Nanocrystals as Effective Delivery Systems of Poorly Water-soluble Natural Molecules

Author(s): Francesco Lai, Michele Schlich, Rosa Pireddu, Anna Maria Fadda*, Chiara Sinico

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 24 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Abstract:

Natural products are an important source of therapeutically effective compounds throughout the world. Since ancient times, a huge amount of both plant extracts and isolated compounds have been largely employed in treatment and prevention of human disorders and, currently, more than 60% of the world’s population trusts on plant medicaments as demonstrated by the increasing quantity of herbal therapeutics in the market.

Unfortunately, several promising natural molecules for the treatment of the most diverse ailments are characterized by extremely unfavourable features, such as low water solubility and poor/irregular bioavailability, which hinder their clinical use. To overcome these limitations and to make herbal therapy more effective, different formulative approaches have been employed.

Among the different strategies for increasing drug solubility, nanocrystals can be considered one of the most interesting and successful approaches. Drug nanocrystals are nanosized drug particles usually formulated as nanosuspensions, namely submicron dispersions in liquid media where surfactants, polymers, or a mixture of both act as stabilisers.

In this review, we described the most significant results and progresses concerning drug nanocrystal formulations for the delivery of natural compounds with a significant pharmacological activity. The text is organized in nine sections, each focusing on a specific poorly water- soluble natural compound (apigenin, quercetin, rutin, curcumin, baicalin and baicalein, hesperetin and hesperidin, resveratrol, lutein, silybin).

To foster the clinical translation of these natural nanomedicines, our opinion is that future research should pair the essential pharmacokinetic studies with carefully designed pre-clinical experiments, able to prove the formulation efficacy in relevant animal models in vivo.

Keywords: Nanocrystals, nanosuspension, natural products, top-down technologies, bottom-up technologies, in vivo.

[1]
Khan, J.; Alexander, A. Ajazuddin; Saraf, S.; Saraf, S. Recent advances and future prospects of phyto-phospholipid complexation technique for improving pharmacokinetic profile of plant actives. J. Control. Release, 2013, 168(1), 50-60.
[http://dx.doi.org/10.1016/j.jconrel.2013.02.025] [PMID: 23474031]
[2]
Sasidharan, S.; Chen, Y.; Saravanan, D.; Sundram, K.M.; Yoga Latha, L. Extraction, Isolation and Characterization of Bioactive Compounds from Plants’ Extracts. African J. Tradit. Complement. Altern. Med. AJTCAM, 2011, 8(1), 1-10.
[3]
Bilia, A.R.; Bergonzi, M.C.; Guccione, C.; Manconi, M.; Fadda, A.M.; Sinico, C. Vesicles and Micelles: Two Versatile Vectors for the Delivery of Natural Products. J. Drug Deliv. Sci. Technol., 2016, 32, 241-255.
[http://dx.doi.org/10.1016/j.jddst.2015.09.007]
[4]
Manach, C.; Scalbert, A.; Morand, C.; Rémésy, C.; Jiménez, L. Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr., 2004, 79(5), 727-747.
[http://dx.doi.org/10.1093/ajcn/79.5.727] [PMID: 15113710]
[5]
Nema, S.; Brendel, R.J. Excipients and their role in approved injectable products: current usage and future directions. PDA J. Pharm. Sci. Technol., 2011, 65(3), 287-332.
[http://dx.doi.org/10.5731/pdajpst.2011.00634] [PMID: 22293237]
[6]
Rubino, J.T. Encyclopedia of Pharmaceutical Technology: Volume 20 - Supplement 3; Swarbrick, J., Boylan, J. C., Eds.; Marcel Dekker, Inc.: New York, Basel , 2000.
[7]
Friščić, T.; Jones, W. Benefits of cocrystallisation in pharmaceutical materials science: an update. J. Pharm. Pharmacol., 2010, 62(11), 1547-1559.
[http://dx.doi.org/10.1111/j.2042-7158.2010.01133.x] [PMID: 21039540]
[8]
Li, P.; Zhao, L. Developing early formulations: practice and perspective. Int. J. Pharm., 2007, 341(1-2), 1-19.
[http://dx.doi.org/10.1016/j.ijpharm.2007.05.049] [PMID: 17658228]
[9]
Newman, A.; Knipp, G.; Zografi, G. Assessing the performance of amorphous solid dispersions. J. Pharm. Sci., 2012, 101(4), 1355-1377.
[http://dx.doi.org/10.1002/jps.23031] [PMID: 22213468]
[10]
O’Driscoll, C.M.; Griffin, B.T. Biopharmaceutical challenges associated with drugs with low aqueous solubility--the potential impact of lipid-based formulations. Adv. Drug Deliv. Rev., 2008, 60(6), 617-624.
[http://dx.doi.org/10.1016/j.addr.2007.10.012] [PMID: 18155800]
[11]
Nakano, M. Places of emulsions in drug delivery. Adv. Drug Deliv. Rev., 2000, 45(1), 1-4.
[http://dx.doi.org/10.1016/S0169-409X(00)00096-X] [PMID: 11104893]
[12]
Davis, M.E.; Brewster, M.E. Cyclodextrin-based pharmaceutics: past, present and future. Nat. Rev. Drug Discov., 2004, 3(12), 1023-1035.
[http://dx.doi.org/10.1038/nrd1576] [PMID: 15573101]
[13]
Petersen, R.D. Nanocrystals for Use in Topical Cosmetic Formulations and Method of Production Thereof; European Patent EP2099420 2008.
[14]
Möschwitzer, J.P. Drug nanocrystals in the commercial pharmaceutical development process. Int. J. Pharm., 2013, 453(1), 142-156.
[http://dx.doi.org/10.1016/j.ijpharm.2012.09.034] [PMID: 23000841]
[15]
Müller, R.H.; Gohla, S.; Keck, C.M. State of the art of nanocrystals--special features, production, nanotoxicology aspects and intracellular delivery. Eur. J. Pharm. Biopharm., 2011, 78(1), 1-9.
[http://dx.doi.org/10.1016/j.ejpb.2011.01.007] [PMID: 21266197]
[16]
Rabinow, B.E. Nanosuspensions in drug delivery. Nat. Rev. Drug Discov., 2004, 3(9), 785-796.
