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Drug Delivery Letters

Editor-in-Chief

ISSN (Print): 2210-3031
ISSN (Online): 2210-304X

Research Article

Development of Polymeric Nanocarriers for Brain Targeted Delivery of Atorvastatin: A Quality-By-Design Approach

Author(s): Guilherme A.G. Martins, Fabio S. Murakami, Mauro S. Oliveira, Ana F. Furian, Helen Treichel, Rubiana M. Mainardes, Rossana G.D.J.V. Marcano, Larissa S. Bernardi and Paulo R. Oliveira*

Volume 10, Issue 2, 2020

Page: [149 - 158] Pages: 10

DOI: 10.2174/2210303109666191202102517

Price: $65

Abstract

Objective: Atorvastatin (ATV) is effective in reducing total cholesterol and low-density lipoprotein levels. Furthermore, it produces pleiotropic effects in neurodegenerative conditions such as Parkinson's, Alzheimer's, and epilepsy. However, due to the effective defense system of the central nervous system (CNS), the development of new medicines for clinical conditions has proven difficult. In this context, nanotechnology was applied as a promising solution to promote drug vectorization to the brain.

Methods: The solvent emulsification-diffusion method was used to develop nanoparticles (NPs) based on polylactic acid and coated with polysorbate 80 containing ATV. Quality-by-Design (QbD) was used in the optimization of nanoparticles production through the application of the experimental design Box-Behnken Design.

Results: After optimizing the independent factors including sonication time, surfactant concentration and surfactant volume, the NPs presented physicochemical characteristics such as entrapment efficiency of 86.4 ± 2.4%, mean size of 225.2 ± 4.8 nm, and zeta potential of -14.4 ± 0.36 mV. In the in vitro release study, approximately 20% of the encapsulated ATV was released.

Conclusion: The application of QbD was very useful in demonstrating its applicability in the nanotechnological pharmaceutical area for controlling and predicting the influence of the variables in the production of NPs. The NPs developed in this study presented adequate physicochemical characteristics, which is promising for future in vivo studies.

The physicochemical characteristics included entrapment efficiency of 86.4 ± 2.4%, mean size of 225.2 ± 4.8 nm, and zeta potential of -14.4 ± 0.36 mV. In the in vitro release study, approximately 20% of the encapsulated ATV was released. The application of QbD was very useful in demonstrating its applicability in the nanotechnological pharmaceutical area for controlling and predicting the influence of the variables in the production of NPs. The NPs developed in this study presented adequate physicochemical characteristics, which is promising for future in vivo studies.

Keywords: Atorvastatin, box-benhken design, nanotechnology, polylactic acid, polysorbate 80, quality by design.

