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Current Drug Delivery

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ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

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Research Article

Assessment of a Novel Vitamin D3 Formulation with Nanostructured Lipid Carriers for Transdermal Delivery

Author(s): Laura Junqueira*, Hudson Polonini, Cristiano Ramos, Anderson O. Ferreira, Nádia Raposo and Marcos Brandão

Volume 19, Issue 5, 2022

Published on: 11 January, 2022

Page: [614 - 624] Pages: 11

DOI: 10.2174/1567201818666210708121304

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Abstract

Objective: Develop and assess a transdermal emulsion loaded with nanostructured lipid carriers for vitamin D3 supplementation.

Methods: Vitamin D3 loaded nanostructured lipid carriers, produced via high shear homogenization and ultrasonication, were assessed for their particle size, distribution, morphology, zeta potential, entrapment efficiency, and cytotoxicity. They were incorporated into a transdermal vehicle, and the stability and ex vivo permeation were evaluated.

Results: Spherical nanoparticles were developed with a particle size of 192.5 nm, a polydispersity index of 0.13, a zeta potential of -29.0 mV, and an entrapment efficiency of 99.75%. They were stable (particle size and distribution) for 15 days when stored in a refrigerator, and for 30 days at room temperature and 32°C. The nanoparticles decreased the drug cytotoxicity against fibroblasts, as shown by IC50 (nanoparticle: 32.48 μg mL−1; vitamin D3: 16.73 μg mL−1). The emulsion loaded with nanoparticles minimized the degradation of vitamin D3 when compared with the nanoparticle dispersion. Additionally, the emulsion provided the skin permeation of vitamin D3 following the recommended daily allowance.

Conclusion: To the best of our knowledge, this is the first study to use nanostructured lipid carriers for transdermal delivery of vitamin D. The developed formulation is a promising strategy to overcome the vitamin D3 variable oral bioavailability. It also represents a comfortable route of administration; thus it could be beneficial for patients and clinicians. However, further studies are needed to allow the permeation of larger amounts of vitamin D3, and the combination of these nanoparticles with microneedles would be interesting.

Keywords: Vitamin D3, vitamin D, transdermal delivery, ex vivo permeation, nanostructured lipid carrier, lipid nanoparticle.