[http://dx.doi.org/10.1038/nrd1494] [PMID: 15340388]
[17]
Lai, F.; Schlich, M.; Pireddu, R.; Corrias, F.; Fadda, A.M.; Sinico, C. Production of nanosuspensions as a tool to improve drug bioavailability: focus on topical delivery. Curr. Pharm. Des., 2015, 21(42), 6089-6103.
[http://dx.doi.org/10.2174/1381612821666151027152350] [PMID: 26503149]
[18]
Mosharraf, M.; Nyström, C. The Effect of Particle Size and Shape on the Surface Specific Dissolution Rate of Microsized Practically Insoluble Drugs. Int. J. Pharm., 1995, 122(1-2), 35-47.
[http://dx.doi.org/10.1016/0378-5173(95)00033-F]
[19]
Müller, R.H.; Jacobs, C.; Kayser, O. Nanosuspensions for the Formulation of Poorly Soluble Drugs; Pharmaceutical Emulsions and Suspensions, 2000, pp. 383-407.
[http://dx.doi.org/10.1201/b14005-13]
[20]
Liversidge, G.G.; Cundy, K.C. Particle Size Reduction for Improvement of Oral Bioavailability of Hydrophobic Drugs: I. Absolute Oral Bioavailability of Nanocrystalline Danazol in Beagle Dogs. Int. J. Pharm., 1995, 125(1), 91-97.
[http://dx.doi.org/10.1016/0378-5173(95)00122-Y]
[21]
Lai, F.; Sinico, C.; Ennas, G.; Marongiu, F.; Marongiu, G.; Fadda, A.M. Diclofenac nanosuspensions: influence of preparation procedure and crystal form on drug dissolution behaviour. Int. J. Pharm., 2009, 373(1-2), 124-132.
[http://dx.doi.org/10.1016/j.ijpharm.2009.01.024] [PMID: 19429297]
[22]
Mou, D.; Chen, H.; Wan, J.; Xu, H.; Yang, X. Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with pH-dependent solubility. Int. J. Pharm., 2011, 413(1-2), 237-244.
[http://dx.doi.org/10.1016/j.ijpharm.2011.04.034] [PMID: 21540090]
[23]
Vergote, G.J.; Vervaet, C.; Van Driessche, I.; Hoste, S.; De Smedt, S.; Demeester, J.; Jain, R.A.; Ruddy, S.; Remon, J.P. In vivo evaluation of matrix pellets containing nanocrystalline ketoprofen. Int. J. Pharm., 2002, 240(1-2), 79-84.
[http://dx.doi.org/10.1016/S0378-5173(02)00114-X] [PMID: 12062503]
[24]
Li, X.; Gu, L.; Xu, Y.; Wang, Y. Preparation of Fenofibrate Nanosuspension and Study of Its Pharmacokinetic Behavior in Rats, 2009.
[http://dx.doi.org/10.1080/03639040802623941]
[25]
Gao, Y.; Li, Z.; Sun, M.; Li, H.; Guo, C.; Cui, J.; Li, A.; Cao, F.; Xi, Y.; Lou, H.; Zhai, G. Preparation, characterization, pharmacokinetics, and tissue distribution of curcumin nanosuspension with TPGS as stabilizer. Drug Dev. Ind. Pharm., 2010, 36(10), 1225-1234.
[http://dx.doi.org/10.3109/03639041003695139] [PMID: 20545506]
[26]
Rabinow, B.; Kipp, J.; Papadopoulos, P.; Wong, J.; Glosson, J.; Gass, J.; Sun, C-S.; Wielgos, T.; White, R.; Cook, C.; Barker, K.; Wood, K. Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat. Int. J. Pharm., 2007, 339(1-2), 251-260.
[http://dx.doi.org/10.1016/j.ijpharm.2007.02.030] [PMID: 17398045]
[27]
Gao, L.; Zhang, D.; Chen, M.; Duan, C.; Dai, W.; Jia, L.; Zhao, W. Studies on pharmacokinetics and tissue distribution of oridonin nanosuspensions. Int. J. Pharm., 2008, 355(1-2), 321-327.
[http://dx.doi.org/10.1016/j.ijpharm.2007.12.016] [PMID: 18242896]
[28]
Ganta, S.; Paxton, J.W.; Baguley, B.C.; Garg, S. Formulation and pharmacokinetic evaluation of an asulacrine nanocrystalline suspension for intravenous delivery. Int. J. Pharm., 2009, 367(1-2), 179-186.
[http://dx.doi.org/10.1016/j.ijpharm.2008.09.022] [PMID: 18848873]
[29]
Merisko-Liversidge, E.; Liversidge, G.G.; Cooper, E.R. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur. J. Pharm. Sci., 2003, 18(2), 113-120.
[http://dx.doi.org/10.1016/S0928-0987(02)00251-8] [PMID: 12594003]
[30]
Bhakay, A.; Merwade, M.; Bilgili, E.; Dave, R.N. Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs. Drug Dev. Ind. Pharm., 2011, 37(8), 963-976.
[http://dx.doi.org/10.3109/03639045.2010.551775] [PMID: 21323486]
[31]
Hennart, S.L.A.; van Hee, P.; Drouet, V.; Domingues, M.C.; Wildeboer, W.J.; Meesters, G.M.H. Characterization and Modeling of a Sub-Micron Milling Process Limited by Agglomeration Phenomena. Chem. Eng. Sci., 2012, 71, 484-495.
[http://dx.doi.org/10.1016/j.ces.2011.11.010]
[32]
Junghanns, J-U.A.H.; Müller, R.H. Nanocrystal technology, drug delivery and clinical applications. Int. J. Nanomedicine, 2008, 3(3), 295-309.
[PMID: 18990939]
[33]
Kesisoglou, F.; Panmai, S.; Wu, Y. Nanosizing--oral formulation development and biopharmaceutical evaluation. Adv. Drug Deliv. Rev., 2007, 59(7), 631-644.
[http://dx.doi.org/10.1016/j.addr.2007.05.003] [PMID: 17601629]
[34]
Muller, R. H.; Becker, R.; Kruss, B.; Peters, K. Pharmaceutical Nanosuspensions for Medicament Administration as Systems with Increased Saturation Solubility and Rate of Solution. US5858410A; , 1999.
[35]
Method for Controlled Production of Ultrafine Microparticles and Nanoparticles 2000.
