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Design of Chitosan Nanocapsules with Compritol 888 ATO® for Imiquimod Transdermal Administration. Evaluation of Their Skin Absorption by Raman Microscopy

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Abstract

Purpose

Design imiquimod-loaded chitosan nanocapsules for transdermal delivery and evaluate the depth of imiquimod transdermal absorption as well as the kinetics of this absorption using Raman Microscopy, an innovative strategy to evaluate transdermal absorption. This nanovehicle included Compritol 888ATO®, a novel excipient for formulating nanosystems whose administration through the skin has not been studied until now.

Methods

Nanocapsules were made by solvent displacement method and their physicochemical properties was measured by DLS and laser-Doppler. For transdermal experiments, newborn pig skin was used. The Raman spectra were obtained using a laser excitation source at 532 nm and a 20/50X oil immersion objective.

Results

The designed nanocapsules, presented nanometric size (180 nm), a polydispersity index <0.2 and a zeta potential +17. The controlled release effect of Compritol was observed, with the finding that half of the drug was released at 24 h in comparison with control (p < 0.05). It was verified through Raman microscopy that imiquimod transdermal penetration is dynamic, the nanocapsules take around 50 min to penetrate the stratum corneum and 24 h after transdermal administration, the drug was in the inner layers of the skin.

Conclusions

This study demonstrated the utility of Raman Microscopy to evaluate the drugs transdermal penetration of in the different layers of the skin.

New imiquimod nanocapsules: evaluation of their skin absorption by Raman Microscopy and effect of the compritol 888ATO® in the imiquimod release profile

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References

  1. Alvarez-Figueroa MJ, Abarca-Riquelme JM, González-Aramundiz JV. Influence of protamine shell on nanoemulsions as a carrier for cyclosporine-a skin delivery. Pharm Dev Technol. 2019;24(5):630–8.

    CAS  Google Scholar 

  2. Wiedersberg S, Guy RH. Transdermal drug delivery: 30+ years of war and still fighting! J Control Release. 2014;190:150–6.

    CAS  Google Scholar 

  3. Münch S, Wohlrab J, Neubert RHH. Dermal and transdermal delivery of pharmaceutically relevant macromolecules. Eur J Pharm Biopharm. 2017;119:235–42.

    Google Scholar 

  4. Guy RH. Transdermal drug delivery. In: Schäfer-Korting M, editor. Drug Delivery. Berlin, Heidelberg: Springer Berlin Heidelberg; 2010. p. 399–410.

  5. Pegoraro C, MacNeil S, Battaglia G. Transdermal drug delivery: from micro to nano. Nanoscale. 2012;4(6):1881–94.

    CAS  Google Scholar 

  6. Su R, Fan W, Yu Q, Dong X, Qi J, Zhu Q, et al. Size-dependent penetration of nanoemulsions into epidermis and hair follicles: implications for transdermal delivery and immunization. Oncotarget. 2017;8(24):38214–26.

    Google Scholar 

  7. Bussio J, Molina-Perea C, González-Aramundiz J. Lower-sized chitosan Nanocapsules for transcutaneous antigen delivery. Nanomaterials. 2018;8(9):659.

    Google Scholar 

  8. Gupta R, Rai B. Effect of size and surface charge of gold nanoparticles on their skin permeability: a molecular dynamics study. Sci Rep. 2017;7:45292.

    CAS  Google Scholar 

  9. Howard GP, Verma G, Ke X, Thayer WM, Hamerly T, Baxter VK, et al. Critical size limit of biodegradable nanoparticles for enhanced lymph node trafficking and paracortex penetration. Nano Res. 2019;12(4):837–44.

    CAS  Google Scholar 

  10. Hanna E, Abadi R, Abbas O. Imiquimod in dermatology: an overview. Int J Dermatol. 2016;55(8):831–44.

    CAS  Google Scholar 

  11. Stein P, Gogoll K, Tenzer S, Schild H, Stevanovic S, Langguth P, et al. Efficacy of imiquimod-based transcutaneous immunization using a nano-dispersed emulsion gel formulation. PLoS ONE. 2014;9(7):e102664-e.

    Google Scholar 

  12. Al-Mayahy MH, Sabri AH, Rutland CS, Holmes A, McKenna J, Marlow M, et al. Insight into imiquimod skin permeation and increased delivery using microneedle pre-treatment. Eur J Pharm Biopharm. 2019;139:33–43.

    CAS  Google Scholar 

  13. Lapteva M, Mignot M, Mondon K, Möller M, Gurny R, Kalia YN. Self-assembled mPEG-hexPLA polymeric nanocarriers for the targeted cutaneous delivery of imiquimod. Eur J Pharm Biopharm. 2019;142:553–62.

