Formulation and Characterization of a 3D-Printed Cryptotanshinone-Loaded Niosomal Hydrogel for Topical Therapy of Acne

Abstract

Cryptotanshinone (CPT) is an efficacious acne treatment, while niosomal hydrogel is a known effective topical drug delivery system that produces a minimal amount of irritation. Three-dimensional (3D) printing technologies have the potential to improve the field of personalized acne treatment. Therefore, this study endeavored to develop a 3D-printed niosomal hydrogel (3DP-NH) containing CPT as a topical delivery system for acne therapy. Specifically, CPT-loaded niosomes were prepared using a reverse phase evaporation method, and the formulation was optimized using a response surface methodology. In vitro characterization showed that optimized CPT-loaded niosomes were below 150 nm in size with an entrapment efficiency of between 67 and 71%. The CPT-loaded niosomes were added in a dropwise manner into the hydrogel to formulate CPT-loaded niosomal hydrogel (CPT-NH), which was then printed as 3DP-CPT-NH with specific drug dose, shape, and size using an extrusion-based 3D printer. The in vitro release behavior of 3DP-CPT-NH was found to follow the Korsmeyer-Peppas model. Permeation and deposition experiments showed significantly higher rates of transdermal flux, Q24, and CPT deposition (p < 0.05) compared with 3D-printed CPT-loaded conventional hydrogel (3DP-CPT-CH), which did not contain niosomes. In vivo anti-acne activity evaluated through an acne rat model revealed that 3DP-CPT-NH exhibited a greater anti-acne effect with no skin irritation. Enhanced skin hydration, wide inter-corneocyte gaps in the stratum corneum and a disturbed lipid arrangement may contribute towards the enhanced penetration properties of CPT. Collectively, this study demonstrated that 3DP-CPT-NH is a promising topical drug delivery system for personalized acne treatments.

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References

  1. 1.

    Zouboulis CC, Jourdan E, Picardo M. Acne is an inflammatory disease and alterations of sebum composition initiate acne lesions. J Eur Acad Dermatol Venereol. 2014;28(5):527–32. https://doi.org/10.1111/jdv.12298.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Tan JKL, Bhate K. A global perspective on the epidemiology of acne. Br J Dermatol. 2015;172:3–12. https://doi.org/10.1111/bjd.13462.

    Article  PubMed  Google Scholar 

  3. 3.

    Arora MK, Yadav A, Saini V. Role of hormones in acne vulgaris. Clin Biochem. 2011;44(13):1035–40. https://doi.org/10.1016/j.clinbiochem.2011.06.984.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Kircik LH. Advances in the understanding of the pathogenesis of inflammatory acne. J Drugs Dermatol. 2016;15(1 Suppl 1):s7–10.

    CAS  PubMed  Google Scholar 

  5. 5.

    Jain A, Basal E. Inhibition of Propionibacterium acnes-induced mediators of inflammation by Indian herbs. Phytomedicine. 2003;10(1):34–8. https://doi.org/10.1078/094471103321648638.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Fitz-Gibbon S, Tomida S, Chiu B-H, Nguyen L, Du C, Liu M, et al. Propionibacterium acnes Strain Populations in the Human Skin Microbiome Associated with Acne. J Investig Dermatol. 2013;133(9):2152–60. https://doi.org/10.1038/jid.2013.21.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    de Sousa I. Novel pharmacological approaches for the treatment of acne vulgaris. Expert Opin Investig Drugs. 2014;23(10):1389–410. https://doi.org/10.1517/13543784.2014.923401.

    CAS  Article  Google Scholar 

  8. 8.

    Lee DS, Lee SH, Noh JG, Hong SD. Antibacterial activities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge. Biosci Biotechnol Biochem. 1999;63(12):2236–9. https://doi.org/10.1271/bbb.63.2236.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Gao HW, Huang LT, Ding F, Yang K, Feng YL, Tang HZ, et al. Simultaneous purification of dihydrotanshinone, tanshinone I, cryptotanshinone, and tanshinone IIA from Salvia miltiorrhiza and their anti-inflammatory activities investigation. Sci Rep. 2018;8:13. https://doi.org/10.1038/s41598-018-26828-0.

    CAS  Article  Google Scholar 

  10. 10.

