Medicated Foams and Film Forming Dosage Forms as Tools to Improve the Thermodynamic Activity of Drugs to be Administered Through the Skin

Author(s): Chiara G.M. Gennari, Francesca Selmin, Paola Minghetti, Francesco Cilurzo*.

Journal Name: Current Drug Delivery

Volume 16 , Issue 5 , 2019

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Graphical Abstract:


Medicated foams and film forming systems are dosage forms formulated to undergo a controlled metamorphosis when applied on the skin. Indeed, due to the presence of propellant or a particular air-spray foam pump, a liquid can generate foam when applied on the stratum corneum, or a liquid or conventional dosage form can form on the skin a continuous film as a consequence of the solvent evaporation. Thanks to these controlled modifications, the drug thermodynamic activity increases favoring the skin penetration and, therefore, the bioavailability with respect to conventional semi-solid and liquid dosage forms. Furthermore, the available clinical data also evidence that these dosage forms improve the patient’s compliance. The main formulative aspects of medicated foams and film forming systems are reviewed with the aim to underline the possible advantages in terms of biopharmaceutical performances and patient’s adherence.

Keywords: Cutaneous administration, film forming system, medicated foam, skin permeation, substantivity, supersaturation.

Cilurzo, F.; Gennari, C.G.M.; Selmin, F.; Franzé, S.; Musazzi, U.M.; Minghetti, P. On the characterization of medicated plasters containing NSAIDs according to novel indications of USP and EMA: Adhesive property and in vitro skin permeation studies. Drug Dev. Ind. Pharm., 2015, 41(2), 183-189.
Cilurzo, F.; Casiraghi, A.; Selmin, F.; Minghetti, P. Supersaturation as a tool for skin penetration enhancement. Curr. Pharm. Design., 2015, 20, 2733-2744.
Hadgraft, J.; Lane, M.E. Drug crystallization - implications for topical and transdermal delivery. Exp Opin. Drug Deliv., 2016, 13(6), 817-830.
Cilurzo, F.; Alberti, E.; Minghetti, P.; Gennari, C.G.M.; Casiraghi, A.; Montanari, L. Effect of drug chirality on the skin permeability of ibuprofen. Int. J. Pharm., 2010, 386(1-2), 71-76.
Angamuthu, M.; Shankar, V.K.; Murthy, S.N. Water activity and its significance in topical dosage forms. J. Pharm. Sci., 2018, 107(6), 1656-1666.
Belsey, N.A.; Garrett, N.L.; Contreras-Rojas, L.R.; Pickup-Gerlaugh, A.J.; Price, G.J.; Moger, J.; Guy, R.H. Evaluation of drug delivery to intact and porated skin by coherent Raman scattering and fluorescence microscopies. J. Control. Release, 2014, 174(1), 37-42.
Huang, X.; Tanojo, H.; Lenn, J.; Deng, C.H.; Krochmal, L. A novel foam vehicle for delivery of topical corticosteroids. J. Am. Acad. Dermat., 2005, 53(1), S26-S38.
Tamarkin, D.; Friedman, D.; Shemer, A. Emollient foam in topical drug delivery. Expert Opin. Drug Deliv., 2006, 3, 799-807.
Zhao, Y.; Moddaresi, M.; Jones, S.A.; Brown, M.B. A dynamic topical hydrofluoroalkane foam to induce nanoparticle modification and drug release in situ. Eur. J. Pharm. Biopharm., 2009, 72, 521-528.
Zhao, Y.; Brown, M.B.; Jones, S.A. The topical delivery of benzoyl peroxide using elegant dynamic hydrofluoroalkane foams. J. Pharm. Sci., 2010, 99(3), 1384-1398.
Zhao, Y.; Brown, M.B.; Jones, S.A. The effects of particle properties on nanoparticle drug retention and release in dynamic minoxidil foams. Int. J. Pharm., 2010, 383, 277-284.
