Microemulsions and microheterogeneous microemulsion-based polymeric matrices for transdermal delivery of lipophilic drug (Felodipine)

  • Natalia M. ZadymovaEmail author
  • Maria V. Poteshnova
Invited Article


Transdermal administration of drugs is more effective than traditional methods: metabolism of a drug in the gastrointestinal tract and liver is excluded, and its constant concentration in blood is provided. In most cases, the main part of the transdermal patch (TP) is a polymer film (matrix) with good adhesion to skin, which contains a skin permeability enhancer (SPE) and a drug. Types of TPs differ in a way of drug incorporating into the matrix. In this work, a new type of polymer matrices for the delivery of lipophilic drugs based on microemulsions is developed. An optimized direct microemulsion (IV type according to Winsor) is obtained; practically, all its components are SPEs. Microemulsion (ME) type is confirmed by conductometry and dynamic light-scattering methods. Solubilization capacity of ME in relation to the antihypertensive drug felodipine (FEL) is studied. This drug is characterized by poor water solubility and, consequently, by low bioavailability at oral administration (~ 15%). FEL solubility in ME exceeds its solubility in water by 2.2 × 104 times. ME efficiency as a carrier of FEL is shown using Franz diffusion cell and UV spectroscopy. The FEL-loaded microemulsion was used as the dispersed phase of the emulsion, and the dispersion medium of the emulsion was a solution of polymer adhesive (a mixture of polyisobutylenes with different molecular weights and polybutene) in heptane with optimized rheological properties. This emulsified ME (i.e., inverse emulsion) is served as a basis for the microheterogeneous polymer matrix, which provides FEL release at a constant target rate during the day.


Microemulsion Felodipine Emulsion Polymer matrix Transdermal drug delivery 



This work was supported by the Russian Foundation for Basic Research, project no. 15-08-04546.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Chien YW (1976) Advances in transdermal systemic medications. In: Chien YW (ed) Transdermal controlled systemic medications. Marcel Dekker, New York, pp 1–22Google Scholar
  2. 2.
    Williams A (2003) Transdermal and topical drug delivery. Pharmaceutical Press, LondonGoogle Scholar
  3. 3.
    Cleary GW (1993) Transdermal delivery system: a medical rationale. In: Shah VP, Maibach HI (eds) Topical drug bioavailability, bioequivalence, and penetration. Plenum Press, New York, pp 17–68. CrossRefGoogle Scholar
  4. 4.
    Hadgraft J (2003) Dermal and transdermal delivery. In: Rathbone MJ, Hadgraft J, Roberts MS (eds) Modified-release drug delivery technology. Marcel Dekker Inc., New York, pp 471–480Google Scholar
  5. 5.
    Margetts L, Sawyer R (2007) Transdermal drug delivery: principles and opioid therapy. Contin Educ Anesth Crit Care Pain 7:171–176. CrossRefGoogle Scholar
  6. 6.
    Dhiman S, Singh TG, Rehni AK (2011) Transdermal patches: a recent approach to new drug delivery system. Int J Pharm Pharm Sci 3:26–34Google Scholar
  7. 7.
    Patel D, Chaudhary SF, Parmar B, Bhura N (2012) Transdermal drug delivery system: a review. Pharma Innov 1:66–75Google Scholar
  8. 8.
    Chien YW (1987) Transdermal therapeutic systems. In: Robinson JL, Lee VHL (eds) Controlled drug delivery: fundamentals and applications. Marcel Dekker Inc., New York, pp 523–552. CrossRefGoogle Scholar
  9. 9.
    Schaefer H, Redelmaier TE (1996) Structure and dynamics of the skin barrier. In: Schaefer H, Redelmaier TE (eds) Skin barrier. Principles of percutaneous absorption. Kanger, Basel, pp 1–42. CrossRefGoogle Scholar
  10. 10.
    Walters KA, Roberts MS (2002) The structure and function of skin. In: Walters KA (ed) Dermatological and transdermal formulations. Marcel Dekker Inc., New York, pp 1–39CrossRefGoogle Scholar
  11. 11.
