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Quality-by-Design Approach for Investigating the Efficacy of Tacrolimus and Hyaluronic Acid–Loaded Ethosomal Gel in Dermal Management of Psoriasis: In Vitro, Ex Vivo, and In Vivo Evaluation

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Abstract

Psoriasis is an auto-immune condition with high keratinocyte hyperproliferation due to lower p53 and p22 levels. Tacrolimus, an immune suppressor, is considered one of the most effective drugs in suppressing psoriasis. Systematic administration of tacrolimus often leads to challenging side effects, namely increased infection risk, renal toxicity, neurological symptoms such as tremors and headaches, gastrointestinal disturbances, hypertension, skin-related problems, etc. To address this, a nanocarrier-based formulation of tacrolimus along with inclusion of hyaluronic acid was developed. The optimization and formulation of ethosomes via the ethanol injection technique were done based on the Box-Behnken experimental design. The results revealed hyaluronic acid–based tacrolimus ethosomes (HA-TAC-ETH) had nanometric vesicle size (315.7 ± 2.2 nm), polydispersity index (PDI) (0.472 ± 0.07), and high entrapment efficiency (88.3 ± 2.52%). The findings of drug release and skin permeation showed sustained drug release with increased dermal flux and enhancement ratio. The effectiveness of HA-TAC-ETH was confirmed in an imiquimod (5%)–prompted psoriasis model. The skin irritation score and Psoriasis Area and Severity Index (PASI) score indicated that HA-TAC-ETH gel has validated a decline in the entire factors (erythema, edema, and thickness) in the imiquimod-induced psoriasis model in contrast with TAC-ETH gel and TAC ointment. The fabricated HA-TAC-ETH opt gel proved to be safe and effective in in vivo studies and could be employed to treat psoriasis further.

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Abbreviations

TAC:

Tacrolimus

ETH:

Ethosomes

HA:

Hyaluronic acid

BBD:

Box-Behnken Design

References

  1. Deng Y, Chang C, Lu Q. The inflammatory response in psoriasis: a comprehensive review. Clin Rev Allergy Immunol. 2016;50:377–89.

    Article  CAS  PubMed  Google Scholar 

  2. Lønnberg AS, Skov L. Co-morbidity in psoriasis: mechanisms and implications for treatment. Expert Rev Clin Immunol. 2017;13(1):27–34.

    Article  PubMed  Google Scholar 

  3. Ghosh D, Ganguly T, Chatterjee R. Emerging roles of non-coding RNAs in psoriasis pathogenesis. Funct Integr Genom. 2023;23(2):129.

    Article  CAS  Google Scholar 

  4. Fleming P, Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, et al. Effect of biologics on depressive symptoms in patients with psoriasis: a systematic review. J Eur Acad Dermatol Venereol. 2015;29(6):1063–70.

    Article  CAS  PubMed  Google Scholar 

  5. de Morales JMGR, Puig L, Daudén E, Cañete JD, Pablos JL, Martín AO, et al. Critical role of interleukin (IL)-17 in inflammatory and immune disorders: an updated review of the evidence focusing in controversies. Autoimmun Rev. 2020;19(1): 102429.

    Article  Google Scholar 

  6. Nordin UU, Ahmad N, Salim N, Yusof NS. Lipid-based nanoparticles for psoriasis treatment: a review on conventional treatments, recent works, and future prospects. RSC Adv. 2021;11(46):29080–101.

  7. Yamanaka K, Yamamoto O, Honda T. Pathophysiology of psoriasis: a review. J Dermatol. 2021;48(6):722–31.

    Article  CAS  PubMed  Google Scholar 

  8. Blauvelt A. New concepts in the pathogenesis and treatment of psoriasis: key roles for IL-23, IL-17A and TGF-β1. Expert Rev Dermatol. 2007;2(1):69–78.

