Effect of penetration enhancers and amorphization on transdermal permeation flux of raloxifene-encapsulated solid lipid nanoparticles: an ex vivo study on human skin

  • Krishna Kumar Patel
  • Shilpkala Gade
  • Md. Meraj Anjum
  • Sanjay Kumar Singh
  • Pralay Maiti
  • Ashish Kumar Agrawal
  • Sanjay SinghEmail author
Original Article


Despite 60% oral absorption, high first-pass metabolisms resulted in 2% oral bioavailability of raloxifene and also suffer poor water solubility. In this study, we developed the penetration enhancer rich hydrogel containing raloxifene-loaded solid lipid nanoparticles (RL-SLNs) for transdermal route. Interestingly, SLN offers higher solubility and thermodynamic activity due to amorphization of drug and evasion of first-pass metabolism by transdermal route. Cumulative effect will contribute to enhanced permeation flux, controlled drug release and enhanced bioavailability. Nanoparticles were synthesized using solvent emulsification–evaporation method and evaluated further for various physicochemical properties, ex vivo permeation and hydration studies. RL-SLN3 with particle size 227.9 ± 12.6 nm, polydispersity index 0.283 ± 0.021, zeta potential 15.4 ± 1.7 mV and entrapment efficiency 77.04 ± 5.08% was selected for further studies as optimized formulation. Differential scanning calorimetric method revealed that 54.75% of RL had changed to amorphous state adding to enhanced solubility. Furthermore, the results of ex vivo permeation studies on human skin elucidated that 10% d-limonene in combination with RL-SLN had excellent permeation flux (7.24 ± 0.49 µg/cm2 h) compared to RL-SLN alone and other penetration enhancers tested. Thus, the output of above studies suggested that transdermal delivery of RL-SLN using d-limonene as penetration enhancer can be a promising approach to evade the first-pass metabolism and increase the systemic bioavailability of RL.


Raloxifene SLN Skin permeation Penetration enhancer Hydrogel Ex vivo 



The author Prof. Sanjay Singh heartily acknowledges Indian Institute of Technology, (BHU), Varanasi, for supporting the research work in terms of research support grant. The author also acknowledges Prof. O.N. Srivastava (Emeritus Professor), Department of Physics, Institute of Science, Banaras Hindu University, for extending the X-ray diffraction facility to carry out my research study.

Compliance with ethical standards

Conflict of interest

There is no financial conflict of interest.


