Recent Advances in Intranasal Administration for Brain-Targeting Delivery: A Comprehensive Review of Lipid-Based Nanoparticles and Stimuli-Responsive Gel Formulations

References

• Kaushik A, Jayant RD, Bhardwaj V, Nair M. Personalized nanomedicine for CNS diseases. Drug Discovery Today. 2018;23(5):1007–1015. doi:10.1016/j.drudis.2017.11.010
   PubMed Web of Science ®Google Scholar
• Nichols E, Szoeke CE, Vollset SE, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2019;18(1):88–106. doi:10.1016/S1474-4422(18)30403-4
   PubMed Web of Science ®Google Scholar
• Dorsey ER, Elbaz A, Nichols E, et al. Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2018;17(11):939–953. doi:10.1016/S1474-4422(18)30295-3
   PubMed Web of Science ®Google Scholar
• Charlson FJ, Ferrari AJ, Santomauro DF, et al. Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016. Schizophrenia Bulletin. 2018;44(6):1195–1203. doi:10.1093/schbul/sby058
   PubMed Web of Science ®Google Scholar
• Wallin MT, Culpepper WJ, Nichols E, et al. Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2019;18(3):269–285. doi:10.1016/S1474-4422(18)30443-5
   PubMed Web of Science ®Google Scholar
• Patel AP, Fisher JL, Nichols E, et al. Global, regional, and national burden of brain and other CNS cancer, 1990–2016: a systematic analysis for the global burden of disease Study 2016. Lancet Neurol. 2019;18(4):376–393. doi:10.1016/S1474-4422(18)30468-X
   PubMed Web of Science ®Google Scholar
• Agrawal M, Saraf S, Saraf S, et al. Nose-to-brain drug delivery: an update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J Cont Rel. 2018;281:139–177. doi:10.1016/j.jconrel.2018.05.011
   PubMed Web of Science ®Google Scholar
• Liu H-J, Xu P. Strategies to overcome/penetrate the BBB for systemic nanoparticle delivery to the brain/brain tumor. Advan Drug Del Rev. 2022;191:114619. doi:10.1016/j.addr.2022.114619
   PubMed Web of Science ®Google Scholar
• Kapoor M, Cloyd JC, Siegel RA. A review of intranasal formulations for the treatment of seizure emergencies. Journal of Controlled Release. 2016;237:147–159. doi:10.1016/j.jconrel.2016.07.001
   PubMed Web of Science ®Google Scholar
• Wong KH, Riaz MK, Xie Y, et al. Review of current strategies for delivering Alzheimer’s disease drugs across the blood-brain barrier. Internat J Mol Sci. 2019;20(2):381. doi:10.3390/ijms20020381
   PubMed Web of Science ®Google Scholar
• Reddy S, Tatiparti K, Sau S, Iyer AK. Recent advances in nano delivery systems for blood-brain barrier (BBB) penetration and targeting of brain tumors. Drug Discovery Today. 2021;26(8):1944–1952. doi:10.1016/j.drudis.2021.04.008
   PubMed Web of Science ®Google Scholar
• Formica ML, Real DA, Picchio ML, Catlin E, Donnelly RF, Paredes AJ. On a highway to the brain: a review on nose-to-brain drug delivery using nanoparticles. Applied Materials Today. 2022;29:101631. doi:10.1016/j.apmt.2022.101631
   Web of Science ®Google Scholar
• Agrawal M, Saraf S, Saraf S, et al. Stimuli-responsive in situ gelling system for nose-to-brain drug delivery. J Cont Rel. 2020;327:235–265. doi:10.1016/j.jconrel.2020.07.044
   PubMed Web of Science ®Google Scholar
• Akel H, Ismail R, Csoka I. Progress and perspectives of brain-targeting lipid-based nanosystems via the nasal route in Alzheimer’s disease. Europ J Pharmaceut Biopharmac. 2020;148:38–53. doi:10.1016/j.ejpb.2019.12.014
   PubMed Web of Science ®Google Scholar
• Sabir F, Ismail R, Csoka I. Nose-to-brain delivery of antiglioblastoma drugs embedded into lipid nanocarrier systems: status quo and outlook. Drug Discovery Today. 2020;25(1):185–194. doi:10.1016/j.drudis.2019.10.005
   PubMed Web of Science ®Google Scholar
• Feng Y, He H, Li F, Lu Y, Qi J, Wu W. An update on the role of nanovehicles in nose-to-brain drug delivery. Drug Discovery Today. 2018;23(5):1079–1088. doi:10.1016/j.drudis.2018.01.005
   PubMed Web of Science ®Google Scholar
• Khan AR, Liu M, Khan MW, Zhai G. Progress in brain targeting drug delivery system by nasal route. J Cont Rel. 2017;268:364–389. doi:10.1016/j.jconrel.2017.09.001
   PubMed Web of Science ®Google Scholar
• Pardridge WM. Treatment of Alzheimer’s disease and blood-brain barrier drug delivery. Pharmaceuticals. 2020;13(11):394. doi:10.3390/ph13110394
   Web of Science ®Google Scholar
• Delhaas E, Huygen F. Complications associated with intrathecal drug delivery systems. BJA Educ. 2020;20(2):51–57. doi:10.1016/j.bjae.2019.11.002
   PubMed Web of Science ®Google Scholar
• Terstappen GC, Meyer AH, Bell RD, Zhang W. Strategies for delivering therapeutics across the blood-brain barrier. Nat Rev Drug Discov. 2021;20(5):362–383. doi:10.1038/s41573-021-00139-y
   PubMed Web of Science ®Google Scholar
• Costa CP, Moreira JN, Lobo JMS, Silva AC. Intranasal delivery of nanostructured lipid carriers, solid lipid nanoparticles and nanoemulsions: a current overview of in vivo studies. Acta Pharmac Sinica B. 2021;11(4):925–940. doi:10.1016/j.apsb.2021.02.012
   PubMed Web of Science ®Google Scholar
• Dkhar LK, Bartley J, White D, Seyfoddin A. Intranasal drug delivery devices and interventions associated with post-operative endoscopic sinus surgery. Pharmac Develop Technol. 2018;23(3):282–294. doi:10.1080/10837450.2017.1389956
   PubMed Web of Science ®Google Scholar
• Goel H, Kalra V, Verma SK, Dubey SK, Tiwary AK. Convolutions in the rendition of nose to brain therapeutics from bench to bedside: feats & fallacies. J Control Rel. 2022;341:782–811. doi:10.1016/j.jconrel.2021.12.009
   PubMed Web of Science ®Google Scholar
• Dogan R, Senturk E, Ozturan O, Yildirim YS, Tugrul S, Hafiz AM. Conchal contractility after inferior turbinate hypertrophy treatment: a prospective, randomized clinical trial. Am J Otolaryngol. 2017;38(6):678–682.
