AAPS PharmSciTech

, Volume 19, Issue 3, pp 1367–1376 | Cite as

Formulation and Evaluation of Organogels Containing Hyaluronan Microparticles for Topical Delivery of Caffeine

  • Erol Eli Simsolo
  • İpek Eroğlu
  • Sakine Tuncay Tanrıverdi
  • Özgen Özer
Research Article


Cellulite is a dermal disorder including the extracellular matrix, the lymphatic and microcirculatory systems and the adipose tissue. Caffeine is used as the active moiety depending its preventive effect on localization of fat in the cellular structure. Hyaluronic acid (hyaluronan-HA) is a natural constituent of skin that generates formation and poliferation of new cells having a remarkable moisturizing ability. The aim of this study is to formulate HA microparticles loaded with caffeine via spray-drying method. Resulting microparticle formulations (33.97 ± 0.3 μm, span < 2, 88.56 ± 0.42% encapsulation efficiency) were distributed in lecithin organogels to maintain the proper viscosity for topical application. Following the characterization and cell culture studies, in vitro drug release and ex vivo permeation studies were performed. The accumulated amount of caffeine was twice higher than the aqueous solution for the microparticle-loaded organogels at 24 h (8262,673 μg/cm2versus 4676,691 μg/cm2). It was related to the sustained behaviour of caffeine release from the microparticles. As a result, lecithin organogel containing HA-encapsulated microparticles could be considered as suitable candidate formulations for efficient topical drug delivery system of caffeine. In addition to that, synergistic effect of this combination appears as a promising approach for long-acting treatment of cellulite.


caffeine hyaluronan microparticles organogel cellulite skin permeation 



This study was supported by the Research Foundation of Ege University (Grant Number 12/ECZ/029). The authors are grateful to Prof. Hande Gürer Orhan from Ege University, Faculty of Pharmacy, Department of Toxicology for conducting cell culture studies and Ege University, Faculty of Pharmacy, Pharmaceutical Sciences Research Centre (FABAL) for equipmental support in UPLC analysis. The authors would also like to thank TUBITAK for purchasing of the spray dryer under the project number 111S183.

