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Ming Ming Wen

Olfactory Targeting Through Intranasal Delivery of Biopharmaceutical Drugs to the Brain — Current Development

Abstract: Many therapeutic drugs are difficult to reach the central nervous system (CNS) from the systemic blood circulation because the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier which prevents most molecules from passing through. To bypass BBB, drugs can be delivered through olfactory region for nose-to-brain targeting. Peptide and protein drugs have been developed for the treatment of various neurodegenerative diseases. Drug delivery of these therapeutic proteins is facing several challenges because of the instability, high enzymatic metabolism, low gastrointestinal absorption, rapid renal elimination, and potential immunogenicity. New genetically engineered biotechnology products, such as recombinant human nerve growth factor, human VEGF, and interferons, are now possible to be delivered into the brain from the non-invasive intranasal route. For gene therapy, intranasal route is also a promising alternative method to deliver plasmid DNA to the brain. This review provides an overview of strategies to improve the drug delivery to the brain and the latest development of protein, peptide, and gene intranasal delivery for brain targeting.


As drug delivery system is expanding its central role to assist physicians to deliver therapeutic active substances to their target sites, it is not surprising that a large number of research studies based on this domain were reported in various pharmaceutical journals. However, even with the fast pace in drug delivery design, targeting of drugs to the central nervous system (CNS) is still a challenging task. A great number of drugs are candidates for treatment of CNS diseases, but the drug delivery is still the major problem for brain targeting, especially for biotechnology products.

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) that encircle the brain form a very effective barrier to regulate brain homeostasis, and the ABC efflux transporters which are present in the BBB and BCSFB efficiently remove unwanted substances from the CNS. The BBB allows only small (<500 Da), lipophilic molecules from the bloodstream to enter the CNS (Pardridge, 2002). Many larger therapeutic agents are prevented to reach the brain for treating CNS disorders such as Parkinson’s, Alzheimer’s diseases, depression, stroke, and epilepsy (Pardridge, 2005; Illum, 2004). Of the many strategies trying to overcome these barriers are phage targeting (Nathanson and Mischel, 2011) and choroid plexus targeting (Gonzalez et al., 2011). However, intranasal route for brain targeting is gaining much attention in the scientific world due to the particular anatomical and physiological functions of the nasal cavity (Mygind and Dahl, 1998; Deli et al., 2005). A number of advantages are particularly attractive such as non-invasive rapid systemic absorption, fast onset of action, avoidance of first-pass metabolism, increasing drug bioavailability, and less systemic side effects.

Figure 1. Schematic of a sagittal section of human nasal cavity showing the nasal vestibule (A); atrium (B); respiratory region -- inferior turbinate (C1), middle turbinate (C2), and the superior turbinate (C3); the olfactory region (D); and nasopharynx (E) (Ugwoke et al., 2001).

Figure 1. Schematic of a sagittal section of human nasal cavity showing the nasal vestibule (A); atrium (B); respiratory region -- inferior turbinate (C1), middle turbinate (C2), and the superior turbinate (C3); the olfactory region (D); and nasopharynx (E) (Ugwoke et al., 2001).

Intranasally applied drugs can be rapidly transported into the CNS in minutes via the unique connection of olfactory and the trigeminal nervous system between the brain and external environment. The existence of this pathway for viral infection of the brain has long been recognized. The olfactory region in man is situated in the roof of the nasal cavity (Heydel et al., 2011; Ugwoke et al., 2001) (Figure 1). Although only 3% of the nasal cavity is occupied by olfactory epithelium (Morrison and Costanzo, 1990), this route is direct, since the olfactory neurons do not have a synapse between the receptive element and the afferent path (Ding and Dahl, 2003).

The feasibility of using olfactory neurons to serve as a direct drug transport route to the CSF and brain has been investigated extensively during the last decades. Now we understand that the mechanisms of drug uptake into the brain from the nasal cavity mainly through two different pathways (Figure 2). One is the systemic pathway by which some of the drug is absorbed into the systemic circulation by the rich vasculature of the respiratory epithelium and subsequently reaches the brain by crossing the BBB. The other is the olfactory pathway by which the drug is directly delivered to brain tissue, bypassing the BBB (Illum, 2000). Drugs across olfactory epithelial cells may simply move slowly through tight interstitial space of cells, or across the cell membrane by endocytosis, or transported by vesicle carriers and neurons (Vyas et al., 2005).

Figure 2. The transportation of intranasal delivery of drugs.

Figure 2. The transportation of intranasal delivery of drugs.

Many patent applications on intranasal administration for CNS drug delivery were filed and granted in the past 10 years. Examples include cytokines (tumor necrosis factors, interleukins, and interferons) (Frey, US Patent 6991785) and modafinil (Greco et al., US Patent 20100204334). Most of the current brain research studies are focused on the enhancement of drug delivery to the brain. The novel approaches used to improve the uptake of the drugs include:

(1) Mucoadhesive formulation

The incorporation of mucoadhesive polymers into nasal formulation can increase the mucosal contact time and prolong the residence time of the dosage forms in the nasal cavity. The pharmacokinetic profiles of apomorphine after nasal administration were improved with mucoadhesive polymers of polyacrylic acid, Carbopol, and carboxymethylcellulose (Ugwoke et al., 1999; 2000). Hyaluronan is another example of mucoadhesive polymer used in a nasal formulation. It has demonstrated its ability to improve the brain penetration of a hydrophilic peptide via the nasal route (Horvát et al., 2009).

