pharmaceutics Review Intranasal Nanoemulsions for Direct Nose-to-Brain Delivery of Actives for CNS Disorders Shiv Bahadur 1 , Dinesh M. Pardhi 2, Jarkko Rautio 2 , Jessica M. Rosenholm 3 and Kamla Pathak 4,* 1 Institute of Pharmaceutical Research, GLA University, Mathura 281406, India; [email protected] 2 Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; [email protected] (D.M.P.); jarkko.rautio@uef.fi (J.R.) 3 Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland; jerosenh@abo.fi 4 Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Saifai, Etawah 206130, India * Correspondence: [email protected]; Tel.: +91-9897612318 Received: 24 November 2020; Accepted: 15 December 2020; Published: 18 December 2020 Abstract: The treatment of various central nervous system (CNS) diseases has been challenging, despite the rapid development of several novel treatment approaches. The blood–brain barrier (BBB) is one of the major issues in the treatment of CNS diseases, having major role in the protection of the brain but simultaneously constituting the main limiting hurdle for drugs targeting the brain. Nasal drug delivery has gained significant interest for brain targeting over the past decades, wherein the drug is directly delivered to the brain by the trigeminal and olfactory pathway. Various novel and promising formulation approaches have been explored for drug targeting to the brain by nasal administration. Nanoemulsions have the potential to avoid problems, including low solubility, poor bioavailability, slow onset of action, and enzymatic degradation. The present review highlights research scenarios of nanoemulsions for nose-to-brain delivery for the management of CNS ailments classified on the basis of brain disorders and further identifies the areas that remain unexplored. The significance of the total dose delivered to the target region, biodistribution studies, and long-term toxicity studies have been identified as the key areas of future research. Keywords: nanoemulsions; nose-to-brain delivery; CNS disorders; blood-brain barrier; olfactory pathway 1. Introduction Existing therapies have a noteworthy role in the panacea of CNS ailments, resulting in declined fatality rates. However, there are still unresolved issues, and an absolute cure is still elusive for most CNS ailments [1]. The main hindrance is the ability of drugs to cross the blood–brain barrier (BBB) in quantities sufficient to achieve therapeutic levels. It is estimated that the barrier obstructs the permeation of approximately 98% of low molecular weight drugs and of about 100% of macromolecules, leading to a significantly low CNS bioavailability [2]. Consequently, several strategies are being used for the local delivery of active therapeutics to the brain, such as intraparenchymal or intracerebroventricular injections, catheter infusions, mini-pump-assisted intracranial delivery, precise ultrasound methods, or electromagnetic force-field techniques. Nevertheless, these methodologies are invasive, risky, and induce neurotoxic effects at the delivery site, and many of them are not appropriate for chronic treatments. Thus, the presence of the BBB constitutes the primary limiting factor for drug delivery to the brain through systemic circulation [1]. Several methods are under process to bypass the BBB, and among these, one significant approach is nose-to-brain delivery. The intranasal route is a promising substitute to the Pharmaceutics 2020, 12, 1230; doi:10.3390/pharmaceutics12121230 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, x 2 of 27 Pharmaceutics 2020, 12, 1230 2 of 27 substitute to the above-listed invasive methods for brain drug delivery, as the nasal cavity provides above-listeda highly vascularized invasive methods large absorption for brain drug surface delivery, area as for the nasaldrug cavityadministration. provides a highlyThis route vascularized permits largecircumvention absorption of surface the BBB, area thereby for drug providing administration. rapid and This direct route delivery permits to the circumvention brain [3]. Bypassing of the BBB, the therebyBBB, the providing administered rapid drug and reaches direct the delivery brain, to thereb the brainy prolonging [3]. Bypassing its residence the BBB, time the within administered the active drugsite. This reaches route the also brain, restricts thereby the prolonging unnecessary its residence systemic timeexposure within of the drugs active and site. reduces This route systemic also restrictstoxicity the[4]. unnecessaryThe olfactory systemic region of exposure the nasal of drugscavity andextends reduces to the systemic cranial toxicity cavity [and4]. The can olfactory provide regiondirect access of