Development of Lecithin Nanoemulsion Based Organogels for Permeation Enhancement of Metoprolol through Rat Skin

Background. Drugs with low oral bioavailability due to the first pass metabolism are good candidates for transdermal delivery. Objectives. The aim of this work was preparation of transdermal nanoemulsion of metoprolol which has high first pass metabolism. Methods. Three commercially available types of lecithin (200, 100p, and 170), three short chain alcohol (n-butanol, isopropyl alcohol, and n-propanol), and isopropyl myristate (IPM) were used as surfactant, cosurfactant, and oil phase, respectively. The aqueous phase was composed of metoprolol tartrate. Nanoemulsions with different surfactant/cosurfactant weight ratio, various amounts of drug, and different types of alcohol were prepared, and their phase diagrams were studied. Drug release, permeability, and diffusion coefficient of the drug were studied using hairless rat skin. Results. A significant increase in drug solution rate was observed with increasing the metoprolol content in the nanoemulsions, while it decreased when lecithin concentration increased from 40% to 60%. Increasing the water content resulted in a significant increase in metoprolol release. N-butanol enhanced the drug flux from nanoemulsions more than n-propanol and isopropyl alcohol. The o/w nanoemulsions of metoprolol showed high flux and permeability through the skin. Conclusion. Both w/o and o/w nanoemulsions of metoprolol could enhance permeation and diffusion of metoprolol through rat skin

Vesicles for transdermal delivery of peptides and proteins

Elastic vesicles have been developed and evaluated as novel topical and transdermal delivery systems. They are similar to conventional liposomes but with the incorporation of an edge activator in the lipid bilayer structure to provide elasticity. Elastic vesicles are applied non-occluded to the skin and have been shown to permeate through the stratum corneum lipid lamellar regions as a result of the hydration or osmotic force in the skin. They have been investigated as drug carriers for a range of small molecules, peptides, proteins and vaccines, both in vitro and in vivo. Following topical application, structural changes in the stratum corneum have been identified and intact elastic vesicles visualised within the stratum corneum lipid lamellar regions, but no intact vesicles have been identified in the deeper viable tissues. Their method of transporting their drug payload into and through the skin has been investigated but remains an area of contention. This chapter provides an overview of the development of elastic vesicles for delivery into and via the skin

Co-loading of finasteride and baicalin in phospholipid vesicles tailored for the treatment of hair disorders