   PubMed Web of Science ®Google Scholar
• Jeong S-H, Jang J-H, Lee Y-B. Drug delivery to the brain via the nasal route of administration: exploration of key targets and major consideration factors. J Pharmac Invest. 2023;53(1):119–152. doi:10.1007/s40005-022-00589-5
   PubMed Web of Science ®Google Scholar
• Crowe TP, Hsu WH. Evaluation of recent intranasal drug delivery systems to the central nervous system. Pharmaceutics. 2022;14(3):629. doi:10.3390/pharmaceutics14030629
   PubMed Web of Science ®Google Scholar
• Vincent AJ, West AK, Chuah MI. Morphological and functional plasticity of olfactory ensheathing cells. J Neurocytol. 2005;34(1–2):65–80. doi:10.1007/s11068-005-5048-6
   PubMedGoogle Scholar
• Inoue D, Furubayashi T, Tanaka A, Sakane T, Sugano K. Effect of cerebrospinal fluid circulation on nose-to-brain direct delivery and distribution of caffeine in rats. Molec Pharmaceut. 2020;17(11):4067–4076. doi:10.1021/acs.molpharmaceut.0c00495
   PubMed Web of Science ®Google Scholar
• Fukuda M, Kanazawa T, Iioka S, et al. Quantitative analysis of inulin distribution in the brain focused on nose-to-brain route via olfactory epithelium by reverse esophageal cannulation. Journal of Controlled Release. 2021;332:493–501. doi:10.1016/j.jconrel.2021.02.024
   PubMed Web of Science ®Google Scholar
• Tashima T. Shortcut approaches to substance delivery into the brain based on intranasal administration using nanodelivery strategies for insulin. Molecules. 2020;25(21):5188. doi:10.3390/molecules25215188
   PubMed Web of Science ®Google Scholar
• Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci. 2018;195:44–52. doi:10.1016/j.lfs.2017.12.025
   PubMed Web of Science ®Google Scholar
• Costa C, Moreira J, Amaral M, Lobo JS, Silva AC. Nose-to-brain delivery of lipid-based nanosystems for epileptic seizures and anxiety crisis. J Cont Rel. 2019;295:187–200. doi:10.1016/j.jconrel.2018.12.049
   PubMed Web of Science ®Google Scholar
• Cone RA. Barrier properties of mucus. Advan Drug Deliv Rev. 2009;61(2):75–85. doi:10.1016/j.addr.2008.09.008
   PubMed Web of Science ®Google Scholar
• Froehlich E, Roblegg E. Mucus as barrier for drug delivery by nanoparticles. J Nanosci Nanotechnol. 2014;14(1):126–136. doi:10.1166/jnn.2014.9015
   PubMed Web of Science ®Google Scholar
• Wu L, Shan W, Zhang Z, Huang Y. Engineering nanomaterials to overcome the mucosal barrier by modulating surface properties. Advan Drug Deliv Rev. 2018;124:150–163. doi:10.1016/j.addr.2017.10.001
   PubMed Web of Science ®Google Scholar
• Patel AA, Patel RJ, Patel SR. Nanomedicine for intranasal delivery to improve brain uptake. Curr Drug Deliv. 2018;15(4):461–469. doi:10.2174/1567201814666171013150534
   PubMed Web of Science ®Google Scholar
• Arora P, Sharma S, Garg S. Permeability issues in nasal drug delivery. Drug Discovery Today. 2002;7(18):967–975. doi:10.1016/S1359-6446(02)02452-2
   PubMed Web of Science ®Google Scholar
• Kaur P, Garg T, Rath G, Goyal AK. In situ nasal gel drug delivery: a novel approach for brain targeting through the mucosal membrane. Artif Cells Nanomed Biotechnol. 2016;44(4):1167–1176. doi:10.3109/21691401.2015.1012260
   PubMed Web of Science ®Google Scholar
• Jain H, Prabhakar B, Shende P. Modulation of olfactory area for effective transportation of actives in CNS disorders. J Drug Deliv Sci Technol. 2022;68:103091. doi:10.1016/j.jddst.2021.103091
   Web of Science ®Google Scholar
• Warnken ZN, Smyth HD, Watts AB, Weitman S, Kuhn JG, Williams RO. Formulation and device design to increase nose to brain drug delivery. J Drug Deliv Sci Technol. 2016;35:213–222. doi:10.1016/j.jddst.2016.05.003
   Web of Science ®Google Scholar
• Xu J, Tao J, Wang J. Design and application in delivery system of intranasal antidepressants. Front Bioeng Biotechnol. 2020;8:626882. doi:10.3389/fbioe.2020.626882
   PubMed Web of Science ®Google Scholar
• Sánchez-Dengra B, González-Álvarez I, Bermejo M, González-Álvarez M. Access to the CNS: strategies to overcome the BBB. Internat J Pharmac. 2023;636:122759. doi:10.1016/j.ijpharm.2023.122759
   PubMed Web of Science ®Google Scholar
• Pandit R, Chen L, Götz J. The blood-brain barrier: physiology and strategies for drug delivery. Advan Drug Deliv Rev. 2020;165–166:1–14. doi:10.1016/j.addr.2019.11.009
   PubMed Web of Science ®Google Scholar
• Mitusova K, Peltek OO, Karpov TE, Muslimov AR, Zyuzin MV, Timin AS. Overcoming the blood–brain barrier for the therapy of malignant brain tumor: current status and prospects of drug delivery approaches. J Nanobiotechnol. 2022;20(1):412.