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[1]
Christakos, S.; Dhawan, P.; Verstuyf, A.; Verlinden, L.; Carmeliet, G.; Vitamin, D. Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol. Rev., 2016, 96(1), 365-408.
[http://dx.doi.org/10.1152/physrev.00014.2015] [PMID: 26681795]
[2]
Holick, M.F. Cancer, sunlight and vitamin D. J. Clin. Transl. Endocrinol., 2014, 1(4), 179-186.
[http://dx.doi.org/10.1016/j.jcte.2014.10.001] [PMID: 29159099]
[3]
Bikle, D.D.; Vitamin, D. Assays. Front. Horm. Res., 2018, 50, 14-30.
[http://dx.doi.org/10.1159/000486062] [PMID: 29597233]
[4]
Gil, Á.; Plaza-Diaz, J.; Mesa, M.D.; Vitamin, D. Vitamin D: Classic and Novel Actions. Ann. Nutr. Metab., 2018, 72(2), 87-95.
[http://dx.doi.org/10.1159/000486536] [PMID: 29346788]
[5]
Bouillon, R. Extra-Skeletal Effects of Vitamin D. Front. Horm. Res., 2018, 50, 72-88.
[http://dx.doi.org/10.1159/000486072] [PMID: 29597236]
[6]
Norman, P.E.; Powell, J.T. Vitamin D and cardiovascular disease. Circ. Res., 2014, 114(2), 379-393.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.301241] [PMID: 24436433]
[7]
Schnatz, P.F.; Manson, J.E. Vitamin D and cardiovascular disease: an appraisal of the evidence. Clin. Chem., 2014, 60(4), 600-609.
[http://dx.doi.org/10.1373/clinchem.2013.211037] [PMID: 24193116]
[8]
Ma, Y.; Johnson, C.S.; Trump, D.L. Mechanistic Insights of Vitamin D Anticancer Effects. Vitam. Horm., 2016, 100, 395-431.
[http://dx.doi.org/10.1016/bs.vh.2015.11.003] [PMID: 26827961]
[9]
Wimalawansa, S.J.; Razzaque, M.S.; Al-Daghri, N.M. Calcium and vitamin D in human health: Hype or real? J. Steroid Biochem. Mol. Biol., 2018, 180, 4-14.
[http://dx.doi.org/10.1016/j.jsbmb.2017.12.009] [PMID: 29258769]
[10]
Palacios, C.; Gonzalez, L. Is vitamin D deficiency a major global public health problem? J. Steroid Biochem. Mol. Biol., 2014, 144(Pt A), 138-145.
[http://dx.doi.org/10.1016/j.jsbmb.2013.11.003] [PMID: 24239505]
[11]
Nair, R.; Maseeh, A.; Vitamin, D. Vitamin D: The “sunshine” vitamin. J. Pharmacol. Pharmacother., 2012, 3(2), 118-126.
[PMID: 22629085]
[12]
Galesanu, C.; Mocanu, V. Vitamin d deficiency and the clinical consequences. Rev. Med. Chir. Soc. Med. Nat. Iasi, 2015, 119(2), 310-318.
[PMID: 26204630]
[13]
Khokhar, A.; Castells, S.; Perez-Colon, S. Genetic disorders of Vitamin D Metabolism: Case series and literature review. Clin. Pediatr. (Phila.), 2016, 55(5), 404-414.
[http://dx.doi.org/10.1177/0009922815623231] [PMID: 26701718]
[14]
Rejnmark, L.; Bislev, L.S.; Cashman, K.D.; Eiríksdottir, G.; Gaksch, M.; Grübler, M.; Grimnes, G.; Gudnason, V.; Lips, P.; Pilz, S.; van Schoor, N.M.; Kiely, M.; Jorde, R. Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data. PLoS One, 2017, 12(7), e0180512.
[http://dx.doi.org/10.1371/journal.pone.0180512] [PMID: 28686645]
[15]
Ross, A.C.; Manson, J.E.; Abrams, S.A.; Aloia, J.F.; Brannon, P.M.; Clinton, S.K.; Durazo-Arvizu, R.A.; Gallagher, J.C.; Gallo, R.L.; Jones, G.; Kovacs, C.S.; Mayne, S.T.; Rosen, C.J.; Shapses, S.A. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J. Clin. Endocrinol. Metab., 2011, 96(1), 53-58.
[http://dx.doi.org/10.1210/jc.2010-2704] [PMID: 21118827]
[16]
Holick, M.F.; Binkley, N.C.; Bischoff-Ferrari, H.A.; Gordon, C.M.; Hanley, D.A.; Heaney, R.P.; Murad, M.H.; Weaver, C.M. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab., 2011, 96(7), 1911-1930.
[http://dx.doi.org/10.1210/jc.2011-0385] [PMID: 21646368]
[17]
Pludowski, P.; Holick, M.F.; Grant, W.B.; Konstantynowicz, J.; Mascarenhas, M.R.; Haq, A.; Povoroznyuk, V.; Balatska, N.; Barbosa, A.P.; Karonova, T.; Rudenka, E.; Misiorowski, W.; Zakharova, I.; Rudenka, A.; Łukaszkiewicz, J.; Marcinowska-Suchowierska, E.; Łaszcz, N.; Abramowicz, P.; Bhattoa, H.P.; Wimalawansa, S.J. Vitamin D supplementation guidelines. J. Steroid Biochem. Mol. Biol., 2018, 175, 125-135.
