci Res 2011; 1: 26-34
    PubMedGoogle Scholar
  • 3 Christudas S, Veeramuthu D, Paul A, Savarimuthu I. Antidiabetic effect of plumbagin isolated from Plumbago zeylanica L. root and its effect on GLUT4 translocation in streptozotocin-induced diabetic rats. Food Chem. Toxicol 2012; 50: 4356-4363
    PubMedGoogle Scholar
  • 4 Vijayakumar R, Senthilvelan M, Ravindran R, Sheela DR. Plumbago zeylanica action on blood coagulation profile with and without blood volume reduction. Vascul Pharmacol 2006; 45: 86-90
    CrossrefPubMedGoogle Scholar
  • 5 Dai Y, Hou LF, Chan JP. Inhibition of immediate allergic reactions by ethanol extract from Plumbago zeylanica stems. Biol Pharm Bull 2004; 27: 429-432
    CrossrefPubMedGoogle Scholar
  • 6 Bopaiah CP, Pradhan N. Central nervous system stimulatory action from the root extract of Plumbago zeylanica in rats. Phytother Res 2001; 15: 153-156
    CrossrefPubMedGoogle Scholar
  • 7 Lin LC, Yang LL, Chou CJ. Cytotoxic naphthoquinones and plumbagic acid glucosides from Plumbago zeylanica . Phytochemistry 2003; 62: 619-622
    CrossrefPubMedGoogle Scholar
  • 8 Luo P, Wong YF, Ge L, Zhang ZF, Liu Y, Liu L, Zhou L. Anti-inflammatory and analgesic effect of plumbagin through inhibition of nuclear factor-κB activation. J Pharmacol Exp Ther 2010; 335: 735-742
    CrossrefPubMedGoogle Scholar
  • 9 Jeyachandran R, Mahesh A, Cindrella L, Sudhakar S, Pazhanichamy K. Antibacterial activity of plumbagin and root extracts of Plumbago Zeylanica L. Acta Biol Crac Ser Bot 2009; 51: 17-22
    PubMedGoogle Scholar
  • 10 Shinde PV, Wadekar MP. Structural, thermal and antifungal activity studies of isomeric Sm(III) Juglonates. Der Pharma Chemica 2015; 7: 231-239
    PubMedGoogle Scholar
  • 11 Bothiraja C, Pawar AP, Mali AJ, Shaikh KS. Improved pharmaceutical properties of surface modified plumbagin bioactive crystals. Int J Surf Sci Eng 2013; 7: 181-195
    CrossrefPubMedGoogle Scholar
  • 12 Singh UV, Udupa N. Reduced toxicity and enhanced antitumor efficacy of betacyclodextrin plumbagin inclusion complex in mice bearing Ehrlich ascites carcinoma. Indian J Physiol Pharmacol 1997; 41: 171-175
    PubMedGoogle Scholar
  • 13 Sheik DSP, Abdulla A, Basuvaraj SK, Jasmespandi A, Kasi P. Synthesis, characterization, and DNA binding studies of nanoplumbagin. J Nanomater 2014; DOI: 10.1155/2014/179149.