Lind, M. Supersaturation of Calcipotriene and Betamethasone Dipropionate in a novel aerosol foam formulation for topical treatment of psoriasis provides enhanced bioavailability of the active ingredients. Dermatol. Ther. (Heidelb.), 2016, 6(3), 413-425.
Aguzzi, C.; Rossi, S.; Bagnasco, M.; Lanata, L.; Sandri, G.; Bona, F.; Ferrari, F.; Bonferoni, M.C.; Caramella, C. Penetration and distribution of thiocolchicoside through human skin: Comparison between a commercial foam (Miotens®) and a drug solution. AAPS PharmSciTech, 2008, 9(4), 1185-1190.
Mirtič, J.; Papathanasiou, F.; Temova Rakuša, Ž. GosencaMatjaž, M.; Roškar, R.; Kristl, J. Development of medicated foams that combine incompatible hydrophilic and lipophilic drugs for psoriasis treatment. Int. J. Pharm., 2017, 524(1-2), 65-76.
Blume-Peytavi, U.; Massoudy, L.; Patzelt, A.; Lademann, J.; Dietz, E.; Rasulev, U.; Bartels, N.G. Follicular and percutaneous penetration pathways of topically applied minoxidil foam. Eur. J. Pharm. Biopharm., 2010, 76, 450-453.
Jarratt, M.; Werner, C.P.; Alió Saenz, A.B. Tazarotene Foam versus tazarotene gel: A randomized relative bioavailability study in acne vulgaris. Clin. Drug Investig., 2013, 33, 283.
Draelos, Z.D.; Elewski, B.E.; Harper, J.C.; Sand, M.; Staedtler, G.; Nkulikiyinka, R.; Shakery, K. A phase 3 randomized, double-blind, vehicle-controlled trial of azelaic acid foam 15% in the treatment of papulopustular rosacea. Cutis, 2015, 96, 54-61.
Bensignor, E.J.; Fabriès, L.J. Use of antipruritic and rehydrating foams on localized lesions of atopic dermatitis in dogs: A small-scale pilot and comparative double-blinded study. Vet. Dermatol., 2018, 29(5), 446-e150.
Elewski, B.E.; Vlahovic, T.C. Econazole nitrate foam 1% for the treatment of tinea pedis: Tesults from two double-blind, vehicle-controlled, phase 3 clinical trials. J. Drugs Dermatol., 2014, 13(7), 803-808.
Feldman, S.R.; Werner, C.P.; Saenz, A.B.A. The efficacy and tolerability of tazarotene foam, 0.1%, in the treatment of acne vulgaris in 2 multicenter, randomized, vehicle-controlled, double-blind studies. J. Drugs Dermatol., 2013, 12(4), 438-446.
Zhao, Y.; Brown, M.B.; Jones, S.A. Pharmaceutical foams: Are they the answer to the dilemma of topical nanoparticles? Nanomedicine, 2010, 6, 227-236.
Bikerman, J.J. Foams, 1st ed; Springer-Verlag Berlin Heidelberg: New York, 1973.
Arzhavitina, A.; Steckel, H. Foams for pharmaceutical and cosmetic application. Int. J. Pharm., 2010, 394(1-2), 1-17.
Vervaet, C.; Byron, P.R. Drug-surfactant-propellant interactions in HFA-formulations. Int. J. Pharm., 1999, 186(1), 13-30.
McDonald, K.J.; Martin, G.P. Transition to CFC-free metered dose inhalers - into the new millennium. Int. J. Pharm., 2000, 201, 89-107.
Murray, B.S.; Ettelaie, R. Foam stability: proteins and nanoparticles. Curr. Opin. Colloid Interface Sci., 2004, 9, 314-320.
Roberts, K.; Axberg, C.; Österlund, R. In: Foams; Akers, R.J., Ed.; Academic Press: London, 1976; pp. 39-51.