Graphical Abstract
[1]
Juran, J.M. Quality by Design, the New Steps for Planning Quality into Goods and Services; Schuster, S. and, Ed.; The Free Press, 1992.
[2]
Sangshetti, J.N.; Deshpande, M.; Zaheer, Z.; Shinde, D.B.; Arote, R. Quality by Design Approach: Regulatory Need. Arab. J. Chem., 2017, 10, S3412-S3425.
[http://dx.doi.org/10.1016/j.arabjc.2014.01.025]
[3]
Dejaegher, B.; Heyden, Y.V. Experimental designs and their recent advances in set-up, data interpretation, and analytical applications. J. Pharm. Biomed. Anal., 2011, 56(2), 141-158.
[http://dx.doi.org/10.1016/j.jpba.2011.04.023] [PMID: 21632194]
[4]
Myers, R.H.; Montgomery, D.C.; Anderson-Cook, C.M. Response Surface Methodology: Process and Product Optimization Using Designed Experiments. In: Introduction; Wiley-Blackwell, Ed.; New York, 2012; p. 1-17.
[5]
Vozza, G.; Danish, M.; Byrne, H.J.; Frías, J.M.; Ryan, S.M. Application of Box-Behnken experimental design for the formulation and optimisation of selenomethionine-loaded chitosan nanoparticles coated with zein for oral delivery. Int. J. Pharm., 2018, 551(1-2), 257-269.
[http://dx.doi.org/10.1016/j.ijpharm.2018.08.050] [PMID: 30153488]
[6]
Simões, A.; Veiga, F.; Figueiras, A.; Vitorino, C. A practical framework for implementing Quality by Design to the development of topical drug products: Nanosystem-based dosage forms. Int. J. Pharm., 2018, 548(1), 385-399.
[http://dx.doi.org/10.1016/j.ijpharm.2018.06.052] [PMID: 29953928]
[7]
Pramod, K.; Tahir, M.A.; Charoo, N.A.; Ansari, S.H.; Ali, J. Pharmaceutical product development: A quality by design approach. Int. J. Pharm. Investig., 2016, 6(3), 129-138.
[http://dx.doi.org/10.4103/2230-973X.187350] [PMID: 27606256]
[8]
Yu, L.X.; Amidon, G.; Khan, M.A.; Hoag, S.W.; Polli, J.; Raju, G.K.; Woodcock, J. Understanding pharmaceutical quality by design. AAPS J., 2014, 16(4), 771-783.
[http://dx.doi.org/10.1208/s12248-014-9598-3] [PMID: 24854893]
[9]
Lionberger, R.A.; Lee, S.L.; Lee, L.; Raw, A.; Yu, L.X. Quality by design: concepts for ANDAs. AAPS J., 2008, 10(2), 268-276.
[http://dx.doi.org/10.1208/s12248-008-9026-7] [PMID: 18465252]
[10]
Nosengo, N. Can you teach old drugs new tricks? Nature, 2016, 534(7607), 314-316.
[http://dx.doi.org/10.1038/534314a] [PMID: 27306171]
[11]
Banach, M.; Czuczwar, S.J.; Borowicz, K.K. Statins - are they anticonvulsant? Pharmacol. Rep., 2014, 66(4), 521-528.
[http://dx.doi.org/10.1016/j.pharep.2014.02.026] [PMID: 24948050]
[12]
Romana, B.; Batger, M.; Prestidge, C.A.; Colombo, G.; Sonvico, F. Expanding the therapeutic potential of statins by means of nanotechnology enabled drug delivery systems. Curr. Top. Med. Chem., 2014, 14(9), 1182-1193.
[http://dx.doi.org/10.2174/1568026614666140329232252] [PMID: 24678704]
[13]
McGuinness, B.; Craig, D.; Bullock, R.; Passmore, P. Statins for the Prevention of Dementia.Cochrane Database of Systematic Reviews; McGuinness, B., Ed.; John Wiley & Sons, Ltd: Chichester, UK, 2009.
[http://dx.doi.org/10.1002/14651858.CD003160.pub2]
[14]
Moghimi, S.M.; Hunter, A.C.; Murray, J.C. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev., 2001, 53(2), 283-318.
[PMID: 11356986]
[15]
Lasprilla, A.J.R.; Martinez, G.A.R.; Lunelli, B.H.; Jardini, A.L.; Filho, R.M. Poly-lactic acid synthesis for application in biomedical devices - a review. Biotechnol. Adv., 2012, 30(1), 321-328.
[http://dx.doi.org/10.1016/j.biotechadv.2011.06.019] [PMID: 21756992]