    Walters KA (1990) Transdermal drug delivery. In: Florence AT, Sabole EG (eds) Routes of drug administration. Marcel Dekker, New York, pp 80–132Google Scholar
  12. 12.
    Barry BW (2002) Drug delivery routes in skin: a novel approach. Adv Drug Deliv Rev 54:31–40. CrossRefGoogle Scholar
  13. 13.
    Saroha K, Yadav B, Sharma B (2011) Transdermal patch: a discrete dosage form. Int J Curr Pharm Res 3:98–108Google Scholar
  14. 14.
    Patel AA, Trivedi DG, Bhatt JK, Shah DA (2012) Transdermal patches: a technical note. Int J Pharm Innov 2:23–33Google Scholar
  15. 15.
    Shah S (2008) Transdermal drug delivery technology revisited: recent advances. Latest Rev 6:1–12Google Scholar
  16. 16.
    Aggarwal G, Dhawan S (2009) Development, fabrication and evaluation of transdermal drug delivery system – a review. Pharm Rev 7:39–43Google Scholar
  17. 17.
    Gaur PK, Mishra S, Purohit S, Dave K (2009) Transdermal drug delivery system: a review. Asian J Pharm Clin Res 2:14–20Google Scholar
  18. 18.
    Zadymova NM (2013) Colloid-chemical aspects of transdermal drug delivery (review). Colloid J 75:491–503. CrossRefGoogle Scholar
  19. 19.
    Huynh J, Aebi C (2008) Transdermal patches: to cut or not cut. Oregon DUR Board Newsletter 10:1–2Google Scholar
  20. 20.
    Chein YW, Tojo K (1987) Transdermal verapamil delivery device. Patent US 4690683Google Scholar
  21. 21.
    Aguadisch LMJ, Rankin FS (1989) Pharmaceutical delivery device having a siloxane polymer matrix. Patent US 4814184Google Scholar
  22. 22.
    Mjuller V (2002) Transdermal therapeutic system (TTS) with fentanyl as active substance. Patent RU 2311908C2Google Scholar
  23. 23.
    Willams AC, Barry BW (2004) Penetration enhancers. Adv Drug Del Rev 56:603–618. CrossRefGoogle Scholar
  24. 24.
    Trommer H, Neubert RHH (2006) Overcoming the stratum corneum: the modulation of skin penetration. Skin Pharmacol Physiol 19:106–121. CrossRefPubMedGoogle Scholar
  25. 25.
    Mbah CJ, Uzor PF, Omeje EO (2011) Perspectives on transdermal drug delivery. J Chem Pharm Res 3:680–700Google Scholar
  26. 26.
    Solans C, Kunieda H (eds) (1997) Industrial application of microemulsions. Marcel Dekker Inc., New York. CrossRefGoogle Scholar
  27. 27.
    Pate MR, Patel MR, Patel RB, Parikh JR, Bhatt KK, Kundawala AJ (2007) Microemulsions: as novel drug delivery vehicle. Pharm Rev 5Google Scholar
  28. 28.
    Saini JK, Nautiyal U, Kumar S, Singh D, Anwar F (2014) Microemulsions: a potential novel drug delivery system. Int J Pharm Med Res 2:15–20Google Scholar
  29. 29.
    Lawrence MJ (1994) Surfactant systems: their use in drug delivery. Chem Soc Rev 23:417–423. CrossRefGoogle Scholar
  30. 30.
    Malmsten M (1999) Microemulsions in pharmaceuticals. In: Kumar P, Mittal KL (eds) Handbook of microemulsion science and technology. Marcel Dekker, New York, pp 755–771Google Scholar
  31. 31.
    Lawrence MJ, Rees GD (2000) Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev 45:89–121. CrossRefPubMedGoogle Scholar
  32. 32.
    Gasco MR (1999) Microemulsions in the pharmaceutical field: perspectives and applications. In: Kumar P, Mittal KL (eds) Handbook of microemulsion science and technology. Marcel Dekker, New York, pp 97–121Google Scholar
  33. 33.
