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AAPS PharmSciTech
Jan 13, 2021;22 (1): 45.

Improved Oral Bioavailability and Hypolipidemic Effect of Syringic Acid via a Self-microemulsifying Drug Delivery System.

Congyong Sun, Wenjing Li, Huiyun Zhang, Michael Adu-Frimpong, Ping Ma, Yuan Zhu, Wenwen Deng, Jiangnan Yu, Ximing Xu
Author Information
  1. Congyong Sun: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
  2. Wenjing Li: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
  3. Huiyun Zhang: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
  4. Michael Adu-Frimpong: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
  5. Ping Ma: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
  6. Yuan Zhu: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
  7. Wenwen Deng: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
  8. Jiangnan Yu: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China. yjn@ujs.edu.cn.
  9. Ximing Xu: Key Lab for Drug Delivery & Tissue Regeneration, Jiangsu Provincial Research Center for Medicinal Function Development of New Food Resources, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, People's Republic of China. xmxu@ujs.edu.cn.
PMID: 33439366 DOI: 10.1208/s12249-020-01901-y

Abstract

This study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) to enhance the solubility, oral bioavailability, and hypolipidemic effects of syringic acid (SA), a bioactive and poorly-soluble polyphenol. Based on the response surface methodology-central composite design (RSM-CCD), an optimum formulation of SA-SMEDDS, consisting of ethyl oleate (oil, 12.30%), Cremophor-EL (surfactant, 66.25%), 1,2-propanediol (cosurfactant, 21.44%), and drug loading (50 mg/g), was obtained. The droplets of SA-SMEDDS were nanosized (16.38 ± 0.12 nm), spherically shaped, and homogeneously distributed (PDI = 0.058 ± 0.013) nanoparticles with high encapsulation efficiency (98.04 ± 1.39%) and stability. In vitro release study demonstrated a prolonged and controlled release of SA from SMEDDS. In vitro cell studies signified that SA-SMEDDS droplets substantially promoted cellular internalization. In comparison with the SA suspension, SA-SMEDDS showed significant prolonged T, t, and MRT after oral administration. Also, SA-SMEDDS exhibited a delayed in vivo elimination, increased bioavailability (2.1-fold), and enhanced liver accumulation. Furthermore, SA-SMEDDS demonstrated significant improvement in alleviating serum lipid profiles and hepatic steatosis in high-fat diet-induced hyperlipidemia in mice. Collectively, SMEDDS demonstrated potential as a nanosystem for the oral delivery of SA with enhanced bioavailability and hypolipidemic effects.

Keywords

controlled release hypolipidemic effect oral bioavailability self-microemulsifying drug delivery system (SMEDDS) syringic acid