[36]
Müller, R.H.; Becker, R.; Kruss, K.P. Pharmaceutical Nanosuspensions for Medicament Administration as Systems with Increased Saturation Solubility and Rate of Solution. ; US Patent 5858410 1992.
[37]
Radtke, M.; Nanopure, T.M. Pure Drug Nanoparticles for the Formulation of Porly Soluble Drugs. New Drugs, 2001, 3, 62-68.
[38]
Chan, H-K.; Kwok, P.C.L. Production methods for nanodrug particles using the bottom-up approach. Adv. Drug Deliv. Rev., 2011, 63(6), 406-416.
[http://dx.doi.org/10.1016/j.addr.2011.03.011] [PMID: 21457742]
[39]
Dong, Y.; Ng, W.K.; Hu, J.; Shen, S.; Tan, R.B.H. A continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs. Int. J. Pharm., 2010, 386(1-2), 256-261.
[http://dx.doi.org/10.1016/j.ijpharm.2009.11.007] [PMID: 19922777]
[40]
Hu, J.; Ng, W.K.; Dong, Y.; Shen, S.; Tan, R.B.H. Continuous and scalable process for water-redispersible nanoformulation of poorly aqueous soluble APIs by antisolvent precipitation and spray-drying. Int. J. Pharm., 2011, 404(1-2), 198-204.
[http://dx.doi.org/10.1016/j.ijpharm.2010.10.055] [PMID: 21056643]
[41]
Lai, F.; Pireddu, R.; Corrias, F.; Fadda, A.M.; Valenti, D.; Pini, E.; Sinico, C. Nanosuspension improves tretinoin photostability and delivery to the skin. Int. J. Pharm., 2013, 458(1), 104-109.
[http://dx.doi.org/10.1016/j.ijpharm.2013.10.007] [PMID: 24135683]
[42]
Tran, T.T.; Tran, P.H.; Nguyen, M.N.; Tran, K.T.; Pham, M.N.; Tran, P.C.; Vo, T.V.; Tran, P.C.; Van Vo, T. Amorphous isradipine nanosuspension by the sonoprecipitation method. Int. J. Pharm., 2014, 474(1-2), 146-150.
[http://dx.doi.org/10.1016/j.ijpharm.2014.08.017] [PMID: 25138256]
[43]
Dalvi, S.V.; Rajesh, N.D. Controlling Particle Size of a Poorly Water-Soluble Drug Using Ultrasound and Stabilizers in Antisolvent Precipitation. Ind. Eng. Chem. Res., 2009, 48, 7581-7593.
[http://dx.doi.org/10.1021/ie900248f]
[44]
Zhang, X.; Xia, Q.; Gu, N. Preparation of All-Trans Retinoic Acid nanosuspensions using a modified precipitation method. Drug Dev. Ind. Pharm., 2006, 32(7), 857-863.
[http://dx.doi.org/10.1080/03639040500534184] [PMID: 16908423]
[45]
Chen, X.; Benhayoune, Z.; Williams, R.O., III; Johnston, K.P. Rapid Dissolution of High Potency Itraconazole Particles Produced by Evaporative Precipitation into Aqueous Solution. J. Drug Deliv. Sci. Technol., 2004, 14, 299-304.
[http://dx.doi.org/10.1016/S1773-2247(04)50051-5]
[46]
Sinswat, P.; Gao, X.; Yacaman, M.J.; Williams, R.O., III; Johnston, K.P. Stabilizer choice for rapid dissolving high potency itraconazole particles formed by evaporative precipitation into aqueous solution. Int. J. Pharm., 2005, 302(1-2), 113-124.
[http://dx.doi.org/10.1016/j.ijpharm.2005.06.027] [PMID: 16109466]
[47]
de Waard, H.; Hinrichs, W.L.J.; Frijlink, H.W. A novel bottom-up process to produce drug nanocrystals: controlled crystallization during freeze-drying. J. Control. Release, 2008, 128(2), 179-183.
[http://dx.doi.org/10.1016/j.jconrel.2008.03.002] [PMID: 18423767]
[48]
Hu, J.; Rogers, T.L.; Brown, J.; Young, T.; Johnston, K.P.; Williams, R.O., III Improvement of dissolution rates of poorly water soluble APIs using novel spray freezing into liquid technology. Pharm. Res., 2002, 19(9), 1278-1284.
[http://dx.doi.org/10.1023/A:1020390422785] [PMID: 12403063]
[49]
Ali, H.S.M.; York, P.; Blagden, N. Preparation of hydrocortisone nanosuspension through a bottom-up nanoprecipitation technique using microfluidic reactors. Int. J. Pharm., 2009, 375(1-2), 107-113.
[http://dx.doi.org/10.1016/j.ijpharm.2009.03.029] [PMID: 19481696]
[50]
Hu, J.; Johnston, K.P.; Williams, R.O. III Spray freezing into liquid (SFL) particle engineering technology to enhance dissolution of poorly water soluble drugs: organic solvent versus organic/aqueous co-solvent systems. Eur. J. Pharm. Sci., 2003, 20(3), 295-303.
[http://dx.doi.org/10.1016/S0928-0987(03)00203-3] [PMID: 14592695]
[51]
Method for Preparing Submicron Particle Suspensions; , 2001.
[52]
Funakoshi-Tago, M.; Nakamura, K.; Tago, K.; Mashino, T.; Kasahara, T. Anti-inflammatory activity of structurally related flavonoids, Apigenin, Luteolin and Fisetin. Int. Immunopharmacol., 2011, 11(9), 1150-1159.
[http://dx.doi.org/10.1016/j.intimp.2011.03.012] [PMID: 21443976]
[53]
Kim, B-K.; Cho, A-R.; Park, D-J. Enhancing oral bioavailability using preparations of apigenin-loaded W/O/W emulsions: In vitro and in vivo evaluations. Food Chem., 2016, 206, 85-91.
[http://dx.doi.org/10.1016/j.foodchem.2016.03.052] [PMID: 27041302]
[54]
Wu, W.; Zu, Y.; Wang, L.; Wang, L.; Wang, H.; Li, Y.; Wu, M.; Zhao, X.; Fu, Y. Preparation, characterization and antitumor activity evaluation of apigenin nanoparticles by the liquid antisolvent precipitation technique. Drug Deliv., 2017, 24(1), 1713-1720.