    CAS  Google Scholar 

  14. Pescina S, Garrastazu G, del Favero E, Rondelli V, Cantù L, Padula C, et al. Microemulsions based on TPGS and isostearic acid for imiquimod formulation and skin delivery. Eur J Pharm Sci. 2018;125:223–31.

    CAS  Google Scholar 

  15. Aburahma MH, Badr-Eldin SM. Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and nanopharmaceuticals. Expert Opin Drug Deliv. 2014;11(12):1865–83.

    CAS  Google Scholar 

  16. Chen Y-C, Liu D-Z, Liu J-J, Chang T-W, Ho H-O, Sheu M-T. Development of terbinafine solid lipid nanoparticles as a topical delivery system. Int J Nanomedicine. 2012;7:4409–18 Epub 2012/08/15.

    CAS  Google Scholar 

  17. Kakadia PG, Conway BR. Solid lipid nanoparticles for targeted delivery of triclosan into skin for infection prevention. J Microencapsul. 2018;35(7–8):695–704.

    CAS  Google Scholar 

  18. Franzen L, Selzer D, Fluhr JW, Schaefer UF, Windbergs M. Towards drug quantification in human skin with confocal Raman microscopy. Eur J Pharm Biopharm. 2013;84(2):437–44.

    CAS  Google Scholar 

  19. Uragami C, Yamashita E, Gall A, Robert B, Hashimoto H. Application of resonance raman microscopy to in vivo carotenoid. Acta Biochim Pol. 2012;59(1):53–6.

    CAS  Google Scholar 

  20. Pyatski Y, Zhang Q, Mendelsohn R, Flach CR. Effects of permeation enhancers on flufenamic acid delivery in ex vivo human skin by confocal Raman microscopy. Int J Pharm. 2016;505(1):319–28.

    CAS  Google Scholar 

  21. Liu S, Bao X, Zhang S, Zhang H, Lu X. Li T, et al. Drug Deliv Transl Res: The study of ultrasound and iontophoresis on oxaprozin transdermal penetration using surface-enhanced Raman spectroscopy; 2019.

    Google Scholar 

  22. Darlenski R, Fluhr JW. In vivo Raman confocal spectroscopy in the investigation of the skin barrier. Curr Probl Dermatol. 2016;49:71–9.

    Google Scholar 

  23. Ali SM, Bonnier F, Lambkin H, Flynn K, McDonagh V, Healy C, et al. A comparison of Raman, FTIR and ATR-FTIR micro spectroscopy for imaging human skin tissue sections. Anal Methods. 2013;5(9):2281–91.

    CAS  Google Scholar 

  24. Caspers PJ, Bruining HA, Puppels GJ, Lucassen GW, Carter EA. In vivo confocal Raman microspectroscopy of the skin: noninvasive determination of molecular concentration profiles. J Invest Dermatol. 2001;116(3):434–42.

    CAS  Google Scholar 

  25. Franzen L, Windbergs M. Applications of Raman spectroscopy in skin research — from skin physiology and diagnosis up to risk assessment and dermal drug delivery. Adv Drug Deliv Rev. 2015;89:91–104.

    CAS  Google Scholar 

  26. Atef E, Altuwaijri N. Using Raman spectroscopy in studying the effect of propylene glycol, oleic acid, and their combination on the rat skin. AAPS PharmSciTech. 2018;19(1):114–22.

    CAS  Google Scholar 

  27. Mujica Ascencio S, Choe C, Meinke MC, Müller RH, Maksimov GV, Wigger-Alberti W, et al. Confocal Raman microscopy and multivariate statistical analysis for determination of different penetration abilities of caffeine and propylene glycol applied simultaneously in a mixture on porcine skin ex vivo. Eur J Pharm Biopharm. 2016;104:51–8.

    CAS  Google Scholar 

  28. Vanden-Hehir S, Tipping WJ, Lee M, Brunton VG, Williams A, Hulme AN. Raman imaging of Nanocarriers for drug delivery. Nanomaterials (Basel). 2019;9(3):341.

    CAS  Google Scholar 

  29. Tan TB, Yussof NS, Abas F, Mirhosseini H, Nehdi IA, Tan CP. Forming a lutein nanodispersion via solvent displacement method: the effects of processing parameters and emulsifiers with different stabilizing mechanisms. Food Chem. 2016;194:416–23.

    CAS  Google Scholar 

  30. Hassan PA, Rana S, Verma G. Making sense of Brownian motion: colloid characterization by dynamic light scattering. Langmuir. 2015;31(1):3–12.

