Development and Characterization of Nano-Sized Emulsion Systems Incorporated Polyphenolic Compound for Application Through the Skin

Year 2022, , 57 - 72, 01.03.2022

Bülent Samancı , Fatma Gülgün Yener İsmail Tuncer Değim

https://doi.org/10.55262/fabadeczacilik.1078888

Abstract

In addition to having strong anti-oxidant properties, resveratrol has anti-cancer, anti-angiogenic, cardioprotective, anti-diabetic, antiviral, and neuroprotective activities. Despite its rapid absorption, first-pass effect and intestinal metabolism reduce the bioavailability of resveratrol. Moreover, the lipophilic property of resveratrol reduces its water solubility and metabolized in high incidence reduces its oral bioavailability. Therefore, it was aimed to develop an optimum formulation for the skin application of resveratrol to overcome the
negatives after oral administration.Since their easy formulation, thermodynamically stable properties, and facilitating the delivery of both lipophilic and hydrophilic active ingredients, loading resveratrol to microemulsions (MEs) will be a suitable delivery system to overcome the drawback of stability problems and skin bioavailability of resveratrol. A Triangle phase diagram was constructed, and the MEs region was determined by points studies. Subsequently, some formulations were selected within the transparent region by
considering characteristics required to achieve optimized transdermal drug delivery. Chosen formulations were exposed to pre-stability tests such as centrifuge and thermal stress tests. Characterization studies such as droplet size, size distribution, zeta potential, viscosity, pH measurement were performed on remained intact formulations after pre-stability tests. In terms of the characterization test results such as pH, viscosity, conductivity, there wasn’t found significant difference observed between formulations. However, polydispersity index and zeta potential values provided to choosing optimal formulation.

Keywords

Microemulsion, Penetration enhancers, Resveratrol, Transdermal Drug delivery, Triangle phase diagrams

Deriden Uygulama İçin Polifenolik Bileşik İçeren Nano Boyutlu Emülsiyon Sistemlerinin Geliştirilmesi ve Karakterizasyonu

Abstract

Resveratrol güçlü bir antioksidan özelliğe sahip olmasının yanı sıra antikanser, anti-anjiyojenik, kardiyoprotektif, anti-diyabetik, anti-viral ve nöroprotektif aktivitelere sahiptir. İnsan vücudunda hızlı emilime uğramasına rağmen, bağırsak ve karaciğer metabolizması, resveratrolün sistemik biyoyararlanımı için hız sınırlayıcıdırlar. Ayrıca, resveratrolün yüksek lipofilikliği, suda çözünürlüğünü ve oral yoldan yüksek oranda metabolize edilmesi nedeni ile oral biyoyararlanımını azaltır. Bu nedenle, oral uygulama ile görülen olumsuzlukların üstesinden gelmek için resveratrolün deri uygulaması için optimum bir formülasyon geliştirilmesi amaçlanmıştır.Kolay formüle edilebilmeleri, termodinamik olarak kararlı
olmaları ve hem lipofilik hem de hidrofilik etkin maddelerin vücuda verilmesini kolaylaştırmalarından dolayı, resveratrolün mikroemülsiyonlara (ME’ler) yüklenmesi, stabilite sorunları ve deriden emiliminin zor olması gibi dezavantajlarının üstesinden gelmek için uygun bir ilaç taşıyıcı sistemi olacaktır.Bu çalışmada önce üçgen faz diyagramı oluşturularak MEs bölgesi noktasal çalışma ile belirlendi. Daha sonra optimize edilmiş formülasyonu elde etmek için gerekli özellikler göz önünde bulundurularak ME sistemleri oluşturan bölge içinde bazı formülasyonları seçildi. Seçilen formülasyonlar, santrifüj ve termal stres testleri gibi ön stabilite testlerine tabi tutuldu. Damlacık boyutu, damlacık boyut dağılımı, zeta potansiyeli, viskozite, pH ölçümü gibi karakterizasyon çalışmaları, ön stabilite testlerinden sonra fiziksel olarak bozulmadan kalan formülasyonlar üzerinde gerçekleştirildi. Viskozite, pH, iletkenlik gibi karakterizasyon testleri sonuçları açısından formülasyonlar transdermal uygulamalar için kabul edilebilir aralıktaydı. Ancak damlacık boyutu, polidispersite indeksi ve zeta potansiyel değerleri optimal formülasyonun belirlenmesini sağlamıştır.