[http://dx.doi.org/10.1080/10717544.2017.1399302] [PMID: 29115900]
[55]
Zhang, J.; Liu, D.; Huang, Y.; Gao, Y.; Qian, S. Biopharmaceutics classification and intestinal absorption study of apigenin. Int. J. Pharm., 2012, 436(1-2), 311-317.
[http://dx.doi.org/10.1016/j.ijpharm.2012.07.002] [PMID: 22796171]
[56]
Al Shaal, L.; Shegokar, R.; Müller, R.H. Production and characterization of antioxidant apigenin nanocrystals as a novel UV skin protective formulation. Int. J. Pharm., 2011, 420(1), 133-140.
[http://dx.doi.org/10.1016/j.ijpharm.2011.08.018] [PMID: 21871547]
[57]
Al Shaal, L.; Müller, R.H.; Shegokar, R. smartCrystal combination technology--scale up from lab to pilot scale and long term stability. Pharmazie, 2010, 65(12), 877-884.
[PMID: 21284256]
[58]
Scholz, P.; Keck, C.M. Flavonoid nanocrystals produced by ARTcrystal®-technology. Int. J. Pharm., 2015, 482(1-2), 27-37.
[http://dx.doi.org/10.1016/j.ijpharm.2014.11.008] [PMID: 25448550]
[59]
Zhang, J.; Huang, Y.; Liu, D.; Gao, Y.; Qian, S. Preparation of apigenin nanocrystals using supercritical antisolvent process for dissolution and bioavailability enhancement. Eur. J. Pharm. Sci., 2013, 48(4-5), 740-747.
[http://dx.doi.org/10.1016/j.ejps.2012.12.026] [PMID: 23305994]
[60]
Nijveldt, R.J.; van Nood, E.; van Hoorn, D.E.; Boelens, P.G.; van Norren, K.; van Leeuwen, P.A. Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr., 2001, 74(4), 418-425.
[http://dx.doi.org/10.1093/ajcn/74.4.418] [PMID: 11566638]
[61]
Harwood, M.; Danielewska-Nikiel, B.; Borzelleca, J.F.; Flamm, G.W.; Williams, G.M.; Lines, T.C. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem. Toxicol., 2007, 45(11), 2179-2205.
[http://dx.doi.org/10.1016/j.fct.2007.05.015] [PMID: 17698276]
[62]
Okamoto, T. Safety of quercetin for clinical application.Review). Int. J. Mol. Med., 2005, 16(2), 275-278.[Review]..
[http://dx.doi.org/ 10.3892/ijmm.16.2.275] [PMID: 16012761]
[63]
Utesch, D.; Feige, K.; Dasenbrock, J.; Broschard, T.H.; Harwood, M.; Danielewska-Nikiel, B.; Lines, T.C. Evaluation of the potential in vivo genotoxicity of quercetin. Mutat. Res., 2008, 654(1), 38-44.
[http://dx.doi.org/10.1016/j.mrgentox.2008.04.008] [PMID: 18556240]
[64]
Kelly, G.S. Quercetin. Monograph. Altern. Med. Rev., 2011, 16(2), 172-194.
[PMID: 21649459]
[65]
Cai, X.; Fang, Z.; Dou, J.; Yu, A.; Zhai, G. Bioavailability of quercetin: problems and promises. Curr. Med. Chem., 2013, 20(20), 2572-2582.
[http://dx.doi.org/10.2174/09298673113209990120] [PMID: 23514412]
[66]
Chessa, M.; Caddeo, C.; Valenti, D.; Manconi, M.; Sinico, C.; Fadda, A.M. Effect of Penetration Enhancer Containing Vesicles on the Percutaneous Delivery of Quercetin through New Born Pig Skin. Pharmaceutics, 2011, 3(3), 497-509.
[http://dx.doi.org/10.3390/pharmaceutics3030497] [PMID: 24310593]
[67]
Fatma, S.; Talegaonkar, S.; Iqbal, Z.; Panda, A.K.; Negi, L.M.; Goswami, D.G.; Tariq, M. Novel flavonoid-based biodegradable nanoparticles for effective oral delivery of etoposide by P-glycoprotein modulation: an in vitro, ex vivo and in vivo investigations. Drug Deliv., 2016, 23(2), 500-511.
[http://dx.doi.org/10.3109/10717544.2014.923956] [PMID: 24937381]
[68]
Ribeiro, M.E.N.P.; Vieira, Í.G.P.; Cavalcante, I.M.; Ricardo, N.M.P.S.; Attwood, D.; Yeates, S.G.; Booth, C. Solubilisation of griseofulvin, quercetin and rutin in micellar formulations of triblock copolymers E62P39E62 and E137S18E137. Int. J. Pharm., 2009, 378(1-2), 211-214.
[http://dx.doi.org/10.1016/j.ijpharm.2009.05.047] [PMID: 19501147]
[69]
Zheng, Y.; Chow, A.H.L. Production and characterization of a spray-dried hydroxypropyl-β-cyclodextrin/quercetin complex. Drug Dev. Ind. Pharm., 2009, 35(6), 727-734.
[http://dx.doi.org/10.1080/03639040802526805] [PMID: 19514988]
[70]
Kakran, M.; Shegokar, R.; Sahoo, N.G.; Shaal, L.A.; Li, L.; Müller, R.H. Fabrication of quercetin nanocrystals: comparison of different methods. Eur. J. Pharm. Biopharm., 2012, 80(1), 113-121.
[http://dx.doi.org/10.1016/j.ejpb.2011.08.006] [PMID: 21896330]
[71]
Lai, F.; Franceschini, I.; Corrias, F.; Sala, M.C.; Cilurzo, F.; Sinico, C.; Pini, E. Maltodextrin fast dissolving films for quercetin nanocrystal delivery. A feasibility study. Carbohydr. Polym., 2015, 121, 217-223.
[http://dx.doi.org/10.1016/j.carbpol.2014.11.070] [PMID: 25659692]
[72]
Cilurzo, F.; Cupone, I.E.; Minghetti, P.; Buratti, S.; Selmin, F.; Gennari, C.G.M.; Montanari, L. Nicotine fast dissolving films made of maltodextrins: a feasibility study. AAPS PharmSciTech, 2010, 11(4), 1511-1517.
