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Melatonin Delivery: Transdermal and Transbuccal Evaluation in Different Vehicles

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ABSTRACT

Purpose

Melatonin (MLT) could be candidate drug for treatment of several diseases because of its high antioxidant and anticarcinogenic activity and its important biological roles. The aim of this study was to assess the influence of different vehicles on the permeation of MLT through buccal and skin tissues.

Methods

Formulations were characterized in terms of rheology, drug release and permeation through human skin as well as porcine buccal mucosa. Irradiation experiments were also performed.

Results

The lowest amount of MLT released was from oral adhesive paste Orabase® (OB) and the highest from the emulsion system Montanov® 68 (M68). Skin permeation revealed high pattern for Carbopol® 940 (C940) and M68, and poor for poloxamer 407 (P407) and Pluronic® lecithin organogel (PLO). Statistical differences of MLT remaining in skin between M68 vs C940 (p < 0.05) and M68 vs PLO (p < 0.05) were observed. Transmucosal results showed that sodium carboxymethylcellulose (NaCMC) was the best and OB the worst vehicle. P407 and PLO followed similar behaviour. Photostability studies revealed high percentage of degradation of MLT in solution which was also similar when was loaded in OB. The rest of formulations showed low rates of degradation.

Conclusions

C940 or M68 and NaCMC can be proposed as formulations for a potential systemic effect of MLT by skin and buccal mucosa routes, respectively. However, if the intended objective is to obtain local action in the skin and buccal mucosa, the proposed formulations are M68 or P407 and PLO.

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Abbreviations

AIC:

Akaike’s information criterion

AUC:

Area under the curve

C940:

Carbopol® 940

E:

Efficiency

M68:

Montanov® 68

MC:

Methylcellulose

MCTs:

Medium chain triglycerides

MLT:

Melatonin

NaCMC:

Carboxymethylcellulose

NYL:

Nylon

OB:

Orabase®

P407:

Poloxamer 407

PHE:

Perhydroesqualene

PLO:

Poloxamer lecithin organogel

PS:

Polysulfone

TEWL:

Transepidermal water loss

TMWL:

Transmucosal water loss

TPMT:

Transmucosal permeation mean time

REFERENCES

  1. Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological Interactions. Endocr Rev. 1991;12:151–80.

    Article  CAS  PubMed  Google Scholar 

  2. Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z. Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions. Acta Biochim Pol. 2007;54:1–9.

    CAS  PubMed  Google Scholar 

  3. Jarzynka MJ, Passey DK, Johnson DA, Konduru NV, Fitz NF, Radio NM, et al. Microtubules modulate melatonin receptors involved in phaseshifting circadian activity rhythms in vitro and in vivo evidence. J Pineal Res. 2009;46:161–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cajochen C, Kraüchi K, Wirz-Justice A. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol. 2003;15:432–7.

    Article  CAS  PubMed  Google Scholar 

  5. Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem. 2002;2:167–79.

    Article  CAS  PubMed  Google Scholar 

  6. Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Koppisepi S. Medical implications of melatonin: receptor-mediated and receptor independent actions. Adv Med Sci. 2007;52:11–28.

    CAS  PubMed  Google Scholar 

  7. Tan DX, Manchester LC, Hardeland R, Lopez-Burillo S, Mayo JC, Sainz RM, et al. Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res. 2003;34:75–8.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang HM, Zhang Y. Melatonin: a well-documented antioxidant with conditional prooxidant actions. J Pineal Res. 2014;57:131–46.

    Article  CAS  PubMed  Google Scholar 

  9. Lee YM, Chen HR, Hsiao G, Sheu JR, Wang JJ, Yen MH. Protective effects of melatonin on myocardial ischemia/reperfusion injury in vivo. J Pineal Res. 2002;33:72–80.