Müller, R.H. In: Pharmazeutische Technologie: Moderne Arzneiformen; , 1997; 26, p. 323.
Kroepke, R.; Bleckmann, A.; Riedel, H.; Rohde, O.; Trau, J. Cosmetic post-foaming preparations with secondary propellant to achieve cooling effect.Patent EP 1391192 A1, 25 February 2004.
Kealy, T.; Abramb, A.; Hunt, B.; Buchta, R. The rheological properties of pharmaceutical foam: Implications for use. Int. J. Pharm., 2008, 355, 67-80.
Buchta, R.; Ding, S.; Hickey, A.; Houghton, M.; Noland, P.; Tice, T.; Warner, K.; Brown, W. Pharmaceutical Foams. Pharmacopeial forum, 2017, 43(1), 1-21.
Gennari, C.; Selmin, F.; Franzè, S.; Musazzi, U.M.; Quaroni, G.M.G.; Casiraghi, A.; Cilurzo, F. A glimpse in critical attributes to design cutaneous film forming systems based on ammonium methacrylate. J. Drug Deliv. Sci. Technol., 2017, 41, 157-163.
Lecomte, F.; Siepmann, J.; Walther, M.; MacRae, R.J.; Bodmeier, R. Polymer blends used for the coating of multiparticulates: comparison of aqueous and organic coating techniques. Pharm. Res., 2004, 21(5), 882-890.
Siepmann, F.; Siepmann, J.; Walther, M.; MacRae, R.J.; Bodmeier, R. Polymer blends for controlled release coatings. J. Control. Release, 2008, 125(1), 1-15.
Felton, L.A. Mechanisms of polymeric film formation. Int. J. Pharm., 2013, 457(2), 423-427.
Bauer, K.H.; Lehmann, K.; Osterwald, H.P.; Rothgang, G. Coated Pharmaceutical Dosage Forms; CRC Press: Boca Raton, FL, 1998.
Cilurzo, F.; Selmin, F.; Vistoli, G.; Minghetti, P.; Montanari, L. Binary polymeric blends to microencapsulate nitroflurbiprofen: Physicochemical and in silico studies. Eur. J. Pharm. Sci., 2007, 31(3-4), 202-210.
Frederiksen, K.; Guy, R.H.; Petersson, K. The potential of polymeric film-forming systems as sustained delivery platforms for topical drugs. Expert Opin. Drug Deliv., 2016, 13(3), 349-360.
Zurdo Schroeder, I.; Franke, P.; Schaefer, U.F.; Lehr, C-M. Development and characterization of film forming polymeric solutions for skin drug delivery. Eur. J. Pharm. Biopharm., 2007, 65(1), 111-121.
Algin, Y.E. Inal. Ö. Transdermal spray in hormone delivery. Trop. J. Pharm. Res., 2014, 13(3), 469-474.
Lu, W.; Luo, H.; Wu, Y. Preparation and characterization of a metered dose transdermal spray for testosterone. Acta Pharm. Sin. B, 2013, 3(6), 392-399.
Cilurzo, F.; Selmin, F.; Gennari, C.G.M.; Montanari, L.; Minghetti, P. Application of methyl methacrylate copolymers to the development of transdermal or loco-regional drug delivery systems. Expert Opin. Drug Deliv., 2014, 11(7), 1033-1045.
Mundada, A.S.; Avari, J.G. Novel biomaterial for transdermal application: In vitro and in vivo characterization. Drug Deliv., 2011, 18(6), 424-431.
Gennari, C.G.M.; Selmin, F.; Ortenzi, M.A.; Franzè, S.; Musazzi, U.M.; Casiraghi, A.; Minghetti, P.; Cilurzo, F. In situ film forming fibroin gel intended for cutaneous administration. Int. J. Pharm., 2006, 511, 296-302.