[http://dx.doi.org/10.1208/s12249-010-9525-6] [PMID: 20936440]
[73]
Cilurzo, F.; Cupone, I.E.; Minghetti, P.; Selmin, F.; Montanari, L. Fast dissolving films made of maltodextrins. Eur. J. Pharm. Biopharm., 2008, 70(3), 895-900.
[http://dx.doi.org/10.1016/j.ejpb.2008.06.032] [PMID: 18667164]
[74]
Gullón, B.; Lú-Chau, T.A.; Moreira, M.T.; Lema, J.M.; Eibes, G. Rutin: A Review on Extraction, Identification and Purification Methods, Biological Activities and Approaches to Enhance Its Bioavailability. Trends Food Sci. Technol., 2017, 67, 220-235.
[http://dx.doi.org/10.1016/j.tifs.2017.07.008]
[75]
Mauludin, R.; Müller, R.H.; Keck, C.M. Development of an oral rutin nanocrystal formulation. Int. J. Pharm., 2009, 370(1-2), 202-209.
[http://dx.doi.org/10.1016/j.ijpharm.2008.11.029] [PMID: 19114097]
[76]
Mauludin, R.; Müller, R.H.; Keck, C.M. Kinetic solubility and dissolution velocity of rutin nanocrystals. Eur. J. Pharm. Sci., 2009, 36(4-5), 502-510.
[http://dx.doi.org/10.1016/j.ejps.2008.12.002] [PMID: 19130880]
[77]
Mauludin, R.; Müller, R.H. Preparation and Storage Stability of Rutin Nanosuspensions. J. Pharm. Investig., 2013, 43(5), 395-404.
[http://dx.doi.org/10.1007/s40005-013-0084-1]
[78]
Pyo, S.; Meinke, M.; Keck, C.; Müller, R. Rutin—Increased Antioxidant Activity and Skin Penetration by Nanocrystal Technology (SmartCrystals). Cosmetics, 2016, 3(1), 9.
[http://dx.doi.org/10.3390/cosmetics3010009]
[79]
Pyo, S.M.; Meinke, M.; Klein, A.F.; Fischer, T.C.; Müller, R.H. A novel concept for the treatment of couperosis based on nanocrystals in combination with solid lipid nanoparticles (SLN). Int. J. Pharm., 2016, 510(1), 9-16.
[http://dx.doi.org/10.1016/j.ijpharm.2016.05.017] [PMID: 27265313]
[80]
Prasad, S.; Gupta, S.C.; Tyagi, A.K.; Aggarwal, B.B. Curcumin, a component of golden spice: from bedside to bench and back. Biotechnol. Adv., 2014, 32(6), 1053-1064.
[http://dx.doi.org/10.1016/j.biotechadv.2014.04.004] [PMID: 24793420]
[81]
Hewlings, S.J.; Kalman, D.S. Curcumin: A Review of Its’ Effects on Human Health. Foods, 2017, 6(10), 1-11.
[http://dx.doi.org/10.3390/foods6100092] [PMID: 29065496]
[82]
ClinicalTrials.gov;
[83]
Gupta, S.C.; Patchva, S.; Aggarwal, B.B. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J., 2013, 15(1), 195-218.
[http://dx.doi.org/10.1208/s12248-012-9432-8] [PMID: 23143785]
[84]
Drugs@FDA. FDA Approved Drug Products, Available from: https://www.accessdata.fda.gov/scripts/cder/daf/in
[85]
Mehanny, M.; Hathout, R.M.; Geneidi, A.S.; Mansour, S. Exploring the use of nanocarrier systems to deliver the magical molecule; Curcumin and its derivatives. J. Control. Release, 2016, 225, 1-30.
[http://dx.doi.org/10.1016/j.jconrel.2016.01.018] [PMID: 26778694]
[86]
Nelson, K.M.; Dahlin, J.L.; Bisson, J.; Graham, J.; Pauli, G.F.; Walters, M.A. The Essential Medicinal Chemistry of Curcumin. J. Med. Chem., 2017, 60(5), 1620-1637.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00975] [PMID: 28074653]
[87]
Naksuriya, O.; Okonogi, S.; Schiffelers, R.M.; Hennink, W.E. Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment. Biomaterials, 2014, 35(10), 3365-3383.
[http://dx.doi.org/10.1016/j.biomaterials.2013.12.090] [PMID: 24439402]
[88]
Gao, Y.; Li, Z.; Sun, M.; Guo, C.; Yu, A.; Xi, Y.; Cui, J.; Lou, H.; Zhai, G. Preparation and characterization of intravenously injectable curcumin nanosuspension. Drug Deliv., 2011, 18(2), 131-142.
[http://dx.doi.org/10.3109/10717544.2010.520353] [PMID: 20939679]
[89]
Wei, X.L.; Han, Y.R.; Quan, L.H.; Liu, C.Y.; Liao, Y.H. Oily nanosuspension for long-acting intramuscular delivery of curcumin didecanoate prodrug: preparation, characterization and in vivo evaluation. Eur. J. Pharm. Sci., 2013, 49(2), 286-293.
[http://dx.doi.org/10.1016/j.ejps.2013.03.010] [PMID: 23542494]
[90]
Aditya, N.P.; Yang, H.; Kim, S.; Ko, S. Fabrication of amorphous curcumin nanosuspensions using β-lactoglobulin to enhance solubility, stability, and bioavailability. Colloids Surf. B Biointerfaces, 2015, 127, 114-121.
[http://dx.doi.org/10.1016/j.colsurfb.2015.01.027] [PMID: 25660094]
[91]
Li, X.; Yuan, H.; Zhang, C.; Chen, W.; Cheng, W.; Chen, X.; Ye, X. Preparation and in-vitro/in-vivo evaluation of curcumin nanosuspension with solubility enhancement. J. Pharm. Pharmacol., 2016, 68(8), 980-988.
[http://dx.doi.org/10.1111/jphp.12575] [PMID: 27283220]
[92]
Musazzi, U.M.; Marini, V.; Casiraghi, A.; Minghetti, P. Is the European regulatory framework sufficient to assure the safety of citizens using health products containing nanomaterials? Drug Discov. Today, 2017, 22(6), 870-882.