[16]
Akagi, T.; Baba, M.; Akashi, M. Biodegradable Nanoparticles as Vaccine Adjuvants and Delivery Systems: Regulation of Immune Responses by Nanoparticle-Based Vaccine. Vaccines (Basel), 2011, 4, 31-64.
[17]
Lampe, K.J.; Namba, R.M.; Silverman, T.R.; Bjugstad, K.B.; Mahoney, M.J. Impact of lactic acid on cell proliferation and free radical-induced cell death in monolayer cultures of neural precursor cells. Biotechnol. Bioeng., 2009, 103(6), 1214-1223.
[http://dx.doi.org/10.1002/bit.22352] [PMID: 19408314]
[18]
Nobs, L.; Buchegger, F.; Gurny, R.; Allémann, E. Surface modification of poly(lactic acid) nanoparticles by covalent attachment of thiol groups by means of three methods. Int. J. Pharm., 2003, 250(2), 327-337.
[http://dx.doi.org/10.1016/S0378-5173(02)00542-2] [PMID: 12527160]
[19]
Nobs, L.; Buchegger, F.; Gurny, R.; Allémann, E. Poly(lactic acid) nanoparticles labeled with biologically active Neutravidin for active targeting. Eur. J. Pharm. Biopharm., 2004, 58(3), 483-490.
[http://dx.doi.org/10.1016/j.ejpb.2004.04.006] [PMID: 15451522]
[20]
Conniot, J.; Silva, J.M.; Fernandes, J.G.; Silva, L.C.; Gaspar, R.; Brocchini, S.; Florindo, H.F.; Barata, T.S. Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking. Front Chem., 2014, 2, 105.
[http://dx.doi.org/10.3389/fchem.2014.00105] [PMID: 25505783]
[21]
Tian, X.H.; Lin, X.N.; Wei, F.; Feng, W.; Huang, Z.C.; Wang, P.; Ren, L.; Diao, Y. Enhanced brain targeting of temozolomide in polysorbate-80 coated polybutylcyanoacrylate nanoparticles. Int. J. Nanomedicine, 2011, 6, 445-452.
[PMID: 21445277]
[22]
Martins, S.M.; Sarmento, B.; Nunes, C.; Lúcio, M.; Reis, S.; Ferreira, D.C. Brain targeting effect of camptothecin-loaded solid lipid nanoparticles in rat after intravenous administration. Eur. J. Pharm. Biopharm., 2013, 85(3 Pt A), 488-502.
[http://dx.doi.org/10.1016/j.ejpb.2013.08.011] [PMID: 23994244]
[23]
Wilson, B.; Lavanya, Y.; Priyadarshini, S.R.B.; Ramasamy, M.; Jenita, J.L. Albumin nanoparticles for the delivery of gabapentin: preparation, characterization and pharmacodynamic studies. Int. J. Pharm., 2014, 473(1-2), 73-79.
[http://dx.doi.org/10.1016/j.ijpharm.2014.05.056] [PMID: 24999053]
[24]
Niwa, T.; Takeuchi, H.; Hino, T.; Kunou, N.; Kawashima, Y. Preparations of Biodegradable Nanospheres of Water-Soluble and Insoluble Drugs with D,L-Lactide/Glycolide Copolymer by a Novel Spontaneous Emulsification Solvent Diffusion Method, and the Drug Release Behavior. J. Control. Release, 1993, 25, 89-98.
[http://dx.doi.org/10.1016/0168-3659(93)90097-O]
[25]
Murakami, H.; Kobayashi, M.; Takeuchi, H.; Kawashima, Y. Preparation of poly(DL-lactide-co-glycolide) nanoparticles by modified spontaneous emulsification solvent diffusion method. Int. J. Pharm., 1999, 187(2), 143-152.
[http://dx.doi.org/10.1016/S0378-5173(99)00187-8] [PMID: 10502620]
[26]
Zhang, H-X.; Wang, J-X.; Zhang, Z-B.; Le, Y.; Shen, Z-G.; Chen, J-F. Micronization of atorvastatin calcium by antisolvent precipitation process. Int. J. Pharm., 2009, 374(1-2), 106-113.
[http://dx.doi.org/10.1016/j.ijpharm.2009.02.015] [PMID: 19446766]
[27]
Davson, H. Physiology of the Cerebrospinal Fluid. Handb. Neurochem., 1969, (3), 23-48.
[28]
Altman, P.L.; Dittmer, D.S. Biology Data Book; 2nd ed.; Federation of American Societies: Washington, DC, 1974.
[29]