   PubMed Web of Science ®Google Scholar
• Correia A, Monteiro A, Silva R, Moreira J, Lobo JS, Silva A. Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: crossing or circumventing the blood-brain barrier (BBB) to manage neurological disorders. Advan Drug Deliv Rev. 2022;189:114485. doi:10.1016/j.addr.2022.114485
   PubMed Web of Science ®Google Scholar
• Nguyen TT, Nguyen TTD, Tran N, Van Vo G. Lipid-based nanocarriers via nose-to-brain pathway for central nervous system disorders. Neuroch Res. 2022;2022:1–22.
   Google Scholar
• Pires PC, Santos AO. Nanosystems in nose-to-brain drug delivery: a review of non-clinical brain targeting studies. J Cont Rel. 2018;270:89–100. doi:10.1016/j.jconrel.2017.11.047
   PubMed Web of Science ®Google Scholar
• Shah D, Guo Y, Ban I, Shao J. Intranasal delivery of insulin by self-emulsified nanoemulsion system: in vitro and in vivo studies. Internat J Pharmac. 2022;616:121565. doi:10.1016/j.ijpharm.2022.121565
   PubMed Web of Science ®Google Scholar
• Jiang Y, Liu C, Zhai W, Zhuang N, Han T, Ding Z. The optimization design of lactoferrin loaded Hup A nanoemulsion for targeted drug transport via intranasal route. Internat J Nanomed. 2019;Volume 14:9217–9234. doi:10.2147/IJN.S214657
   Web of Science ®Google Scholar
• Kaur A, Nigam K, Bhatnagar I, et al. Treatment of Alzheimer’s disease using donepezil nanoemulsion: an intranasal approach. Drug Deliv Translat Res. 2020;10(6):1862–1875. doi:10.1007/s13346-020-00754-z
   PubMed Web of Science ®Google Scholar
• Mallick A, Gupta A, Hussain A, et al. Intranasal delivery of gabapentin loaded optimized nanoemulsion for augmented permeation. J Drug Deliv Sci Technol. 2020;56:101606. doi:10.1016/j.jddst.2020.101606
   Web of Science ®Google Scholar
• Arora A, Kumar S, Ali J, Baboota S. Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington’s disease: pharmacokinetic and brain delivery study. Chem Phys Lip. 2020;230:104917. doi:10.1016/j.chemphyslip.2020.104917
   PubMed Web of Science ®Google Scholar
• Ashhar MU, Kumar S, Ali J, Baboota S. CCRD based development of bromocriptine and glutathione nanoemulsion tailored ultrasonically for the combined anti-Parkinson effect. Chem Phys Lip. 2021;235:105035. doi:10.1016/j.chemphyslip.2020.105035
   PubMed Web of Science ®Google Scholar
• Gaba B, Khan T, Haider MF, et al. Vitamin E loaded naringenin nanoemulsion via intranasal delivery for the management of oxidative stress in a 6-OHDA Parkinson’s disease model. BioMed Res Internat. 2019;2019:1–20. doi:10.1155/2019/2382563
   Web of Science ®Google Scholar
• Diedrich C, Zittlau IC, Machado CS, et al. Mucoadhesive nanoemulsion enhances brain bioavailability of luteolin after intranasal administration and induces apoptosis to SH-SY5Y neuroblastoma cells. Internat J Pharmac. 2022;626:122142. doi:10.1016/j.ijpharm.2022.122142
   PubMed Web of Science ®Google Scholar
• Fachel FNS, Medeiros-Neves B, Dal Prá M, et al. Box-Behnken design optimization of mucoadhesive chitosan-coated nanoemulsions for rosmarinic acid nasal delivery-in vitro studies. Carbohy Pol. 2018;199:572–582. doi:10.1016/j.carbpol.2018.07.054
   PubMed Web of Science ®Google Scholar
• Ahmad N, Ahmad R, Amir M, et al. Ischemic brain treated with 6-gingerol loaded mucoadhesive nanoemulsion via intranasal delivery and their comparative pharmacokinetic effect in brain. J Drug Deliv Sci Technol. 2021;61:102130. doi:10.1016/j.jddst.2020.102130
   Web of Science ®Google Scholar
• Patel RJ, Parikh RH. Intranasal delivery of topiramate nanoemulsion: pharmacodynamic, pharmacokinetic and brain uptake studies. Internat J Pharmac. 2020;585:119486. doi:10.1016/j.ijpharm.2020.119486
   PubMed Web of Science ®Google Scholar
• Kaur A, Nigam K, Srivastava S, Tyagi A, Dang S. Memantine nanoemulsion: a new approach to treat Alzheimer’s disease. J Microencapsul. 2020;37(5):355–365. doi:10.1080/02652048.2020.1756971
   PubMed Web of Science ®Google Scholar
• Iqbal R, Ahmed S, Jain GK, Vohora D. Design and development of letrozole nanoemulsion: a comparative evaluation of brain targeted nanoemulsion with free letrozole against status epilepticus and neurodegeneration in mice. Internat J Pharmac. 2019;565:20–32. doi:10.1016/j.ijpharm.2019.04.076
   PubMed Web of Science ®Google Scholar
• Shen X, Cui Z, Wei Y, et al. Exploring the potential to enhance drug distribution in the brain subregion via intranasal delivery of nanoemulsion in combination with borneol as a guider. As J Pharmac Sci. 2023;18(6):100778. doi:10.1016/j.ajps.2023.100778
   PubMed Web of Science ®Google Scholar
• Nogueira C, Lemos-Senna E, da Silva Vieira E, et al. β-caryophyllene cationic nanoemulsion for intranasal delivery and treatment of epilepsy: development and in vivo evaluation of anticonvulsant activity. J Nanopart Res. 2023;25(1):19. doi:10.1007/s11051-023-05668-8