    Paul BK, Moulik SP (2001) Uses and applications of microemulsions. Curr Sci 80:990–1001Google Scholar
  34. 34.
    Kreilgaard M (2002) Influence of microemulsions on cutaneous drug delivery. Adv Drug Deliv Rev 54(Suppl 1):S77–S98CrossRefGoogle Scholar
  35. 35.
    Lee PJ, Langer R, Shastri VP (2003) Novel microemulsion enhancer formulation for simultaneous transdermal delivery of hydrophilic and hydrophobic drugs. Pharm Res 20:264–269. CrossRefPubMedGoogle Scholar
  36. 36.
    Sintov AC, Shapiro L (2004) New microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo. J Control Release 95:173–183. CrossRefPubMedGoogle Scholar
  37. 37.
    Kogan A, Garti N (2006) Microemulsions as transdermal drug delivery vehicles. Adv Colloid Interf Sci 123–126:369–385. CrossRefGoogle Scholar
  38. 38.
    Santos P, Watkinson AC, Hadgraft J, Lane ME (2008) Application of microemulsions in dermal and transdermal drug delivery. Skin Pharmacol Physiol 21:246–259. CrossRefPubMedGoogle Scholar
  39. 39.
    Heuschkel S, Goebel A, Neubert RHH (2008) Microemulsions – modern colloidal carrier for dermal and transdermal drug delivery. J Pharm Sci 97:603–631. CrossRefPubMedGoogle Scholar
  40. 40.
    Azeem A, Khan ZI, Aqil M, Ahmad FJ, Khar RK, Talegaonkar S (2009) Microemulsions as a surrogate carrier for dermal drug delivery. Drug Dev Ind Pharm 35:525–547. CrossRefPubMedGoogle Scholar
  41. 41.
    Hoar TP, Schulman JH (1943) Transparent water-in-oil dispersions: the oleopathic hydro-micelle. Nature 152:102–103. CrossRefGoogle Scholar
  42. 42.
    Schulman JH, Stoeckenius W, Prince LM (1959) Mechanism of formation and structure of micro еmulsions by electron microscopy. J Phys Chem 63:1677–1680. CrossRefGoogle Scholar
  43. 43.
    Danielsson I, Lindman B (1981) The definition of microemulsion. Colloids Surf 3:391–392. CrossRefGoogle Scholar
  44. 44.
    Scriven LE (1976) Equilibrium bicontinuous structure. Nature 263:123–125. CrossRefGoogle Scholar
  45. 45.
    Friberg S, Bothorel P (eds) (1987) Microemulsions structure and dynamics. CRC Press, FloridaGoogle Scholar
  46. 46.
    Moulik SP, Paul BK (1998) Structure, dynamics and transport properties of microemulsions. Adv Colloid Interf Sci 78:99–195. CrossRefGoogle Scholar
  47. 47.
    Ruckenstein E, Chi JC (1975) Stability of microemulsions. J Chem Soc Faraday Trans 2 71:1690–1707. CrossRefGoogle Scholar
  48. 48.
    Nagarajan R, Ruckenstein E (2000) Molecular theory of microemulsions. Langmuir 16:6400–6415. CrossRefGoogle Scholar
  49. 49.
    Kegel WK, Overbeek JTG, Lekkerkerker HNW (1999) Thermodynamics of microemulsions. In: Kumar P, Mittal KL (eds) Handbook of microemulsion science and technology. Marcel Dekker, New York, pp 13–44Google Scholar
  50. 50.
    Shchukin ED, Pertsov AV, Amelina EA, Zelenev AS (2001) Colloid and surface chemistry. Elsevier, Amsterdam
  51. 51.
    Winsor PA (1948) Hydrotropy, solubilization and related emulsification processes. Trans Faraday Soc 44:376–398. CrossRefGoogle Scholar
  52. 52.
    Winsor PA (1954) Solvent properties of amphiphilic compounds, vol 58. Butterworth Sci Pubs, London, pp 1103–1104. CrossRefGoogle Scholar
  53. 53.