[EN] Hair loss affects a large number of people worldwide and it has a negative impact on the quality of life. Despite the availability of different drugs for the treatment of hair disorders, therapeutic options are still limited and scarcely effective. An innovative strategy to improve the efficacy of alopecia treatment is presented in this work. Finasteride, the only oral synthetic drug approved by Unites States Federal Drug Administration, was loaded in phospholipid vesicles. In addition, baicalin was co-loaded as an adjuvant. Their effect on hair growth was evaluatedin vitroandin vivo. Liposomes, hyalurosomes, glycerosomes and glycerol-hyalurosomes were manufactured by using a simple method that avoids the use of organic solvents. All the vesicles were small in size (similar to 100 nm), homogeneously dispersed (polydispersity index <= 0.27) and negatively charged (similar to-16 mV). The formulations were able to stimulate the proliferation of human dermal papilla cells, which are widely used in hair physiology studies. The analysis of hair growth and hair follicles of C57BL/6 mice, treated with the formulations for 21 days, underlined the ability of the vesicles to improve hair growth by the simultaneous follicular delivery of finasteride and baicalin. Therefore, the developed nanosystems can represent a promising tool to ensure the efficacy of the local treatment of hair loss.Mir-Palomo, S.; Nácher Alonso, MA.; Vila-Busó, MAO.; Caddeo, C.; Manca, ML.; Ruiz Saurí, A.; Escribano-Ferrer, E.... (2020). Co-loading of finasteride and baicalin in phospholipid vesicles tailored for the treatment of hair disorders. Nanoscale. 12(30):16143-16152. https://doi.org/10.1039/d0nr03357jS16143161521230Zhang, Y., Han, L., Chen, S.-S., Guan, J., Qu, F.-Z., & Zhao, Y.-Q. (2016). Hair growth promoting activity of cedrol isolated from the leaves of Platycladus orientalis. Biomedicine & Pharmacotherapy, 83, 641-647. doi:10.1016/j.biopha.2016.07.022Santos, Z., Avci, P., & Hamblin, M. R. (2015). Drug discovery for alopecia: gone today, hair tomorrow. Expert Opinion on Drug Discovery, 10(3), 269-292. doi:10.1517/17460441.2015.1009892Dong, L., Hao, H., Xia, L., Liu, J., Ti, D., Tong, C., … Han, W. (2014). Treatment of MSCs with Wnt1a-conditioned medium activates DP cells and promotes hair follicle regrowth. Scientific Reports, 4(1). doi:10.1038/srep05432S. Müller-Röver , K.Foitzik and R.Paus , B. H.-J. of I. and undefined , Elsevier , 2001Ocampo-Garza, J., Griggs, J., & Tosti, A. (2019). New drugs under investigation for the treatment of alopecias. Expert Opinion on Investigational Drugs, 28(3), 275-284. doi:10.1080/13543784.2019.1568989Y. Feng , L.Ma , X.Li and W.Ding , X. C.-B. & Pharmacotherapy and undefined , Elsevier , 2017M. Górecki , A.Dziedzic and R.Luboradzki , A. O.-Steroids and undefined , Elsevier , 2017RATTANACHITTHAWAT, N., PINKHIEN, T., OPANASOPIT, P., NGAWHIRUNPAT, T., & CHANVORACHOTE, P. (2019). Finasteride Enhances Stem Cell Signals of Human Dermal Papilla Cells. In Vivo, 33(4), 1209-1220. doi:10.21873/invivo.11592Khan, M. Z. U., Khan, S. A., Ubaid, M., Shah, A., Kousar, R., & Murtaza, G. (2018). Finasteride Topical Delivery Systems for Androgenetic Alopecia. Current Drug Delivery, 15(8), 1100-1111. doi:10.2174/1567201815666180124112905Hosking, A.-M., Juhasz, M., & Atanaskova Mesinkovska, N. (2018). Complementary and Alternative Treatments for Alopecia: A Comprehensive Review. Skin Appendage Disorders, 5(2), 72-89. doi:10.1159/000492035Jakab, G., Bogdán, D., Mazák, K., Deme, R., Mucsi, Z., Mándity, I. M., … Antal, I. (2019). Physicochemical Profiling of Baicalin Along with the Development and Characterization of Cyclodextrin Inclusion Complexes. AAPS PharmSciTech, 20(8). doi:10.1208/s12249-019-1525-6Shin, S. H., Bak, S.-S., Kim, M. K., Sung, Y. K., & Kim, J. C. (2014). Baicalin, a flavonoid, affects the activity of human dermal papilla cells and promotes anagen induction in mice. Naunyn-Schmiedeberg’s Archives of Pharmacology, 388(5), 583-586. doi:10.1007/s00210-014-1075-0Kim, A.-R., Kim, S.-N., Jung, I.-K., Kim, H.-H., Park, Y.-H., & Park, W.-S. (2014). The Inhibitory Effect of Scutellaria baicalensis Extract and Its Active Compound, Baicalin, on the Translocation of the Androgen Receptor with Implications for Preventing Androgenetic Alopecia. Planta Medica, 80(02/03), 153-158. doi:10.1055/s-0033-1360300Y. Qian , Y.Chen and L.Wang , J. T.-A. cirurgica brasileira and undefined , SciELO Bras , 2018Gao, C., Zhou, Y., Li, H., Cong, X., Jiang, Z., Wang, X., … Tian, W. (2017). Antitumor effects of baicalin on ovarian cancer cells through induction of cell apoptosis and inhibition of cell migration in vitro. Molecular Medicine Reports, 16(6), 8729-8734. doi:10.3892/mmr.2017.7757Mir-Palomo, S., Nácher, A., Díez-Sales, O., Ofelia Vila Busó, M. A., Caddeo, C., Manca, M. L., … Saurí, A. R. (2016). Inhibition of skin inflammation by baicalin ultradeformable vesicles. International Journal of Pharmaceutics, 511(1), 23-29. doi:10.1016/j.ijpharm.2016.06.136Wang, J., Jiao, H., Meng, J., Qiao, M., Du, H., He, M., … Wu, Y. (2019). Baicalin Inhibits Biofilm Formation and the Quorum-Sensing System by Regulating the MsrA Drug Efflux Pump in Staphylococcus saprophyticus. Frontiers in Microbiology, 10. doi:10.3389/fmicb.2019.02800T. Ahmed , M. K.-E. J. of P. Sciences and undefined , Elsevier , 2016R. El-Gogary and S.Gaber , M. N.-S. reports and undefined , nature.com , 2019Benson, H. A. E., Grice, J. E., Mohammed, Y., Namjoshi, S., & Roberts, M. S. (2019). Topical and Transdermal Drug Delivery: From Simple Potions to Smart Technologies. Current Drug Delivery, 16(5), 444-460. doi:10.2174/1567201816666190201143457Fang, C.-L., Aljuffali, I. A., Li, Y.-C., & Fang, J.