   Web of Science ®Google Scholar
• Kurano T, Kanazawa T, Ooba A, et al. Nose-to-brain/spinal cord delivery kinetics of liposomes with different surface properties. J Cont Rel. 2022;344:225–234. doi:10.1016/j.jconrel.2022.03.017
   PubMed Web of Science ®Google Scholar
• Barros C, Aranha N, Severino P, et al. Quality by design approach for the development of liposome carrying ghrelin for intranasal administration. Pharmaceutics. 2021;13(5):686. doi:10.3390/pharmaceutics13050686
   PubMed Web of Science ®Google Scholar
• Pashirova TN, Zueva IV, Petrov KA, et al. Mixed cationic liposomes for brain delivery of drugs by the intranasal route: the acetylcholinesterase reactivator 2-PAM as encapsulated drug model. Coll Surf B. 2018;171:358–367. doi:10.1016/j.colsurfb.2018.07.049
   PubMed Web of Science ®Google Scholar
• Katona G, Sabir F, Sipos B, et al. Development of lomustine and n-propyl gallate co-encapsulated liposomes for targeting glioblastoma multiforme via intranasal administration. Pharmaceutics. 2022;14(3):631. doi:10.3390/pharmaceutics14030631
   PubMed Web of Science ®Google Scholar
• Sabir F, Katona G, Pallagi E, et al. Quality-by-design-based development of n-propyl-gallate-loaded hyaluronic-acid-coated liposomes for intranasal administration. Molecules. 2021;26(5):1429. doi:10.3390/molecules26051429
   PubMed Web of Science ®Google Scholar
• Saka R, Chella N, Khan W. Development of imatinib mesylate-loaded liposomes for nose to brain delivery: in vitro and in vivo evaluation. AAPS Pharm Sci Tech. 2021;22(5):192. doi:10.1208/s12249-021-02072-0
   PubMed Web of Science ®Google Scholar
• Singh V, Krishan P, Shri R. Amelioration of ischaemia reperfusion-induced cerebral injury in mice by liposomes containing Allium cepa fraction administered intranasally. Artif Cells Nanomed Biotechnol. 2018;46(sup3):982–992. doi:10.1080/21691401.2018.1523181
   PubMed Web of Science ®Google Scholar
• Yuwanda A, Surini S, Harahap Y, Jufri M. Study of valproic acid liposomes for delivery into the brain through an intranasal route. Heliyon. 2022;8(3):e09030. doi:10.1016/j.heliyon.2022.e09030
   PubMed Web of Science ®Google Scholar
• Taha MS, Kutlehria S, D’Souza A, Bleier BS, Amiji MM. Topical administration of verapamil in poly (ethylene glycol)-modified liposomes for enhanced sinonasal tissue residence in chronic rhinosinusitis: ex vivo and in vivo evaluations. Molecu Pharmaceut. 2023;20(3):1729–1736. doi:10.1021/acs.molpharmaceut.2c00943
   PubMed Web of Science ®Google Scholar
• Trapani A, De Giglio E, Cometa S, et al. Dopamine-loaded lipid based nanocarriers for intranasal administration of the neurotransmitter: a comparative study. Europ J Pharmac Biopharm. 2021;167:189–200. doi:10.1016/j.ejpb.2021.07.015
   PubMed Web of Science ®Google Scholar
• Wang L, Zhao X, Du J, Liu M, Feng J, Hu K. Improved brain delivery of pueraria flavones via intranasal administration of borneol-modified solid lipid nanoparticles. Nanomedicine. 2019;14(16):2105–2119. doi:10.2217/nnm-2018-0417
   PubMed Web of Science ®Google Scholar
• Hasan N, Imran M, Kesharwani P, et al. Intranasal delivery of naloxone-loaded solid lipid nanoparticles as a promising simple and non-invasive approach for the management of opioid overdose. Internat J Pharmac. 2021;599:120428. doi:10.1016/j.ijpharm.2021.120428
   PubMed Web of Science ®Google Scholar
• Said DE, Amer EI, Sheta E, Makled S, Arafa FM, Diab HE. Nano-encapsulated antioxidant: retinoic acid as a natural mucosal adjuvant for intranasal immunization against chronic experimental toxoplasmosis. Trop Med Infect Dis. 2023;8(2):106. doi:10.3390/tropicalmed8020106
   PubMedGoogle Scholar
• Arora D, Bhatt S, Kumar M, et al. QbD-based rivastigmine tartrate loaded solid lipid nanoparticles for enhanced intranasal delivery to the brain for Alzheimer’s therapeutics. Frontiers in Aging Neuroscience. 2022;2022:869.
   Google Scholar
• Yasir M, Sara UVS, Chauhan I, et al. Solid lipid nanoparticles for nose to brain delivery of donepezil: formulation, optimization by Box–Behnken design, in vitro and in vivo evaluation. Artif Cells Nanomed Biotechnol. 2018;46(8):1838–1851.
   Web of Science ®Google Scholar
• Kataria I, Shende P. Nose-to-brain lipid nanocarriers: an active transportation across BBB in migraine management. Chemist Phys Lip. 2022;243:105177. doi:10.1016/j.chemphyslip.2022.105177
   PubMed Web of Science ®Google Scholar
• Yasir M, Chauhan I, Zafar A, et al. Glyceryl behenate-based solid lipid nanoparticles as a carrier of haloperidol for nose to brain delivery: formulation development, in-vitro, and in-vivo evaluation. Brazil J Pharmaceut Sci. 2023;2023:58.