    Article  CAS  Google Scholar 

  9. Kamata M, Tada Y. Safety of biologics in psoriasis. J Dermatol. 2018;45(3):279–86.

    Article  PubMed  Google Scholar 

  10. Jafari A, Daneshamouz S, Ghasemiyeh P, Mohammadi-Samani S. Ethosomes as dermal/transdermal drug delivery systems: applications, preparation and characterization. J Liposome Res. 2023;33(1):34–52.

    Article  CAS  PubMed  Google Scholar 

  11. Garg V, Singh H, Bimbrawh S, Kumar Singh S, Gulati M, Vaidya Y, et al. Ethosomes and transfersomes: principles, perspectives and practices. Curr Drug Deliv. 2017;14(5):613–33.

    Article  CAS  PubMed  Google Scholar 

  12. Pandey V, Golhani D, Shukla R. Ethosomes: versatile vesicular carriers for efficient transdermal delivery of therapeutic agents. Drug Deliv. 2015;22(8):988–1002.

    Article  CAS  PubMed  Google Scholar 

  13. Arcas JM, González A, Gers-Barlag K, González-González O, Bech F, Demirkhanyan L, et al. The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels. J Neurosci. 2019;39(6):949–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. De Gregori S, De Silvestri A, Cattadori B, Rapagnani A, Albertini R, Novello E, et al. Therapeutic drug monitoring of tacrolimus-personalized therapy in heart transplantation: new strategies and preliminary results in endomyocardial biopsies. Pharmaceutics. 2022;14(6):1247.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hurst AL, Clark N, Carpenter TC, Sundaram SS, Reiter PD. Supra-therapeutic tacrolimus concentrations associated with concomitant nicardipine in pediatric liver transplant recipients. Pediatr Transplant. 2015;19(4):E83–7.

    Article  CAS  PubMed  Google Scholar 

  16. Lee J, Kim E, Hwang S-U, Cai L, Kim M, Choi H, et al. Effect of D-glucuronic acid and N-acetyl-D-glucosamine treatment during in vitro maturation on embryonic development after parthenogenesis and somatic cell nuclear transfer in pigs. Animals. 2021;11(4):1034.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Du H, Liu P, Zhu J, Lan J, Li Y, Zhang L, et al. Hyaluronic acid-based dissolving microneedle patch loaded with methotrexate for improved treatment of psoriasis. ACS Appl Mater Interfaces. 2019;11(46):43588–98.

    Article  CAS  PubMed  Google Scholar 

  18. How KN, Yap WH, Lim CLH, Goh BH, Lai ZW. Hyaluronic acid-mediated drug delivery system targeting for inflammatory skin diseases: a mini review. Front pharmacol. 2020;11:1105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Abdelbary AA, AbouGhaly MH. Design and optimization of topical methotrexate loaded niosomes for enhanced management of psoriasis: application of box-behnken design, in-vitro evaluation and in-vivo skin deposition study. Int J Pharm. 2015;485(1–2):235–43.

    Article  CAS  PubMed  Google Scholar 

  20. Arora D, Nanda S. Quality by design driven development of resveratrol loaded ethosomal hydrogel for improved dermatological benefits via enhanced skin permeation and retention. Int J Pharm. 2019;567: 118448.

    Article  CAS  PubMed  Google Scholar 

  21. Jain P, Taleuzzaman M, Kala C, Kumar Gupta D, Ali A, Aslam M. Quality by design (qbd) assisted development of phytosomal gel of aloe vera extract for topical delivery. J Liposome Res. 2021;31(4):381–8.

    Article  CAS  PubMed  Google Scholar 

  22. Elkomy MH, Elmowafy M, Shalaby K, Azmy AF, Ahmad N, Zafar A, et al. Development and machine-learning optimization of mucoadhesive nanostructured lipid carriers loaded with fluconazole for treatment of oral candidiasis. Drug Dev Ind Pharm. 2021;47(2):246–58.

    Article  CAS  PubMed  Google Scholar 

  23. Tkachenko Y, Niedzielski P. FTIR as a method for qualitative assessment of solid samples in geochemical research: A review. Molecules. 2022;27(24):8846.