-Y. (2014). Delivery and targeting of nanoparticles into hair follicles. Therapeutic Delivery, 5(9), 991-1006. doi:10.4155/tde.14.61A. Zeb , O.Qureshi and H.Kim , J. C.-I. journal of and undefined , ncbi.nlm.nih.gov , 2016Manca, M. L., Usach, I., Peris, J. E., Ibba, A., Orrù, G., Valenti, D., … Manconi, M. (2019). Optimization of Innovative Three-Dimensionally-Structured Hybrid Vesicles to Improve the Cutaneous Delivery of Clotrimazole for the Treatment of Topical Candidiasis. Pharmaceutics, 11(6), 263. doi:10.3390/pharmaceutics11060263Ascenso, A., Batista, C., Cardoso, P., Mendes, T., Praça, F., Bentley, V., … Simões, S. (2015). Development, characterization, and skin delivery studies of related ultradeformable vesicles: transfersomes, ethosomes, and transethosomes. International Journal of Nanomedicine, 5837. doi:10.2147/ijn.s86186Castangia, I., Manca, M. L., Caddeo, C., Maxia, A., Murgia, S., Pons, R., … Manconi, M. (2015). Faceted phospholipid vesicles tailored for the delivery of Santolina insularis essential oil to the skin. Colloids and Surfaces B: Biointerfaces, 132, 185-193. doi:10.1016/j.colsurfb.2015.05.025Manconi, M., Marongiu, F., Manca, M. L., Caddeo, C., Sarais, G., Cencetti, C., … Fadda, A. M. (2017). Nanoincorporation of bioactive compounds from red grape pomaces: In vitro and ex vivo evaluation of antioxidant activity. International Journal of Pharmaceutics, 523(1), 159-166. doi:10.1016/j.ijpharm.2017.03.037Manca, M. L., Cencetti, C., Matricardi, P., Castangia, I., Zaru, M., Sales, O. D., … Manconi, M. (2016). Glycerosomes: Use of hydrogenated soy phosphatidylcholine mixture and its effect on vesicle features and diclofenac skin penetration. International Journal of Pharmaceutics, 511(1), 198-204. doi:10.1016/j.ijpharm.2016.07.009Bavarsad, N., Akhgari, A., Seifmanesh, S., Salimi, A., & Rezaie, A. (2016). Statistical optimization of tretinoin-loaded penetration-enhancer vesicles (PEV) for topical delivery. DARU Journal of Pharmaceutical Sciences, 24(1). doi:10.1186/s40199-016-0142-0Manca, M. L., Castangia, I., Zaru, M., Nácher, A., Valenti, D., Fernàndez-Busquets, X., … Manconi, M. (2015). Development of curcumin loaded sodium hyaluronate immobilized vesicles (hyalurosomes) and their potential on skin inflammation and wound restoring. Biomaterials, 71, 100-109. doi:10.1016/j.biomaterials.2015.08.034Castangia, I., Caddeo, C., Manca, M. L., Casu, L., Latorre, A. C., Díez-Sales, O., … Manconi, M. (2015). Delivery of liquorice extract by liposomes and hyalurosomes to protect the skin against oxidative stress injuries. Carbohydrate Polymers, 134, 657-663. doi:10.1016/j.carbpol.2015.08.037V. Truong , M.Bak , C.Lee and M.Jun , W. J.- Molecules and undefined , mdpi.com , 2017Manconi, M., Aparicio, J., Vila, A. ., Pendás, J., Figueruelo, J., & Molina, F. (2003). Viscoelastic properties of concentrated dispersions in water of soy lecithin. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 222(1-3), 141-145. doi:10.1016/s0927-7757(03)00249-8Catalan-Latorre, A., Ravaghi, M., Manca, M. L., Caddeo, C., Marongiu, F., Ennas, G., … Manconi, M. (2016). Freeze-dried eudragit-hyaluronan multicompartment liposomes to improve the intestinal bioavailability of curcumin. European Journal of Pharmaceutics and Biopharmaceutics, 107, 49-55. doi:10.1016/j.ejpb.2016.06.016Abd, E., Roberts, M. S., & Grice, J. E. (2015). A Comparison of the Penetration and Permeation of Caffeine into and through Human Epidermis after Application in Various Vesicle Formulations. Skin Pharmacology and Physiology, 29(1), 24-30. doi:10.1159/000441040Sennett, R., & Rendl, M. (2012). Mesenchymal–epithelial interactions during hair follicle morphogenesis and cycling. Seminars in Cell & Developmental Biology, 23(8), 917-927. doi:10.1016/j.semcdb.2012.08.011S. Arias-Santiago , A.Buendía-Eisman , M. T.Gutiérrez-Salmerón and S.Serrano-Ortega , in Handbook of Hair in Health and Disease , MDText.com, Inc. , 2012 , pp. 99–116Manca, M. L., Manconi, M., Zaru, M., Valenti, D., Peris, J. E., Matricardi, P., … Fadda, A. M. (2017). Glycerosomes: Investigation of role of 1,2-dimyristoyl-sn-glycero-3-phosphatidycholine (DMPC) on the assembling and skin delivery performances. International Journal of Pharmaceutics, 532(1), 401-407. doi:10.1016/j.ijpharm.2017.09.026Shapiro, J., & Kaufman, K. D. (2003). Use of Finasteride in the Treatment of Men With Androgenetic Alopecia (Male Pattern Hair Loss). Journal of Investigative Dermatology Symposium Proceedings, 8(1), 20-23. doi:10.1046/j.1523-1747.2003.12167.xPrice, V. H., Roberts, J. L., Hordinsky, M., Olsen, E. A., Savin, R., Bergfeld, W., … Waldstreicher, J. (2000). Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. Journal of the American Academy of Dermatology, 43(5), 768-776. doi:10.1067/mjd.2000.107953Oliveira-Soares, R., e Silva, Jm., Correia, Mp., & André, M. (2013). Finasteride 5 mg/day treatment of patterned hair loss in normo-androgenetic postmenopausal women. International Journal of Trichology, 5(1), 22. doi:10.4103/0974-7753.114709Tabbakhian, M., Tavakoli, N., Jaafari, M. R., & Daneshamouz, S. (2006). Enhancement of follicular delivery of finasteride by liposomes and niosomes. International Journal of Pharmaceutics, 323(1-2), 1-10. doi:10.1016/j.ijpharm.2006.05.041Manconi, M., Mura, S., Sinico, C., Fadda, A. M., Vila, A. O., & Molina, F. (2009). Development and characterization of liposomes containing glycols as carriers for diclofenac. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 342(1-3), 53-58. doi:10.1016/j.colsurfa.2009.04.006Rao, Y., Zheng, F., Zhang, X., Gao, J., & Liang, W. (2008). 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Transdermal Delivery of an Anti-Cancer Drug via W/O Emulsions Based on Alkyl Polyglycosides and Lecithin: Design, Characterization, and In Vivo Evaluation of the Possible Irritation Potential in Rats