Keywords

Mikroemülsiyon, Penetrasyon artırıcılar, Resveratrol, Transdermal taşıyıcı sistemler, Üçgen Faz Diyagramı

References

• Ambade, K. W., Jadhav, S. L., Gambhire, M. N., Kurmi, S. D., Kadam, V. J., & Jadhav, K. R. (2008). Formulation and evaluation of flurbiprofen microemulsion. Current Drug Delivery, 5(1), 32-41.doi:10.2174/156720108783331032
• Bakshi, P., Jiang, Y., Nakata, T., Akaki, J., Matsuoka, N.,& Banga, A. K. (2018). Formulation Development and Characterization of Nanoemulsion-Based Formulation for Topical Delivery of Heparinoid. Journal of Pharmaceutical Science, 107(11), 2883- 2890. doi:10.1016/j.xphs.2018.07.015
• Balata, G. F., Essa, E. A., Shamardl, H. A., Zaidan, S. H., & Abourehab, M. A. S. (2016). Self-emulsifying drug delivery systems as a tool to improve solubility and bioavailability of resveratrol. Drug Design Development and Therapy, 10. doi:10.2147/Dddt.S95905
• Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A.,Lerin, C., Kalra, A., . . . Sinclair, D. A. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 444(7117), 337-342. doi:10.1038/nature05354
• Baur, J. A., & Sinclair, D. A. (2006). Therapeutic potential of resveratrol: the in vivo evidence. Nature Reviews Drug Discovery , 5(6), 493-506. doi:10.1038/nrd2060
• Baxter, R. A. (2008). Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. Journal of Cosmetic Dermatology, 7(1), 2-7. doi:10.1111/j.1473-2165.2008.00354.x
• Bayrak, Y., & Iscan, M. (2005). Studies on the phase behavior of the system non-ionic surfactant/alcohol/alkane/H2O. Colloids and Surfaces a-Physicochemical and Engineering Aspects, 268(1-3), 99-103. doi:10.1016/j.colsurfa.2005.06.021
• Benson, H. A. (2012). Skin structure, function, and permeation. Topical and Transdermal Drug Delivery: Principles and Practice, 1st ed.; Benson, HAE, Watkinson, AC, Eds, 1-22.
• Carter, P., Narasimhan, B., & Wang, Q. (2019). Biocompatible nanoparticles and vesicular systems in transdermal drug delivery for various skin diseases. International Journal of Pharmaceutics , 555, 49-62. doi:10.1016/j.ijpharm.2018.11.032
• Chen, Y., Zhang, H., Yang, J., & Sun, H. (2015). Improved antioxidant capacity of optimization of a self-microemulsifying drug delivery system for resveratrol. Molecules, 20(12), 21167-21177.
• Cho, Y. H., Kim, S., Bae, E. K., Mok, C., & Park, J. (2008). Formulation of a cosurfactant‐free o/w microemulsion using nonionic surfactant mixtures. Journal of Food Science, 73(3), E115-E121.
• Cicero, N., Albergamo, A., Salvo, A., Bua, G. D., Bartolomeo, G., Mangano, V., . . . Dugo, G. (2018). Chemical characterization of a variety of coldpressed gourmet oils available on the Brazilian market. Food Research International, 109, 517-525.doi:10.1016/j.foodres.2018.04.064
• Constantinides, P. P. (1995). Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharmaceutical Research, 12(11), 1561-1572.
• Danaei, M., Dehghankhold, M., Ataei, S., Hasanzadeh Davarani, F., Javanmard, R., Dokhani, A., . . . Mozafari, M. R. (2018). Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems. Pharmaceutics, 10(2). doi:10.3390/pharmaceutics10020057
• Das, S., Chaudhury, A., & Ng, K.-Y. (2011). Polyethyleneimine- modified pectin beads for colon-specific drug delivery: In vitro and in vivo implications. Journal of Microencapsulation, 28(4), 268-279.
• Das, S., Lee, S. H., Chow, P. S., & Macbeath, C. (2020). Microemulsion composed of combination of skin beneficial oils as vehicle: Development of resveratrol- loaded microemulsion based formulations for skin care applications. Colloids and Surfaces B: Biointerfaces, 194, 111161.