[http://dx.doi.org/10.1016/j.jsbmb.2017.01.021] [PMID: 28216084]
[18]
Fahan Rashid, H.M.; Syed, U.; Ahmad, Z.; Chauhdary, K.K.; Musharraf, U.; Kumar, S. Comparison of different formulations of vitamin d. J. Ayub Med. Coll. Abbottabad, 2017, 29(4), 650-653.
[PMID: 29330997]
[19]
Kadappan, A.S.; Guo, C.; Gumus, C.E.; Bessey, A.; Wood, R.J.; McClements, D.J.; Liu, Z. The Efficacy of Nanoemulsion-Based Delivery to Improve Vitamin D Absorption: Comparison of in vitro and in vivo studies. Mol. Nutr. Food Res., 2018, 62(4), 1-24.
[http://dx.doi.org/10.1002/mnfr.201700836] [PMID: 29266712]
[20]
Tsiaras, W.G.; Weinstock, M.A. Factors influencing vitamin D status. Acta Derm. Venereol., 2011, 91(2), 115-124.
[http://dx.doi.org/10.2340/00015555-0980] [PMID: 21384086]
[21]
Mathias, N.R.; Hussain, M.A. Non-invasive systemic drug delivery: developability considerations for alternate routes of administration. J. Pharm. Sci., 2010, 99(1), 1-20.
[http://dx.doi.org/10.1002/jps.21793] [PMID: 19499570]
[22]
Alkilani, A.Z.; McCrudden, M.T.; Donnelly, R.F. Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum. Pharmaceutics, 2015, 7(4), 438-470.
[http://dx.doi.org/10.3390/pharmaceutics7040438] [PMID: 26506371]
[23]
Wiedersberg, S.; Guy, R.H. Transdermal drug delivery: 30+ years of war and still fighting! J. Control. Release, 2014, 190, 150-156.
[http://dx.doi.org/10.1016/j.jconrel.2014.05.022] [PMID: 24852092]
[24]
Alsaqr, A.; Rasoully, M.; Musteata, F.M. Investigating transdermal delivery of vitamin D3. AAPS PharmSciTech, 2015, 16(4), 963-972.
[http://dx.doi.org/10.1208/s12249-015-0291-3] [PMID: 25609377]
[25]
Kathe, N.; Henriksen, B.; Chauhan, H. Physicochemical characterization techniques for solid lipid nanoparticles: principles and limitations. Drug Dev. Ind. Pharm., 2014, 40(12), 1565-1575.
[http://dx.doi.org/10.3109/03639045.2014.909840] [PMID: 24766553]
[26]
Uner, M.; Damgalı, S.; Ozdemir, S.; Celik, B. Therapeutic potential of drug delivery by means of lipid nanoparticles: reality or illusion? Curr. Pharm. Des., 2017, 23(43), 6573-6591.
[http://dx.doi.org/10.2174/1381612823666171122110638] [PMID: 29173153]
[27]
Abdelbary, G.; Fahmy, R.H. Diazepam-loaded solid lipid nanoparticles: design and characterization. AAPS PharmSciTech, 2009, 10(1), 211-219.
[http://dx.doi.org/10.1208/s12249-009-9197-2] [PMID: 19277870]
[28]
Martins, S.M.; Wendling, T.; Gonçalves, V.M.; Sarmento, B.; Ferreira, D.C. Development and validation of a simple reversed-phase HPLC method for the determination of camptothecin in animal organs following administration in solid lipid nanoparticles. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2012, 880(1), 100-107.
[http://dx.doi.org/10.1016/j.jchromb.2011.11.023] [PMID: 22153332]
[29]
Araújo, J.; Garcia, M.L.; Mallandrich, M.; Souto, E.B.; Calpena, A.C. Release profile and transscleral permeation of triamcinolone acetonide loaded nanostructured lipid carriers (TA-NLC): in vitro and ex vivo studies. Nanomedicine (Lond.), 2012, 8(6), 1034-1041.
[http://dx.doi.org/10.1016/j.nano.2011.10.015] [PMID: 22115598]
[30]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[31]
Pereira, R.O.; Pelisson E Silva, T.C.C.; de Oliveira Ferreira, A.; Brandao, M.A.F.; Raposo, N.R.B.; Polonini, H.C. Ex vivo Skin Permeation Evaluation of An innovative transdermal vehicle using nimesulide and piroxicam as model drugs. Curr. Drug Deliv., 2017, 14(4), 516-520.
[PMID: 27557671]
[32]
OECD. Guidance notes on dermal absorption, OECD Series on Testing and Assessment, No. 156; OECD Publishing: Paris, 2011.
[33]