   Google Scholar
• Yasir M, Chauhan I, Zafar A, et al. Buspirone loaded solid lipid nanoparticles for amplification of nose to brain efficacy: formulation development, optimization by Box-Behnken design, in-vitro characterization and in-vivo biological evaluation. J Drug Deliv Sci Technol. 2021;61:102164. doi:10.1016/j.jddst.2020.102164
   Web of Science ®Google Scholar
• Trapani A, Guerra L, Corbo F, et al. Cyto/biocompatibility of dopamine combined with the antioxidant grape seed-derived polyphenol compounds in solid lipid nanoparticles. Molecules. 2021;26(4):916. doi:10.3390/molecules26040916
   PubMed Web of Science ®Google Scholar
• Costa C, Cunha S, Moreira J, et al. Quality by design (QbD) optimization of diazepam-loaded nanostructured lipid carriers (NLC) for nose-to-brain delivery: toxicological effect of surface charge on human neuronal cells. Internat J Pharmac. 2021;607:120933. doi:10.1016/j.ijpharm.2021.120933
   PubMed Web of Science ®Google Scholar
• Patel HP, Gandhi PA, Chaudhari PS, et al. Clozapine loaded nanostructured lipid carriers engineered for brain targeting via nose-to-brain delivery: optimization and in vivo pharmacokinetic studies. J Drug Deliv Sci Technol. 2021;64:102533. doi:10.1016/j.jddst.2021.102533
   Web of Science ®Google Scholar
• Masjedi M, Azadi A, Heidari R, Mohammadi-Samani S. Nose-to-brain delivery of sumatriptan-loaded nanostructured lipid carriers: preparation, optimization, characterization and pharmacokinetic evaluation. J Pharm Pharmacol. 2020;72(10):1341–1351. doi:10.1111/jphp.13316
   PubMed Web of Science ®Google Scholar
• Nair SC, Vinayan KP, Mangalathillam S. Nose to brain delivery of phenytoin sodium loaded nano lipid carriers: formulation, drug release, permeation and in vivo pharmacokinetic studies. Pharmaceutics. 2021;13(10):1640. doi:10.3390/pharmaceutics13101640
   PubMed Web of Science ®Google Scholar
• Torres J, Pereira JM, Marques-Oliveira R, et al. An in vitro evaluation of the potential neuroprotective effects of intranasal lipid nanoparticles containing astaxanthin obtained from different sources: comparative studies. Pharmaceutics. 2023;15(4):1035. doi:10.3390/pharmaceutics15041035
   PubMed Web of Science ®Google Scholar
• Sheth T, Seshadri S, Prileszky T, Helgeson ME. Multiple nanoemulsions. Nat Rev Mater. 2020;5(3):214–228. doi:10.1038/s41578-019-0161-9
   Web of Science ®Google Scholar
• Shah B. Microemulsion as a promising carrier for nose to brain delivery: journey since last decade. J Pharmac Invest. 2021;2021:1–24.
   Google Scholar
• Li M, Du C, Guo N, et al. Composition design and medical application of liposomes. Europ J Med Chemist. 2019;164:640–653. doi:10.1016/j.ejmech.2019.01.007
   PubMed Web of Science ®Google Scholar
• Large DE, Abdelmessih RG, Fink EA, Auguste DT. Liposome composition in drug delivery design, synthesis, characterization, and clinical application. Advan Drug Deliv Rev. 2021;176:113851. doi:10.1016/j.addr.2021.113851
   PubMed Web of Science ®Google Scholar
• Thapa RK, Kim JO. Nanomedicine-based commercial formulations: current developments and future prospects. J Pharmaceut Investig. 2023;53(1):19–33. doi:10.1007/s40005-022-00607-6
   PubMed Web of Science ®Google Scholar
• Ahmed KS, Hussein SA, Ali AH, Korma SA, Lipeng Q, Jinghua C. Liposome: composition, characterisation, preparation, and recent innovation in clinical applications. J Drug Target. 2019;27(7):742–761. doi:10.1080/1061186X.2018.1527337
   PubMed Web of Science ®Google Scholar
• Briuglia M-L, Rotella C, McFarlane A, Lamprou DA. Influence of cholesterol on liposome stability and on in vitro drug release. Drug Deliv Translat Res. 2015;5(3):231–242. doi:10.1007/s13346-015-0220-8
   PubMed Web of Science ®Google Scholar
• Ryu S, Jin M, Lee H-K, Wang M-H, Baek J-S, Cho C-W. Effects of lipid nanoparticles on physicochemical properties, cellular uptake, and lymphatic uptake of 6-methoxyflavone. J Pharmaceut Investig. 2022;52(2):233–241. doi:10.1007/s40005-021-00557-5
   Web of Science ®Google Scholar
• Geszke-Moritz M, Moritz M. Solid lipid nanoparticles as attractive drug vehicles: composition, properties and therapeutic strategies. Mater Sci Engin. 2016;68:982–994. doi:10.1016/j.msec.2016.05.119
   Google Scholar
• Salvi VR, Pawar P. Nanostructured lipid carriers (NLC) system: a novel drug targeting carrier. J Drug Deliv Sci Technol. 2019;51:255–267. doi:10.1016/j.jddst.2019.02.017
   Web of Science ®Google Scholar
• Gordillo-Galeano A, Mora-Huertas CE. Solid lipid nanoparticles and nanostructured lipid carriers: a review emphasizing on particle structure and drug release. Europ J Pharmac Biopharm. 2018;133:285–308. doi:10.1016/j.ejpb.2018.10.017
   PubMed Web of Science ®Google Scholar
• Abouhussein DM, Khattab A, Bayoumi NA, Mahmoud AF, Sakr TM. Brain targeted rivastigmine mucoadhesive thermosensitive in situ gel: optimization, in vitro evaluation, radiolabeling, in vivo pharmacokinetics and biodistribution. J Drug Deliv Sci Technol. 2018;43:129–140. doi:10.1016/j.jddst.2017.09.021
   Web of Science ®Google Scholar
• Verekar RR, Gurav SS, Bolmal U. Thermosensitive mucoadhesive in situ gel for intranasal delivery of Almotriptan malate: formulation, characterization, and evaluation. J Drug Deliv Sci Technol. 2020;58:101778. doi:10.1016/j.jddst.2020.101778
   Web of Science ®Google Scholar
• Gadhave D, Khot S, Tupe S, et al. Nose-to-brain delivery of octreotide acetate in situ gel for pituitary adenoma: pharmacological and in vitro cytotoxicity studies. Internat J Pharmac. 2022;629:122372. doi:10.1016/j.ijpharm.2022.122372
   PubMed Web of Science ®Google Scholar
• Gholizadeh H, Messerotti E, Pozzoli M, et al. Application of a thermosensitive in situ gel of chitosan-based nasal spray loaded with tranexamic acid for localised treatment of nasal wounds. AAPS Pharm Sci Tech. 2019;20(7):299. doi:10.1208/s12249-019-1517-6
   PubMed Web of Science ®Google Scholar
• Nair AB, Chaudhary S, Shah H, et al. Intranasal delivery of darunavir-loaded mucoadhesive in situ gel: experimental design, in vitro evaluation, and pharmacokinetic studies. Gels. 2022;8(6):342. doi:10.3390/gels8060342
   PubMed Web of Science ®Google Scholar
• Wang Q, Wong C-H, Chan HE, Lee W-Y, Zuo Z. Statistical design of experiment (DoE) based development and optimization of DB213 in situ thermosensitive gel for intranasal delivery. Internat J Pharmac. 2018;539(1–2):50–57. doi:10.1016/j.ijpharm.2018.01.032
   PubMed Web of Science ®Google Scholar
• Thakkar H, Vaghela D, Patel BP. Brain targeted intranasal in-situ gelling spray of paroxetine: formulation, characterization and in-vivo evaluation. J Drug Deliv Sci Technol. 2021;62:102317. doi:10.1016/j.jddst.2020.102317
   Web of Science ®Google Scholar
• Nafee N, Ameen AER, Abdallah OY. Patient-friendly, olfactory-targeted, stimuli-responsive hydrogels for cerebral degenerative disorders ensured > 400% brain targeting efficiency in rats. AAPS Pharm Sci Tech. 2020;22(1):6. doi:10.1208/s12249-020-01872-0
   PubMed Web of Science ®Google Scholar
• Thakkar JH, Prajapati ST. Formulation development and characterization of in-situ gel of rizatriptan benzoate for intranasal delivery. J Drug Deliv Ther. 2021;11(1–s):1–6. doi:10.22270/jddt.v11i1-s.4685
   Google Scholar
• Parashar P, Diwaker N, Kanoujia J, et al. In situ gel of lamotrigine for augmented brain delivery: development characterization and pharmacokinetic evaluation. J Pharm Investig. 2020;50(1):95–105. doi:10.1007/s40005-019-00436-0
   Web of Science ®Google Scholar
• Swamy N, Abbas Z. Mucoadhesive in situ gels as nasal drug delivery systems: an overview. Asian J Pharm Sci. 2012;7:3.