References

  1. Shi F, Li JL, Yang LQ, Hou GH, Ye M. Hypolipidemic effect and protection ability of liver-kidney functions of melanin from Lachnum YM226 in high-fat diet fed mice. Food Funct. 2018;9(2):880–9. [PMID: 29299589]
  2. Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. J Hepatol. 2015;62:S65–75. [PMID: 25920092]
  3. Cetkovic Z, Cvijic S, Vasiljevic D. In vitro/in silico approach in the development of simvastatin-loaded self-microemulsifying drug delivery systems. Drug Dev Ind Pharm. 2018;44(5):849–60. [PMID: 29228833]
  4. Knapik-Czajka M, Gozdzialska A, Jaskiewicz J. Adverse effect of fenofibrate on branched-chain alpha-ketoacid dehydrogenase complex in rat’s liver. Toxicology. 2009;266(1–3):1–5. [PMID: 19819289]
  5. Yu Q, Ma X, Wang Y, et al. Dietary cholesterol exacerbates statin-induced hepatic toxicity in syrian golden hamsters and in patients in an observational cohort study. Cardiovasc Drugs Ther. (2020). https://doi.org/10.1007/s10557-020-07060-3 .
  6. Crisan E, Patil VK. Neuromuscular complications of statin therapy. Curr Neurol Neurosci Rep. 2020;20(10):47.
  7. Attridge RL, Frei CR, Ryan L, Koeller J, Linn WD. Fenofibrate-associated nephrotoxicity: a review of current evidence. Am J Health Syst Pharm. 2013;70(14):1219–25. [PMID: 23820458]
  8. Liu YT, Sun J, Rao SQ, Su YJ, Yang YJ. Antihyperglycemic, antihyperlipidemic and antioxidant activities of polysaccharides from Catathelasma ventricosum in streptozotocin-induced diabetic mice. Food Chem Toxicol. 2013;57:39–45. [PMID: 23500773]
  9. Deng WW, Yang X, Zhu Y, Yu JN, Xu XM. Structural characterization and hypolipidemic activities of purified stigma maydis polysaccharides. Food Sci Nutr. 2019;7(8):2674–83. [PMID: 31428354]
  10. Omari-Siaw E, Zhu Y, Wang HY, Peng W, Firempong CK, Wang YW, et al. Hypolipidemic potential of perillaldehyde-loaded self-nanoemulsifying delivery system in high-fat diet induced hyperlipidemic mice: formulation, in vitro and in vivo evaluation. Eur J Pharm Sci. 2016;85:112–22. [PMID: 26851382]
  11. Cao J, Wang SC, Yao CW, Xu Z, Xu XM. Hypolipidemic effect of porphyran extracted from Pyropia yezoensis in ICR mice with high fatty diet. J Appl Phycol. 2016;28(2):1315–22.
  12. Feng YS, Zhu Y, Wan JY, Yang X, Firempong CK, Yu JN, et al. Enhanced oral bioavailability, reduced irritation and increased hypolipidemic activity of self-assembled capsaicin prodrug nanoparticles. J Funct Foods. 2018;44:137–45.
  13. Cheemanapalli S, Mopuri R, Golla R, Anuradha CM, Chitta SK. Syringic acid (SA) - a review of its occurrence, biosynthesis, pharmacological and industrial importance. Biomed Pharmacother. 2018;108:547–57.
  14. Song LX, Wang HM, Xu P, Yang Y, Zhang ZQ. Experimental and theoretical studies on the inclusion complexation of syringic acid with alpha-, beta-, gamma- and heptakis(2,6-di-O-methyl)-beta-cyclodextrin. Chem Pharm Bull. 2008;56(4):468–74.
  15. Brauer GM, Stansbury JW. Materials science cements containing syringic acid esters- o-Ethoxybenzoic acid and zinc oxide. J Dent Res. 1984;63(2):137–40. [PMID: 6363481]
  16. Cotoras M, Vivanco H, Melo R, Aguirre M, Silva E, Mendoza L. In vitro and in vivo evaluation of the antioxidant and prooxidant activity of phenolic compounds obtained from grape (Vitis vinifera) pomace. Molecules. 2014;19(12):21154–67. [PMID: 25521116]
  17. Shi C, Sun Y, Zheng ZW, Zhang XR, Song KK, Jia ZY, et al. Antimicrobial activity of syringic acid against Cronobacter sakazakii and its effect on cell membrane. Food Chem. 2016;197:100–6. [PMID: 26616929]
  18. Cao Y, Zhang L, Sun S, Yi Z, Jiang X, Jia D. Neuroprotective effects of syringic acid against OGD/R-induced injury in cultured hippocampal neuronal cells. Int J Mol Med. 2016;38(2):567–73. [PMID: 27278454]
  19. Shahzad S, Mateen S, Naeem SS, Akhtar K, Rizvi W, Moin S. Syringic acid protects from isoproterenol induced cardiotoxicity in rats. Eur J Pharmacol. 2019;849:135–45. [PMID: 30731086]
  20. Abaza M-S, Al-Attiyah R, Bhardwaj R, Abbadi G, Koyippally M, Afzal M. Syringic acid from Tamarix aucheriana possesses antimitogenic and chemo-sensitizing activities in human colorectal cancer cells. Pharm Biol. 2013;51(9):1110–24. [PMID: 23745612]
  21. S-l Y, Wang Z-h, H-f Y, Lee Y-j, M-c Y. Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice. Food Chem Toxicol. 2016;98:119–26.
  22. Ham JR, Lee HI, Choi RY, Sim MO, Seo KI, Lee MK. Anti-steatotic and anti-inflammatory roles of syringic acid in high-fat diet-induced obese mice. Food Funct. 2016;7(2):689–97. [PMID: 26838182]