Fernandes, A.; Pydi, C.; Verma, R.; Jose, J.; Kumar, L. Design, preparation and in vitro characterizations of fluconazole loaded nanostructured lipid carriers. Braz. J. Pharm. Sci., 2020, 56, e18069-e18083.
[http://dx.doi.org/10.1590/s2175-97902019000318069]
[34]
Khan, N.; Shah, F.A.; Rana, I.; Ansari, M.M.; Din, F.U.; Rizvi, S.Z.H.; Aman, W.; Lee, G.Y.; Lee, E.S.; Kim, J.K.; Zeb, A. Nanostructured lipid carriers-mediated brain delivery of carbamazepine for improved in vivo anticonvulsant and anxiolytic activity. Int. J. Pharm., 2020, 577, 119033-119043.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119033] [PMID: 31954864]
[35]
Chauhan, I.; Yasir, M.; Verma, M.; Singh, A.P. Nanostructured Lipid Carriers: A groundbreaking approach for transdermal drug delivery. Adv. Pharm. Bull., 2020, 10(2), 150-165.
[http://dx.doi.org/10.34172/apb.2020.021] [PMID: 32373485]
[36]
Dobreva, M.; Stefanov, S.; Andonova, V. Natural lipids as structural components of solid lipid nanoparticles and nanostructured lipid carriers for topical delivery. Curr. Pharm. Des., 2020, 26(36), 4524-4535.
[http://dx.doi.org/10.2174/1381612826666200514221649] [PMID: 32410552]
[37]
Czajkowska-Kośnik, A.; Szekalska, M.; Winnicka, K. Nanostructured lipid carriers: A potential use for skin drug delivery systems. Pharmacol. Rep., 2019, 71(1), 156-166.
[http://dx.doi.org/10.1016/j.pharep.2018.10.008] [PMID: 30550996]
[38]
Patel, P.; Patel, M. Nanostructured lipid carriers- A versatile carrier for oral delivery of lipophilic drugs. Recent Pat. Nanotechnol., 2020, 14
[http://dx.doi.org/10.2174/1872210514666200909154959] [PMID: 32912129]
[39]
Danaei, M.; Dehghankhold, M.; Ataei, S.; Hasanzadeh Davarani, F.; Javanmard, R.; Dokhani, A.; Khorasani, S.; Mozafari, M.R. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics, 2018, 10(2), 1-17.
[http://dx.doi.org/10.3390/pharmaceutics10020057] [PMID: 29783687]
[40]
Thatipamula, R.; Palem, C.; Gannu, R.; Mudragada, S.; Yamsani, M. Formulation and in vitro characterization of domperidone loaded solid lipid nanoparticles and nanostructured lipid carriers. Daru, 2011, 19(1), 23-32.
[PMID: 22615636]
[41]
Carvalho, I.P. Desenvolvimento de nanopartículas lipídicas sólidas no carreamento de extrato alcaloídico de solanum lycocarpum e avaliação biológica in vitro em células de câncer de bexiga.. Master dissertation, Universidade de São Paulo.: Ribeirão Preto., 2016.
[42]
Soldati, P.P.; Polonini, H.C.; Paes, C.Q.; Restrepob, J.A.; Creczynksi-Pasa, T.B.; Chaves, M.G.; Brandão, M.A.; Pittella, F.; Raposo, N.R. Controlled release of resveratrol from lipid nanoparticles improves antioxidant effect. IFAC-PapersOnLine, 2018, 51, 16-21.
[http://dx.doi.org/10.1016/j.ifacol.2018.11.600]
[43]
Ali, H.; Shirode, A.B.; Sylvester, P.W.; Nazzal, S. Preparation, characterization, and anticancer effects of simvastatin-tocotrienol lipid nanoparticles. Int. J. Pharm., 2010, 389(1-2), 223-231.
[http://dx.doi.org/10.1016/j.ijpharm.2010.01.018] [PMID: 20123009]
[44]
Sena, L.W. Obtenção e caracterização de carreadores lipídicos nanoestruturados a partir de gordura vegetal de murumuru (Astrocaryum murumuru mart.. Master dissertation, Universidade Federal do Pará.: Belém, PA., 2016.
[45]
Andonova, V.; Peneva, P. Characterization methods for solid lipid nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC). Curr. Pharm. Des., 2017, 23(43), 6630-6642.
[http://dx.doi.org/10.2174/1381612823666171115105721] [PMID: 29141534]
[46]
Pelczynska, M.; Switalska, M.; Maciejewska, M.; Jaroszewicz, I.; Kutner, A.; Opolski, A. Antiproliferative activity of vitamin D compounds in combination with cytostatics. Anticancer Res., 2006, 26(4A), 2701-2705.
[PMID: 16886680]
[47]
Popadic, S.; Ramic, Z.; Medenica, L.; Mostarica Stojkovic, M.; Trajković, V.; Popadic, D. Antiproliferative effect of vitamin A and D analogues on adult human keratinocytes in vitro. Skin Pharmacol. Physiol., 2008, 21(4), 227-234.
