Advertisement

AAPS PharmSciTech

, Volume 19, Issue 5, pp 2346–2357 | Cite as

Isolation, Formulation, and Efficacy Enhancement of Morin Emulsified Carriers Against Lung Toxicity in Rats

  • Alaadin E. El-Haddad
  • Nermin M. Sheta
  • Sylvia A. Boshra
Research Article
  • 44 Downloads

Abstract

The present study demonstrates a preparative medium-pressure liquid chromatography (MPLC) method for isolation of Morin besides evaluating its efficacy in comparison with its self-nanoemulsifying drug delivery (SNEDD) and nanoemulsion (NE) systems against in-vivo HgCl2-induced lung toxicity in rats. Morin was isolated from hydroalcoholic (70%) extract of Psidium guajava leaves by MPLC. The purity (> 90%) was done using HPLC. Screening of Morin solubility was studied to identify the components of each system. The prepared formulae were assessed for their thermodynamic stability, rheological properties, emulsification time, size, zeta potential beside its dissolution. The selected formulae according to the smallest size, highest zeta potential, and release at Q10 min were assessed for their morphology by transmission electron microscopy (TEM) and protective potential against in-vivo HgCl2-induced lung toxicity in rats. All formulae were stable with Newtonian flow, emulsification time was (< 134 ± 10 s), size (< 40 nm) with zeta potential (> − 10.36 ± 0.99 mV). The extent of free Morin dissolved from capsule showed significantly the lowest percent released (22.21 ± 1.45%) while in case of SNEDDs and NEs (> 55% dissolved). The morphology of the selected Morin formulae showed spherical shape within the nano-range. Supplementation of Morin and its formulae to rats caused significant decrease in C-reactive protein, hepatoglobin, hydroproxide, lung nitric oxide, tumor necrosis factor-α, immunoglobulin (E and G), histamine, malondialdehyde, and interleukin-6 gene expression while significant increase in immunoglobulin A, caspase-3, catalase, and glutathione peroxidase compared to HgCl2. SNEDD and NE formulae could ameliorate lung toxicity in a mechanism related to their antioxidant and anti-inflammatory potential.