Bigucci, F.; Abruzzo, A.; Saladini, B.; Gallucci, M.C.; Cerchiara, T.; Luppi, B. Development and characterization of chitosan/hyaluronan film for transdermal delivery of thiocolchicoside. Carbohydr. Polym., 2015, 130, 32-40.
Patel, V.F.; Liu, F.; Brown, M.B. Advances in oral transmucosal drug delivery. J. Control. Release, 2011, 153, 106-116.
Cilurzo, F.; Gennari, C.G.M.; Minghetti, P. Adhesive properties: A critical issue in transdermal patch development. Exp Op. Drug Deliv., 2012, 9(1), 33-45.
Administration USFaD. Inactive ingredient search for approved drug products. FDA Drug Databases [Internet]. 2013 8/23/2013. Available from:., http://www.
Committee for Human Medicinal Products (CHMP), EMA/CHMP/507988/2013. 23/01/2013. Questions and Answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00). Available from:.
Williams, A.C.; Barry, B.W. Penetration enhancers. Adv. Drug Del. Rev., 2004, 56(5), 603-618.
Pham, Q.D.; Topgaard, D.; Sparr, E. Tracking solvents in the skin through atomically resolved measurements of molecular mobility in intact stratum corneum. Proc. Natl. Acad. Sci. USA, 2017, 114(2), E112-E121.
Garvie-Cook, H.; Frederiksen, K.; Petersson, K.; Guy, R.H.; Gordeev, S. Characterization of topical film-forming systems using atomic force microscopy and Raman microspectroscopy. Mol. Pharm., 2015, 12(3), 751-757.
Herrmann, S.; Daniels, R.; Lunter, D. Methods for the determination of the substantivity of topical formulations. Pharm. Develop. Technol., 2017, 22(4), 487-491.
Frederiksen, K.; Guy, R.H.; Petersson, K. Formulation considerations in the design of topical, polymeric film-forming systems for sustained drug delivery to the skin. Eur. J. Pharm. Biopharm., 2015, 91, 9-15.
Garvie-Cook, H.; Frederiksen, K.; Petersson, K.; Guy, R.H.; Gordeeva, S.N. Biophysical elucidation of the mechanism of enhanced drug release and topical delivery from polymeric film-forming systems. J. Control. Release, 2015, 212, 103-112.
Schroeder, I.Z.; Franke, P.; Schaefer, U.F. Delivery of ethinylestradiol from film forming polymeric solutions across human epidermis in vitro and in vivo in pigs. J. Control. Release, 2007, 118(2), 196-203.
Ammar, H.O.; Ghorab, M.; Mahmoud, A.A.; Makram, T.S.; Ghoneim, A.M. Rapid pain relief using film forming polymeric solution of ketorolac. Pharm. Dev. Tech., 2013, 18(5), 1005-1016.
Sritharadol, R.; Nakpheng, T.; Heng, P.W.S.; Srichana, T. Development of a topical mupirocin spray for antibacterial and wound-healing applications. Drug Dev. Ind. Pharm., 2017, 43(10), 1715-1728.
Bakshi, A.; Bajaj, A.; Malhotra, G. A novel metered dose transdermal spray formulation for oxybutynin. Indian J. Pharm. Sci., 2008, 70(6), 733-739.
Edwards, A.; Qi, S.; Liu, F.; Brown, M.B.; McAuley, W.J. Rationalising polymer selection for supersaturated film forming systems produced by an aerosol spray for the transdermal delivery of methylphenidate. Eur. J. Pharm. Biopharm., 2017, 114, 164-174.
Ranade, S.; Bajaj, A.; Londhe, V.; Babul, N.; Kao, D. Fabrication of topical metered dose film forming sprays for pain management. Eur. J. Pharm. Sci., 2017, 100, 132-141.
Reid, M.L.; Benaouda, F.; Khengar, R. Topical corticosteroid delivery into human skin using hydrofluoroalkane metered dose aerosol sprays. Int. J. Pharm., 2013, 452(1-2), 157-165.