  24. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Satyam G, Shivani S, Garima G. Ethosomes: a novel tool for drug delivery through the skin. J Pharm Res. 2010;3(4):688–91.

    CAS  Google Scholar 

  26. Pathan IB, Jaware BP, Shelke S, Ambekar W. Curcumin loaded ethosomes for transdermal application: formulation, optimization, in-vitro and in-vivo study. J Drug Deliv Sci Technol. 2018;44:49–57.

    Article  CAS  Google Scholar 

  27. Zhang Z, Feng S-S. The drug encapsulation efficiency, in vitro drug release, cellular uptake and cytotoxicity of paclitaxel-loaded poly (lactide)–tocopheryl polyethylene glycol succinate nanoparticles. Biomater. 2006;27(21):4025–33.

    Article  CAS  Google Scholar 

  28. Inkson BJ. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) for materials characterization. In: Materials characterization using nondestructive evaluation (NDE) methods.  Woodhead Publishing; 2016. p 17–43.

  29. Hayat ME. Basic techniques for transmission electron microscopy. Academic Press 1986, The University of California. 1985;(1):67–8.

  30. Vanaja K, Shobha Rani R, Sacchidananda S. Formulation and clinical evaluation of ultradeformable liposomes in the topical treatment of psoriasis. Clin Res Regul Aff. 2008;25(1):41–52.

    Article  Google Scholar 

  31. Leyva-Porras C, Cruz-Alcantar P, Espinosa-Solís V, Martínez-Guerra E, Piñón-Balderrama CI, Compean Martínez I, et al. Application of differential scanning calorimetry (DSC) and modulated differential scanning calorimetry (MDSC) in food and drug industries. Polymers. 2019;12(1):5.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Durowoju IB, Bhandal KS, Hu J, Carpick B, Kirkitadze M. Differential scanning calorimetry—a method for assessing the thermal stability and conformation of protein antigen. J Vis Exp. 2017;121: e55262.

    Google Scholar 

  33. Guo T, Lu J, Fan Y, Zhang Y, Yin S, Sha X, et al. TPGS assists the percutaneous administration of curcumin and glycyrrhetinic acid coloaded functionalized ethosomes for the synergistic treatment of psoriasis. Int J Pharm. 2021;604: 120762.

    Article  CAS  PubMed  Google Scholar 

  34. Elgewelly MA, Elmasry SM, El Sayed NS, Abbas H. Resveratrol-loaded vesicular elastic nanocarriers gel in imiquimod-induced psoriasis treatment: in vitro and in vivo evaluation. J Pharm Sci. 2022;111(2):417–31.

    Article  CAS  PubMed  Google Scholar 

  35. Patel NA, Patel NJ, Patel RP. Formulation and evaluation of curcumin gel for topical application. Pharm Dev Techno. 2009;14(1):83–92.

    Article  Google Scholar 

  36. Wohlrab J, Gebert A. pH and buffer capacity of topical formulations. pH of the skin: issues and challenges. Karger Publishers; 2018. p. 123–31.

  37. Dantas MG, Reis SA, Damasceno CM, Rolim LA, Rolim-Neto PJ, Carvalho FO, Quintans-Junior LJ, Almeida JR. Development and evaluation of stability of a gel formulation containing the monoterpene borneol. Sci World J. 2016;2016.

  38. Kaur M, Singh K, Jain SK. Luliconazole vesicular based gel formulations for its enhanced topical delivery. J Liposome Res. 2020;30(4):388–406.

    Article  CAS  PubMed  Google Scholar 

  39. Jain AK, Thareja S. In vitro and in vivo characterization of pharmaceutical nanocarriers used for drug delivery. Artif Cells Nanomed Biotechnol. 2019;47(1):524–39.

    Article  CAS  PubMed  Google Scholar 

  40. Bhardwaj P, Tripathi P, Pandey S, Gupta R, Khar RK, Patil PR. Improved dermal delivery of pentoxifylline niosomes for the management of psoriasis: development, optimization and in-vivo studies in imiquimod induced psoriatic plaque model. J Drug Deliv Sci Technol. 2022;75: 103643.