KEY WORDS

Morin MPLC drug delivery system emulsified carriers lung toxicity 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Rattanachaikunsopon P, Phumkhachorn P. Contents and antibacterial activity of flavonoids extracted from leaves of Psidium guajava. J Medinical Plants Res. 2010;4(5):393–6.Google Scholar
  2. 2.
    Caselli A, Cirri P, Santi A, Paoli P. Morin: a promising natural drug. Curr Med Chem. 2016;23(8):774–91.CrossRefPubMedGoogle Scholar
  3. 3.
    Gálvez J, Coelho G, Crespo ME, Cruz T, Rodríguez-Cabezas ME, Concha A, et al. Intestinal anti-inflammatory activity of Morin on chronic experimental colitis in the rat. Aliment Pharmacol Ther. 2001;15(12):2027–39.CrossRefPubMedGoogle Scholar
  4. 4.
    Wu TW, Fung KP, Zeng LH, Wu J, Hempel A, Grey AA, et al. Molecular properties and myocardial salvage effects of Morin hydrate. Biochem Pharmacol. 1995;49(4):537–43.CrossRefPubMedGoogle Scholar
  5. 5.
    Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm. 2011;420(1):1–10.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang J, Li J, Ju Y, Fu Y, Gong T, Zhang Z. Mechanism of enhanced oral absorption of Morin by phospholipid complex based self-nanoemulsifying drug delivery system. Mol Pharm. 2015;12(2):504–13.CrossRefPubMedGoogle Scholar
  7. 7.
    Oh DH, Kang JH, Kim DW, Lee BJ, Kim JO, Yong CS, et al. Comparison of solid self-microemulsifying drug delivery system (solid SMEDDS) prepared with hydrophilic and hydrophobic solid carrier. Int J Pharm. 2011;420(2):412–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Mahmoud EA, Bendas ER, Mohamed MI. Preparation and evaluation of self-nanoemulsifying tablets of carvedilol. AAPS PharmSciTech. 2009;10(1):183–92.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Pouton CW, Porter CJH. Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Adv Drug Deliv Rev. 2008;60(6):625–37.CrossRefPubMedGoogle Scholar
  10. 10.
    ICH Q8. International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2005.Google Scholar
  11. 11.
    Shakeel F, Baboota S, Ahuja A, Ali J, Aqil M, Shafiq S. Nanoemulsions as vehicles for transdermal delivery of aceclofenac. AAPS PharmSciTech. 2007;8(4):191–9.CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Nornoo AO, Chow DS-L. Cremophor-free intravenous microemulsions for paclitaxel: II. Stability, in-vitro release and pharmacokinetics. Int J Pharm. 2008;349(1):117–23.CrossRefPubMedGoogle Scholar
  13. 13.
    Khattab A, Hassanin L, Zaki N. Self-nanoemulsifying drug delivery system of coenzyme (Q10) with improved dissolution, bioavailability, and protective efficiency on liver fibrosis. AAPS PharmSciTech. 2017;18(5):1657–72.CrossRefPubMedGoogle Scholar
  14. 14.
    Djekic L, Primorac M. The influence of cosurfactants and oils on the formation of pharmaceutical microemulsions based on PEG-8 caprylic/capric glycerides. Int J Pharm. 2008;352(1):231–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Mohd AB, Sanka K, Bandi S, Diwan PV, Shastri N. Solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of glimepiride: development and antidiabetic activity in albino rabbits. Drug Deliv. 2015;22(4):499–508.CrossRefPubMedGoogle Scholar
  16. 16.
    Badawi AA, Sakran WS, Ramadan MA, El-Mancy SM. Improvement of the microbiological activity of topical ketoconazole using microemulsion systems. Journal of Drug Delivery Science and Technology 2012;22(6):473–8.CrossRefGoogle Scholar
  17. 17.
    Date AA, Nagarsenker MS. Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for cefpodoxime proxetil. Int J Pharm. 2007;329(1):166–72.CrossRefPubMedGoogle Scholar
  18. 18.
    Bali V, Ali M, Ali J. Study of surfactant combinations and development of a novel nanoemulsion for minimising variations in bioavailability of ezetimibe. Colloids Surf B Biointerfaces. 2010;76(2):410–20.CrossRefPubMedGoogle Scholar
  19. 19.
    Khamkar GS. Self-micro-emulsifying drug delivery system (SMEDDS) o/w microemulsion for BCS class II drugs: an approach to enhance an oral bioavailability. Int J Pharm Pharm Sci. 2011;3(3):1–3.Google Scholar
  20. 20.