Lu, W.; Luo, H.; Zhu, Z.; Wu, Y.; Luo, J.; Wang, H. Preparation and the biopharmaceutical evaluation for the metered dose transdermal spray of dexketoprofen. J. Drug Deliv., 2014, 2014, 1-12.
Gohel, M.C.; Nagori, S.A. Fabrication of modified transport fluconazole transdermal spray containing ethyl cellulose and Eudragit® RS100 as film formers. AAPS PharmSciTech, 2009, 10(2), 684-691.
Malik, R.; Venkatesh, K.S.; Dwivedi, A.K.; Misra, A. Episodic transdermal delivery of testosterone. Mol. Pharm., 2012, 9, 1537-1543.
Heck, R.; Hermann, S.; Lunter, D.J.; Daniels, R. Film-forming formulations containing porous silica for the sustained delivery of actives to the skin. Eur. J. Pharm. Biopharm., 2016, 108, 1-8.
Heck, R.; Lukić, M.Ž.; Savić, S.D.; Daniels, R.; Lunter, D.J. Ex vivo skin permeation and penetration of nonivamide from and in vivo skin tolerability of film-forming formulations containing porous silica. Eur. J. Pharm. Sci., 2017, 106, 34-40.
Lunter, D.J.; Daniels, R. New film forming emulsions containing Eudragit® NE and/or RS 30D for sustained dermal delivery of nonivamide. Eur. J. Pharm. Biopharm., 2012, 82(2), 291-298.
Guo, R.; Du, X.; Zhang, R.; Deng, L.; Dong, A.; Zhang, J. Bioadhesive film formed from a novel organic-inorganic hybrid gel for transdermal drug delivery system. Eur. J. Pharm. Biopharm., 2011, 79, 574-583.
Oh, D-W.; Kang, J-H.; Lee, H-J.; Han, S-D.; Kang, M-H.; Kwon, Y-H.; Jun, J-H.; Kim, D-W.; Rhee, Y-S.; Kim, J-Y.; Park, E-S.; Park, C-W. Formulation and in vitro/in vivo evaluation of chitosan-based film forming gel containing ketoprofen. Drug Deliv., 2017, 24(1), 1056-1066.
Li, X.; Zhang, R.; Liang, R.; Liu, W.; Wang, C.; Su, Z.; Sun, F.; Li, Y. Preparation and characterization of sustained-release rotigotine film-forming gel. Int. J. Pharm., 2014, 460, 273-279.
Liu, X.; Fu, L.; Dai, W.; Liu, W.; Zhao, J.; Wu, Y.; Teng, L.; Sun, F.; Li, Y. Design of transparent film-forming hydrogels of tolterodine and their effects on stratum corneum. Int. J. Pharm., 2014, 471, 322-331.
Rao, P.R.; Diwan, P.V. Permeability studies of cellulose acetate free films for transdermal use: influence of plasticizers. Pharm. Acta Helv., 1997, 72, 47-51.
Otto, A.; du Plessis, J.; Wiechers, J.W. Formulation effects of topical emulsions on transdermal and dermal delivery. Int. J. Cosmet. Sci., 2009, 31(1), 1-19.
Bonina, F.P.; Puglia, C.; Trombetta, D.; Dragani, M.C.; Gentile, M.M.; Clavenna, G. Vehicle effects on in vitro skin permeation of thiocolchicoside. Pharmazie, 2002, 57(11), 750-752.
Mitra, A.; Wu, Y. Topical delivery for the treatment of psoriasis. Expert Opin. Drug Deliv., 2010, 7(8), 977-992.
Su, Y-H.; Fang, J-Y. Drug delivery and formulations for the topical treatment of psoriasis. Expert Opin. Drug Deliv., 2008, 5(2), 235-249.
Kaur, I.P.; Kakkar, S. Topical delivery of antifungal agents. Expert Opin. Drug Deliv., 2010, 7(11), 1303-1327.