• Das, S., Lin, H. S., Ho, P. C., & Ng, K. Y. (2008). The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharmaceutical Research, 25(11), 2593-2600. doi:10.1007/s11095-008-9677-1
• Das, S., & Ng, K. Y. (2010a). Colon-specific delivery of resveratrol: optimization of multi-particulate calcium-pectinate carrier. International Journal of Pharmacology, 385(1-2), 20-28. doi:10.1016/j.ijpharm.2009.10.016
• Das, S., & Ng, K. Y. (2010b). Impact of glutaraldehyde on in vivo colon-specific release of resveratrol from biodegradable pectin-based formulation. Journal of Pharmaceutical Sciences, 99(12), 4903-4916. doi:10.1002/jps.22212
• Das, S., & Ng, K. Y. (2010c). Resveratrol-loaded calcium- pectinate beads: effects of formulation parameters on drug release and bead characteristics. Journal of Pharmaceutical Sciences, 99(2), 840-860. doi:10.1002/jps.21880
• Das, S., Ng, K. Y., & Ho, P. C. (2010). Formulation and optimization of zinc-pectinate beads for the controlled delivery of resveratrol. AAPS PharmSciTech, 11(2), 729-742. doi:10.1208/s12249-010-9435-7
• Davidov-Pardo, G., & McClements, D. J. (2014). Resveratrol encapsulation: Designing delivery systems to overcome solubility, stability and bioavailability issues. Trends in Food Science & Technology, 38(2), 88-103. doi:10.1016/j.tifs.2014.05.003
• Delmas, D., Lancon, A., Colin, D., Jannin, B., & Latruffe, N. (2006). Resveratrol as a chemopreventive agent: A promising molecule for fighting cancer. Current Drug Targets, 7(4), 423-442. doi:10.2174/138945006776359331
• Djekic, L., & Primorac, M. (2008). The influence of cosurfactants and oils on the formation of pharmaceutical microemulsions based on PEG-8 caprylic/capric glycerides. International Journal of Pharmaceutics, 352(1-2), 231-239
• El Maghraby, G. M. (2008). Transdermal delivery of hydrocortisone from eucalyptus oil microemulsion: effects of cosurfactants. International Journalof Pharmaceutics, 355(1-2), 285-292.
• Figueiredo, K. A., Neves, J. K. O., da Silva, J. A., de Freitas, R. M., & Carvalho, A. L. M. (2016). Phenobarbital loaded microemulsion: development, kinetic release and quality control. Brazilian Journal of Pharmaceutical Sciences, 52(2), 251-263. doi:10.1590/S1984-82502016000200003
• Fisher, G. J., Wang, Z. Q., Datta, S. C., Varani, J., Kang, S., & Voorhees, J. J. (1997). Pathophysiology of premature skin aging induced by ultraviolet light. New England Journal of Medicine, 337(20), 1419-1428. doi:10.1056/NEJM199711133372003
• Flanagan, J., & Singh, H. (2006). Microemulsions: a potential delivery system for bioactives in food. Critical Reviews in Food Science and Nutrition,46(3), 221-237.
• Francioso, A., Mastromarino, P., Restignoli, R., Boffi, A., d’Erme, M., & Mosca, L. (2014). Improved stability of trans-resveratrol in aqueous solutions by carboxymethylated (1,3/1,6)-beta-D-glucan. The Journal of Agricultural and Food Chemistry, 62(7),1520-1525. doi:10.1021/jf404155e
• Gallarate, M., Carlotti, M. E., Trotta, M., Grande, A., & Talarico, C. (2004). Photostability of naturally occurring whitening agents in cosmetic microemulsions. Journal of Cosmetic Science, 55(2), 139-148.
• Ganta, S., Talekar, M., Singh, A., Coleman, T. P., & Amiji, M. M. (2014). Nanoemulsions in Translational Research-Opportunities and Challenges in Targeted Cancer Therapy. AAPS PharmSciTech, 15(3), 694-708. doi:10.1208/s12249-014-0088-9