    Article  CAS  PubMed  Google Scholar 

  10. Maestroni GJ. The role of melatonin in immuno enhancement: potential application in cancer. Int J Exp Pathol. 2006;87:81–7.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sierra AF, Ramírez ML, Campmany AC, Martínez AR, Naveros BC. In vivo and in vitro evaluation of the use of a newly developed melatonin loaded emulsion combined with UV filters as a protective agent against skin irradiation. J Dermatol Sci. 2013;69:202–14.

    Article  CAS  PubMed  Google Scholar 

  12. Boga JA, Coto-Montes A, Rosales-Corral SA, Tan DX, Reiter RJ. Beneficial actions of melatonin in the management of viral infections: a new use for this “molecular handyman”? Rev Med Virol. 2012;22:323–38.

    Article  CAS  PubMed  Google Scholar 

  13. Cutando A, López-Valverde A, DE Vicente J, Gimenez JL, Carcía IA, DE Diego RG. Action of melatonin on squamous cell carcinoma and other tumors of the oral cavity. Oncol Lett. 2014;7:923–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Gómez-Moreno G, Guardia J, Ferrera MJ, Cutando A, Reiter RJ. Melatonin in diseases of the oral cavity. Oral Dis. 2010;16:242–7.

    Article  PubMed  Google Scholar 

  15. Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R. Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab. 2008;19:17–24.

    Article  CAS  PubMed  Google Scholar 

  16. Harpsøe NG, Andersen LP, Gögenur I. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015;71:901–9.

    Article  PubMed  Google Scholar 

  17. Dubey V, Mishra D, Asthana A, Jain NK. Transdermal delivery of a pineal hormone: melatonin via elastic liposomes. Biomaterials. 2006;27:3491–6.

    Article  CAS  PubMed  Google Scholar 

  18. Martin L, Wilson CG, Koosha F, Uchegbu IF. Sustained buccal delivery of the hydrophobic drug denbufylline using physically cross-linked palmitoyl glycol chitosan hydrogels. Eur J Pharm Biopharm. 2003;55:35–45.

    Article  CAS  PubMed  Google Scholar 

  19. Sudhakar Y, Kuotsu K, Bandyopadhyay AK. Buccal bioadhesive drug delivery: a promising option for orally less efficient drugs. J Control Release. 2006;114:15–40.

    Article  CAS  PubMed  Google Scholar 

  20. Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. J Control Release. 2011;153:106–16.

    Article  CAS  PubMed  Google Scholar 

  21. Mallo C, Zaĭdan R, Galy G, Vermeulen E, Brun J, Chazot G, et al. Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection. Eur J Clin Pharmacol. 1990;38:297–301.

    Article  CAS  PubMed  Google Scholar 

  22. Cavallo A, Ritschel WA. Pharmacokinetics of melatonin in human sexual maduration. J Clin Endocrinol Metab. 1996;5:1882–6.

    Google Scholar 

  23. Fernández Campos F, Calpena Campmany AC, Rodríguez Delgado G, López Serrano O, Naveros Clares B. Development and characterization of a novel nystatin-loaded nanoemulsion for the buccal treatment of candidosis: ultraultrastructural effects and release studies. J Pharm Sci. 2012;101:3739–52.

    Article  PubMed  Google Scholar 

  24. International Conference on Harmonization (ICH) of technical requirements for registration of pharmaceuticals for human use. Validation of Analytical Procedures: Text and Methodology. Q2(R1). Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf.

  25. Yonese M. Sustained drug delivery by gels. In: Osada Y, Kajiwara K, editors. Gels Handbook. San Diego: Academic; 2001. p. 230–40.

    Chapter  Google Scholar 

  26. Needleman I, Smales F. In vitro assessment of bioadhesion for periodontal and buccal drug delivery. Biomaterials. 1995;16:617–24.

    Article  CAS  PubMed  Google Scholar 

  27. Sweetman SC. Martindale, the extra pharmacopoeia. London: The pharmaceutical press; 1977.

    Google Scholar 

  28. Aframian DJ, Davidowitz T, Benoliel R. The distribution of oral mucosal pH values in healthy saliva secretors. Oral Dis. 2006;12:420–3.