    Rahman MA, Iqbal Z, Hussain A. Formulation optimization and in-vitro characterization of sertraline loaded self-nanoemulsifying drug delivery system (SNEDDS) for oral administration. J Pharm Investig. 2012;42(4):191–202.CrossRefGoogle Scholar
  21. 21.
    Amin MM, Sheta NM, Abd El Gawad NA, Badawi AA. Preparation and characterization of benzophenone-3 loaded polymeric nanoparticles of lactide-co-ɛ-caprolactone as drug carriers. Journal of Pharmaceutical Research and Opinion 2012;2(2):28–41.Google Scholar
  22. 22.
    Ammar H, Ghorab M, Mostafa DM, Ghoneim AM. Self-nanoemulsifying drug delivery system for sertraline hydrochloride: design, preparation and characterization. Int J Pharm Pharm Sci. 2014;6(9):589–95.Google Scholar
  23. 23.
    Montenegro L, Carbone C, Puglisi G. Vehicle effects on in-vitro release and skin permeation of octylmethoxycinnamate from microemulsions. Int J Pharm. 2011;405(1):162–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem. 1982;28(10):2077–80.PubMedGoogle Scholar
  25. 25.
    Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20(4):470–5.PubMedGoogle Scholar
  26. 26.
    Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.PubMedGoogle Scholar
  27. 27.
    Roberts WL, Moulton L, Law TC, Farrow G, Anderson MC, Savory J, et al. Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Part 2. Clin Chem. 2001;47(3):418–25.PubMedGoogle Scholar
  28. 28.
    Jiang ZY, Hunt JV, Wolff SP. Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxide in low density lipoprotein. Anal Biochem. 1992;202(2):384–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Plebani M, Bernardi D, Basso D, Borghesan F, Faggian D. Measurement of specific immunoglobulin E: intermethod comparison and standardization. Clin Chem. 1998;44(9):1974–9.PubMedGoogle Scholar
  30. 30.
    McGhee JR, Michalek SM, Ghanta VK. Rat immunoglobulins in serum and secretions: purification of rat IgM, IgA, and IgG and their quantitation in serum, colostrum, milk and saliva. Immunochemistry. 1975;12(10):817–23.CrossRefPubMedGoogle Scholar
  31. 31.
    Makimura S, Suzuki N. Quantitative determination of bovine serum Haptoglobin and its elevation in some inflammatory diseases. Nihon Juigaku Zasshi. 1982;44(1):15–21.CrossRefPubMedGoogle Scholar
  32. 32.
    Corti A, Fassina G, Marcucci F, Barbanti E, Cassani G. Oligomeric tumour necrosis factor α slowly converts into inactive forms at bioactive levels. Biochem J. 1992;284(3):905–10.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Moshage H, Kok B, Huizenga JR, Jansen PL. Nitrite and nitrate determinations in plasma: a critical evaluation. Clin Chem. 1995;41(6):892–6.PubMedGoogle Scholar
  34. 34.
    Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81–128.CrossRefPubMedGoogle Scholar
  35. 35.
    Harrington HA, Ho KL, Ghosh S, Tung KC. Construction and analysis of a modular model of caspase activation in apoptosis. Theor Biol Med Model. 2008;5(1):26.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70(1):158–69.PubMedGoogle Scholar
  37. 37.
    Chanarin I. Text book of laboratory haematology: an account of laboratory techniques. New York: Churchill Livingstone; 1989.Google Scholar
  38. 38.
    Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972;47(2):389–94.CrossRefPubMedGoogle Scholar
  39. 39.
    Ronis MJ, Butura A, Sampey BP, Shankar K, Prior RL, Korourian S, et al. Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition. Free Radic Biol Med. 2005;39(5):619–30.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Williams CA, Harborne JB, Harborne JB. The Flavonoids. Advances in Research since 1986. 1st ed. London: Chapman & Hall; 1994.Google Scholar
  41. 41.
    Shafiq-un-Nabi S, Shakeel F, Talegaonkar S, Ali J, Baboota S, Ahuja A, et al. Formulation development and optimization using nanoemulsion technique: a technical note. AAPS PharmSciTech. 2007;8(2):E12–7.CrossRefPubMedCentralGoogle Scholar
  42. 42.
    Parmar N, Singla N, Amin S, Kohli K. Study of cosurfactant effect on nanoemulsifying area and development of lercanidipine loaded (SNEDDS) self nanoemulsifying drug delivery system. Colloids Surf B Biointerfaces. 2011;86(2):327–38.CrossRefPubMedGoogle Scholar