• Gorini, I., Iorio, S., Ciliberti, R., Licata, M., & Armocida, G. (2019). Olive oil in pharmacological and cosmetic traditions. Journal of Cosmetic Dermatology,18(5), 1575-1579.
• Hathout, R. M., Woodman, T. J., Mansour, S., Mortada, N. D., Geneidi, A. S., & Guy, R. H. (2010). Microemulsion formulations for the transdermal delivery of testosterone. European Journal of Pharmaceutical Sciences, 40(3), 188-196.
• Hegde, R. R., Verma, A., & Ghosh, A. (2013). Microemulsion: new insights into the ocular drug delivery. International Scholarly Research Notices, 2013.
• Heuschkel, S., Goebel, A., & Neubert, R. H. (2008). Microemulsions—modern colloidal carrier for dermal and transdermal drug delivery. Journal of Pharmaceutical Sciences, 97(2), 603-631.
• Ibrahim, T. M., Abdallah, M. H., El-Megrab, N. A., & El-Nahas, H. M. (2018). Upgrading of dissolution and anti-hypertensive effect of Carvedilol via two combined approaches: self-emulsification and liquisolid techniques. Drug Development and Industrial Pharmacy , 44(6), 873-885. doi:10.1080/03639045.2017.1417421
• Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W., . . . Pezzuto, J. M. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275(5297), 218-220. doi:10.1126/science.275.5297.218
• Juškaitė, V., Ramanauskienė, K., & Briedis, V. (2015). Design and formulation of optimized microemulsions for dermal delivery of resveratrol. Evidence-Based Complementary and Alternative Medicine, 2015.
• Kaur, R., & Ajitha, M. (2019). Transdermal delivery of fluvastatin loaded nanoemulsion gel: Preparation, characterization and in vivo anti-osteoporosis activity. European Journal of Pharmaceutical Sciences, 136, 104956. doi:10.1016/j.ejps.2019.104956
• Kreilgaard, M. (2002). Influence of microemulsions on cutaneous drug delivery. Advanced Drug Delivery Reviews, 54 Suppl 1, S77-98. doi:10.1016/ s0169-409x(02)00116-3
• Kural, F. H., & Gürsoy, R. N. (2011). Formulation and Characterization of Surfactin-Containing Self-Microemulsifying Drug Delivery Systems SF-SMEDDS. Hacettepe Üniversitesi Eczacılık Fakültesi Dergisi(2), 171-186.
• Lane, M. E. (2013). Skin penetration enhancers. International Journal of Pharmaceutics, 447(1-2), 12-21.
• Langcake, P., & Pryce, R. (1976). The production of resveratrol by Vitis vinifera and other members of the Vitaceae as a response to infection or injury. Physiological Plant Pathology, 9(1), 77-86.
• Lawrence, M. J. (1994). Surfactant systems: microemulsions and vesicles as vehicles for drug delivery. European Journal of Drug Metabolism and Pharmacokinetics, 19(3), 257-269.
• Lawrence, M. J., & Rees, G. D. (2000). Microemulsion- based media as novel drug delivery systems. Advanced Drug Delivery Reviews, 45(1), 89-121.
• Lawrence, M. J., & Rees, G. D. (2012). Microemulsion-based media as novel drug delivery systems.Advanced Drug Delivery Reviews, 64, 175-193. doi:10.1016/j.addr.2012.09.018
• Lemerya, E., Briancon, S., Chevalier, Y., Bordes, C.,Oddos, T., Gohier, A., & Bolzinger, M. A. (2015). Skin toxicity of surfactants: Structure/toxicity relationships. Colloids and Surfaces a-Physicochemical and Engineering Aspects, 469, 166-179.doi:10.1016/j.colsurfa.2015.01.019
• Liu, C. H., & Chang, F. Y. (2011). Development and characterization of eucalyptol microemulsions for topic delivery of curcumin. Chemical and Pharmaceutical Bulletin(Tokyo), 59(2), 172-178. doi:10.1248/cpb.59.172
