Novel nanocrystal-based formulations of apremilast for improved topical delivery

Abstract

Nanocrystals can enhance skin penetration of drug by increased saturation solubility, dissolution rate and adhesion on the skin. Apremilast is ‘difficult-to-deliver’ in viable layers (epidermis, dermis) and stratum corneum (SC) owing to its poor aqueous solubility and modest lipophilicity, respectively. Apremilast is currently available as oral tablet formulation for the indication of psoriasis but its effectiveness is limited by systemic side effects. Therefore, the present study aimed to develop novel nanocrystal-based formulations of apremilast for improved topical delivery. Nanosuspension was prepared using wet media milling and exhibited a mean particle size of 200 nm. The saturation solubility of nanocrystals was improved by 2-fold than micronized apremilast and showed significant advantage during dissolution study. Nanosuspension and micronized apremilast was incorporated into gel and cream and characterized for rheological properties. Skin permeation and ex vivo dermatokinetic study of topical formulations were performed on pig ear skin at a dose of 1% w/w using Franz diffusion cells. Skin permeation studies indicated that non-detectable amount of apremilast permeated through pig ear skin during exposure of formulations. Nanosuspension showed 2.6- and 3.2-fold drug penetration in SC and viable layers, respectively, over microsuspension. Nanogel showed 2.7- and 2.4-fold drug penetration in SC and viable layers, respectively, over microgel. Nanocream showed 1.2- and 2.8-fold drug penetration in SC and viable layers, respectively, over microcream. Thus, nanocrystal-based formulations of apremilast aid in selective delivery into viable layers by crossing the SC barrier. This is of paramount importance in enhancing therapeutic effectiveness utilizing localized delivery and provides an alternative delivery approach for the treatment of psoriasis.

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References

  1. 1.

    Wu X, Guy RH. Applications of nanoparticles in topical drug delivery and in cosmetics. J Drug Deliv Sci Technol. 2009;19(6):371–84.

    Google Scholar 

  2. 2.

    Gao L, Liu G, Ma J, Wang X, Zhou L, Li X. Drug nanocrystals: in vivo performances. J Control Release. 2012;160(3):418–30.

    CAS  PubMed  Google Scholar 

  3. 3.

    Sinha B, Müller RH, Möschwitzer JP. Bottom-up approaches for preparing drug nanocrystals: formulations and factors affecting particle size. Int J Pharm. 2013;453(1):126–41.

    CAS  PubMed  Google Scholar 

  4. 4.

    Shete G, Jain H, Punj D, Prajapat H, Akotiya P, Bansal AK. Stabilizers used in nanocrystal based drug delivery systems. J Excip Food Chem. 2014;5(4):184–209.

    Google Scholar 

  5. 5.

    Müller RH, Zhai X, Romero GB, Keck CM. Nanocrystals for passive dermal penetration enhancement. In: Dragicevic N, Maibach HI, editors. Percutaneous penetration enhancers chemical methods in penetration enhancement: nanocarriers. 1st ed. Berlin: Springer-Verlag Berlin Heidelberg; 2016. p. 283–95.

  6. 6.

    Zhai X, Lademann J, Keck CM, Müller RH. Nanocrystals of medium soluble actives - novel concept for improved dermal delivery and production strategy. Int J Pharm. 2014;470(1–2):141–50.

    CAS  PubMed  Google Scholar 

  7. 7.

    Al-Shaal L, Shegokar R, Müller RH. Production and characterization of antioxidant apigenin nanocrystals as a novel UV skin protective formulation. Int J Pharm. 2011;420(1):133–40.

    CAS  PubMed  Google Scholar 

  8. 8.

    Mitri K, Shegokara R, Gohla S, Anselmi C, Müller RH. Lutein nanocrystals as antioxidant formulation for oral and dermal delivery. Int J Pharm. 2011;420(1):141–6.

    CAS  PubMed  Google Scholar 

  9. 9.

    Lai F, Pireddu R, Corrias F, Fadda AM, Valenti D, Pini E, et al. Nanosuspension improves tretinoin photostability and delivery to the skin. Int J Pharm. 2013;458(1):104–9.

  10. 10.

    Pireddu R, Sinico C, Ennas G, Marongiu F, Muzzalupo R, Lai F, et al. Novel nanosized formulations of two diclofenac acid polymorphs to improve topical bioavailability. Eur J Pharm Sci. 2015;77:208–15.

    CAS  PubMed  Google Scholar 

  11. 11.

    Vidlářová L, Romero GB, Hanuš J, Štěpánek F, Müller RH. Nanocrystals for dermal penetration enhancement - effect of concentration and underlying mechanisms using curcumin as model. Eur J Pharm Sci. 2016;104:216–25.

    Google Scholar 

  12. 12.

    Hatahet T, Morille M, Hommoss A, Dorandeu C, Müller RH, Bégu S. Dermal quercetin smartCrystals®: formulation development, antioxidant activity and cellular safety. Eur J Pharm Biopharm. 2016;102:51–63.

    CAS  PubMed  Google Scholar 

  13. 13.

    Sinico C, Pireddu R, Pini E, Valenti D, Caddeo C, Fadda AM, et al. Enhancing topical delivery of resveratrol through a nanosizing approach. Planta Med. 2017;83(5):476–81.

    CAS  PubMed  Google Scholar 

  14. 14.

    Pyo SM, Meinke M, Keck CM, Müller RH. Rutin - increased antioxidant activity and skin penetration by nanocrystal technology (smartCrystals). Cosmetics. 2016;3(1):1–10.

  15. 15.

    Shen C, Shen B, Liu X, Yuan H. Nanosuspensions based gel as delivery system of nitrofurazone for enhanced dermal bioavailability. J Drug Deliv Sci Technol. 2018;43:1–11.