  1. Agrawal P et al (2017) TPGS-chitosan cross-linked targeted nanoparticles for effective brain cancer therapy. Mater Sci Eng C 74:167–176CrossRefGoogle Scholar
  2. Baroli B (2010) Penetration of nanoparticles and nanomaterials in the skin: fiction or reality? J Pharm Sci 99(1):21–50CrossRefGoogle Scholar
  3. Barry BW (2001a) Is transdermal drug delivery research still important today? Elsevier, AmsterdamCrossRefGoogle Scholar
  4. Barry BW (2001b) Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci 14(2):101–114CrossRefGoogle Scholar
  5. Benson HA (2005) Transdermal drug delivery: penetration enhancement techniques. Curr Drug Deliv 2(1):23–33CrossRefGoogle Scholar
  6. Blaine RL (2013) Determination of polymer crystallinity by DSC. TA Instruments, New CastleGoogle Scholar
  7. Burra M et al (2013) Enhanced intestinal absorption and bioavailability of raloxifene hydrochloride via lyophilized solid lipid nanoparticles. Adv Powder Technol 24(1):393–402CrossRefGoogle Scholar
  8. Chauhan B, Bajpai M (2010) Formulation and evaluation of transdermal drug delivery of raloxifene hydrochloride. Int J Pharm Sci Res 1(12):72–79Google Scholar
  9. De Vringer T (1997) Topical preparation containing a suspension of solid lipid particles, Google PatentsGoogle Scholar
  10. Delmanto A et al (2008) Effect of raloxifene on the vaginal epithelium of postmenopausal women. Eur J Obstet Gynecol Reprod Biol 139(2):187–192CrossRefGoogle Scholar
  11. Garg A, Singh S (2014) Targeting of eugenol-loaded solid lipid nanoparticles to the epidermal layer of human skin. Nanomedicine 9(8):1223–1238CrossRefGoogle Scholar
  12. Garg A et al (2009) Solid state interaction of raloxifene HCl with different hydrophilic carriers during co-grinding and its effect on dissolution rate. Drug Dev Ind Pharm 35(4):455–470CrossRefGoogle Scholar
  13. Jones DS et al (1997) Mucoadhesive, syringeable drug delivery systems for controlled application of metronidazole to the periodontal pocket: in vitro release kinetics, syringeability, mechanical and mucoadhesive properties. J Control Release 49(1):71–79CrossRefGoogle Scholar
  14. Keleb E et al (2010) Transdermal drug delivery system-design and evaluation. Int J Adv Pharm Sc 1(3):201–211Google Scholar
  15. Kikwai L et al (2005) In vitro and in vivo evaluation of topical formulations of spantide II. Aaps Pharmscitech 6(4):E565–E572CrossRefGoogle Scholar
  16. Kim J-H, Choi H-K (2002) Effect of additives on the crystallization and the permeation of ketoprofen from adhesive matrix. Int J Pharm 236(1–2):81–85CrossRefGoogle Scholar
  17. Kushwaha AK et al (2013) Development and evaluation of solid lipid nanoparticles of raloxifene hydrochloride for enhanced bioavailability. BioMed Res Int 2013:584549CrossRefGoogle Scholar
  18. Leroueil-Le Verger M et al (1998) Preparation and characterization of nanoparticles containing an antihypertensive agent. Eur J Pharm Biopharm 46(2):137–143CrossRefGoogle Scholar
  19. Müller RH et al (2002) Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deliv Rev 54:S131–S155CrossRefGoogle Scholar
  20. Parekh G et al (2018) Nano-carriers for targeted delivery and biomedical imaging enhancement. Ther Deliv 9(6):451–468CrossRefGoogle Scholar
  21. Pathan IB, Setty CM (2009) Chemical penetration enhancers for transdermal drug delivery systems. Trop J Pharm Res 8(2):173–179CrossRefGoogle Scholar
  22. Patil PH et al (2013) Solubility enhancement of raloxifene using inclusion complexes and cogrinding method. J Pharm​ 2013:527380Google Scholar
  23. Reading M et al (2001) Measurement of crystallinity in polymers using modulated temperature differential scanning calorimetry. Materials characterization by dynamic and modulated thermal analytical techniques. ASTM International, West ConshohockenGoogle Scholar
  24. Singh Y et al (2015) Mucoadhesive gel containing immunotherapeutic nanoparticulate satranidazole for treatment of periodontitis: development and its clinical implications. RSC Adv 5(59):47659–47670CrossRefGoogle Scholar
  25. Sinha V, Kaur MP (2000) Permeation enhancers for transdermal drug delivery. Drug Dev Ind Pharm 26(11):1131–1140CrossRefGoogle Scholar
  26. Swarbrick J et al (1982) Drug permeation through human skin: I. Effects of storage conditions of skin. J Investig Dermatol 78(1):63–66CrossRefGoogle Scholar
  27. Trommer H, Neubert R (2006) Overcoming the stratum corneum: the modulation of skin penetration. Skin Pharmacol Physiol 19(2):106–121CrossRefGoogle Scholar
  28. Vergaro V et al (2011) Drug-loaded polyelectrolyte microcapsules for sustained targeting of cancer cells. Adv Drug Deliv Rev 63(9):847–864CrossRefGoogle Scholar
  29. Vijayakumar MR et al (2016a) Resveratrol loaded PLGA: d-α-tocopheryl polyethylene glycol 1000 succinate blend nanoparticles for brain cancer therapy. RSC Adv 6(78):74254–74268CrossRefGoogle Scholar
  30. Vijayakumar MR et al (2016b) Intravenous administration of trans-resveratrol-loaded TPGS-coated solid lipid nanoparticles for prolonged systemic circulation, passive brain targeting and improved in vitro cytotoxicity against C6 glioma cell lines. RSC Adv 6(55):50336–50348CrossRefGoogle Scholar
  31. Williams AC, Barry BW (2012) Penetration enhancers. Adv Drug Deliv Rev 64:128–137CrossRefGoogle Scholar
  32. Xue D, Jie W (2011) Selective estrogen receptor modulator: raloxifene. J Reprod Contracept 22(1):51–60CrossRefGoogle Scholar
  33. Yang SC et al (1999) Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain. J Control Release 59(3):299–307CrossRefGoogle Scholar
  34. Yang Y et al (2017) New epigallocatechin gallate (EGCG) nanocomplexes co-assembled with 3-mercapto-1-hexanol and β-lactoglobulin for improvement of antitumor activity. J Biomed Nanotechnol 13(7):805–814CrossRefGoogle Scholar

Copyright information

© King Abdulaziz City for Science and Technology 2019

Authors and Affiliations

  • Krishna Kumar Patel
    • 1
  • Shilpkala Gade
    • 1
  • Md. Meraj Anjum
    • 1
  • Sanjay Kumar Singh
    • 1
  • Pralay Maiti
    • 2
  • Ashish Kumar Agrawal
    • 1
  • Sanjay Singh
    • 1
    Email author
  1. 1.Department of Pharmaceutical Engineering and TechnologyIIT (BHU)VaranasiIndia
  2. 2.School of Materials Science and TechnologyIIT (BHU)VaranasiIndia

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