Compliance with Ethical Standards

Wistar Albino rats used for the study were approved by the Local Animal Ethical Committee.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Herman A, Herman AP. Caffeine's mechanisms of action and its cosmetic use. Skin Pharmacol Physiol. 2013;26(1):8–14. Scholar
  2. 2.
    Rawlings AV. Cellulite and its treatment. Int J Cosmet Sci. 2006;28(3):175–90. Scholar
  3. 3.
    Khan MH, Victor F, Rao B, Sadick NS. Treatment of cellulite: part II. Adv Controversies J Am Acad Dermatol. 2010;62(3):373–84; quiz 385-6. Scholar
  4. 4.
    B. Sandrine, M. B. Alexandrine, P. Jocelyne, V.J. Pierre, and S. Briançon. Caffeine Microspheres –An Attractive Carrier To Achieve Optimum Skin Penetration. in Cosmetic Science Conference −2009 Proceedings. 2013.Google Scholar
  5. 5.
    Luo L, Lane ME. Topical and transdermal delivery of caffeine. Int J Pharm. 2015;490(1-2):155–64. Scholar
  6. 6.
    Rodrigues F, Alves AC, Nunes C, Sarmento B, Amaral MH, Reis S, et al. Permeation of topically applied caffeine from a food by-product in cosmetic formulations: is nanoscale in vitro approach an option? Int J Pharm. 2016;513(1-2):496–503. Scholar
  7. 7.
    Prow TW, Grice JE, Lin LL, Faye R, Butler M, Becker W, et al. Nanoparticles and microparticles for skin drug delivery. Adv Drug Deliv Rev. 2011;63(6):470–91. Scholar
  8. 8.
    Swatschek D, Schatton W, Muller W, Kreuter J. Microparticles derived from marine sponge collagen (SCMPs): preparation, characterization and suitability for dermal delivery of all-trans retinol. Eur J Pharm Biopharm. 2002;54(2):125–33. Scholar
  9. 9.
    Lam PL, Gambari R. Advanced progress of microencapsulation technologies: in vivo and in vitro models for studying oral and transdermal drug deliveries. J Control Release. 2014;178:25–45. Scholar
  10. 10.
    Eroglu I, Gokce EH, Tsapis N, Tanriverdi ST, Gokce G, Fattal E, et al. Evaluation of characteristics and in vitro antioxidant properties of RSV loaded hyaluronic acid-DPPC microparticles as a wound healing system. Colloids Surf B Biointerfaces. 2015;126:50–7. Scholar
  11. 11.
    Esposito E, Menegatti E, Cortesi R. Hyaluronan-based microspheres as tools for drug delivery: a comparative study. Int J Pharm. 2005;288(1):35–49. Scholar
  12. 12.
    Gokce EH, Tanrıverdi ST, Eroglu I, Tsapis N, Gokce G, Tekmen I, et al. Wound healing effects of collagen-laminin dermal matrix impregnated with resveratrol loaded hyaluronic acid-DPPC microparticles in diabetic rats. Eur J Pharm Biopharm. 2017;119:17–27. Scholar
  13. 13.
    Gomez-Gaete C, Tsapis N, Silva L, Bourgaux C, Besnard M, Bochot A, et al. Supramolecular organization and release properties of phospholipid-hyaluronan microparticles encapsulating dexamethasone. Eur J Pharm Biopharm. 2008;70(1):116–26. Scholar
  14. 14.
    Gomez Gaete C, Tsapis N, Silva L, Bourgaux C, Fattal E. Morphology, structure and supramolecular organization of hybrid 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine-hyaluronic acid microparticles prepared by spray drying. Eur J Pharm Sci. 2008;34(1):12–21. Scholar
  15. 15.
    Hwang SM, Kim DD, Chung SJ, Shim CK. Delivery of ofloxacin to the lung and alveolar macrophages via hyaluronan microspheres for the treatment of tuberculosis. J Control Release. 2008;129(2):100–6. Scholar
  16. 16.
    Allegra L, Della PS, Petrigni G. Hyaluronic acid: perspectives in lung diseases. Handb Exp Pharmacol. 2012;207(207):385. Scholar
  17. 17.
    Nageeb M, Nouh SR, Bergman K, Nagy NB, Khamis D, Kisiel M, et al. Bone engineer- ing by biomimetic injectable hydrogel. Mol Cryst Liq Cryst. 2012;555(1):177–88. Scholar
  18. 18.
    Shona Pek Y, Kurisawa M, Gao S, Chung JE, Ying JY. The development of a nano- apatite reinforced crosslinked hyaluronic acid–tyramine composite as an injectable bone cement. Biomaterials. 2009;30(5):822–8. Scholar
  19. 19.
    Fatnassi M, Jacquart S, Brouillet F, Rey C, Combes C, Girod Fullana S. Optimization of spray-dried hyaluronic acid microspheres to formulate drug-loaded bone substitute materials. Powder Technol. 2014;255:44–51.CrossRefGoogle Scholar
  20. 20.
    Cheolbyong C, Deuk Yong L, Jin-Tae K, Mi-Kyung K, Young-Zu K, Seok-Soon K. Effect of molecular weight of hyaluronic acid (HA) on viscoelasticity and particle texturing feel of HA dermal biphasic fillers. Biomater Res. 2016;20(24).Google Scholar
  21. 21.
    Pedro BS, Rui RL, Manuela GE. Production and characterization of hyaluronic acid microparticles for the controlled delivery of growth factors using a spray/dehydration method. J Biomater Appl. 2016;31(5):693–707.CrossRefGoogle Scholar