    Article  CAS  Google Scholar 

  41. Khatoon K, Ali A, Ahmad FJ, Hafeez Z, Rizvi MMA, Akhter S, et al. Novel nanoemulsion gel containing triple natural bio-actives combination of curcumin, thymoquinone, and resveratrol improves psoriasis therapy: in vitro and in vivo studies. Drug Deliv Transl Res. 2021;11:1245–60.

    Article  CAS  PubMed  Google Scholar 

  42. Ahad A, Al-Saleh AA, Al-Mohizea AM, Al-Jenoobi FI, Raish M, Yassin AEB, et al. Formulation and characterization of phospholipon 90 G and tween 80 based transfersomes for transdermal delivery of eprosartan mesylate. Pharm Dev Technol. 2018;23(8):787–93.

    Article  CAS  PubMed  Google Scholar 

  43. Alam MS, Ali MS, Alam N, Siddiqui MR, Shamim M, Safhi M. In vivo study of clobetasol propionate loaded nanoemulsion for topical application in psoriasis and atopic dermatitis. Drug Invent Today. 2013;5(1):8–12.

    Article  CAS  Google Scholar 

  44. Struck MB, Andrutis KA, Ramirez HE, Battles AH. Effect of a short-term fast on ketamine–xylazine anesthesia in rats. J Am Assoc Lab Anim Sci. 2011;50(3):344–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Okasha EF, Bayomy NA, Abdelaziz EZ. Effect of topical application of black seed oil on imiquimod-induced psoriasis-like lesions in the thin skin of adult male albino rats. Anat Rec. 2018;301(1):166–74.

    Article  CAS  Google Scholar 

  46. Smajlović A, Haverić A, Alić A, Hadžić M, Smajlović A, Mujezinović I, et al. Molecular and histopathological profiling of imiquimod induced dermatosis in swiss wistar rats: contribution to the rat model for novel anti-psoriasis treatments. Mol Biol Rep. 2021;48(5):4295–303.

    Article  PubMed  Google Scholar 

  47. Chen H, Lu C, Liu H, Wang M, Zhao H, Yan Y, et al. Quercetin ameliorates imiquimod-induced psoriasis-like skin inflammation in mice via the NF-κB pathway. Int Immunopharmacol. 2017;48:110–7.

    Article  CAS  PubMed  Google Scholar 

  48. Ge Djiobie Tchienou, Rk TsatsopTsague, Tf MbamPega, Bama V, Bamseck A, DongmoSokeng S, et al. Multi-response optimization in the formulation of a topical cream from natural ingredients. Cosmetics. 2018;5(1):7.

    Article  Google Scholar 

  49. Pawar P, Kashyap H, Malhotra S, Sindhu R. Hp--CD-voriconazole in situ gelling system for ocular drug delivery: in vitro, stability, and antifungal activities assessment. BioMed Res Int. 2013;2013.

  50. Chawla A, Sharma P, Pawar P. Eudragit S-100 coated sodium alginate microspheres of naproxen sodium: formulation, optimization and in vitro evaluation. Acta Pharm. 2012;62(4):529–45.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142 001, India

    Nikhil Dadwal,  Amisha, Dilpreet Singh & Amrinder Singh

  2. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India

    Amrinder Singh

  3. University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, 140413, Mohali, India

    Dilpreet Singh

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  2. Amisha
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Contributions

ND: investigation, software, validation, formal analysis, writing—original draft. A: validation, investigation, data curation. DS: methodology, resources. AS: conceptualization, methodology, resources, writing—review and editing, supervision.

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Correspondence to Amrinder Singh.

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Dadwal, N., Amisha, Singh, D. et al. Quality-by-Design Approach for Investigating the Efficacy of Tacrolimus and Hyaluronic Acid–Loaded Ethosomal Gel in Dermal Management of Psoriasis: In Vitro, Ex Vivo, and In Vivo Evaluation. AAPS PharmSciTech 24, 220 (2023). https://doi.org/10.1208/s12249-023-02678-6

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