Ritger, P.L.; Peppas, N.A. A Simple Equation for Description of Solute Release II. Fickian and Anomalous Release from Swellable Devices. J. Control. Release, 1987, 5, 37-42.
[http://dx.doi.org/10.1016/0168-3659(87)90035-6]
[30]
Jain, J.P.; Kumar, N. Development of amphotericin B loaded polymersomes based on (PEG)(3)-PLA co-polymers: Factors affecting size and in vitro evaluation. Eur. J. Pharm. Sci., 2010, 40(5), 456-465.
[http://dx.doi.org/10.1016/j.ejps.2010.05.005] [PMID: 20580669]
[31]
Ravi Kumar, M.N.V.; Bakowsky, U.; Lehr, C.M. Preparation and characterization of cationic PLGA nanospheres as DNA carriers. Biomaterials, 2004, 25(10), 1771-1777.
[http://dx.doi.org/10.1016/j.biomaterials.2003.08.069] [PMID: 14738840]
[32]
Bala, I.; Bhardwaj, V.; Hariharan, S.; Kharade, S.V.; Roy, N.; Ravi Kumar, M.N.V. Sustained release nanoparticulate formulation containing antioxidant-ellagic acid as potential prophylaxis system for oral administration. J. Drug Target., 2006, 14(1), 27-34.
[http://dx.doi.org/10.1080/10611860600565987] [PMID: 16603449]
[33]
Cooper, D.L.; Harirforoosh, S. Effect of formulation variables on preparation of celecoxib loaded polylactide-co-glycolide nanoparticles. PLoS One, 2014, 9(12)e113558
[http://dx.doi.org/10.1371/journal.pone.0113558] [PMID: 25502102]
[34]
Hermans, K.; Van den Plas, D.; Everaert, A.; Weyenberg, W.; Ludwig, A. Full factorial design, physicochemical characterisation and biological assessment of cyclosporine A loaded cationic nanoparticles. Eur. J. Pharm. Biopharm., 2012, 82(1), 27-35.
[http://dx.doi.org/10.1016/j.ejpb.2012.05.003] [PMID: 22634236]
[35]
Quintanar-Guerrero, D.; Fessi, H.; Allémann, E.; Doelker, E. Influence of Stabilizing Agents and Preparative Variables on the Formation of Poly(d,l-Lactic Acid) Nanoparticles by an Emulsification-Diffusion Technique. Int. J. Pharm., 1996, 143, 133-141.
[http://dx.doi.org/10.1016/S0378-5173(96)04697-2]
[36]
Nabi-Meibodi, M.; Vatanara, A.; Najafabadi, A.R.; Rouini, M.R.; Ramezani, V.; Gilani, K.; Etemadzadeh, S.M.H.; Azadmanesh, K. The effective encapsulation of a hydrophobic lipid-insoluble drug in solid lipid nanoparticles using a modified double emulsion solvent evaporation method. Colloids Surf. B Biointerfaces, 2013, 112, 408-414.
[http://dx.doi.org/10.1016/j.colsurfb.2013.06.013] [PMID: 24036624]
[37]
Sharma, D.; Maheshwari, D.; Philip, G.; Rana, R.; Bhatia, S.; Singh, M.; Gabrani, R.; Sharma, S.K.; Ali, J.; Sharma, R.K.; Dang, S. Formulation and optimization of polymeric nanoparticles for intranasal delivery of lorazepam using Box-Behnken design: in vitro and in vivo evaluation. BioMed Res. Int., 2014, 2014156010
[http://dx.doi.org/10.1155/2014/156010] [PMID: 25126544]
[38]
Honary, S.; Zahir, F. Effect of Zeta Potential on the Properties of Nano-Drug Delivery Systems - A Review (Part 1). Trop. J. Pharm. Res., 2013, 12, 265-273.
[39]
Müller, R.H.; Maassen, S.; Weyhers, H.; Mehnert, W. Phagocytic uptake and cytotoxicity of solid lipid nanoparticles (SLN) sterically stabilized with poloxamine 908 and poloxamer 407. J. Drug Target., 1996, 4(3), 161-170.
[http://dx.doi.org/10.3109/10611869609015973] [PMID: 8959488]
[40]
Gupta, R.B.; Kompella, U.B. Nanoparticles Technology for Drug Delivery; Taylor & Francis Group: New York, 2006.
[http://dx.doi.org/10.1201/9780849374555]
[41]
Allen, T.M. The Use of Glycolipids and Hydrophilic Polymers in Avoiding Rapid Uptake of Liposomes by the Mononuclear Phagocyte System. Adv. Drug Deliv. Rev., 1994, 13, 285-309.