    Zhang WJ, Suo M, Yu GL, Zhang MY. Antinociceptive and anti-inflammatory effects of cryptotanshinone through PI3K/Akt signaling pathway in a rat model of neuropathic pain. Chem Biol Interact. 2019;305:127–33. https://doi.org/10.1016/j.cbi.2019.03.016.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Dai H, Li X, Li X, Bai L, Li Y, Xue M. Coexisted components of Salvia miltiorrhiza enhance intestinal absorption of cryptotanshinone via inhibition of the intestinal P-gp. Phytomedicine. 2012;19(14):1256–62. https://doi.org/10.1016/j.phymed.2012.08.007.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Yu Z, Lv H, Han G, Ma K. Ethosomes Loaded with Cryptotanshinone for Acne Treatment through Topical Gel Formulation. PLoS One. 2016;11(7):e0159967. https://doi.org/10.1371/journal.pone.0159967.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Zuo T, Chen H, Xiang S, Hong J, Cao S, Weng L, et al. Cryptotanshinone-Loaded Cerasomes Formulation: In Vitro Drug Release, in Vivo Pharmacokinetics, and in Vivo Efficacy for Topical Therapy of Acne. ACS Omega. 2016;1(6):1326–35. https://doi.org/10.1021/acsomega.6b00232.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Moghassemi S, Hadjizadeh A. Nano-niosomes as nanoscale drug delivery systems: An illustrated review. J Control Release. 2014;185:22–36. https://doi.org/10.1016/j.jconrel.2014.04.015.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Negi P, Aggarwal M, Sharma G, Rathore C, Sharma G, Singh B, et al. Niosome-based hydrogel of resveratrol for topical applications: An effective therapy for pain related disorder(s). Biomed Pharmacother. 2017;88:480–7. https://doi.org/10.1016/j.biopha.2017.01.083.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Tavano L, Gentile L, Oliviero Rossi C, Muzzalupo R. Novel gel-niosomes formulations as multicomponent systems for transdermal drug delivery. Colloids Surf B: Biointerfaces. 2013;110:281–8. https://doi.org/10.1016/j.colsurfb.2013.04.017.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kumbhar D, Wavikar P, Vavia P. Niosomal Gel of Lornoxicam for Topical Delivery: In vitro Assessment and Pharmacodynamic Activity. AAPS PharmSciTech. 2013;14(3):1072–82. https://doi.org/10.1208/s12249-013-9986-5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Al-mahallawi AM, Fares AR, Abd-Elsalam WH. Enhanced Permeation of Methotrexate via Loading into Ultra-permeable Niosomal Vesicles: Fabrication, Statistical Optimization, Ex Vivo Studies, and In Vivo Skin Deposition and Tolerability. AAPS PharmSciTech. 2019;20(5):10. https://doi.org/10.1208/s12249-019-1380-5.

    CAS  Article  Google Scholar 

  19. 19.

    Madni A, Rahim MA, Mahmood MA, Jabar A, Rehman M, Shah H, et al. Enhancement of Dissolution and Skin Permeability of Pentazocine by Proniosomes and Niosomal Gel. AAPS PharmSciTech. 2018;19(4):1544–53. https://doi.org/10.1208/s12249-018-0967-6.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Jamal M, Imam SS, Aqil M, Amir M, Mir SR, Mujeeb M. Transdermal potential and anti-arthritic efficacy of ursolic acid from niosomal gel systems. Int Immunopharmacol. 2015;29(2):361–9. https://doi.org/10.1016/j.intimp.2015.10.029.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Fetih G. Fluconazole-loaded niosomal gels as a topical ocular drug delivery system for corneal fungal infections. J Drug Deliv Sci Technol. 2016;35:8–15. https://doi.org/10.1016/j.jddst.2016.06.002.

    CAS  Article  Google Scholar 

  22. 22.