• Mahapatra, A. K., Murthy, P. N., Swadeep, B., & Swain, R. (2014). Self-emulsifying drug delivery systems (SEDDS): An update from formulation development to therapeutic strategies. International Journal of PharmTech Research, 6(2), 546-568.
• Malcolmson, C., & Lawrence, M. J. (1993). A comparison of the incorporation of model steroids into non-ionic micellar and microemulsion systems.Journal of Pharmacy and Pharmacology, 45(2), 141-143.
• Malcolmson, C., & Lawrence, M. J. (1995). Three-component non-ionic oil-in-water microemulsions using polyoxyethylene ether surfactants. Colloids and surfaces B: Biointerfaces, 4(2), 97-109.
• Mukhopadhyay, P., Mukherjee, S., Ahsan, K., Bagchi, A., Pacher, P., & Das, D. K. (2010). Restoration of altered microRNA expression in the ischemicheart with resveratrol. Plos One, 5(12), e15705.
• Ndiaye, M., Philippe, C., Mukhtar, H., & Ahmad, N. (2011). The grape antioxidant resveratrol for skin disorders: promise, prospects, and challenges. Archives of Biochemistry and Biophysics , 508(2), 164-170. doi:10.1016/j.abb.2010.12.030
• Nguyen, S. H., Dang, T. P., & Maibach, H. I. (2007).Comedogenicity in rabbit: some cosmetic ingredients/vehicles. Cutaneous and ocular toxicology,26(4), 287-292.
• Parmar, K., Patel, J., & Sheth, N. (2015). Self nano-emulsifying drug delivery system for Embelin: Design, characterization and in-vitro studies. Asian Journal of Pharmaceutical Sciences, 10(5),396-404. doi:10.1016/j.ajps.2015.04.006
• Patel, M. R., Patel, R. B., Parikh, J. R., Solanki, A. B.,& Patel, B. G. (2009). Effect of formulation components on the in vitro permeation of microemulsion drug delivery system of fluconazole. AAPS PharmSciTech, 10(3), 917-923. doi:10.1208/s12249-009-9286-2
• Patravale, V. B., & Mandawgade, S. D. (2008). Novel cosmetic delivery systems: an application update. International Journal of Cosmetic Science, 30(1), 19-33. doi:10.1111/j.1468-2494.2008.00416.x
• Perazzo, A., Preziosi, V., & Guido, S. (2015). Phase inversion emulsification: Current understanding and applications. Advances in Colloid and Interface Science, 222, 581-599. doi:10.1016/j.cis.2015.01.001
• Rani, S., Rana, R., Saraogi, G. K., Kumar, V., & Gupta, U. (2019). Self-Emulsifying Oral Lipid Drug Delivery Systems: Advances and Challenges. AAPS PharmSciTech, 20(3), 129. doi:10.1208/s12249-019-1335-x
• Rastogi, V., & Yadav, P. (2014). Transdermal drug delivery system: An overview. Asian Journal of Pharmaceutics, 6(3), 161-170.
• Salimi, A., Sharif Makhmal Zadeh, B., & Moghimipour, E. (2013). Preparation and characterization of cyanocobalamin (vit B12) microemulsion properties and structure for topical and transdermal application. Iranian Journal of Basic Medical Sciences, 16(7), 865-872.
• Saribey, G., Kahraman, E., ERDAL, M., & GÜNGÖR, S. (2021). Design and characterisation of colloidal nanocarriers for enhanced skin delivery of etodolac. Journal of Research in Pharmacy, 25(1), https://doi.org/10.35333/jrp.2021.289
• Sessa, M., Tsao, R., Liu, R., Ferrari, G., & Donsì, F. (2011). Evaluation of the stability and antioxidant activity of nanoencapsulated resveratrol during in vitro digestion. Journal of Agricultural and Food Chemistry, 59(23), 12352-12360.
• Shah, N., Carvajal, M., Patel, C., Infeld, M., & Malick, A. (1994). Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. International Journal of Pharmaceutics, 106(1), 15-23.