The purpose of this work was to develop w/o emulsions that could be safely used to promote transdermal delivery of 5-fluorouracil (5-FU). Two pseudo-ternary phase diagrams comprising oleoyl-macrogol glycerides, water, and a surfactant/co-surfactant (S/CoS) mixture of lecithin, ethanol, and either coco glucoside or decyl glucoside were investigated for their potential to develop promising 5-FU emulsions. Six systems were selected and subjected to thermodynamic stability tests; heat–cool cycles, centrifugation, and finally freeze–thaw cycles. All systems passed the challenges and were characterized for transmission electron microscopy, droplet size, rheological behavior, pH, and transdermal permeation through newly born mice skin in Franz diffusion cells. The systems had spherical droplets ranging in diameter from 1.81 to 2.97 μm, pH values ranging from 7.50 to 8.49 and possessed Newtonian flow. A significant (P < 0.05) increase in 5-FU permeability parameters as steady-state flux, permeability coefficient was achieved with formula B5 comprising water (5% w/w), S/CoS mixture of lecithin/ethanol/decyl glucoside (14.67:12.15:18.18% w/w, respectively) and oleoyl-macrogol glycerides (50% w/w). When applied to shaved rat skin, this system was well tolerated with only moderate skin irritation that was recovered within 12 h. Indeed, minor histopathologic changes were observed after 5-day treatment. Further studies should be carried out, in the future, to investigate the potentiality of this promising system to promote transdermal delivery of 5-FU through human skin

Niosomes

The chapter spans the chemistries, which are harnessed to create niosomes, the concepts upon which their application rests and model examples of the exploitation of this new knowledge to bring healthcare benefits