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Effect of propylene glycol on the skin penetration of drugs

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Abstract

Propylene glycol (PG) has been used in formulations as a co-solvent and/or to enhance drug permeation through the skin from topical preparations. Two skin in vitro permeation approaches are used to determine the effect of PG on drug penetration. The in vitro Skin-PAMPA was performed using 24 actives applied in aqueous buffer or PG. PG modulates permeability by increasing or diminishing it in the compounds with poor or high permeability, respectively. Percutaneous absorption using pigskin on Franz diffusion cells was performed on seven actives and their commercial formulations. The commercial formulations evaluated tend to have a lower permeability than their corresponding PG solutions but maintain the compound distribution in the different strata: stratum corneum, epidermis and dermis. The results indicate the enhancer properties of PG for all compounds, especially for the hydrophilic ones. Additionally, the Synchrotron-Based Fourier Transform Infrared microspectroscopy technique is applied to study the penetration of PG and the molecular changes that the vehicle may promote in the different skin layers. Results showed an increase of the areas under the curve indicating the higher amount of lipids in the deeper layers and altering the lipidic order of the bilayer structure to a more disordered lipid structure.

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References

  1. Samaras EG, Riviere JE, Ghafourian T (2012) The effect of formulations and experimental conditions on in vitro human skin permeation—data from updated EDETOX database. Int J Pharm 434:280–291. https://doi.org/10.1016/j.ijpharm.2012.05.012

    Article  CAS  PubMed  Google Scholar 

  2. Williams AC, Barry BW (2004) Penetration enhancers. Adv Drug Deliv Rev 56:603–618. https://doi.org/10.1016/j.addr.2003.10.025

    Article  CAS  PubMed  Google Scholar 

  3. Lane ME (2013) Skin penetration enhancers. Int J Pharm 447:12–21. https://doi.org/10.1016/j.ijpharm.2013.02.040

    Article  CAS  PubMed  Google Scholar 

  4. Prausnitz MR, Langer R (2008) Transdermal drug delivery. Nat Biotechnol 26:1261–1268. https://doi.org/10.1038/nbt.1504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hoelgaard A, Mollgard B (1985) Dermal drug delivery—improvement by choice of vehicle or drug derivative. J Control Release 2:111–120. https://doi.org/10.1016/0168-3659(85)90037-9

    Article  CAS  Google Scholar 

  6. Nicolazzo JC, Morgan TM, Reed BL, Finnin BC (2005) Synergistic enhancement of testosterone transdermal delivery. J Control Release 103:577–585. https://doi.org/10.1016/j.jconrel.2004.12.007

    Article  CAS  PubMed  Google Scholar 

  7. Manca ML, Castangia I, Matricardi P, Lampis S, Fernàndez-Busquets X, Fadda AM, Manconi M (2014) Molecular arrangements and interconnected bilayer formation induced by alcohol or polyalcohol in phospholipid vesicles. Colloids Surf B Biointerfaces 117:360–367. https://doi.org/10.1016/j.colsurfb.2014.03.010

    Article  CAS  PubMed  Google Scholar 

  8. Ostrenga J, Steinmetz C, Poulsen B, Yett S (1971) Significance of vehicle composition II. Prediction of optimal vehicle composition. J Pharm Sci 60:1180–1183. https://doi.org/10.1002/jps.2600600813

    Article  CAS  PubMed  Google Scholar 

  9. Bowstra JA, Peschier LJC, Brusee J, Boddé HE (1989) Effect of N-alkyl-azocycloheptan-2-ones including azone on the thermal behavior of human stratum corneum. J Pharm 52:47–54. https://doi.org/10.1016/0378-5173(89)90087-2

    Article  Google Scholar 

  10. Zhang Q, Li P, Roberts MS (2011) Maximum transepidermal flux for similar size phenolic compounds is enhanced by solvent uptake into the skin. J Control Release 25;154(1):50–7. https://doi.org/10.1016/j.jconrel.2011.04.018

    Article  CAS  Google Scholar 

  11. Bowstra JA, de Vries MA, Gooris GS, Bras W, Brussee J, Ponec M (1991) Thermodynamic and structural aspects of the skin barrier. J Control Release 15:209–219. https://doi.org/10.1016/0168-3659(91)90112-Q

    Article  Google Scholar 

  12. Brinkmann I, Muller-Goymann CC (2005) An attempt to clarify the influence of glycerol, propylene glycol, isopropyl myristate and a combination of propylene glycol and isopropyl myristate on human stratum corneum. Pharmazie 60:215–220