    CrossrefPubMedGoogle Scholar
  • 14 Rajalakshmi S, Pawar AP, Mali AJ, Chellampillai B. Crystal engineering of bioactive plumbagin using anti-solvent precipitation, melt solidification and sonocrystallization techniques. Mater Res Express 2014; 1: 1-19
    CrossrefPubMedGoogle Scholar
  • 15 Kumar MR, Aithal BK, Udupa N, Reddy MS, Raakesh V, Murthy RS, Raju DP, Rao BS. Formulation of plumbagin loaded long circulating pegylated liposomes: in vivo evaluation in C57BL/6J mice bearing B16F1 melanoma. Drug Deliv 2011; 18: 511-522
    CrossrefPubMedGoogle Scholar
  • 16 Mandala RSK, Aithal K, Anandam A, Shavi G, Nayanabhirama U, Arumugam K. Preparation, in vitro characterization, pharmacokinetic, and pharmacodynamics evaluation of chitosan-based plumbagin microspheres in mice bearing B16F1 melanoma. Drug Deliv 2010; 17: 103-113
    CrossrefPubMedGoogle Scholar
  • 17 Rajendra N, Mohammed H, Touseef H, Devi R. Design, optimization and evaluation of glipizide solid self-nanoemulsifying drug delivery for enhanced solubility and dissolution. Saudi Pharm J 2015; 23: 528-540
    CrossrefPubMedGoogle Scholar
  • 18 Khan AW, Kotta S, Ansari SH, Sharma RK, Ali J. Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid naringenin: design, characterization, in vitro and in vivo evaluation. Drug Deliv 2015; 22: 552-561
    CrossrefPubMedGoogle Scholar
  • 19 Kazi M, Al-Swairi M, Ahmad A, Raish M, Alanazi FK, Badran MM, Khan AA, Alanazi AM, Hussain MD. Evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for poorly water-soluble talinolol: preparation, in vitro and in vivo assessment. Front Pharmacol 2019; 10: 459
    CrossrefPubMedGoogle Scholar
  • 20 Kassema AA, Mohsen AM, Ahmed RS, Essam TM. Self-nanoemulsifying drug delivery system (SNEDDS) with enhanced solubilization of nystatin for treatment of oral candidiasis: design, optimization, in vitro and in vivo evaluation. J Mol Liq 2016; 218: 219-232
    CrossrefPubMedGoogle Scholar
  • 21 Constantinides PP, Scalart JP, Lancaster C, Marcello J, Marks G, Ellens H, Smith PL. Formulation and intestinal absorption enhancement evaluation of water in-oil microemulsions incorporating medium-chain glycerides. Pharm Res 1994; 11: 1385-1390
    CrossrefPubMedGoogle Scholar
  • 22 Baloch J, Sohail MF, Sarwar HS, Kiani MS, Khan GM, Jahan S, Rafay M, Chaudhry MT, Yasinzai M, Shahnaz G. Self-nanoemulsifying drug delivery system (SNEDDS) for improved oral bioavailability of chlorpromazine: in vitro and in vivo evaluation. Medicina 2019; 55: 210
    CrossrefPubMedGoogle Scholar
  • 23 Tonga Y, Zhangb Q, Shib W, Wanga J. Mechanisms of oral absorption improvement for insoluble drugs by the combination of phospholipid complex and SNEDDS. Drug Deliv 2019; 26: 1155-1166
    CrossrefPubMedGoogle Scholar
  • 24 Sakloetsakuna D, Dünnhauptb S, Barthelmesb J, Pererab G, Bernkop-Schnürchb A. Combining two technologies: multifunctional polymers and self-nanoemulsifying drug delivery system (SNEDDS) for oral insulin administration. Int J Biol Macromol 2013; 61: 363-372
    CrossrefPubMedGoogle Scholar
  • 25 Inugala S, Eedara BB, Sunkavalli S, Dhurke R, Kandadi P, Jukanti R, Bandari S. Solid self-nanoemulsifying drug delivery system (S-SNEDDS) of darunavir for improved dissolution and oral bioavailability: in vitro and in vivo evaluation. Eur J Pharm Sci 2015; 74: 1-10
    CrossrefPubMedGoogle Scholar
  • 26 Kamble PR, Shaikh KS. Effect of surfactants and cosurfactants on phase behaviour and physicochemical properties of self-nanoemulsifying drug delivery system loaded with plumbagin. Indo Global J Pharm Sci 2020; 10: 1-11
    CrossrefPubMedGoogle Scholar
  • 27 El-Assal MI, El-Gendy MA, Tadros MI, El-Gazayerly ON. Olmesartan medoxomil-loaded self-nanoemulsifying drug delivery systems: design, in vitro characterization, and pharmacokinetic assessments in rabbits via LC-Ms/Ms. IJPSR 2018; 9: 945-955
    PubMedGoogle Scholar