    Fang J-Y, Hong C-T, Chiu W-T, Wang Y-Y. Effect of liposomes and niosomes on skin permeation of enoxacin. Int J Pharm. 2001;219(1):61–72. https://doi.org/10.1016/S0378-5173(01)00627-5.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Tavano L, Muzzalupo R, Picci N, de Cindio B. Co-encapsulation of lipophilic antioxidants into niosomal carriers: Percutaneous permeation studies for cosmeceutical applications. Colloids Surf B: Biointerfaces. 2014;114:144–9. https://doi.org/10.1016/j.colsurfb.2013.09.055.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Paolino D, Cosco D, Muzzalupo R, Trapasso E, Picci N, Fresta M. Innovative bola-surfactant niosomes as topical delivery systems of 5-fluorouracil for the treatment of skin cancer. Int J Pharm. 2008;353(1):233–42. https://doi.org/10.1016/j.ijpharm.2007.11.037.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Azeem A, Jain N, Iqbal Z, Ahmad FJ, Aqil M, Talegaonkar S. Feasibility of proniosomes-based transdermal delivery of frusemide: Formulation optimization and pharmacotechnical evaluation. Pharm Dev Technol. 2008;13(2):155–63. https://doi.org/10.1080/10837450701831211.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Li Q, Li Z, Zeng W, Ge S, Lu H, Wu C, et al. Proniosome-derived niosomes for tacrolimus topical ocular delivery: In vitro cornea permeation, ocular irritation, and in vivo anti-allograft rejection. Eur J Pharm Sci. 2014;62:115–23. https://doi.org/10.1016/j.ejps.2014.05.020.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Patel KK, Kumar P, Thakkar HP. Formulation of Niosomal Gel for Enhanced Transdermal Lopinavir Delivery and Its Comparative Evaluation with Ethosomal Gel. AAPS PharmSciTech. 2012;13(4):1502–10. https://doi.org/10.1208/s12249-012-9871-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Manosroi A, Chankhampan C, Manosroi W, Manosroi J. Transdermal absorption enhancement of papain loaded in elastic niosomes incorporated in gel for scar treatment. Eur J Pharm Sci. 2013;48(3):474–83. https://doi.org/10.1016/j.ejps.2012.12.010.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Long J, Nand AV, Ray S, Mayhew S, White D, Bunt CR, et al. Development of customised 3D printed biodegradable projectile for administrating extended-release contraceptive to wildlife. Int J Pharm. 2018;548(1):349–56. https://doi.org/10.1016/j.ijpharm.2018.07.002.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Ventola CL. Medical applications for 3D printing: current and projected uses. P T. 2014;39(10):704–11.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Alhnan MA, Okwuosa TC, Sadia M, Wan KW, Ahmed W, Arafat B. Emergence of 3D Printed Dosage Forms: Opportunities and Challenges. Pharm Res. 2016;33(8):1817–32. https://doi.org/10.1007/s11095-016-1933-1.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Jamróz W, Szafraniec J, Kurek M, Jachowicz R. 3D Printing in Pharmaceutical and Medical Applications – Recent Achievements and Challenges. Pharm Res. 2018;35(9):176. https://doi.org/10.1007/s11095-018-2454-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Vithani K, Goyanes A, Jannin V, Basit AW, Gaisford S, Boyd BJ. An Overview of 3D Printing Technologies for Soft Materials and Potential Opportunities for Lipid-based Drug Delivery Systems. Pharm Res. 2019;36(1):20. https://doi.org/10.1007/s11095-018-2531-1.

    CAS  Article  Google Scholar 

  34. 34.

    Tao J, Zhang J, Du T, Xu X, Deng X, Chen S, et al. Rapid 3D printing of functional nanoparticle-enhanced conduits for effective nerve repair. Acta Biomater. 2019;90:49–59. https://doi.org/10.1016/j.actbio.2019.03.047.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001;14(2):101–14. https://doi.org/10.1016/S0928-0987(01)00167-1.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Long J, Etxeberria AE, Nand AV, Bunt CR, Ray S, Seyfoddin A. A 3D printed chitosan-pectin hydrogel wound dressing for lidocaine hydrochloride delivery. Mater Sci Eng C. 2019;104:109873. https://doi.org/10.1016/j.msec.2019.109873.

    CAS  Article  Google Scholar 

  37. 37.

    Baswan SM, Leverett J, Pawelek J. Clinical evaluation of the lightening effect of cytidine on hyperpigmented skin. J Cosmet Dermatol. 2019;18(1):278–85. https://doi.org/10.1111/jocd.12784.

    Article  PubMed  Google Scholar 

  38. 38.

    Kwon TR, Choi EJ, Oh CT, Bak DH, Im SI, Ko EJ, et al. Targeting of sebaceous glands to treat acne by micro-insulated needles with radio frequency in a rabbit ear model. Lasers Surg Med. 2017;49(4):395–401. https://doi.org/10.1002/lsm.22599.

    Article  PubMed  Google Scholar 

  39. 39.

    Shan X, Choi JH, Kim KJ, Lee YJ, Ryu YH, Lee SJ, et al. Adipose Stem Cells with Conditioned Media for Treatment of Acne Vulgaris Scar. Tissue Eng Regen Med. 2018;15(1):49–61. https://doi.org/10.1007/s13770-017-0105-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Li SS, Li GF, Liu L, Jiang X, Zhang B, Liu ZG, et al. Evaluation of Paeonol Skin-Target Delivery from Its Microsponge Formulation: In Vitro Skin Permeation and In Vivo Microdialysis. PLoS One. 2013;8(11):8. https://doi.org/10.1371/journal.pone.0079881.

    CAS  Article  Google Scholar 

  41. 41.

    Hubbard A. Surfactants and Polymers in Drug Delivery. By Martin Malmsten: Dekker, New York, 2002, 348 pages. J Colloid Interface Sci. 2003;259(2):414. https://doi.org/10.1016/S0021-9797(02)00057-7.

    CAS  Article  Google Scholar 

  42. 42.

    Yoshioka T, Sternberg B, Florence AT. Preparation and properties of vesicles (niosomes) of sorbitan monoesters (Span 20, 40, 60 and 80) and a sorbitan triester (Span 85). Int J Pharm. 1994;105(1):1–6. https://doi.org/10.1016/0378-5173(94)90228-3.