  22. 22.
    Paice JA, Von Roenn JH, Hudgins JC, Luong L, Krejcie TC, Avram MJ. Morphine bioavailability from a topical gel formulation in volunteers. J Pain Symptom Manag. 2008;35(3):314–20. Scholar
  23. 23.
    Vintiloiu A, Leroux JC. Organogels and their use in drug delivery--a review. J Control Release. 2008;125(3):179–92. Scholar
  24. 24.
    Surjyanarayan M, Snigdha SM, Krutika KS. Lecithin stabilized Organogel: design and development for topical application of Clobetasol propionate. Int J PharmTech Res. 2010;2:1133–8.Google Scholar
  25. 25.
    Sahoo S, Kumar N, Bhattacharya C, Sagiri SS, Jain K, Pal K, et al. Organogels: properties and applications in drug delivery. Des Monomers Polym. 2011;14(2):95–108. Scholar
  26. 26.
    Raut S, Bhadoriya SS, Uplanchiwar V, Mishra V, Gahane A, Jain SK. Lecithin organogel: a unique micellar system for the delivery of bioactive agents in the treatment of skin aging. Acta Pharm Sin B. 2012;2(1):8–15. Scholar
  27. 27.
    Eroğlu H, Haidar MK, Nemutlu E, Öztürk Ş, Bayram C, Ulubayram K, et al. Dual release behavior of atorvastatin and alpha-lipoic acid from PLGA microspheres for the combination therapy in peripheral nerve injury. J Drug Delivery Sci Technol. 2017;39:455–66. Scholar
  28. 28.
    ICH Expert Working Group. Stability testing of new drug substances and Products Q1A (R2). 2003.
  29. 29.
    Gowda DV, Khan MS, Nagendra R. Spray dried indapamide microparticles for controlled release– a novel approach. Int J Pharm Bio Sci. 2010;1:459–66.Google Scholar
  30. 30.
    Zhang P, Chen L, Gu W, Xu Z, Gao Y, Li Y. In vitro and in vivo evaluation of donepezil-sustained release microparticles for the treatment of Alzheimer's disease. Biomaterials. 2007;28(10):1882–8. Scholar
  31. 31.
    Rossi T, Iannuccelli V, Coppi G, Bruni E, Baggio G. Role of the pharmaceutical excipients in the tamoxifen activity on MCF-7 and vero cell cultures. Anticancer Res. 2009;29(11):4529–33.Google Scholar
  32. 32.
    Satapathy D, Biswas D, Behera B, Sagiri SS, Pal K, Pramanik K. Sunflower-oil-based lecithin organogels as matrices for controlled drug delivery. J Appl Polym Sci. 2013;129(2):585–94. Scholar
  33. 33.
    Tamura T, Ichikawa M. Effect of lecithin on Organogel formation of 12-Hydroxystearic acid. JAOCS. 1997;74(5).Google Scholar
  34. 34.
    Schurtenberger P, Scartazzini R, Magid LJ, Leser ME, Luisi PL. Structure and dynamic properties of polymer-like reverse micelles. J Phys Chem. 1990;94(9):3695–701. Scholar
  35. 35.
    Raut Singh S, Bhadoriya S, Uplanchiwar V, Mishra V, Gahane A, Kumar Jain S. Lecithin organogel: a unique micellar system for the delivery of bioactive agents in the treatment of skin aging. Acta Pharm Sin B. 2012;2(1):8–15.CrossRefGoogle Scholar
  36. 36.
    Justin-Temu M, Damian F, Kinget R, van Den Mooter G. Intra-vaginal gels as drug delivery systems. J Women Health (Larchmt). 2004;13:834–44.CrossRefGoogle Scholar
  37. 37.
    Scartazzini R, Luisi PL. Organogels from Lecithins. J Phys Chem. 1988;92(3):829–33. Scholar
  38. 38.
    Lim PFC, Liu XY, Kang LF, Ho PCL, Chan YW, Chan SY. Limonene GP1/PG organogel as a vehicle in transdermal delivery of haloperidol. Int J Pharm. 2006;311(1-2):157–64. Scholar
  39. 39.
    Ozcan I, Azizoglu E, Senyigit T, Ozyazici M, Ozer O. Enhanced dermal delivery of diflucortolone valerate using lecithin/chitosan nanoparticles: in vitro and in vivo evaluations. Int J Nanomedicine. 2013;8:461–75. Scholar
  40. 40.
    Rencber S, Karavana SY, Senyigit ZA, Erac B, Limoncu MH, Baloglu E. Mucoadhesive a priori gel formulation for vaginal delivery of clotrimazole: formulation, preparation, and in vitro/in vivo evaluation. Pharm Dev Technol. 2017;22(4):551–61. Scholar
  41. 41.
    Aksungur P, Demirbilek M, Denkbas EB, Vandervoort J, Ludwig A, Unlu N. Development and characterization of cyclosporine a loaded nanoparticles for ocular drug delivery: cellular toxicity, uptake, and kinetic studies. J Control Release. 2011;151(3):286–94. Scholar
  42. 42.
    Dreher F, Walde P, Walther P, Wehrli E. Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport. J Control Release. 1997;45(2):131–40. Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Erol Eli Simsolo
    • 1
  • İpek Eroğlu
    • 2
  • Sakine Tuncay Tanrıverdi
    • 1
  • Özgen Özer
    • 1
  1. 1.Faculty of Pharmacy, Department of Pharmaceutical TechnologyEge UniversityIzmirTurkey
  2. 2.Faculty of Pharmacy, Department of Basic Pharmaceutical SciencesHacettepe UniversityAnkaraTurkey

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