[http://dx.doi.org/10.1016/j.drudis.2017.01.016] [PMID: 28189800]
[93]
Hong, J.; Liu, Y.; Xiao, Y.; Yang, X.; Su, W.; Zhang, M.; Liao, Y.; Kuang, H.; Wang, X. High drug payload curcumin nanosuspensions stabilized by mPEG-DSPE and SPC: in vitro and in vivo evaluation. Drug Deliv., 2017, 24(1), 109-120.
[http://dx.doi.org/10.1080/10717544.2016.1233589] [PMID: 28155567]
[94]
Wang, Y.; Wang, C.; Zhao, J.; Ding, Y.; Li, L. A cost-effective method to prepare curcumin nanosuspensions with enhanced oral bioavailability. J. Colloid Interface Sci., 2017, 485, 91-98.
[http://dx.doi.org/10.1016/j.jcis.2016.09.003] [PMID: 27657837]
[95]
Zhao, Q.; Chen, X.Y.; Martin, C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci. Bull. (Beijing), 2016, 61(18), 1391-1398.
[http://dx.doi.org/10.1007/s11434-016-1136-5] [PMID: 27730005]
[96]
Liu, H.; Dong, Y.; Gao, Y.; Du, Z.; Wang, Y.; Cheng, P.; Chen, A.; Huang, H. The Fascinating Effects of Baicalein on Cancer: A Review. Int. J. Mol. Sci., 2016, 17(10)E1681
[http://dx.doi.org/10.3390/ijms17101681] [PMID: 27735841]
[97]
Lai, M-Y.; Hsiu, S-L.; Tsai, S-Y.; Hou, Y-C.; Chao, P-D.L. Comparison of metabolic pharmacokinetics of baicalin and baicalein in rats. J. Pharm. Pharmacol., 2003, 55(2), 205-209.
[http://dx.doi.org/10.1211/002235702522] [PMID: 12631413]
[98]
Akao, T.; Kawabata, K.; Yanagisawa, E.; Ishihara, K.; Mizuhara, Y.; Wakui, Y.; Sakashita, Y.; Kobashi, K. Baicalin, the predominant flavone glucuronide of scutellariae radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form. J. Pharm. Pharmacol., 2000, 52(12), 1563-1568.
[http://dx.doi.org/10.1211/0022357001777621] [PMID: 11197087]
[99]
Yue, P.F.; Li, Y.; Wan, J.; Wang, Y.; Yang, M.; Zhu, W.F.; Wang, C.H.; Yuan, H.L. Process optimization and evaluation of novel baicalin solid nanocrystals. Int. J. Nanomedicine, 2013, 8, 2961-2973.
[http://dx.doi.org/10.2147/IJN.S44924] [PMID: 23976849]
[100]
Shi-Ying, J.; Jin, H.; Shi-Xiao, J.; Qing-Yuan, L.; Jin-Xia, B.; Chen, H.G.; Rui-Sheng, L.; Wei, W.; Hai-Long, Y. Characterization and evaluation in vivo of baicalin-nanocrystals prepared by an ultrasonic-homogenization-fluid bed drying method. Chin. J. Nat. Med., 2014, 12(1), 71-80.
[http://dx.doi.org/10.1016/S1875-5364(14)60012-1] [PMID: 24484600]
[101]
Xie, Y.; Ma, Y.; Xu, J.; Liu, Y.; Yue, P.; Zheng, Q.; Hu, P.; Yang, M. Panax Notoginseng Saponins as a Novel Nature Stabilizer for Poorly Soluble Drug Nanocrystals: A Case Study with Baicalein. Molecules, 2016, 21(9)E1149
[http://dx.doi.org/10.3390/molecules21091149] [PMID: 27589712]
[102]
Yue, P.F.; Wan, J.; Wang, Y.; Li, Y.; Ma, Y.Q.; Yang, M.; Hu, P.Y.; Yuan, H.L.; Wang, C.H. D-Alpha-tocopherol acid polyethylene glycol 1000 succinate, an effective stabilizer during solidification transformation of baicalin nanosuspensions. Int. J. Pharm., 2013, 443(1-2), 279-287.
[http://dx.doi.org/10.1016/j.ijpharm.2012.12.036] [PMID: 23291447]
[103]
Zhang, J.; Lv, H.; Jiang, K.; Gao, Y. Enhanced bioavailability after oral and pulmonary administration of baicalein nanocrystal. Int. J. Pharm., 2011, 420(1), 180-188.
[http://dx.doi.org/10.1016/j.ijpharm.2011.08.023] [PMID: 21878378]
[104]
Garg, A.; Garg, S.; Zaneveld, L.J.D.; Singla, A.K. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother. Res., 2001, 15(8), 655-669.
[http://dx.doi.org/10.1002/ptr.1074] [PMID: 11746857]
[105]
Roohbakhsh, A.; Parhiz, H.; Soltani, F.; Rezaee, R.; Iranshahi, M. Neuropharmacological properties and pharmacokinetics of the citrus flavonoids hesperidin and hesperetin--a mini-review. Life Sci., 2014, 113(1-2), 1-6.
[http://dx.doi.org/10.1016/j.lfs.2014.07.029] [PMID: 25109791]
[106]
Mishra, P.R.; Al Shaal, L.; Müller, R.H.; Keck, C.M. Production and characterization of Hesperetin nanosuspensions for dermal delivery. Int. J. Pharm., 2009, 371(1-2), 182-189.
[http://dx.doi.org/10.1016/j.ijpharm.2008.12.030] [PMID: 19162147]
[107]
Kakran, M.; Sahoo, G.; Lin, L. Fabrication of Nanoparticles of Silymarin, Hesperetin and Glibenclamide by Evaporative Precipitation of Nanosuspension for Fast Dissolution. Pharm. Anal. Acta, 2014, 06(01), 1-7.
[108]
Shete, G.; Pawar, Y.B.; Thanki, K.; Jain, S.; Bansal, A.K. Oral bioavailability and pharmacodynamic activity of hesperetin nanocrystals generated using a novel bottom-up technology. Mol. Pharm., 2015, 12(4), 1158-1170.
[http://dx.doi.org/10.1021/mp5008647] [PMID: 25785392]
[109]
Romero, G.B.; Chen, R.; Keck, C.M.; Müller, R.H. Industrial concentrates of dermal hesperidin smartCrystals®--production, characterization & long-term stability. Int. J. Pharm., 2015, 482(1-2), 54-60.