[http://dx.doi.org/10.1016/0169-409X(94)90016-7]
[42]
Schaffazick, S.R.; Guterres, S.S.; Freitas, L. de L.; Pohlmann, A.R. Caracterização e Estabilidade Físico-Química de Sistemas Poliméricos Nanoparticulados Para Administração de Fármacos. Quim. Nova, 2003, 26, 726-737.
[http://dx.doi.org/10.1590/S0100-40422003000500017]
[43]
Strickley, R.G. Solubilizing excipients in oral and injectable formulations. Pharm. Res., 2004, 21(2), 201-230.
[http://dx.doi.org/10.1023/B:PHAM.0000016235.32639.23] [PMID: 15032302]
[44]
Narasaiah.V, L.; Reddy.B, K.; Kumar.M, R.; Kumar.A, K.; Raju.Ch; Reddy.B, S.K. V. Improved Dissolution Rate of Atorvastatin Calcium Using Solid Dispersions with PEG-4000. J. Chem. Pharm. Res., 2010, 2, 304-311.
[45]
Eroğlu, H.; Haidar, M.K.; Nemutlu, E.; Öztürk, Ş.; Bayram, C.; Ulubayram, K.; Öner, L. Dual Release Behavior of Atorvastatin and Alpha-Lipoic Acid from PLGA Microspheres for the Combination Therapy in Peripheral Nerve Injury. J. Drug Deliv. Sci. Technol., 2017, 39, 455-466.
[http://dx.doi.org/10.1016/j.jddst.2017.04.028]
[46]
Shameli, K.; Ahmad, M.B.; Yunus, W.M.; Ibrahim, N.A.; Rahman, R.A.; Jokar, M.; Darroudi, M. Silver/poly (lactic acid) nanocomposites: preparation, characterization, and antibacterial activity. Int. J. Nanomedicine, 2010, 5, 573-579.
[http://dx.doi.org/10.2147/IJN.S12007] [PMID: 20856832]
[47]
Antônio, E.; Antunes, O.D.R.; de Araújo, I.S.; Khalil, N.M.; Mainardes, R.M. Poly(lactic acid) nanoparticles loaded with ursolic acid: Characterization and in vitro evaluation of radical scavenging activity and cytotoxicity. Mater. Sci. Eng. C, 2017, 71, 156-166.
[http://dx.doi.org/10.1016/j.msec.2016.09.080] [PMID: 27987693]
[48]
Guo, Z.; Xiong, J.; Yang, M.; Xiong, S.; Chen, J.; Wu, Y.; Fan, H.; Sun, L.; Wang, J.; Wang, H. Dispersion of Nano-TiN Powder in Aqueous Media. J. Alloys Compd., 2010, 493, 362-367.
[http://dx.doi.org/10.1016/j.jallcom.2009.12.103]
[49]
Kong, R.; Zhu, X.; Meteleva, E.S.; Dushkin, A.V.; Su, W. Physicochemical Characteristics of the Complexes of Simvastatin and Atorvastatin Calcium with Hydroxypropyl- β -Cyclodextrin Produced by Mechanochemical Activation. J. Drug Deliv. Sci. Technol., 2018, 46, 436-445.
[http://dx.doi.org/10.1016/j.jddst.2018.05.018]
[50]
Desai, S.; Disouza, J.; Sable, A.; Hosmani, A. Development of Orodispersible Tablet of Atorvastatin Calcium Using Hot Melt Extrusion. Drug Deliv. Lett., 2015, 5, 19-30.
[http://dx.doi.org/10.2174/2210303104666141029233757]
[51]
Inkinen, S.; Hakkarainen, M.; Albertsson, A-C.; Södergård, A. From lactic acid to poly(lactic acid) (PLA): characterization and analysis of PLA and its precursors. Biomacromolecules, 2011, 12(3), 523-532.
[http://dx.doi.org/10.1021/bm101302t] [PMID: 21332178]
[52]
Marilucia, P. CRUZ, L.; RÉ, M.I.; GUTERRES, S.S. Micropartículas Secas Contendo Fármaco Modelo Lipofílico Preparadas a Partir de Suspensão Aquosa: Estudo de Formulação Marilúcia. Lat. Am. J. Pharm., 2006, 25, 198-205.
[53]
Korsmeyer, R.W.; Peppas, N.A. Macromolecular and Modeling Aspects of Swelling Controlled Systems.Mansdorf, S. Z. Control. release Deliv; Roseman, T.J., Ed.; Syst, 1981, pp. 77-90.
[54]
Siepmann, J.; Peppas, N.A. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv. Drug Deliv. Rev., 2001, 48(2-3), 139-157.
[http://dx.doi.org/10.1016/S0169-409X(01)00112-0] [PMID: 11369079]

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