    CAS  PubMed  Google Scholar 

  13. Trottet L, Merly C, Mirza M, Hadgraft J, Davis AF (2004) Effect of finite doses of propylene glycol on enhancement of in vitro percutaneous permeation of loperamide hydrochloride. Int J Pharm 274:213–219. https://doi.org/10.1016/j.ijpharm.2004.01.013

    Article  CAS  PubMed  Google Scholar 

  14. Pudney PD, Mélot M, Caspers PJ, Van Der Pol A, Puppels GJ (2007) An in vivo confocal Raman study of the delivery of trans retinol to the skin. Appl Spectrosc 61:804–811. https://doi.org/10.1366/000370207781540042

    Article  CAS  PubMed  Google Scholar 

  15. Bonnist EY, Gorce JP, MacKay C, Pendlington RU, Pudney PD (2011) Measuring the penetration of a skin sensitizer and its delivery vehicles simultaneously with confocal raman spectroscopy. Skin Pharmacol Physiol 24:274–283. https://doi.org/10.1159/000328729

    Article  CAS  PubMed  Google Scholar 

  16. Lademann J, Richter H, Schaefer UF, Blume-Peytavi U, Teichmann A, Otberg N, Sterry W (2006) Hair follicles—a long-term reservoir for drug delivery. Skin Pharmacol Physiol 19:232–236. https://doi.org/10.1159/000093119

    Article  CAS  PubMed  Google Scholar 

  17. Alvarez-Román R, Naik A, Kalia YN, Guy RH, Fessi H (2004) Skin penetration and distribution of polymeric nanoparticles. J Control Rel 99:53–62. https://doi.org/10.1016/j.jconrel.2004.06.015

    Article  CAS  Google Scholar 

  18. Narishetty ST, Panchagnula R (2004) Transdermal delivery system for zidovudine: in vitro, ex vivo and in vivo evaluation. Biopharm Drug Dispos 25:9–20. https://doi.org/10.1002/bdd.381

    Article  CAS  PubMed  Google Scholar 

  19. Yu XZ, Jin XP, Yin L, Shen GZ, Lin HF, Wang YL (1994) Influence of in vitro methods, receptor fluids on percutaneous absorption and validation of a novel in vitro method. Biomed Environ Sci 7:248–258

    CAS  PubMed  Google Scholar 

  20. Dumas P, Miller L (2003) The use of synchrotron infrared microspectroscopy in biological and biomedical investigations. Vib Spectrosc 32:3–21. https://doi.org/10.1016/S0924-2031(03)00043-2

    Article  CAS  Google Scholar 

  21. Cotte M, Dumas P, Besnard M, Tchoreloff P, Walter P (2004) Synchrotron FT-IR microscopic study of chemical enhancers in transdermal drug delivery: example of fatty acids. J Control Release 97:269–281. https://doi.org/10.1016/j.jconrel.2004.03.014

    Article  CAS  PubMed  Google Scholar 

  22. Manca ML, Matricardi P, Cencetti C, Peris JE, Melis V, Carbone C, Escribano E, Zaru M, Fadda AM, Manconi M (2016) Combination of argan oil and phospholipids for the development of an effective liposome-like formulation able to improve skin hydration and allantoin dermal delivery. Int J Pharm 505:204–211. https://doi.org/10.1016/j.ijpharm.2016.04.008

    Article  CAS  PubMed  Google Scholar 

  23. Maibach H (1984) Dermatological formulations: percutaneous absorption. By Brian W. Barry. Marcel Dekker, 270 Madison Avenue, New York, NY 10016. 1983. 479 pp. 16 × 23.5 cm. J Pharm Sci 73: 573–573. https://doi.org/10.1002/jps.2600730442

    Article  Google Scholar 

  24. Fitzpatrick D, Corish J, Hayes B (2004) Modelling skin permeability in risk assessment—the future. Chemosphere 55:1309–1314. https://doi.org/10.1016/j.chemosphere.2003.11.051

    Article  CAS  PubMed  Google Scholar 

  25. Sinkó B, Kökösi J, Avdeef A, Takács-Novak K (2009) A PAMPA study of the permeability enhancing effect of new ceramide analogues. Chem Biodivers 6:1867–1874. https://doi.org/10.1002/cbdv.200900149

    Article  CAS  PubMed  Google Scholar 

  26. Hoang KT (1992) Dermal exposure assessment : principles and applications. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Washington, DC, EPA/600/8-91/011B

  27. Gray GM, Yardley HJ (1975) Lipid compositions of cells isolated from pig, human, and rat epidermis. J Lipid Res 16:434–440