  23. Ren J, Yang MJ, Xu FY, Chen JW, Ma SL. Acceleration of wound healing activity with syringic acid in streptozotocin induced diabetic rats. Life Sci. 2019;233:12.
  24. Noubigh A, Abderrabba M, Provost E. Temperature and salt addition effects on the solubility behaviour of some phenolic compounds in water. J Chem Thermodyn. 2007;39(2):297–303.
  25. Parmar A, Singh K, Bahadur A, Marangoni G, Bahadur P. Interaction and solubilization of some phenolic antioxidants in Pluronic (R) micelles. Colloids Surf B Biointerfaces. 2011;86(2):319–26. [PMID: 21561746]
  26. Sun CY, Yuan YY, Omari-Siaw E, Tong SS, Zhu Y, Wang QL, et al. An efficient HPLC method for determination of syringic acid liposome in rats plasma and mice tissue: pharmacokinetic and biodistribution application. Curr Pharm Anal. 2018;14(1):41–52.
  27. Liu YK, Sun CY, Li WJ, Adu-Frimpong M, Wang QL, Yu JN, et al. Preparation and characterization of syringic acid-loaded TPGS liposome with enhanced oral bioavailability and in vivo antioxidant efficiency. AAPS PharmSciTech. 2019;20(3):10.
  28. Sun C, Li W, Ma P, Li Y, Zhu Y, Zhang H, et al. Development of TPGS/F127/F68 mixed polymeric micelles: enhanced oral bioavailability and hepatoprotection of syringic acid against carbon tetrachloride-induced hepatotoxicity. Food Chem Toxicol. 2020;137:111126. [PMID: 31954714]
  29. Sunazuka Y, Ueda K, Higashi K, Tanaka Y, Moribe K. Combined effects of the drug distribution and mucus diffusion properties of self-microemulsifying drug delivery systems on the oral absorption of fenofibrate. Int J Pharm. 2018;546(1–2):263–71. [PMID: 29763688]
  30. Li XM, Ge M, Lu MZ, Jin YH, Quan DQ. The in vitro and in vivo evaluation of fenofibrate with a self-microemulsifying formulation. Curr Drug Deliv. 2015;12(3):308–13.
  31. Kang BK, Lee JS, Chon SK, Jeong SY, Yuk SH, Khang G, et al. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int J Pharm. 2004;274(1–2):65–73. [PMID: 15072783]
  32. Neslihan Gursoy R, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58(3):173–82. [PMID: 15082340]
  33. Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ, Pouton CW. Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res. 1992;9(1):87–93. [PMID: 1589415]
  34. Wang HY, Li Q, Deng WW, Omari-siaw E, Wang QL, Wang SC, et al. Self-nanoemulsifying drug delivery system of trans-cinnamic acid: formulation development and pharmacodynamic evaluation in alloxan-induced type 2 diabetic rat model. Drug Dev Res. 2015;76(2):82–93. [PMID: 25847843]
  35. Xu Y, Wang QL, Feng YS, Firempong CK, Zhu Y, Omari-Siaw E, et al. Enhanced oral bioavailability of 6 -Gingerol-SMEDDS: preparation, in vitro and in vivo evaluation. J Funct Foods. 2016;27:703–10.
  36. Zhang KY, Wang QL, Yang QX, Wei QY, Man N, Adu-Frimpong M, et al. Enhancement of oral bioavailability and anti-hyperuricemic activity of isoliquiritigenin via self-microemulsifying drug delivery system. AAPS PharmSciTech. 2019;20(5):11.
  37. Zhu Y, Xu W, Zhang JJ, Liao YW, Firempong CK, Adu-Frimpong M, et al. Self-microemulsifying drug delivery system for improved oral delivery of limonene: preparation, characterization, in vitro and in vivo evaluation. AAPS PharmSciTech. 2019;20(4):11.
  38. Man N, Wang QL, Li HH, Adu-Frimpong M, Sun CY, Zhang KY, et al. Improved oral bioavailability of myricitrin by liquid self-microemulsifying drug delivery systems. J Drug Deliv Sci Technol. 2019;52:597–606.
  39. Tandel H, Shah D, Vanza J, Misra A. Lipid based formulation approach for BCS class-II drug: modafinil in the treatment of ADHD. J Drug Deliv Sci Technol. 2017;37:166–83.
  40. Yeom DW, Chae BR, Son HY, Kim JH, Chae JS, Song SH, et al. Enhanced oral bioavailability of valsartan using a polymer-based supersaturable selfmicroemulsifying drug delivery system. Int J Nanomedicine. 2017;12:3533–45. [PMID: 28507434]
  41. Tung NT, Tran CS, Pham TMH, Nguyen HA, Nguyen TL, Chi SC, et al. Development of solidified self-microemulsifying drug delivery systems containing L-tetrahydropalmatine: design of experiment approach and bioavailability comparison. Int J Pharm. 2018;537(1–2):9–21. [PMID: 29246439]
  42. Yang QX, Wang QL, Feng YS, Wei QY, Sun CY, Firempong CK, et al. Anti-hyperuricemic property of 6-shogaol via self-micro emulsifying drug delivery system in model rats: formulation design, in vitro and in vivo evaluation. Drug Dev Ind Pharm. 2019;45(8):1265–76. [PMID: 30990749]