[http://dx.doi.org/10.1159/000135639] [PMID: 18509257]
[48]
ISO - International Organization for Standardization. Biological evaluation of medical devices. Tests for in vitro cytotoxicity; 10993-10995., 2009, pp.
[49]
Grady, L.T.; Thakker, K.D. Stability of solid drugs: degradation of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) at high humidities and elevated temperatures. J. Pharm. Sci., 1980, 69(9), 1099-1102.
[http://dx.doi.org/10.1002/jps.2600690932] [PMID: 6251199]
[50]
Abbasi, A.; Emam-Djomeh, Z.; Mousavi, M.A.; Davoodi, D. Stability of vitamin D(3) encapsulated in nanoparticles of whey protein isolate. Food Chem., 2014, 143, 379-383.
[http://dx.doi.org/10.1016/j.foodchem.2013.08.018] [PMID: 24054255]
[51]
Ballard, J.M.; Zhu, L.; Nelson, E.D.; Seburg, R.A. Degradation of vitamin D3 in a stressed formulation: The identification of esters of vitamin D3 formed by a transesterification with triglycerides. J. Pharm. Biomed. Anal., 2007, 43(1), 142-150.
[http://dx.doi.org/10.1016/j.jpba.2006.06.036] [PMID: 16901672]
[52]
Pall Life Sciences. chemical compatibility media materials. https://www.pall.com/content/dam/pall/laboratory/literature-library/non-gated/chemical-compatibility-chart.pdf
[53]
Demirbilek, M.; Laçin Türkoglu, N.; Aktürk, S.; Akça, C. VitD3-loaded solid lipid nanoparticles: Stability, cytotoxicity and cytokine levels. J. Microencapsul., 2017, 34(5), 454-462.
[http://dx.doi.org/10.1080/02652048.2017.1345995] [PMID: 28675984]
[54]
Kiani, A.; Fathi, M.; Ghasemi, S.M. Production of novel vitamin D3 loaded lipid nanocapsules for milk fortification. Int. J. Food Prop., 2016, 20(11), 2466-2476.
[http://dx.doi.org/10.1080/10942912.2016.1240690]
[55]
Almouazen, E.; Bourgeois, S.; Jordheim, L.P.; Fessi, H.; Briançon, S. Nano-encapsulation of vitamin D3 active metabolites for application in chemotherapy: formulation study and in vitro evaluation. Pharm. Res., 2013, 30(4), 1137-1146.
[http://dx.doi.org/10.1007/s11095-012-0949-4] [PMID: 23225028]
[56]
Cosmetic ingredients: Guidelines for percutaneous absorption/ penetration. 1997.
[57]
OECD series on testing and assessment.OECD. Guidance Document for the Conduct of Skin Absorption Studies; Paris, 2004.
[58]
Sawarkar, S.; Ashtekar, A. Transdermal vitamin D supplementation-A potential vitamin D deficiency treatment. J. Cosmet. Dermatol., 2020, 19(1), 28-32.
[http://dx.doi.org/10.1111/jocd.13085] [PMID: 31343822]
[59]
Ramezanli, T.; Kilfoyle, B.E.; Zhang, Z.; Michniak-Kohn, B.B. Polymeric nanospheres for topical delivery of vitamin D3. Int. J. Pharm., 2017, 516(1-2), 196-203.
[http://dx.doi.org/10.1016/j.ijpharm.2016.10.072] [PMID: 27810351]
[60]
D’Angelo Costa, G.M.; Sales de Oliveira Pinto, C.A.; Rodrigues Leite-Silva, V.; Rolim Baby, A.; Robles Velasco, M.V. Is vitamin D3 transdermal formulation feasible? an ex vivo skin retention and permeation. AAPS PharmSciTech, 2018, 19(5), 2418-2425.
[http://dx.doi.org/10.1208/s12249-018-1065-5] [PMID: 29869312]
[61]
Lalloz, A.; Bolzinger, M.A.; Faivre, J.; Latreille, P.L.; Garcia Ac, A.; Rakotovao, C.; Rabanel, J.M.; Hildgen, P.; Banquy, X.; Briançon, S. Effect of surface chemistry of polymeric nanoparticles on cutaneous penetration of cholecalciferol. Int. J. Pharm., 2018, 553(1-2), 120-131.
[http://dx.doi.org/10.1016/j.ijpharm.2018.09.046] [PMID: 30316003]
[62]
Kim, H.G.; Gater, D.L.; Kim, Y.C. Development of transdermal vitamin D3 (VD3) delivery system using combinations of PLGA nanoparticles and microneedles. Drug Deliv. Transl. Res., 2018, 8(1), 281-290.
[http://dx.doi.org/10.1007/s13346-017-0460-x] [PMID: 29247316]

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