  43. 43.
    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.CrossRefGoogle Scholar
  44. 44.
    Elnaggar YSR, El-Massik MA, Abdallah OY. Self-nanoemulsifying drug delivery systems of tamoxifen citrate: design and optimization. Int J Pharm. 2009;380(1):133–41.CrossRefPubMedGoogle Scholar
  45. 45.
    Gumaste SG, Dalrymple DM, Serajuddin ATM. Development of solid SEDDS, V: compaction and drug release properties of tablets prepared by adsorbing lipid-based formulations onto Neusilin® US2. Pharm Res. 2013;30(12):3186–99.CrossRefPubMedCentralGoogle Scholar
  46. 46.
    Tang SY, Manickam S, Wei TK, Nashiru B. Formulation development and optimization of a novel Cremophore EL-based nanoemulsion using ultrasound cavitation. Ultrason Sonochem. 2012;19(2):330–45.CrossRefPubMedGoogle Scholar
  47. 47.
    Souto EB, Müller RH, Gohla S. A novel approach based on lipid nanoparticles (SLN®) for topical delivery of α-lipoic acid. J Microencapsul. 2005;22(6):581–92.CrossRefPubMedGoogle Scholar
  48. 48.
    Villalobos-Hernandez JR, Müller-Goymann CC. Novel nanoparticulate carrier system based on carnauba wax and decyl oleate for the dispersion of inorganic sunscreens in aqueous media. Eur J Pharm Biopharm. 2005;60(1):113–22.CrossRefPubMedGoogle Scholar
  49. 49.
    Skoczyńska A, Poreba R, Steinmentz-Beck A, Martynowicz H, Affelska-Jercha A, Turczyn B, et al. The dependence between urinary mercury concentration and carotid arterial intima-media thickness in workers occupationally exposed to mercury vapour. Int J Occup Med Environ Health. 2009;22(2):135–42.PubMedGoogle Scholar
  50. 50.
    Oliveira TT, Ricardo KFS, Almeida MR, Costa MR, Nagem TJ. Hypolipidemic effect of flavonoids and cholestyramine in rats. Lat Am J Pharm. 2007;26(3):407.Google Scholar
  51. 51.
    Hill SA, McQueen MJ. Reverse cholesterol transport—a review of the process and its clinical implications. Clin Biochem. 1997;30(7):517–25.CrossRefPubMedGoogle Scholar
  52. 52.
    Hultman P, Nielsen JB. The effect of toxicokinetics on murine mercury-induced autoimmunity. Environ Res. 1998;77(2):141–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 2000;52(4):673–751.PubMedGoogle Scholar
  54. 54.
    Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. The effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;65:384–90.CrossRefPubMedGoogle Scholar
  55. 55.
    Casale TB, Stokes JR. Immunomodulators for allergic respiratory disorders. J Allergy Clin Immunol. 2008;121(2):288–96.CrossRefPubMedGoogle Scholar
  56. 56.
    Maarsingh H, Zuidhof AB, Bos IST, van Duin M, Boucher JL, Zaagsma J, et al. Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation. Am J Respir Crit Care Med. 2008;178(6):565–73.CrossRefPubMedGoogle Scholar
  57. 57.
    Qureshi AA, Reis JC, Papasian CJ, Morrison DC, Qureshi N. Tocotrienols inhibit lipopolysaccharide-induced pro-inflammatory cytokines in macrophages of female mice. Lipids Health Dis. 2010;9(1):143.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Sen CK, Khanna S, Roy S. Tocotrienols in health and disease: the other half of the natural vitamin E family. Mol Asp Med. 2007;28(5):692–728.CrossRefGoogle Scholar
  59. 59.
    Mensinga TT, Schouten JP, Rijcken B, Weiss ST, Speizer FE, van der Lende R. The relationship of eosinophilia and positive skin test reactivity to respiratory symptom prevalence in a community-based population study. J Allergy Clin Immunol. 1990;86(1):99–107.CrossRefPubMedGoogle Scholar
  60. 60.
    Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12(1):635–73.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Alaadin E. El-Haddad
    • 1
  • Nermin M. Sheta
    • 2
  • Sylvia A. Boshra
    • 3
  1. 1.Pharmacognosy Department, Faculty of PharmacyOctober 6 UniversityGizaEgypt
  2. 2.Pharmaceutics Department, Faculty of PharmacyOctober 6 UniversityGizaEgypt
  3. 3.Biochemistry Department, Faculty of PharmacyOctober 6 UniversityGizaEgypt

Personalised recommendations