   Google Scholar
• Karavasili C, Fatouros DG. Smart materials: in situ gel-forming systems for nasal delivery. Drug Discov Today. 2016;21(1):157–166. doi:10.1016/j.drudis.2015.10.016
   PubMed Web of Science ®Google Scholar
• Watts P, Smith A. PecSys: in situ gelling system for optimised nasal drug delivery. Expert Opin Drug Deliv. 2009;6(5):543–552. doi:10.1517/17425240902939135
   PubMed Web of Science ®Google Scholar
• Costa CP, Barreiro S, Moreira JN, et al. In vitro studies on nasal formulations of nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN). Pharmaceuticals. 2021;14(8):711. doi:10.3390/ph14080711
   Web of Science ®Google Scholar
• Gao M, Shen X, Mao S. Factors influencing drug deposition in the nasal cavity upon delivery via nasal sprays. J Pharm Investig. 2020;50(3):251–259. doi:10.1007/s40005-020-00482-z
   Web of Science ®Google Scholar
• Nižić L, Ugrina I, Špoljarić D, et al. Innovative sprayable in situ gelling fluticasone suspension: development and optimization of nasal deposition. Int J Pharm. 2019;563:445–456. doi:10.1016/j.ijpharm.2019.04.015
   PubMedGoogle Scholar
• Castile J, Cheng Y-H, Simmons B, Perelman M, Smith A, Watts P. Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology, to reduce nasal run-off and drip. Drug Dev Ind Pharm. 2013;39(5):816–824. doi:10.3109/03639045.2012.707210
   PubMed Web of Science ®Google Scholar
• Perkušić M, Nižić Nodilo L, Ugrina I, et al. Chitosan-based thermogelling system for nose-to-brain donepezil delivery: optimising formulation properties and nasal deposition profile. Pharmaceutics. 2023;15(6):1660. doi:10.3390/pharmaceutics15061660
   PubMed Web of Science ®Google Scholar
• Li X, Du L, Chen X, et al. Nasal delivery of analgesic ketorolac tromethamine thermo-and ion-sensitive in situ hydrogels. Int J Pharm. 2015;489(1–2):252–260. doi:10.1016/j.ijpharm.2015.05.009
   PubMedGoogle Scholar
• Saito S, Ainai A, Suzuki T, et al. The effect of mucoadhesive excipient on the nasal retention time of and the antibody responses induced by an intranasal influenza vaccine. Vaccine. 2016;34(9):1201–1207. doi:10.1016/j.vaccine.2016.01.020
   PubMed Web of Science ®Google Scholar
• Watts PJ, Illum L. Inventors; Google Patents, assignee. Pectin compositions and methods of use for improved delivery of drugs to mucosal surfaces. US patent US-6432440-B1; 2002.
   Google Scholar
• Chen Y, Cheng G, Hu R, et al. A nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of huperzine A: formulation, evaluation, and in vivo pharmacokinetic study. AAPS PharmSciTech. 2019;20(7):301. doi:10.1208/s12249-019-1513-x
   PubMed Web of Science ®Google Scholar
• Qu Y, Li A, Ma L, et al. Nose-to-brain delivery of disulfiram nanoemulsion in situ gel formulation for glioblastoma targeting therapy. Int J Pharm. 2021;597:120250. doi:10.1016/j.ijpharm.2021.120250
   PubMedGoogle Scholar
• Cunha S, Swedrowska M, Bellahnid Y, et al. Thermosensitive in situ hydrogels of rivastigmine-loaded lipid-based nanosystems for nose-to-brain delivery: characterisation, biocompatibility, and drug deposition studies. Int J Pharm. 2022;620:121720. doi:10.1016/j.ijpharm.2022.121720
   PubMedGoogle Scholar
• Tan MS, Pandey P, Lohman R-J, Falconer JR, Siskind DJ, Parekh HS. Fabrication and characterization of clozapine nanoemulsion sol-gel for intranasal administration. Mol Pharm. 2022;19(11):4055–4066. doi:10.1021/acs.molpharmaceut.2c00513
   PubMedGoogle Scholar
• Gadhave D, Tupe S, Tagalpallewar A, Gorain B, Choudhury H, Kokare C. Nose-to-brain delivery of amisulpride-loaded lipid-based poloxamer-gellan gum nanoemulgel: in vitro and in vivo pharmacological studies. Int J Pharm. 2021;607:121050. doi:10.1016/j.ijpharm.2021.121050
   PubMedGoogle Scholar
• Nair AB, Chaudhary S, Jacob S, et al. Intranasal administration of dolutegravir-loaded nanoemulsion-based in situ gel for enhanced bioavailability and direct brain targeting. Gels. 2023;9(2):130. doi:10.3390/gels9020130
   PubMed Web of Science ®Google Scholar
• Mura P, Mennini N, Nativi C, Richichi B. In situ mucoadhesive-thermosensitive liposomal gel as a novel vehicle for nasal extended delivery of opiorphin. Eur J Pharm Biopharm. 2018;122:54–61. doi:10.1016/j.ejpb.2017.10.008
   PubMed Web of Science ®Google Scholar
• Rajput A, Butani S. Donepezil HCl liposomes: development, characterization, cytotoxicity, and pharmacokinetic study. AAPS PharmSciTech. 2022;23(2):74. doi:10.1208/s12249-022-02209-9
   PubMed Web of Science ®Google Scholar
• El-Shenawy AA, Mahmoud RA, Mahmoud EA, Mohamed MS. Intranasal in situ gel of apixaban-loaded nanoethosomes: preparation, optimization, and in vivo evaluation. AAPS PharmSciTech. 2021;22(4):147. doi:10.1208/s12249-021-02020-y
   PubMed Web of Science ®Google Scholar
• Ourani-Pourdashti S, Mirzaei E, Heidari R, Ashrafi H, Azadi A. Preparation and evaluation of niosomal chitosan-based in situ gel formulation for direct nose-to-brain methotrexate delivery. Int J Biol Macromol. 2022;213:1115–1126. doi:10.1016/j.ijbiomac.2022.06.031