  • 28 Kamisetti RR, Gupta RM. Solubility enhancement of ebastine by self–nanoemulsifying delivery strategy formulation, optimization and characterization. Int J Pharm Sci Nanotech 2017; 10 (04) 3779-3787
    PubMedGoogle Scholar
  • 29 Talele S, Derle D. Solubility and thermodynamic modeling of quetiapine fumarate in self-nanoemulsifying drug delivery system (SNEDDS). Int J App Pharm 2018; 10: 127-132
    CrossrefPubMedGoogle Scholar
  • 30 Kamble PR, Shaikh KS, Chaudhari PD. Application of liquisolid technology for enhancing solubility and dissolution of rosuvastatin. Adv Pharm Bull 2014; 4: 197-204
    PubMedGoogle Scholar
  • 31 Lia F, Rongfeng H, Bin W, Yun G, Gang C, Song G, Lei Y, Jihui T. Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake. Acta Pharm Sin B 2017; 7: 353-360
    CrossrefPubMedGoogle Scholar
  • 32 Imada C, Takahashi T, Kuramoto M, Masuda K, Ogawara K, Sato A, Wataya Y, Kim H, Higaki K. Improvement of oral bioavailability of N-251, a novel antimalarial drug, by increasing lymphatic transport with long-chain fatty acid-based self-nanoemulsifying drug delivery system. Pharm Res 2015; 32: 2595-2608
    PubMedGoogle Scholar
  • 33 Valicherla GR, Dave KM, Syed AA, Riyazuddin M, Gupta AP, Singh A, Wahajuddin. Mitra K, Datta D, Jiaur R, Gayen JR. Formulation optimization of docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity. Sci Rep 2016; 6: 26895
    CrossrefPubMedGoogle Scholar
  • 34 Patel G, Shelat P, Lalwani A. Statistical modeling, optimization and characterization of solid self-nanoemulsifying drug delivery system of lopinavir using design of experiment. Drug Deliv 2016; 23: 3027-3042
    CrossrefPubMedGoogle Scholar
  • 35 Hyma P, Chandra A, Abbulu K. Formulation and characterization of telmisartan self-microemulsifying drug delivery system. Int J Pharm Phar Sci 2014; 6: 6120-6125
    PubMedGoogle Scholar
  • 36 Balakumar K, Raghavan CV, Selvan NT, Prasad RH, Abdu S. Self-nanoemulsifying drug delivery system (SNEDDS) of rosuvastatin calcium: design, formulation, bioavailability and pharmacokinetic evaluation. Colloids Surf B Biointerfaces 2013; 112: 337-343
    CrossrefPubMedGoogle Scholar
  • 37 Chintalapudi R, Murthy T, Lakshmi KR, Manohar GG. Formulation, optimization, and evaluation of self emulsifying drug delivery systems of nevirapine. Int J Pharma Investig 2015; 5: 205-213
    CrossrefPubMedGoogle Scholar
  • 38 Beg S, Sandhu PS, Batra RS, Khurana RK, Singh B. QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance. Drug Deliv 2015; 22: 765-784
    CrossrefPubMedGoogle Scholar
  • 39 Singh D, Bedi N. Canagliflozin loaded SMEDDS: formulation optimization for improved solubility, permeability and pharmacokinetic performance. Int J Pharm Investig 2018; 49: 67-85
    CrossrefPubMedGoogle Scholar
  • 40 Tahnee JD, Shasha R, Thomas N, Clive AP. Novel nanostructured solid materials for modulating oral drug delivery from solid-state lipid-based drug delivery systems. AAPS J 2016; 18: 23-40
    CrossrefPubMedGoogle Scholar
  • 41 Jaimeen P, Gordhan C, Shruti D, Ankini P, Chhagan P. Self-nanoemulsifying powder of isotretinoin: preparation and characterization. J Powder Technol 2013; DOI: 10.1155/2013/108569.
    CrossrefPubMedGoogle Scholar
  • 42 Hsieh YJ, Lin LC, Tsai TH. Measurement and pharmacokinetic study of plumbagin in a conscious freely moving rat using liquid chromatography/tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2006; 844: 1-5
    CrossrefPubMedGoogle Scholar
  • 43 Yamaoka K, Nakagawa T, Uno T. Application of Akaikeʼs information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 1978; 6: 165-175
    CrossrefPubMedGoogle Scholar
  • 44 Ruan LP, Chen S, Yu BY, Zhu DN, Cordell GA, Qiu SX. Prediction of human absorption on natural compounds by the non-everted rat intestinal sac model. Eur J Med Chem 2006; 4: 605-610
    CrossrefPubMedGoogle Scholar
  • 45 Sharma P, Chawla HP, Panchagnula R. LC determination of cephalosporins in in-vitro rat intestinal sac absorption model. J Pharm Biomed Anal 2002; 27: 39-50
    CrossrefPubMedGoogle Scholar