    CAS  PubMed  Google Scholar 

  28. Wester RC, Melendres J, Sedik L, Maibach H, Riviere JE (1998) Percutaneous absorption of salicylic acid, theophylline, 2, 4-dimethylamine, diethyl hexyl phthalic acid, and p-aminobenzoic acid in the isolated perfused porcine skin flap compared to man in vivo. Toxicol Appl Pharmacol 151:159–165. https://doi.org/10.1006/taap.1998.8434

    Article  CAS  PubMed  Google Scholar 

  29. Jacobi U, Kaiser M, Toll R, Mangelsdorf S, Audring H, Otberg N, Sterry W, Lademann J (2007) Porcine ear skin: an in vitro model for human skin. Skin Res Technol 13:19–24. https://doi.org/10.1111/j.1600-0846.2006.00179.x

    Article  PubMed  Google Scholar 

  30. Wester RC, Maibach HI (2001) In vivo methods for percutaneous absorption measurements. J Toxicol Cut Ocular Toxicol 20:411–422. https://doi.org/10.1081/CUS-120001866

    Article  Google Scholar 

  31. Ottaviani G, Martel S, Carrupt PA (2006) Parallel artificial membrane permeability assay: a new membrane for the fast prediction of passive human skin permeability. J Med Chem 49:3948–3954. https://doi.org/10.1021/jm060230+

    Article  CAS  PubMed  Google Scholar 

  32. Guidance document for the conduct of skin absorption studies. OECD Series on Testing and assessment, 2004; No. 28: 1–31, https://doi.org/10.1787/9789264078796-en

  33. European Commission the SCCS Notes of Guidance for the Testing of Cosmetic Ingredients (2016) SCCS 1564. 151, https://doi.org/doi:10.2772/47128

  34. Schaefer H, Redelmeier TE (1996) Skin barrier: principles of percutaneous absorption. Karger, Basel

    Google Scholar 

  35. Carrer V, Alonso C, Oliver MA, Coderch L (2018) In vitro penetration through the skin layers of topically applied glucocorticoids. Drug Test Anal 10:1528–1535. https://doi.org/10.1002/dta.2412

    Article  CAS  PubMed  Google Scholar 

  36. Bronaugh RL, Stewart RF, Congdon ER (1982) Methods for in vitro percutaneous absorption studies II. Animal models for human skin. Toxicol Appl Pharmacol 62: 481–488. https://doi.org/10.1016/0041-008X(82)90149-1

    Article  CAS  Google Scholar 

  37. Benseny-Cases N, Álvarez-Marimon E, Castillo-Michel H, Cotte M, Falcon C, Cladera J (2018) Synchrotron-based Fourier transform infrared microspectroscopy (μFTIR) study on the effect of Alzheimer’s Aβ amorphous and fibrillar aggregates on PC12 cells. Anal Chem 90:2772–2779. https://doi.org/10.1021/acs.analchem.7b04818

    Article  CAS  Google Scholar 

  38. AS, CAMO SOFTWARE. https://www.camo.com/downloads/user-manuals.html. Accessed 20 Nov 2018

  39. Vyumvuhore R, Tfayli A, Manfait M, Baillet-Guffroy A (2014) Vibrational spectroscopy coupled to classical least square analysis, a new approach for determination of skin moisturizing agents’ mechanisms. Skin Res Technol 20:282–292. https://doi.org/10.1111/srt.12117

    Article  CAS  PubMed  Google Scholar 

  40. Alonso C, Carrer V, Espinosa S, Zanuy M, Córdoba M, Vidal B, Domínguez MJ, Godessart N, Coderch L, Pont M (2019) Prediction of the skin permeability of topical drugs using in silico and in vitro models. Eur J Pharm Sci 136:104945. https://doi.org/10.1016/j.ejps.2019.05.023

    Article  CAS  PubMed  Google Scholar 

  41. Davis AF, Hadgraft J (1991) Efect of supersaturation on membrane transport: 1. Hydrocortisone acetate. Int J Pharm 76:1–8. https://doi.org/10.1016/0378-5173(91)90337-N

    Article  CAS  Google Scholar 

  42. Lazar A, Lenkey N, Pesti K, Fodor L, Mike A (2015) Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway. Front Pharmacol 6:210. https://doi.org/10.3389/fphar.2015.00210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jackson M, Mantsch HH (1995) The use and misuse of FTIR spectroscopy in the determination of protein structure. Crit Rev Biochem Mol Biol 30:95–120. https://doi.org/10.3109/10409239509085140