    Kabalnov A, Lindman B, Olsson U, Piculell L, Thuresson K, Wennerstrom H (1996) Microemulsions in amphiphilic and polymer-surfactant systems. Colloid Polym Sci 274:297–308. CrossRefGoogle Scholar
  54. 54.
    Moulik SP, Rakshit AK (2006) Physicochemistry and applications of microemulsions. J Surf Sci Technol 22:159–186. CrossRefGoogle Scholar
  55. 55.
    Spermath A, Aserin A, Garti N (2006) Fully dilutable microemulsions embedded with phospholipids and stabilized by short-chain organic acids and polyols. J Colloid Int Sci 299:900–909. CrossRefGoogle Scholar
  56. 56.
    Spermath A, Aserin A, Ziserman L, Danino D, Garti N (2007) Phosphatidylcholine embedded microemulsions: physical properties and improved Caco-2 cell permeability. J Control Release 119:279–290. CrossRefGoogle Scholar
  57. 57.
    Kantarci G, Ozguney I, Karasulu HY, Arzik S, Guneri T (2007) Comparison of different water/oil microemulsions containing diclofenac sodium: preparation, characterization, release rate, and skin irritation studies. AAPS Pharm Sci Tech 8:75–81. CrossRefGoogle Scholar
  58. 58.
    Junyaprasert VB, Boonme P, Songkro S, Krauel K, Rades T (2007) Transdermal delivery of hydrophobic and hydrophilic local anesthetics from o/w and w/o Brij 97-based microemulsions. J Pharm Pharm Sci 10:288–298PubMedGoogle Scholar
  59. 59.
    Li PJ, Langer R, Shastri VP (2003) Novel microemulsion enhancer formulation for simultaneous transdermal delivery of hydrophilic and hydrophobic drugs. Pharm Res 20:264–269. CrossRefGoogle Scholar
  60. 60.
    Boltri L, Morel S, Trotta M, Gasco MR (1994) In vitro transdermal permeation of nifedipine from thickened microemulsions. J Pharm Belg 49:315–320PubMedGoogle Scholar
  61. 61.
    Trotta M, Morel S, Gasco MR (1997) Effect of oil phase composition on the skin permeation of felodipine from o/w microemulsions. Pharmazie 52:50–53PubMedGoogle Scholar
  62. 62.
    Zhao J-H, Ji L, Wang H, Chen Z-Q, Zhang Y-T, Liu Y, Feng N-P (2011) Microemulsion-based novel transdermal delivery system of tetramethylpyrazine: preparation and evaluation in vitro and in vivo. Int J Nanomedicine 6:1611–1619. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Yuan JS, Ansari M, Samaan M, Acosta E (2008) Linker-based lecithin microemulsions for transdermal delivery of lidocaine. Int J Pharm 349:130–143. CrossRefPubMedGoogle Scholar
  64. 64.
    Podlogar F, Rogac BM, Gasperlin M (2005) The effect of internal structure of selected water-tween 40-Imwitor 308-IPM microemulsions of ketoprofene release. Int J Pharm 302:68–77. CrossRefPubMedGoogle Scholar
  65. 65.
    Dreher F, Walde P, Walther P, Wehrli E (1997) Interaction of lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport. J Control Release 45:131–140. CrossRefGoogle Scholar
  66. 66.
    Lee E-A, Balakrishnan P, Song CK, Choi J-H, Noh GY, Park C-G, Choi A-J, Chung S-J, Shim C-K, Kim D-D (2010) Microemulsion-based hydrogel formulation of itraconazole for topical delivery. J of Pharm Investigation 40:305–311. CrossRefGoogle Scholar
  67. 67.
    Zhu W, Guo C, Yu A, Gao Y, Cao F, Zhai GX (2009) Microemulsion-based hydrogel formulation of penciclovir for topical delivery. Int J Pharm 378:52–55. CrossRefGoogle Scholar
  68. 68.