the to nasal the cavitybrain. Different extends to factors the cranial and ph cavityarmacokinetic and can provideparameters direct affect access the torate the of brain. drug Ditransportfferent factors that are and required pharmacokinetic to be evaluated parameters at the cl ainicalffect the level rate [5,6]. of drug Presently, transport nanotechnology-based that are required to bedelivery evaluated systems at the are clinical being levelgiven [5 much,6]. Presently, emphasis nanotechnology-based for intranasal drug delivery delivery to systems the brain. are Nano- being givensized muchdrug delivery emphasis systems for intranasal have been drug extensivel deliveryy to studied the brain. during Nano-sized the past drugfew decades delivery as systems a new havestrategy been for extensively circumventing studied the duringpoor bioavailability the past few decades of various as apharmaceutical new strategy for drugs circumventing [7]. Successful the poorintranasal bioavailability drug delivery of various topharmaceutical the brain throug drugsh [7nanoemulsions,]. Successful intranasal nanoparticles, drug delivery liposomes, to the brainmicrospheres, through dendrimers, nanoemulsions, carbon nanoparticles, based nanoformulat liposomes,ions, microspheres, and others have dendrimers, been documented carbonbased in the nanoformulations,literature [8]. and others have been documented in the literature [8]. ForFor example,example, thethe intranasalintranasal administrationadministration ofof talinololtalinolol inin nanoemulsionsnanoemulsions showedshowed higherhigher brainbrain concentrationsconcentrations inin ratsrats thanthan withwith intravenousintravenous infusioninfusion afterafter 1515 minmin [[9].9]. VariousVarious nanoemulsionsnanoemulsions havehave beenbeen commercializedcommercialized forfor biologicalbiological andand medicalmedical applicationsapplications [[10].10]. DuringDuring anan extensiveextensive literatureliterature searchsearch fromfrom 20152015 toto JanuaryJanuary 2020,2020, wewe foundfound thatthat 159159 articlesarticles werewere publishedpublished onon intranasalintranasal drugdrug deliverydelivery (Figure(Figure1 1).). ItIt waswas observedobserved thatthat 26%26% ofof the the reported reported research research waswas onon thethe nose-to-brain nose-to-brain delivery delivery via via micro- micro-/nanoe/nanoemulsions.mulsions. The The present present review review therefore therefore focuses focuses on theon descriptivethe descriptive aspects aspects on nanoemulsion-based on nanoemulsion-based nose-to-brain nose-to-brain drug delivery. drug delivery. Furthermore, Furthermore, it compiles it thecompiles research the reports research on classifiedreports on CNS classified disorders CNS and disorders presents theand gaps presents that need the togaps be addressedthat need into thebe saidaddressed research in arena.the said research arena. FigureFigure 1.1. PapersPapers publishedpublished onon nanoemulsion-basednanoemulsion-based nose-to-brainnose-to-brain drugdrug deliverydelivery systems.systems. TheThe searchsearch engineengine usedused waswas GoogleGoogle Scholar.Scholar. AA totaltotal ofof 159159 paperspapers werewere found.found. OtherOther drugdrug deliverydelivery systemssystems includedincluded liposomes,liposomes, transferosomes,transferosomes, ethosomes,ethosomes, metalmetal nanoparticles,nanoparticles, etc.etc. 2. Pathways for Brain Delivery through the Intranasal Route The understanding of anatomy and physiology of the nasal cavity is very important for the success of nasal drug delivery systems. The nasal cavity can be divided into three areas: vestibule, respiratory region, and olfactory region. The vestibule region has a small surface area, and drug absorption is insignificant through this region. The respiratory region, on the other hand, is rich in blood capillaries, Pharmaceutics 2020, 12, x 3 of 27 2. Pathways for Brain Delivery through the Intranasal Route The understanding of anatomy and physiology of the nasal cavity is very important for the success of nasal drug delivery systems. The nasal cavity can be divided into three areas: vestibule, Pharmaceutics 2020, 12, 1230 3 of 27 respiratory region, and olfactory region. The vestibule region has a small surface area, and drug absorption is insignificant through this region. The respiratory region, on the other hand, is rich in andblood thus, capillaries, it can provide and thus, systemic it can drug provide absorption systemic and, drug subsequently, absorption indirect and, subsequently, drug delivery indirect to the brain drug afterdelivery intranasal to the administrationbrain after intranasal [11,12]. administration Trigeminal nerves [11,12]. that Trigeminal