  43. Khoo S-M, Humberstone AJ, Porter CJH, Edwards GA, Charman WN. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int J Pharm. 1998;167(1):155–64.
  44. Pramanik S, Thakkar H. Development of solid self-microemulsifying system of tizanidine hydrochloride for oral bioavailability enhancement: in vitro and in vivo evaluation. AAPS PharmSciTech. 2020;21(5):11.
  45. Dhumal DM, Akamanchi KG. Self-microemulsifying drug delivery system for camptothecin using new bicephalous heterolipid with tertiary-amine as branching element. Int J Pharm. 2018;541(1–2):48–55. [PMID: 29462684]
  46. Zhang Y, Huo MR, Zhou JP, Zou AF, Li WZ, Yao CL, et al. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010;12(3):263–71. [PMID: 20373062]
  47. Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93(1):359–404. [PMID: 23303913]
  48. Hauss DJ. Oral lipid-based formulations. Adv Drug Deliv Rev. 2007;59(7):667–76. [PMID: 17618704]
  49. Thipparaboina R, Mittapalli S, Thatikonda S, Nangia A, Naidu VGM, Shastri NR. Syringic acid: structural elucidation and co-crystallization. Cryst Growth Des. 2016;16(8):4679–87.
  50. Pol A, Patel P, Hegde D. Peppermint oil based drug delivery system of aceclofenac with improved anti-inflammatory activity and reduced ulcerogenecity. Int J Pharm Biosci Technol. 2013;1:2321–969.
  51. Gupta S, Chavhan S, Sawant KK. Self-nanoemulsifying drug delivery system for adefovir dipivoxil: design, characterization, in vitro and ex vivo evaluation. Colloids Surf A - Physicochem Eng Asp. 2011;392(1):145–55.
  52. Nasr A, Gardouh A, Ghorab M. Novel solid self-Nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of olmesartan medoxomil: design, formulation, pharmacokinetic and bioavailability evaluation. Pharmaceutics. 2016;8(3):29.
  53. Hoshyar N, Gray S, Han H, Bao G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine (London). 2016;11(6):673–92.
  54. Thanitwatthanasak S, Sagis LMC, Chitprasert P. Pluronic F127/Pluronic P123/vitamin E TPGS mixed micelles for oral delivery of mangiferin and quercetin: mixture-design optimization, micellization, and solubilization behavior. J Mol Liq. 2019;274:223–38.
  55. Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems - a review (part 1). Trop J Pharm Res. 2013;12(2):255–64.
  56. Kakumanu S, Tagne JB, Wilson TA, Nicolosi RJ. A nanoemulsion formulation of dacarbazine reduces tumor size in a xenograft mouse epidermoid carcinoma model compared to dacarbazine suspension. Nanomedicine. 2011;7(3):277–83. [PMID: 21215333]
  57. Choudhury H, Gorain B, Karmakar S, Biswas E, Dey G, Barik R, et al. Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform. Int J Pharm. 2014;460(1):131–43. [PMID: 24239580]
  58. Gao J, Ming J, He B, Fan Y, Gu Z, Zhang X. Preparation and characterization of novel polymeric micelles for 9-nitro-20(S)-camptothecin delivery. Eur J Pharm Sci. 2008;34(2):85–93. [PMID: 18417323]
  59. Papadopoulou V, Kosmidis K, Vlachou M, Macheras P. On the use of the Weibull function for the discernment of drug release mechanisms. Int J Pharm. 2006;309(1):44–50. [PMID: 16376033]
  60. Seljak KB, Ilic IG, Gasperlin M, Pobirk AZ. Self-microemulsifying tablets prepared by direct compression for improved resveratrol delivery. Int J Pharm. 2018;548(1):263–75.
  61. Araujo RS, Garcia GM, Vilela JMC, Andrade MS, Oliveira LAM, Kano EK, et al. Cloxacillin benzathine-loaded polymeric nanocapsules: physicochemical characterization, cell uptake, and intramammary antimicrobial effect. Mater Sci Eng C-Mater Biol Appl. 2019;104:10.
  62. Chen M-L. Lipid excipients and delivery systems for pharmaceutical development: a regulatory perspective. Adv Drug Deliv Rev. 2008;60(6):768–77. [PMID: 18077051]
  63. Liu X, Huang N, Li H, Jin Q, Ji J. Surface and size effects on cell interaction of gold nanoparticles with both phagocytic and nonphagocytic cells. Langmuir. 2013;29(29):9138–48. [PMID: 23815604]
  64. Tran P, Pyo YC, Kim DH, Lee SE, Kim JK, Park JS. Overview of the manufacturing methods of solid dispersion technology for improving the solubility of poorly water-soluble drugs and application to anticancer drugs. Pharmaceutics. 2019;11(3):26.
  65. Huo T, Tao C, Zhang M, Liu Q, Lin B, Liu Z, et al. Preparation and comparison of tacrolimus-loaded solid dispersion and self-microemulsifying drug delivery system by in vitro/in vivo evaluation. Eur J Pharm Sci. 2018;114:74–83. [PMID: 29222025]
  66. Chen J, Mao D, Yong Y, Li J, Wei H, Lu L. Hepatoprotective and hypolipidemic effects of water-soluble polysaccharidic extract of Pleurotus eryngii. Food Chem. 2012;130(3):687–94.