    CAS  Article  Google Scholar 

  43. 43.

    Verma DD, Verma S, Blume G, Fahr A. Particle size of liposomes influences dermal delivery of substances into skin. Int J Pharm. 2003;258(1):141–51. https://doi.org/10.1016/S0378-5173(03)00183-2.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    ElMeshad AN, Mohsen AM. Enhanced corneal permeation and antimycotic activity of itraconazole against Candida albicans via a novel nanosystem vesicle. Drug Deliv. 2016;23(7):2115–23. https://doi.org/10.3109/10717544.2014.942811.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Waddad AY, Abbad S, Yu F, Munyendo WLL, Wang J, Lv H, et al. Formulation, characterization and pharmacokinetics of Morin hydrate niosomes prepared from various non-ionic surfactants. Int J Pharm. 2013;456(2):446–58. https://doi.org/10.1016/j.ijpharm.2013.08.040.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Celia C, Trapasso E, Cosco D, Paolino D, Fresta M. Turbiscan Lab® Expert analysis of the stability of ethosomes® and ultradeformable liposomes containing a bilayer fluidizing agent. Colloids Surf B: Biointerfaces. 2009;72(1):155–60. https://doi.org/10.1016/j.colsurfb.2009.03.007.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Malakar J, Sen SO, Nayak AK, Sen KK. Formulation, optimization and evaluation of transferosomal gel for transdermal insulin delivery. Saudi Pharm J. 2012;20(4):355–63. https://doi.org/10.1016/j.jsps.2012.02.001.

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Williams ML, Elias PM. The extracellular matrix of stratum corneum: role of lipids in normal and pathological function. Crit Rev Ther Drug Carrier Syst. 1987;3(2):95–122.

    CAS  PubMed  Google Scholar 

  49. 49.

    Kakkar S, Kaur IP. A novel nanovesicular carrier system to deliver drug topically. Pharm Dev Technol. 2013;18(3):673–85. https://doi.org/10.3109/10837450.2012.685655.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Sato T, Kuwata M, Akimoto N, Kitamura K, Shirakura Y, Mukai K, et al. Novel anti-acne action of β-cryptoxanthin that inhibits sebum production and lipid-droplet formation in hamster sebocytes. J Dermatol Sci. 2013;69(2):e12. https://doi.org/10.1016/j.jdermsci.2012.11.334.

    Article  Google Scholar 

  51. 51.

    Touitou E, Godin B, Karl Y, Bujanover S, Becker Y. Oleic acid, a skin penetration enhancer, affects Langerhans cells and corneocytes. J Control Release. 2002;80(1):1–7. https://doi.org/10.1016/S0168-3659(02)00004-4.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Naik A, Pechtold LARM, Potts RO, Guy RH. Mechanism of oleic acid-induced skin penetration enhancement in vivo in humans. J Control Release. 1995;37(3):299–306. https://doi.org/10.1016/0168-3659(95)00088-7.

    CAS  Article  Google Scholar 

  53. 53.

    Ogiso T, Niinaka N, Iwaki M. Mechanism for Enhancement Effect of Lipid Disperse System on Percutaneous Absorption. J Pharm Sci. 1996;85(1):57–64. https://doi.org/10.1021/js950178x.

    CAS  Article  PubMed  Google Scholar 

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Funding

This study was funded by the Science and Technology Planning Project of Guangdong Province (grant no. 2017B090912005 and 2017A050506027), National Natural Science Foundation of China (grant no. 81874346 and 81573611), Natural Science Foundation of Guangdong Province (grant no. 2017A030310021), and the Science and Technology Program of Guangzhou (grant no. 201907010018 and 201807010053).

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Correspondence to Qun Shen or Qiang Liu.

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All animal experiments presented here were performed in accordance with the animal handling guidelines established by The Ministry of Science and Technology of the People’s Republic of China, and the procedures were approved by the Ethics Committee of Southern Medical University.

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The methods of TEWL measurements, histopathological examination, skin ultrastructure observation (transmission electron microscopy), enzyme-linked immunosorbent assay, and the results of CCD, characterization of the release media (PBS) of 3DP-CPT-NH, cell viability of HaCaT cells, HE staining of rat skin, ELISA, CPT deposition in the normal and oleic acid treated skin treated with 3DP-CPT-NH and TEWL measurements are given in the supplementary data.

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Wang, Z., Liu, L., Xiang, S. et al. Formulation and Characterization of a 3D-Printed Cryptotanshinone-Loaded Niosomal Hydrogel for Topical Therapy of Acne. AAPS PharmSciTech 21, 159 (2020). https://doi.org/10.1208/s12249-020-01677-1

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KEY WORDS

  • cryptotanshinone
  • niosomal hydrogel
  • topical drug delivery
  • 3D printing
  • personalized acne treatments