    Sabale V, Vora S (2012) Formulation and evaluation of microemulsion-based hydrogel for topical delivery. Int J Pharm Investig 2:140–149. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Singh M, Kanoujia J, Parashar P, Arya M, Tripathi CB, Sinha VR, Saraf SK, Saraf SA (2018) Assessment of improved buccal permeation and bioavailability of felodipine microemulsion-based cross-linked polycarbophil gel. Drug Deliv Transl Res 8:591–601. CrossRefPubMedGoogle Scholar
  70. 70.
    Sintov A (2002) Transdermal drug delivery system. Israeli Patent Application. №150334Google Scholar
  71. 71.
    Shi J, Cong W, Wang Y, Liu Q, Luo G (2012) Microemulsion-based patch for transdermal delivery of huperzine a and ligustrazine phosphate in treatment of Alzheimer’s disease. Drug Dev Ind Pharm 38:752–761. CrossRefPubMedGoogle Scholar
  72. 72.
  73. 73.
    Zadymova NM, Ivanova NI (2013) Tween 80–based mixed micelles as felodipine carriers in aqueous medium. Colloid J 75:159–169. CrossRefGoogle Scholar
  74. 74.
    Kerc J, Srcic S, Kofler B, Smid-Korbar J (1992) Molar solubility of felodipine in different aqueous systems. Int J Pharm 81:R1–R4. CrossRefGoogle Scholar
  75. 75.
    Poteshnova MV, Zadymova NM (2017) Aqueous solutions of hydroxypropyl cellulose, tween 80 and their binary mixtures: colloid-chemical aspects. Colloid Journal 79:797–808. CrossRefGoogle Scholar
  76. 76.
    Zapata RB, Villa AL, Montes de Correa C (2005) Liquid−liquid equilibrium for the water + acetonitrile + limonene system at different temperatures. J Chem Eng Data 50:1353–1356. CrossRefGoogle Scholar
  77. 77.
    Schönfeldt N (1976) Grenzflachenaktive a thylenoxid-addukte. Wissenschaftliche Verlagsgesellschaft mbH, StuttgartGoogle Scholar
  78. 78.
    Fanum M, Al-Diyn WS (2007) Structural transition in system water/mixed nonionic surfactants / R (+) limonene studied by electrical conductivity and self-diffusion-NMR. J Dispers Sci Technol 28:165–174. CrossRefGoogle Scholar
  79. 79.
    Benedek I, Feldstein MM (eds) (2008) Handbook of pressure-sensitive adhesives and products. Applications of pressure-sensitive products. CRC Press, Boca RatonGoogle Scholar
  80. 80.
    Tavares L, Shevchuk I, Alfonso M, Marcenyak G, Valia K (2002) Felodipine transdermal device and methods. Patent WO/2002/034206Google Scholar
  81. 81.
    Wohlfarth C (2015) Static dielectric constants of pure liquids and binary liquid mixtures Suppl to Vol IV/17. Springer, BerlinGoogle Scholar
  82. 82.
    Evans DF, Miller DD (1992) Organized solutions and their manifestations in polar solvents. In: Friberg SE, Lindman B (eds) Organized solutions: surfactants in science and technology. Marcel Dekker, New York, pp 33–45Google Scholar
  83. 83.
    Seguin C, Eastoe J, Heenan RK, Grillo I (2007) SANS studies of the effects of surfactant head group on aggregation properties in water/glycol and pure glycol systems. J Colloid Interface Sci 315:714–720. CrossRefPubMedGoogle Scholar
  84. 84.
    Zadymova NM, Arshakyan GA (2014) Inhibition of Ostwald ripening in heptane/water miniemulsions. Colloid J 76:25–37. CrossRefGoogle Scholar
  85. 85.
    Schramm G (2000) A practical approach to rheology and Rheometry. Gebrueder HAAKE GmbH, KarlsruheGoogle Scholar
  86. 86.
    Zadymova NM, Yampolskaya GP, Poteshnova MV, Kulichikhin VG (2011) Emulsion approach to production of polymer films used as carriers of lysozyme. Colloid J 73:635–645. CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Chemistry DepartmentLomonosov Moscow State UniversityMoscowRussia

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