Franz, T.J.; Parsell, D.A.; Halualani, R.M.; Hannigan, J.F. Kalbach. JP.; Harkonen, W.S. Betamethasone valerate foam 0.12%: A novel vehicle with enhanced delivery and efficacy. Int. J. Dermatol., 1999, 38, 628-632.
Santos, P.; Watkinson, A.C.; Hadgraft, J.; Lane, M.E. Influence of penetration enhancer on drug permeation from volatile formulations. Int. J. Pharm., 2012, 439(1-2), 260-268.
Ibrahim, S.A. Spray-on transdermal drug delivery systems. Expert Opin. Drug Deliv., 2015, 12(2), 195-205.
Cilurzo, F.; Musazzi, U.M.; Franzé, S.; Fedele, G.; Minghetti, P. Design of in vitro skin permeation studies according to the EMA guideline on quality of transdermal patches. Eur. J. Pharm. Sci., 2018, 125, 86-92.
Sitruk-Ware, R.; Nath, A.; Mishell, D.R., Jr Contraception technology: past, present and future. Contraception, 2013, 87(3), 319-330.
Vrijens, B.; De Geest, S.; Hughes, D.A. A new taxonomy for describing and defining adherence to medications. Br. J. Clin. Pharmacol., 2012, 73(5), 691-705.
Tan, X.; Feldman, S.R.; Chang, J.; Balkrishnan, R. Topical drug delivery systems in dermatology: A review of patient adherence issues. Expert Opin. Drug Deliv., 2012, 9(10), 1263-1271.
Devaux, S.; Castela, A.; Archier, E.; Gallini, A.; Joly, P.; Misery, L.; Aractingi, S.; Aubin, F.; Bachelez, H.; Cribier, B.; Jullien, D.; Le Maître, M.; Richard, M.A.; Ortonne, J.P.; Paul, C. Adherence to topical treatment in psoriasis: A systematic literature review. J. Eur. Acad. Dermatol. Venereol., 2012, 26(3), 61-67.
Felix, K.; Unrue, E.; Inyang, M.; Cardwell, L.A.; Oussedik, E.; Richardson, I.; Feldman, S.R. Patients’ preferences for different corticosteroid vehicles are highly variable. J. Dermatolog. Treat., 2018, 17, 1-18.
Kienzler, J.L.; Queille-Roussel, C.; Mugglestone, C.J. Stratum corneum pharmacokinetics of the anti-fungal drug, terbinafine, in a novel topical formulation, for single- dose application in dermatophytoses. Curr. Med. Res. Opin., 2007, 23(6), 1293-1302.
Brown, M.; Evans, C.; Muddle, A. Efficacy, tolerability and consumer acceptability of terbinafine topical spray versus terbinafine topical solution: A phase IIa, randomised, observer-blind, comparative study. Am. J. Clin. Dermatol., 2013, 14(5), 413-419.
Williams, A.C. Transdermal and topical drug delivery - from theory to clinical practice. Pharmaceutical Press: London, 2003, 4, pp. (1)49-50.
Hong, C.H.; Papp, K.A.; Lophaven, K.W.; Skallerup, P.; Philipp, S. Patients with psoriasis have different preferences for topical therapy, highlighting the importance of individualized treatment approaches: randomized phase IIIb PSO-INSIGHTFUL study. J. Eur. Acad. Dermatol. Venereol., 2017, 31(11), 1876-1883.
Gorelick, J.; Cantrell, W.; Kucera, K.; Veverka, K.A.; Gooding, K. Patient-reported satisfaction with the fixed combination calcipotriene/betamethasone dipropionate foam for plaque psoriasis. J. Drugs Dermatol., 2018, 17(8), 880-884.

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Year: 2019
Page: [461 - 471]
Pages: 11
DOI: 10.2174/1567201816666190118124439

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