    Article  CAS  PubMed  Google Scholar 

  29. Shahin M, Hady SA, Hammad M, Mortada N. Novel jojoba oil-based emulsion gel formulations for clotrimazole delivery. AAPS PharmSciTech. 2011;12:239–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bonn D, Denn MM. Yield stress fluids slowly yield to analysis. Science. 2009;324:1401–2.

    Article  CAS  PubMed  Google Scholar 

  31. Nielsen FS, Petersen KS, Mullertz A. Bioavailability of probucol from lipid and surfactant based formulations in minipigs: influence of droplet size and dietary state. Eur J Pharm Sci. 2008;69:553–62.

    CAS  Google Scholar 

  32. Siepmann J, Peppas NA. Modelling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2001;48:139–57.

    Article  CAS  PubMed  Google Scholar 

  33. Papadopoulou V, Kosmidis K, Vlachou M, Macheras P. On the use of the Weibull function for the discernment of drug release mechanisms. Int J Pharm. 2006;309:44–50.

    Article  CAS  PubMed  Google Scholar 

  34. Franz TJ. Percutaneous absorption on the relevance of in vitro data. J Invest Dermatol. 1975;64:190–5.

    Article  CAS  PubMed  Google Scholar 

  35. Galey WR, Londsdale HK, Nacht S. The in vitro permeability of skin and buccal mucosa to selected drugs and tritiated water. J Invest Dermatol. 1976;67:713–7.

    Article  CAS  PubMed  Google Scholar 

  36. Hashida M, Okamoto H, Sezaki H. Analysis of drug penetration through skin considering donor concentration decrease. J Pharmacobiodyn. 1988;11:636–44.

    Article  CAS  PubMed  Google Scholar 

  37. Lee BJ, Parrott KA, Ayres JW, Sack RL. Preliminary evaluation of transdermal delivery of melatonin in human subjects. Res Commun Mol Pathol. 1994;85:337–46.

    CAS  Google Scholar 

  38. Rossi S, Sandri G, Carla M, Caramella CM. Buccal drug delivery: a challenge already won? Drug Dis Today Technol. 2005;2:59–65.

    Article  CAS  Google Scholar 

  39. Martín MJ, Calpena AC, Fernández F, Mallandrich M, Gálvez P, Clares B. Development of alginate microspheres as nystatin carriers for oral mucosa drug delivery. Carbohydr Polym. 2015;117:140–9.

    Article  PubMed  Google Scholar 

  40. Maharaj DS, Anoopkumar-Dukie S, Glass BD, Antunes EM, Lack B, Walker RB, et al. The identification of the UV degradants of melatonin and their ability to scavenge free radicals. J Pineal Res. 2002;32:257–61.

    Article  CAS  PubMed  Google Scholar 

  41. Jeong B, Bae YH, Lee DS, Kim SW. Biodegradable block copolymers as injectable drug-delivery systems. Nature. 1997;388:860–2.

    Article  CAS  PubMed  Google Scholar 

  42. Squier CA, Hall BK. The permeability of skin and oral mucosa to water and horseradish peroxidase as related to the thickness of the permeability barrier. J Invest Dermatol. 1985;84:176–9.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

Judith Gómez is acknowledged for her technical help in this work.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Barcelona, Barcelona, Spain

    Ana Flo, Ana C. Calpena, Lyda Halbaut, Erika I. Araya & Francisco Fernández

  2. Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Granada, Spain

    Beatriz Clares

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  1. Ana Flo
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  2. Ana C. Calpena
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  3. Lyda Halbaut
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  4. Erika I. Araya
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  5. Francisco Fernández
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Correspondence to Beatriz Clares.

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Flo, A., Calpena, A.C., Halbaut, L. et al. Melatonin Delivery: Transdermal and Transbuccal Evaluation in Different Vehicles. Pharm Res 33, 1615–1627 (2016). https://doi.org/10.1007/s11095-016-1901-9

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  • DOI: https://doi.org/10.1007/s11095-016-1901-9

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