   PubMed Web of Science ®Google Scholar
• Fahmy UA, Badr-Eldin SM, Ahmed OA, et al. Intranasal niosomal in situ gel as a promising approach for enhancing flibanserin bioavailability and brain delivery: in vitro optimization and ex vivo/in vivo evaluation. Pharmaceutics. 2020;12(6):485. doi:10.3390/pharmaceutics12060485
   PubMed Web of Science ®Google Scholar
• Abdelnabi DM, Abdallah MH, Elghamry HA. Buspirone hydrochloride loaded in situ nanovesicular gel as an anxiolytic nasal drug delivery system: in vitro and animal studies. AAPS PharmSciTech. 2019;20(3):134. doi:10.1208/s12249-018-1211-0
   PubMed Web of Science ®Google Scholar
• Taymouri S, Shahnamnia S, Mesripour A, Varshosaz J. In vitro and in vivo evaluation of an ionic sensitive in situ gel containing nanotransfersomes for aripiprazole nasal delivery. Pharm Dev Technol. 2021;26(8):867–879. doi:10.1080/10837450.2021.1948571
   PubMed Web of Science ®Google Scholar
• ElShagea HN, Makar RR, Salama AH, Elkasabgy NA, Basalious EB. Investigating the targeting power to brain tissues of intranasal rasagiline mesylate-loaded transferosomal in situ gel for efficient treatment of Parkinson’s disease. Pharmaceutics. 2023;15(2):533. doi:10.3390/pharmaceutics15020533
   PubMed Web of Science ®Google Scholar
• Salem HF, Kharshoum RM, Abou-Taleb HA, Naguib DM. Nanosized transferosome-based intranasal in situ gel for brain targeting of resveratrol: formulation, optimization, in vitro evaluation, and in vivo pharmacokinetic study. AAPS PharmSciTech. 2019;20(5):181. doi:10.1208/s12249-019-1353-8
   PubMed Web of Science ®Google Scholar
• Uppuluri CT, Ravi PR, Dalvi AV. Design, optimization and pharmacokinetic evaluation of piribedil loaded solid lipid nanoparticles dispersed in nasal in situ gelling system for effective management of Parkinson’s disease. Int J Pharm. 2021;606:120881. doi:10.1016/j.ijpharm.2021.120881
   PubMedGoogle Scholar
• Agrawal M, Pradhan M, Singhvi G, Patel R, Alexander A, Alexander A. Thermoresponsive in situ gel of curcumin loaded solid lipid nanoparticle: design, optimization and in vitro characterization. J Drug Deliv Sci Technol. 2022;71:103376. doi:10.1016/j.jddst.2022.103376
   Web of Science ®Google Scholar
• Abou Youssef NAH, Kassem AA, Farid RM, Ismail FA, Magda Abd Elsamea EM, Boraie NA. A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: preparation, characterization and in vivo evaluation. Int J Pharm. 2018;548(1):609–624. doi:10.1016/j.ijpharm.2018.07.014
   PubMedGoogle Scholar
• Sun Y, Li L, Xie H, et al. Primary studies on construction and evaluation of ion-sensitive in situ gel loaded with paeonol-solid lipid nanoparticles for intranasal drug delivery. Int J Nanomed. 2020;Volume 15:3137–3160. doi:10.2147/IJN.S247935
   Web of Science ®Google Scholar
• Rajput AP, Butani SB. Resveratrol anchored nanostructured lipid carrier loaded in situ gel via nasal route: formulation, optimization and in vivo characterization. J Drug Deliv Sci Technol. 2019;51:214–223. doi:10.1016/j.jddst.2019.01.040
   Web of Science ®Google Scholar
• Gadhave D, Rasal N, sonawane R, Sekar M, Kokare C. Nose-to-brain delivery of teriflunomide-loaded lipid-based carbopol-gellan gum nanogel for glioma: pharmacological and in vitro cytotoxicity studies. Int J Biol Macromol. 2021;167:906–920. doi:10.1016/j.ijbiomac.2020.11.047
   PubMed Web of Science ®Google Scholar
• Taymouri S, Minaiyan M, Ebrahimi F, Tavakoli N. In-vitro and in-vivo evaluation of chitosan-based thermosensitive gel containing lorazepam NLCs for the treatment of status epilepticus. IET Nanobiotechnol. 2020;14(2):148–154. doi:10.1049/iet-nbt.2019.0156
   PubMed Web of Science ®Google Scholar
• Tripathi D, Sonar PK, Parashar P, Chaudhary SK, Upadhyay S, Saraf SK. Augmented brain delivery of cinnarizine through nanostructured lipid carriers loaded in situ gel: in vitro and pharmacokinetic evaluation. BioNanoScience. 2021;11(1):159–171. doi:10.1007/s12668-020-00821-2
   Web of Science ®Google Scholar
• Fahmy UA, Ahmed OA, Badr-Eldin SM, et al. Optimized nanostructured lipid carriers integrated into in situ nasal gel for enhancing brain delivery of flibanserin. Int J Nanomed. 2020;Volume 15:5253–5264. doi:10.2147/IJN.S258791
   Web of Science ®Google Scholar
• Rajput A, Bariya A, Allam A, Othman S, Butani SB. In situ nanostructured hydrogel of resveratrol for brain targeting: in vitro-in vivo characterization. Drug Deliv Transl Res. 2018;8(5):1460–1470. doi:10.1007/s13346-018-0540-6
   PubMed Web of Science ®Google Scholar
• Abbas H, Refai H, El Sayed N. Superparamagnetic iron oxide-loaded lipid nanocarriers incorporated in thermosensitive in situ gel for magnetic brain targeting of clonazepam. J Pharm Sci. 2018;107(8):2119–2127. doi:10.1016/j.xphs.2018.04.007
   PubMed Web of Science ®Google Scholar
• Butani S. Fabrication of an ion-sensitive in situ gel loaded with nanostructured lipid carrier for nose to brain delivery of donepezil. Asian J Pharm. 2018;12(04):293–302.