[http://dx.doi.org/10.1016/j.ijpharm.2014.11.039] [PMID: 25448556]
[110]
Gambini, J.; Inglés, M.; Olaso, G.; Lopez-Grueso, R.; Bonet-Costa, V.; Gimeno-Mallench, L.; Mas-Bargues, C.; Abdelaziz, K.M.; Gomez-Cabrera, M.C.; Vina, J.; Borras, C. Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism; Bioavailability, and Biological Effects in Animal Models and Humans. Oxid. Med. Cell. Longev, 2015, p. 2015837042.
[http://dx.doi.org/10.1155/2015/837042] [PMID: 26221416]
[111]
Bertacche, V.; Lorenzi, N.; Nava, D.; Pini, E.; Sinico, C. Host-Guest Interaction Study of Resveratrol with Natural and Modified Cyclodextrins. J. Incl. Phenom. Macrocycl. Chem., 2006, 55(3-4), 279-287.
[http://dx.doi.org/10.1007/s10847-006-9047-8]
[112]
Caddeo, C.; Manconi, M.; Fadda, A.M.; Lai, F.; Lampis, S.; Diez-Sales, O.; Sinico, C. Nanocarriers for antioxidant resveratrol: formulation approach, vesicle self-assembly and stability evaluation. Colloids Surf. B Biointerfaces, 2013, 111, 327-332.
[http://dx.doi.org/10.1016/j.colsurfb.2013.06.016] [PMID: 23838200]
[113]
Kobierski, S.; Ofori-Kwakye, K.; Müller, R.H.; Keck, C.M. Resveratrol nanosuspensions for dermal application--production, characterization, and physical stability. Pharmazie, 2009, 64(11), 741-747.
[PMID: 20099519]
[114]
Kobierski, S.; Ofori-Kwakye, K.; Müller, R.H.; Keck, C.M. Resveratrol nanosuspensions: interaction of preservatives with nanocrystal production. Pharmazie, 2011, 66(12), 942-947.
[PMID: 22312699]
[115]
Sinico, C.; Pireddu, R.; Pini, E.; Valenti, D.; Caddeo, C.; Fadda, A.M.; Lai, F. Enhancing Topical Delivery of Resveratrol through a Nanosizing Approach. Planta Med., 2017, 83(5), 476-481.
[PMID: 27220078]
[116]
Liu, T.; Yao, G.; Liu, X.; Yin, H. Preparation Nanocrystals of Poorly Soluble Plant Compounds Using an Ultra-Small-Scale Approach. AAPS PharmSciTech, 2017, 18(7), 2610-2617.
[http://dx.doi.org/10.1208/s12249-017-0742-0] [PMID: 28243886]
[117]
Singh, S.K.; Makadia, V.; Sharma, S.; Rashid, M.; Shahi, S.; Mishra, P.R.; Wahajuddin, M.; Gayen, J.R. Preparation and in-vitro/in-vivo characterization of trans-resveratrol nanocrystals for oral administration. Drug Deliv. Transl. Res., 2017, 7(3), 395-407.
[http://dx.doi.org/10.1007/s13346-017-0362-y] [PMID: 28194730]
[118]
Dong, Q.; Yuan, H-L.; Qian, J-J.; Zhang, C-Y.; Chen, W-D. Preparation and in vitro-in vivo characterization of trans-resveratrol nanosuspensions. Biomed. Mater. Eng., 2018, 29(3), 333-345.
[http://dx.doi.org/10.3233/BME-181729] [PMID: 29578462]
[119]
Kjær, T.N.; Thorsen, K.; Jessen, N.; Stenderup, K.; Pedersen, S.B. Resveratrol ameliorates imiquimod-induced psoriasis-like skin inflammation in mice. PLoS One, 2015, 10(5)e0126599
[http://dx.doi.org/10.1371/journal.pone.0126599] [PMID: 25965695]
[120]
Roberts, R.L.; Green, J.; Lewis, B. Lutein and zeaxanthin in eye and skin health. Clin. Dermatol., 2009, 27(2), 195-201.
[http://dx.doi.org/10.1016/j.clindermatol.2008.01.011] [PMID: 19168000]
[121]
Mitri, K.; Shegokar, R.; Gohla, S.; Anselmi, C.; Müller, R.H. Lutein nanocrystals as antioxidant formulation for oral and dermal delivery. Int. J. Pharm., 2011, 420(1), 141-146.
[http://dx.doi.org/10.1016/j.ijpharm.2011.08.026] [PMID: 21884768]
[122]
Alves-Rodrigues, A.; Shao, A. The science behind lutein. Toxicol. Lett., 2004, 150(1), 57-83.
[http://dx.doi.org/10.1016/j.toxlet.2003.10.031] [PMID: 15068825]
[123]
Hak, A.E.; Ma, J.; Powell, C.B.; Campos, H.; Gaziano, J.M.; Willett, W.C.; Stampfer, M.J. Prospective study of plasma carotenoids and tocopherols in relation to risk of ischemic stroke. Stroke, 2004, 35(7), 1584-1588.
[http://dx.doi.org/10.1161/01.STR.0000132197.67350.bd] [PMID: 15178820]
[124]
Asplund, K. Antioxidant vitamins in the prevention of cardiovascular disease: a systematic review. J. Intern. Med., 2002, 251(5), 372-392.
[http://dx.doi.org/10.1046/j.1365-2796.2002.00973.x] [PMID: 11982737]
[125]
Dayan, N. Skin Aging Handbook : An Integrated Approach to Biochemistry and Product Development; William Andrew, 2008.
[126]
Lee, E.H.; Faulhaber, D.; Hanson, K.M.; Ding, W.; Peters, S.; Kodali, S.; Granstein, R.D. Dietary lutein reduces ultraviolet radiation-induced inflammation and immunosuppression. J. Invest. Dermatol., 2004, 122(2), 510-517.
[http://dx.doi.org/10.1046/j.0022-202X.2004.22227.x] [PMID: 15009738]
[127]
Palombo, P.; Fabrizi, G.; Ruocco, V.; Ruocco, E.; Fluhr, J.; Roberts, R.; Morganti, P. Beneficial long-term effects of combined oral/topical antioxidant treatment with the carotenoids lutein and zeaxanthin on human skin: a double-blind, placebo-controlled study. Skin Pharmacol. Physiol., 2007, 20(4), 199-210.