    CAS  Google Scholar 

  31. Bhattacharjee S. DLS and zeta potential – what they are and what they are not? J Control Release. 2016;235:337–51.

    CAS  Google Scholar 

  32. Nothnagel L, Wacker MG. How to measure release from nanosized carriers? Eur J Pharm Sci. 2018;120:199–211.

    CAS  Google Scholar 

  33. Alvarez-Figueroa MJ, Muggli-Galaz C, González PM. Effect of the aggregation state of bile salts on their transdermal absorption enhancing properties. J Drug Deliv Sci Technol. 2019;54:101333.

    CAS  Google Scholar 

  34. Abd E, Yousef SA, Pastore MN, Telaprolu K, Mohammed YH, Namjoshi S, et al. Skin models for the testing of transdermal drugs. Clin Pharmacol. 2016;8:163–76.

    CAS  Google Scholar 

  35. Flaten GE, Palac Z, Engesland A, Filipović-Grčić J, Vanić Ž, Škalko-Basnet N. In vitro skin models as a tool in optimization of drug formulation. Eur J Pharm Sci. 2015;75:10–24.

    CAS  Google Scholar 

  36. Essendoubi M, Gobinet C, Reynaud R, Angiboust JF, Manfait M, Piot O. Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy. Skin Res Technol. 2016;22(1):55–62.

    CAS  Google Scholar 

  37. Todo H. Transdermal permeation of drugs in various animal species. Pharmaceutics. 2017;9(3):33.

    Google Scholar 

  38. Jeevanandam J, Chan YS, Danquah MK. Nano-formulations of drugs: Recent developments, impact and challenges. Biochimie. 2016;128–129:99–112.

  39. Crecente-Campo J, Alonso MJ. Engineering, on-demand manufacturing, and scaling-up of polymeric nanocapsules. Bioeng Transl Med. 2019;4(1):38–50.

    CAS  Google Scholar 

  40. Roberts M, Pulcini L, Mostafa S, Cuppok-Rosiaux Y, Marchaud D. Preparation and characterization of Compritol 888 ATO matrix tablets for the sustained release of diclofenac sodium. Pharm Dev Technol. 2015;20(4):507–12.

    CAS  Google Scholar 

  41. Huang T-H, Wang P-W, Yang S-C, Chou W-L, Fang J-Y. Cosmetic and therapeutic applications of fish Oil's fatty acids on the skin. Mar Drugs. 2018;16(8):256.

    Google Scholar 

  42. Pereira LA, Hatanaka E, Martins EF, Oliveira F, Liberti EA, Farsky SH, et al. Effect of oleic and linoleic acids on the inflammatory phase of wound healing in rats. Cell Biochem Funct. 2008;26(2):197–204.

    CAS  Google Scholar 

  43. Seferian PG, Martinez ML. Immune stimulating activity of two new chitosan containing adjuvant formulations. Vaccine. 2000;19(6):661–8.

    CAS  Google Scholar 

  44. Koroleva M, Nagovitsina T, Yurtov E. Nanoemulsions stabilized by non-ionic surfactants: stability and degradation mechanisms. Phys Chem Chem Phys. 2018;20(15):10369–77.

    CAS  Google Scholar 

  45. Wang Y, Zheng Y, Zhang L, Wang Q, Zhang D. Stability of nanosuspensions in drug delivery. J Control Release. 2013;172(3):1126–41.

    CAS  Google Scholar 

  46. Kuo Y-C, Chung C-Y. Solid lipid nanoparticles comprising internal Compritol 888 ATO, tripalmitin and cacao butter for encapsulating and releasing stavudine, delavirdine and saquinavir. Colloids Surf B Biointerfaces. 2011;88(2):682–90.

    CAS  Google Scholar 

  47. Abdelwahed W, Degobert G, Stainmesse S, Fessi H. Freeze-drying of nanoparticles: formulation, process and storage considerations. Adv Drug Deliv Rev. 2006;58(15):1688–713.

    CAS  Google Scholar 

  48. Hu Y, Ma C, Sun M, Guo C, Shen J, Wang J, et al. Preparation and characterization of nano amitriptyline hydrochloride particles by spray freeze drying. Nanomedicine. 2019;14(12):1521–31.

    CAS  Google Scholar 

  49. Sameti M, Bohr G, Ravi Kumar MNV, Kneuer C, Bakowsky U, Nacken M, et al. Stabilisation by freeze-drying of cationically modified silica nanoparticles for gene delivery. Int J Pharm. 2003;266(1):51–60.

    CAS  Google Scholar 

  50. Mensink MA, Frijlink HW, van der Voort MK, Hinrichs WLJ. How sugars protect proteins in the solid state and during drying (review): mechanisms of stabilization in relation to stress conditions. Eur J Pharm Biopharm. 2017;114:288–95.