   Google Scholar
• Matarazzo AP, Elisei LMS, Carvalho FC, et al. Mucoadhesive nanostructured lipid carriers as a cannabidiol nasal delivery system for the treatment of neuropathic pain. Eur J Pharm Sci. 2021;159:105698. doi:10.1016/j.ejps.2020.105698
   PubMed Web of Science ®Google Scholar
• Deshkar SS, Jadhav MS, Shirolkar SV. Development of carbamazepine nanostructured lipid carrier loaded thermosensitive gel for intranasal delivery. Adv Pharm Bulletin. 2021;11(1):150–162. doi:10.34172/apb.2021.016
   PubMed Web of Science ®Google Scholar
• Paiva-Santos AC, Silva AL, Guerra C, et al. Ethosomes as nanocarriers for the development of skin delivery formulations. Pharm Res. 2021;38(6):947–970. doi:10.1007/s11095-021-03053-5
   PubMed Web of Science ®Google Scholar
• Raghuvanshi A, Shah K, Dewangan HK. Ethosome as antigen delivery carrier: optimisation, evaluation and induction of immunological response via nasal route against hepatitis B. J Microencapsul. 2022;39(4):352–363. doi:10.1080/02652048.2022.2084169
   PubMed Web of Science ®Google Scholar
• Natsheh H, Touitou E. Phospholipid vesicles for dermal/transdermal and nasal administration of active molecules: the effect of surfactants and alcohols on the fluidity of their lipid bilayers and penetration enhancement properties. Molecules. 2020;25(13):2959. doi:10.3390/molecules25132959
   PubMed Web of Science ®Google Scholar
• Bhardwaj P, Tripathi P, Gupta R, Pandey S. Niosomes: a review on niosomal research in the last decade. J Drug Deliv Sci Technol. 2020;56:101581. doi:10.1016/j.jddst.2020.101581
   Web of Science ®Google Scholar
• Pires PC, Rodrigues M, Alves G, Santos AO. Strategies to improve drug strength in nasal preparations for brain delivery of low aqueous solubility drugs. Pharmaceutics. 2022;14(3):588. doi:10.3390/pharmaceutics14030588
   PubMed Web of Science ®Google Scholar
• Sastri KT, Gupta NV, Sharadha M, et al. Nanocarrier facilitated drug delivery to the brain through intranasal route: a promising approach to transcend bio-obstacles and alleviate neurodegenerative conditions. J Drug Deliv Sci Technol. 2022;75:103656. doi:10.1016/j.jddst.2022.103656
   Web of Science ®Google Scholar
• Chamanza R, Wright J. A review of the comparative anatomy, histology, physiology and pathology of the nasal cavity of rats, mice, dogs and non-human primates. Relevance to inhalation toxicology and human health risk assessment. J Comparat Pathol. 2015;153(4):287–314. doi:10.1016/j.jcpa.2015.08.009
   PubMed Web of Science ®Google Scholar
• Zahir-Jouzdani F, Wolf JD, Atyabi F, Bernkop-Schnürch A. In situ gelling and mucoadhesive polymers: why do they need each other? Expert Opinion on Drug Deliv. 2018;15(10):1007–1019. doi:10.1080/17425247.2018.1517741
   PubMed Web of Science ®Google Scholar
• Yadav S, Gattacceca F, Panicucci R, Amiji MM. Comparative biodistribution and pharmacokinetic analysis of cyclosporine-A in the brain upon intranasal or intravenous administration in an oil-in-water nanoemulsion formulation. Molec Pharmaceut. 2015;12(5):1523–1533. doi:10.1021/mp5008376
   PubMed Web of Science ®Google Scholar
• Lim C, Koo J, Oh KT. Nanomedicine approaches for medulloblastoma therapy. J Pharmac Investig. 2023;53(2):213–233. doi:10.1007/s40005-022-00597-5
   Web of Science ®Google Scholar
• Lee S-H, Kim J-K, Jee J-P, Jang D-J, Park Y-J, Kim J-E. Quality by Design (QbD) application for the pharmaceutical development process. J Pharmac Investig. 2022;52(6):649–682. doi:10.1007/s40005-022-00575-x
   Web of Science ®Google Scholar
• Cunha S, Costa CP, Moreira JN, Lobo JMS, Silva AC. Using the quality by design (QbD) approach to optimize formulations of lipid nanoparticles and nanoemulsions: a review. Nanomedicine. 2020;28:102206. doi:10.1016/j.nano.2020.102206
   PubMed Web of Science ®Google Scholar
• Rathore AS. Roadmap for implementation of quality by design (QbD) for biotechnology products. Trend Biotechnol. 2009;27(9):546–553. doi:10.1016/j.tibtech.2009.06.006
   PubMed Web of Science ®Google Scholar
• Soni G, Kale K, Shetty S, Gupta M, Yadav KS. Quality by design (QbD) approach in processing polymeric nanoparticles loading anticancer drugs by high pressure homogenizer. Heliyon. 2020;6(4):e03846. doi:10.1016/j.heliyon.2020.e03846
   PubMed Web of Science ®Google Scholar
• Li J, Qiao Y, Wu Z. Nanosystem trends in drug delivery using quality-by-design concept. J Controll Rel. 2017;256:9–18. doi:10.1016/j.jconrel.2017.04.019
   PubMed Web of Science ®Google Scholar