MeSH Term

Administration, Oral
Animals
Biological Availability
Cell Line
Drug Delivery Systems
Drug Liberation
Emulsions
Gallic Acid
Humans
Hypolipidemic Agents
Male
Mice
Mice, Inbred ICR
Rats
Rats, Sprague-Dawley
Surface-Active Agents

Chemicals

Emulsions
Hypolipidemic Agents
Surface-Active Agents
Gallic Acid
syringic acid
Journal Article

Word Cloud

Created with Highcharts 10.0.0SA-SMEDDSSMEDDSoralbioavailabilitySAdrugdeliveryhypolipidemicreleasedemonstratedstudyself-microemulsifyingsystemeffectssyringicaciddropletsvitroprolongedcontrolledsignificantenhancedaimeddevelopenhancesolubilitybioactivepoorly-solublepolyphenolBasedresponsesurfacemethodology-centralcompositedesignRSM-CCDoptimumformulationconsistingethyloleateoil1230%Cremophor-ELsurfactant6625%12-propanediolcosurfactant2144%loading50 mg/gobtainednanosized1638 ± 012 nmsphericallyshapedhomogeneouslydistributedPDI = 0058 ± 0013nanoparticleshighencapsulationefficiency9804 ± 139%stabilitycellstudiessignifiedsubstantiallypromotedcellularinternalizationcomparisonsuspensionshowedTtMRTadministrationAlsoexhibiteddelayedvivoeliminationincreased21-foldliveraccumulationFurthermoreimprovementalleviatingserumlipidprofileshepaticsteatosishigh-fatdiet-inducedhyperlipidemiamiceCollectivelypotentialnanosystemImprovedOralBioavailabilityHypolipidemicEffectSyringicAcidviaSelf-microemulsifyingDrugDeliverySystemeffect

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