    Article  CAS  PubMed  Google Scholar 

  44. Golden GM, Guzek DB, Harris RR, McKie JE, Potts RO (1986) Lipid thermotropic transitions in human stratum corneum. J Invest Dermatol 86: 255–259. https://doi.org/doi:10.1111/1523-1747.ep12285373

    Article  CAS  Google Scholar 

  45. Olsztyńska-Janus S, Pietruszka A, Kiełbowicz Z, Czarnecki MA (2018) ATR-IR study of skin components: lipids, proteins and water. Part I: temperature effect. Spectrochim Acta A Mol Biomol Spectrosc 188: 37–49. https://doi.org/doi:10.1016/j.saa.2017.07.001

    Article  Google Scholar 

  46. van Smeden J, Bouwstra JA (2016) Stratum corneum lipids: their role for the skin barrier function in healthy subjects and atopic dermatitis patients. In: Agner T (eds), Skin barrier function. Curr Probl Dermatol. Basel, Karger 49:8–26. https://doi.org/10.1159/000441540

  47. Rodríguez G, Barbosa-Barros L, Rubio L, Cócera M, Díez A, Estelrich J, Pons R, Caelles J, De la Maza A, López O (2009) Conformational changes in stratum corneum lipids by effect of Bicellar systems. Langmuir 25:10595–10603. https://doi.org/10.1021/la901410h

    Article  CAS  PubMed  Google Scholar 

  48. Moghadam SH, Saliaj E, Wettig SD, Dong C, Ivanova MV, Huzi JTL, Foldvari M (2013) Effect of chemical permeation enhancers on stratum corneum barrier lipid organizational structure and interferon alpha permeability. Mol Pharm 10:2248–2260. https://doi.org/10.1021/mp300441c

    Article  CAS  PubMed  Google Scholar 

  49. Goodman M, Barry BW (1988) Action of penetration enhancers on human skin as assessed by the permeation of model drugs 5-fluorouracil and estradiol. I. Infinite dose technique. J Invest Dermatol 91:323–327. https://doi.org/10.1111/1523-1747.ep12475655

    Article  CAS  PubMed  Google Scholar 

  50. Barry BW, Bennett SL (1987) Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin. J Pharm Pharmacol 39:535–546. https://doi.org/10.1111/j.2042-7158.1987.tb03173.x

    Article  CAS  PubMed  Google Scholar 

  51. Zhang J, Liu M, Jin H, Deng L, Xing J, Dong A (2010) In vitro enhancement of lactate esters on the percutaneous penetration of drugs with different lipophilicity. AAPS PharmSciTech 11:894–903. https://doi.org/10.1208/s12249-010-9449-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen M, Liu X, Fahr A (2011) Skin penetration and deposition of carboxyfluorescein and temoporfin from different lipid vesicular systems. In vitro study with finite and infinite dosage application. Int J Pharm 408:223–234. https://doi.org/10.1016/j.ijpharm.2011.02.006

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The present work could not be performed without the important collaboration and contribution of Isabel Yuste and Service of Dermocosmetic Assessment from IQAC-CSIC. The authors are also grateful to Monserrat Rigol and Núria Solanes from the Department of Cardiology (Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) Hospital Clínic, Universitat de Barcelona, Spain) for supplying the porcine skin biopsies. Moreover, the work carried out in the synchrotron ALBA was possible thanks to the valuable help of M. Kreuzer and I. Yousef and the grant received from the Consortium for the Construction, Equipping and Exploitation of the Synchoton Light Sources (CELLS).

Funding

This work was partially funded by the Spanish Ministry of Economy and Competitiveness, project code RTC-2014-1901-1.

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Authors and Affiliations

  1. Institute of Advanced Chemistry of Catalonia-CSIC (IQAC-CSIC), Jordi Girona 18-26, 08034, Barcelona, Spain

    Victor Carrer, Cristina Alonso, Clara Barba, Marc A. Oliver, Meritxell Martí & Luisa Coderch

  2. Almirall R&D Center, Ctra. Laureà Miró 408-410, 08980, Sant Feliu de Llobregat, Barcelona, Spain

    Mercè Pont, Miriam Zanuy, Mònica Córdoba & Sonia Espinosa

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  1. Victor Carrer
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Correspondence to Cristina Alonso.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Animal handling was approved by the Institutional Review Board and Ethics Committee of Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. The management of the Landrace Large White pigs used in this study conforms to the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (Eighth Edition. Washington, DC: The National Academies Press, 2011).

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Carrer, V., Alonso, C., Pont, M. et al. Effect of propylene glycol on the skin penetration of drugs. Arch Dermatol Res 312, 337–352 (2020). https://doi.org/10.1007/s00403-019-02017-5

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