• Sharma, S., Shukla, P., Misra, A., & Mishra, P. R. (2014). Interfacial and colloidal properties of emulsified systems: pharmaceutical and biological perspective. In Colloid and interface science in pharmaceutical research and development (pp. 149-172): Elsevier.
• Sheshala, R., Anuar, N. K., Abu Samah, N. H., & Wong, T. W. (2019). In Vitro Drug Dissolution/ Permeation Testing of Nanocarriers for Skin Application: a Comprehensive Review. AAPS PharmSciTech, 20(5), 164. doi:10.1208/s12249-019-1362-7
• Singh, M. K., Chandel, V., Gupta, V., & Ramteke, S. (2010). Formulation development and characterization of microemulsion for topical delivery of Glipizide. Der Pharmacia Lettre, 2(3), 33-42.
• Solans, C., Morales, D., & Homs, M. (2016). Spontaneous emulsification. Current Opinion in Colloid & Interface Science, 22, 88-93.
• Surber, C., & Kottner, J. (2017). Skin care products: What do they promise, what do they deliver. Journal of Tissue Viability, 26(1), 29-36. doi:10.1016/j.jtv.2016.03.006
• Syed, H. K., & Peh, K. K. (2014). Identification of Phases of Various Oil, Surfactant/Co-Surfactants and Water System by Ternary Phase Diagram. Acta Poloniae Pharmaceutica, 71(2), 301-309.
• Tenjarla, S. (1999). Microemulsions: an overview and pharmaceutical applications. Critical Reviews™ in Therapeutic Drug Carrier Systems, 16(5).
• Thakkar, P. J., Madan, P., & Lin, S. S. (2014). Transdermal delivery of diclofenac using water-in-oil microemulsion: formulation and mechanisticapproach of drug skin permeation. Pharmaceutical Development and Technology, 19(3), 373-384. doi:10.3109/10837450.2013.788658
• Trommer, H., & Neubert, R. H. (2006). Overcoming the stratum corneum: the modulation of skin penetration. A review. Skin Pharmacology and Physiology, 19(2), 106-121. doi:10.1159/000091978
• Ujilestari, T., Dono, N. D., Ariyadi, B., Martien, R., & Zuprizal. (2018). Formulation and characterization of self-nano emulsifying drug delivery systems of lemongrass (cymbopogon citratus) essential oil. Malaysian Journal of Fundamental and Applied Sciences, 14(3), 360-363. doi:DOI 10.11113/ mjfas.v14n3.1070
• Umerska, A., Cassisa, V., Matougui, N., Joly-Guillou, M. L., Eveillard, M., & Saulnier, P. (2016). Antibacterial action of lipid nanocapsules containing fatty acids or monoglycerides as co-surfactants. European Journal of Pharmaceutics and Biopharmaceutics, 108, 100-110. doi:10.1016/j.ejpb.2016.09.001
• Van Staden, D., Du Plessis, J., & Viljoen, J. (2020). Development of a self-emulsifying drug delivery system for optimized topical delivery of clofazimine. Pharmaceutics, 12(6), 523.
• van Zyl, L., du Preez, J., Gerber, M., du Plessis, J., & Viljoen, J. (2016). Essential Fatty Acids as Transdermal Penetration Enhancers. Journal of Pharmaceutical Sciences, 105(1), 188-193. doi:10.1016/j.xphs.2015.11.032
• Walle, T., Hsieh, F., DeLegge, M. H., Oatis, J. E., & Walle, U. K. (2004). High absorption but very low bioavailability of oral resveratrol in humans. Drug Metabolism and Disposition, 32(12), 1377-1382.
• Warisnoicharoen, W., Lansley, A., & Lawrence, M. (2000). Nonionic oil-in-water microemulsions: the effect of oil type on phase behaviour. International Journal of Pharmaceutics, 198(1), 7-27.
• Zaichik, S., Steinbring, C., Menzel, C., Knabl, L., Orth-Holler, D., Ellemunter, H., ... Bernkop-Schnurch, A. (2018). Development of self-emulsifying drug delivery systems (SEDDS) for ciprofloxacin with improved mucus permeating properties. International Journal of Pharmacology, 547(1-2), 282-290. doi:10.1016/j.ijpharm2018.06.005