[http://dx.doi.org/10.1159/000101807] [PMID: 17446716]
[128]
Teeranachaideekul, V.; Junyaprasert, V.B.; Souto, E.B.; Müller, R.H. Development of ascorbyl palmitate nanocrystals applying the nanosuspension technology. Int. J. Pharm., 2008, 354(1-2), 227-234.
[http://dx.doi.org/10.1016/j.ijpharm.2007.11.062] [PMID: 18242898]
[129]
Aungst, B.J. Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism. J. Pharm. Sci., 1993, 82(10), 979-987.
[http://dx.doi.org/10.1002/jps.2600821008] [PMID: 8254497]
[130]
Lo, D.; Wang, Y-T.; Wu, M-C. Hepatoprotective effect of silymarin on di(2-ethylhexyl)phthalate (DEHP) induced injury in liver FL83B cells. Environ. Toxicol. Pharmacol., 2014, 38(1), 112-118.
[http://dx.doi.org/10.1016/j.etap.2014.05.005] [PMID: 24934613]
[131]
Loguercio, C.; Andreone, P.; Brisc, C.; Brisc, M.C.; Bugianesi, E.; Chiaramonte, M.; Cursaro, C.; Danila, M.; de Sio, I.; Floreani, A.; Freni, M.A.; Grieco, A.; Groppo, M.; Lazzari, R.; Lobello, S.; Lorefice, E.; Margotti, M.; Miele, L.; Milani, S.; Okolicsanyi, L.; Palasciano, G.; Portincasa, P.; Saltarelli, P.; Smedile, A.; Somalvico, F.; Spadaro, A.; Sporea, I.; Sorrentino, P.; Vecchione, R.; Tuccillo, C.; Del Vecchio Blanco, C.; Federico, A. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic. Biol. Med., 2012, 52(9), 1658-1665.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.02.008] [PMID: 22343419]
[132]
Liang, L-D.; He, T.; Du, T-W.; Fan, Y-G.; Chen, D-S.; Wang, Y. Ginsenoside Rg5 induces apoptosis and DNA damage in human cervical cancer cells. Mol. Med. Rep., 2015, 11(2), 940-946.
[http://dx.doi.org/10.3892/mmr.2014.2821] [PMID: 25355274]
[133]
Abenavoli, L.; Capasso, R.; Milic, N.; Capasso, F. Milk thistle in liver diseases: past, present, future. Phytother. Res., 2010, 24(10), 1423-1432.
[http://dx.doi.org/10.1002/ptr.3207] [PMID: 20564545]
[134]
Flora, K.; Hahn, M.; Rosen, H.; Benner, K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am. J. Gastroenterol., 1998, 93(2), 139-143.
[http://dx.doi.org/10.1111/j.1572-0241.1998.00139.x] [PMID: 9468229]
[135]
Tan, C.; Xu, X.; Shang, Y.; Fu, X.; Xia, G.; Yang, H. A novel approach for the efficient extraction of silybin from milk thistle fruits. Pharmacogn. Mag., 2014, 10(40), 536-540.
[http://dx.doi.org/10.4103/0973-1296.141799] [PMID: 25422558]
[136]
Luper, S. A review of plants used in the treatment of liver disease: part 1. Altern. Med. Rev., 1998, 3(6), 410-421.
[PMID: 9855566]
[137]
Basaga, H.; Poli, G.; Tekkaya, C.; Aras, I. Free radical scavenging and antioxidative properties of ‘silibin’ complexes on microsomal lipid peroxidation. Cell Biochem. Funct., 1997, 15(1), 27-33.
[http://dx.doi.org/10.1002/(SICI)1099-0844(199703)15:1<27:AID-CBF714>3.0.CO;2-W] [PMID: 9075334]
[138]
Wang, Y.; Zhang, D.; Liu, Z.; Liu, G.; Duan, C.; Jia, L.; Feng, F.; Zhang, X.; Shi, Y.; Zhang, Q. In vitro and in vivo evaluation of silybin nanosuspensions for oral and intravenous delivery. Nanotechnology, 2010, 21(15)155104
[http://dx.doi.org/10.1088/0957-4484/21/15/155104] [PMID: 20332565]
[139]
Zheng, D.; Wang, Y.; Zhang, D.; Liu, Z.; Duan, C.; Jia, L.; Wang, F.; Liu, Y.; Liu, G.; Hao, L.; Zhang, Q. In vitro antitumor activity of silybin nanosuspension in PC-3 cells. Cancer Lett., 2011, 307(2), 158-164.
[http://dx.doi.org/10.1016/j.canlet.2011.03.028] [PMID: 21507570]
[140]
Sahibzada, M.U.K.; Sadiq, A.; Khan, S.; Faidah, H.S. Naseemullah; Khurram, M.; Amin, M.U.; Haseeb, A. Fabrication, characterization and in vitro evaluation of silibinin nanoparticles: an attempt to enhance its oral bioavailability. Drug Des. Devel. Ther., 2017, 11, 1453-1464.
[http://dx.doi.org/10.2147/DDDT.S133806] [PMID: 28553075]
[141]
Quan, H.; Cao, Y-Y.; Xu, Z.; Zhao, J-X.; Gao, P-H.; Qin, X-F.; Jiang, Y-Y. Potent in vitro synergism of fluconazole and berberine chloride against clinical isolates of Candida albicans resistant to fluconazole. Antimicrob. Agents Chemother., 2006, 50(3), 1096-1099.
[http://dx.doi.org/10.1128/AAC.50.3.1096-1099.2006] [PMID: 16495278]
[142]
de Oliveira, D.R.; Tintino, S.R.; Braga, M.F.; Boligon, A.A.; Athayde, M.L.; Coutinho, H.D.; de Menezes, I.R.A.; Fachinetto, R. In vitro antimicrobial and modulatory activity of the natural products silymarin and silibinin. BioMed Res. Int., 2015.2015292797.
[PMID: 25866771]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 26
ISSUE: 24
Year: 2019
Page: [4657 - 4680]
Pages: 24
DOI: 10.2174/0929867326666181213095809
Price: $65

Article Metrics

PDF: 41
HTML: 6