    Google Scholar 

  16. 16.

    Balato A, Balato N, Megna M, Schiattarella M, Lembo S, Ayala F. Pathogenesis of psoriasis: the role of pro-inflammatory cytokines produced by keratinocytes. In: Soung J, Koo B, editor. Psoriasis. IntechOpen; 2012. p. 9–28.

  17. 17.

    Chandra A, Ray A, Senapati S, Chatterjee R. Genetic and epigenetic basis of psoriasis pathogenesis. Mol Immunol. 2015;64(2):313–23.

    CAS  PubMed  Google Scholar 

  18. 18.

    Rahman M, Alam K, Ahmad MZ, Gupta G, Afzal M, Akhter S, et al. Classical to current approach for treatment of psoriasis: a review. Endocr Metab Immune Disord Drug Targets. 2012;12(3):287–302.

    CAS  PubMed  Google Scholar 

  19. 19.

    Laws PM, Young HS. Topical treatment of psoriasis. Expert Opin Pharmacother. 2010;11(12):1999–2009.

    CAS  PubMed  Google Scholar 

  20. 20.

    Shutty B, West C, Pellerin M, Feldman S. Apremilast as a treatment for psoriasis. Expert Opin Pharmacother. 2012;13(12):1761–70.

    CAS  PubMed  Google Scholar 

  21. 21.

    Celgene-Corporation. OTEZLA® (apremilast) tablets, for oral use: US prescribing information. 2019. http://www.celgene.com/content/uploads/otezla-pi.pdf. Accessed 8 Feb 2020.

  22. 22.

    Keating GM. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs. 2017;77(4):459–72.

    CAS  PubMed  Google Scholar 

  23. 23.

    EMA. Assessment report Otezla. 2014. https://www.ema.europa.eu/en/documents/assessment-report/otezla-epar-public-assessment-report_en.pdf. Accessed 5 April 2020.

  24. 24.

    Drugbank. Apremilast. 2020. https://www.drugbank.ca/drugs/DB05676. Accessed 25 May 2020.

  25. 25.

    Lu Y, Shen X, Hang T, Song M. Identification and characterization of process-related substances and degradation products in apremilast: process optimization and degradation pathway elucidation. J Pharm Biomed Anal. 2017;141:70–8.

    CAS  PubMed  Google Scholar 

  26. 26.

    Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, et al. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010;12(3):263–71.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    FDA. Guidance for industry dissolution testing of immediate release solid oral dosage forms. 1997. https://www.fda.gov/media/70936/download. Accessed 8 Feb 2020.

  28. 28.

    Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003;18(2):113–20.

    CAS  PubMed  Google Scholar 

  29. 29.

    Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol. 2010;62(11):1569–79.

    CAS  PubMed  Google Scholar 

  30. 30.

    Seweryn A. Interactions between surfactants and the skin - theory and practice. Adv Colloid Interf Sci. 2018;256:242–55.

    CAS  Google Scholar 

  31. 31.

    Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23(12):2709–28.

    CAS  PubMed  Google Scholar 

  32. 32.

    Tuomela A, Hirvonen J, Peltonen L. Stabilizing agents for drug nanocrystals: effect on bioavailability. Pharmaceutics. 2016;8(2):1–18.

    Google Scholar 

  33. 33.

    Bodratti AM, Alexandridis P. Formulation of poloxamers for drug delivery. J Funct Biomater. 2018;9(1):1–24.

    Google Scholar 

  34. 34.

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

    CAS  PubMed  Google Scholar 

  35. 35.

    Muller GW, Schafer PH, Man H, Ge C, Xu J, inventors; Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof. United States patent 7,893,101. 2011 22 February.

  36. 36.

    Murdande SB, Shah DA, Dave RH. Impact of nanosizing on solubility and dissolution rate of poorly soluble pharmaceuticals. J Pharm Sci. 2015;104(6):2094–102.

    CAS  PubMed  Google Scholar 

  37. 37.

    Chiarappa G, Piccolo A, Colombo I, Hasa D, Voinovich D, Moneghini M, et al. Exploring the shape influence on melting temperature, enthalpy, and solubility of organic drug nanocrystals by a thermodynamic model. Cryst Growth Des. 2017;17(8):4072–83.

    CAS  Google Scholar 

  38. 38.

    Liu P, Wulf OD, Laru J, Heikkilä T, van Veen B, Kiesvaara J, et al. Dissolution studies of poorly soluble drug nanosuspensions in non-sink conditions. AAPS PharmSciTech. 2013;14(2):748–56.

  39. 39.

    Eccleston GM, Bakhshaee M, Hudson NE, Richards DH. Rheological behavior of nasal sprays in shear and extension. Drug Dev Ind Pharm. 2000;26(9):975–83.

    CAS  PubMed  Google Scholar 

  40. 40.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Prashantkumar K. Parmar would like to gratefully acknowledge Rajiv Gandhi National Fellowship (RGNF, New Delhi, India) for providing Ph.D. Scholarship. Prashantkumar K. Parmar would also like to thank Sonu Dalsania, Pooja Sharma, Dnayaneshwar Kale, Payal Sharma and Jhanvi Wadhawan for their support and help during this project. The authors would like to acknowledge NIPER - S.A.S. Nagar for providing necessary facilities for this project.

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Correspondence to Arvind K. Bansal.

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Parmar, P.K., Bansal, A.K. Novel nanocrystal-based formulations of apremilast for improved topical delivery. Drug Deliv. and Transl. Res. (2020). https://doi.org/10.1007/s13346-020-00809-1

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Keywords

  • Nanocrystals
  • Nanosuspension
  • Apremilast
  • Psoriasis
  • Topical delivery