    CAS  Google Scholar 

  51. Fonte P, Reis S, Sarmento B. Facts and evidences on the lyophilization of polymeric nanoparticles for drug delivery. J Control Release. 2016;225:75–86.

    CAS  Google Scholar 

  52. Yue P-F, Li G, Dan J-X, Wu Z-F, Wang C-H, Zhu W-F, et al. Study on formability of solid nanosuspensions during solidification: II novel roles of freezing stress and cryoprotectant property. Int J Pharm. 2014;475(1):35–48.

    CAS  Google Scholar 

  53. Scoutaris N, Vithani K, Slipper I, Chowdhry B, Douroumis D. SEM/EDX and confocal Raman microscopy as complementary tools for the characterization of pharmaceutical tablets. Int J Pharm. 2014;470(1):88–98.

    CAS  Google Scholar 

  54. Lin-Vien D, Colthup NB, Fateley WG, Grasselli In: Lin-Vien D, Colthup NB, Fateley WG, Grasselli JG, editors. The Handbook of Infrared and Raman Characteristic Frequencies of Organic Molecules. San Diego: Academic Press; 1991. p. 45–60.

  55. Sdobnov AY, Tuchin VV, Lademann J, Darvin ME. Confocal Raman microscopy supported by optical clearing treatment of the skin-influence on collagen hydration. J Phys D Appl Phys. 2017;50(28).

  56. Jamieson LE, Li A, Faulds K, Graham D. Ratiometric analysis using Raman spectroscopy as a powerful predictor of structural properties of fatty acids. Royal Society open science. 2018;5(12):181483-.

  57. Kitaoka M, Wakabayashi R, Kamiya N, Goto M. Solid-in-oil nanodispersions for transdermal drug delivery systems. Biotechnol J. 2016;11(11):1375–85. Epub 08/16.

  58. Tessema EN, Gebre-Mariam T, Paulos G, Wohlrab J, Neubert RHH. Delivery of oat-derived phytoceramides into the stratum corneum of the skin using nanocarriers: formulation, characterization and in vitro and ex-vivo penetration studies. Eur J Pharm Biopharm. 2018;127:260–9.

    CAS  Google Scholar 

  59. Diblíková D, Kopečná M, Školová B, Krečmerová M, Roh J, Hrabálek A, et al. Transdermal delivery and cutaneous targeting of antivirals using a penetration enhancer and Lysolipid Prodrugs. Pharm Res. 2014;31(4):1071–81.

    Google Scholar 

  60. Abdel-Mottaleb MMA, Moulari B, Beduneau A, Pellequer Y, Lamprecht A. Surface-charge-dependent nanoparticles accumulation in inflamed skin. J Pharm Sci. 2012;101(11):4231–9.

    CAS  Google Scholar 

  61. Wu X, Landfester K, Musyanovych A, Guy RH. Disposition of charged nanoparticles after their topical application to the skin. Skin Pharmacol Physiol. 2010;23(3):117–23.

    CAS  Google Scholar 

  62. Dragicevic-Curic N, Gräfe S, Gitter B, Winter S, Fahr A. Surface charged temoporfin-loaded flexible vesicles: in vitro skin penetration studies and stability. Int J Pharm. 2010;384(1):100–8.

    CAS  Google Scholar 

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Author notes

  1. María Javiera Alvarez-Figueroa and José Vicente González-Aramúndiz contributed equally to this work.

Authors and Affiliations

  1. Facultad de Química y de Farmacia, Departamento de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackena 4860, CP: 7820436, Macul, Santiago, Chile

    María Javiera Alvarez-Figueroa, Daniela Narváez-Araya, Nicolás Armijo-Escalona & José Vicente González-Aramundiz

  2. Laboratorio de Espectroscopia Vibracional, Facultad de Ciencias, Universidad de Chile, Santiago, Chile

    Eduardo A. Carrasco-Flores

  3. Centro de Investigación en Nanotecnología y Materiales Avanzados “CIEN-UC”, Pontificia Universidad Católica de Chile, Santiago, Chile

    José Vicente González-Aramundiz

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  1. María Javiera Alvarez-Figueroa
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  2. Daniela Narváez-Araya
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  3. Nicolás Armijo-Escalona
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Correspondence to María Javiera Alvarez-Figueroa or José Vicente González-Aramundiz.

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Alvarez-Figueroa, M.J., Narváez-Araya, D., Armijo-Escalona, N. et al. Design of Chitosan Nanocapsules with Compritol 888 ATO® for Imiquimod Transdermal Administration. Evaluation of Their Skin Absorption by Raman Microscopy. Pharm Res 37, 195 (2020). https://doi.org/10.1007/s11095-020-02925-6

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  • DOI: https://doi.org/10.1007/s11095-020-02925-6

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