Chitosan was also extensively studied by formulators due to the non-toxic nature and its absorption enhancing and mucoadhesive properties (Charlton et al., 2006). Chitosan enhanced the brain bioavailability of intranasally administered nerve growth factor by a 14-fold increase comparing with a preparation without chitosan (Vaka et al., 2009). Chitosan hydrochloride in combination with hydroxypropyl beta-cyclodextrin was used as mucoadhesive formulation in brain targeting studies on buspirone hydrochloride with a high drug targeting index (Khan et al., 2009). Chitosan and hydroxylpropylmethyl cellulose can be formulated as mucoadhesive temperature-mediated in situ gel to enhance intranasal delivery of ropinirole, the dopamine D2 agonist, to the brain (Khan et al., 2010).

2) Penetration enhancers

Penetration enhancers are used to improve the permeability and bioavailability of the drug upon contacting the nasal mucosa. The bioavailability of nerve growth factor in the brain could be enhanced by intranasal administration of peppermint oil (Vaka and Murthy, 2010). Intranasal administration of hexarelin, a growth hormone releasing neuropeptide for nose-to-brain targeting, was also enhanced by N-tridecyl-beta-D-maltoside as a permeation enhancer. Markedly greater hexarelin concentrations in olfactory bulb and olfactory tract on the treated side of brain tissues were observed (Yu and Kim, 2009).

3) Liposomes

Liposomes are soft vesicular structures formed by self-assembly of phospholipids which are the same materials as cell membranes. They can be formed in many shapes and sizes depending on lipid composition. Liposomes are often used as non-viral carriers for DNA delivery because of their dynamic properties of cellular membranes that interact with the biological environment (Balazs et al., 2011).

Cationic liposomes were able to enhance the interferon-inducing and antiviral activity of ridostin (an interferon inducer) in experiments with cell cultures of L-929 (Bulychev et al., 2003). Liposomes can also be coated with several thousand strands of polyethylene glycol (PEG) to extend the circulation time in the blood. About 1-2% of the PEG polymer tips are conjugated with a targeting monoclonal antibody which acts as a molecular Trojan horse, specific to brain receptor. This type of Trojan horse liposome is also called PEGylated immunoliposomes. The molecular Trojan horse then binds to a receptor on the BBB and brain cell membrane, triggering receptor-mediated transcytosis of the liposome across the BBB, and endocytosis into brain cells (Pardridge, 2010).

4) Vasoconstrictor

Phenylephrine hydrochloride, a short-acting vasoconstrictor showed remarkably reduced blood concentrations and increased CNS concentrations of hypocretin-1, a peptide involved in appetite and sleep regulation, and dipeptide L-Tyr-D-Arg, a morphine-like analgesic (Dhuria et al., 2009a). In this case, vasoconstrictor was used to enhance intranasal drug targeting to the CNS by limiting absorption into the systemic circulation and increasing the amount of neuropeptide available for direct transport into the CNS along olfactory pathways.

5) Nanoparticles

Intranasal drug delivery of didanosine-loaded chitosan nanoparticles for brain targeting has shown increased drug delivery to the brain (Al-Ghananeem et al., 2010). Despite the positive experimental results in improving nose-to-brain delivery of nano-sized drugs in animal studies, it is still uncertain at this stage whether drug carried by the nanoparticles is being released in the nasal cavity or the nanoparticles carrying the drug are transported via the olfactory or the trigeminal nerves into the CNS where the drug is then released (Mistry et al., 2009).

Delivery of Proteins and Peptides

Many drugs for the treatment of various neurodegenerative diseases are proteins and peptides. Drug delivery of therapeutic proteins is facing several challenges because of the instability, high enzymatic metabolism, low gastrointestinal absorption, rapid renal elimination, and potential immunogenicity (Lemiale et al., 2003). These biotechnology-derived proteins (e.g., insulin, growth hormone) were previously administered by injection alone, but today, along with other administration routes, intranasal delivery is under investigation in finding a solution for most established products to reach distant organs or tissues without biotransformation. Several strategies were developed over the past years to enhance protein/peptide drug delivery over the BBB. They included modification of lipid solubility of these drugs, prodrug delivery bioconversion strategies, and the use of colloidal drug carriers (liposomes, nanoparticles, and nanogels) (Brasnjevic et al., 2009).

Intranasal delivery of proteins to the CNS has been successfully demonstrated in animal models for neurotrophic factors. Proteins as large as 27 kDa, including insulin-like growth factor-1, have been successfully delivered to the brain using this route in rodents (Thorne et al., 2004; Liu et al., 2004) and humans (Reger et al., 2008). A significant amount of recombinant human nerve growth factor has been delivered to the brain along the olfactory neural pathway for the treatment of Alzheimer’s disease (Chen et al., 1998). Intranasal delivery of a neuropeptide (hypocretin-1) rapidly targets the drug to the CNS with minimal systemic exposure (Dhuria et al., 2009b). Basic fibroblast growth factor (bFGF) can also be directly delivered into brain following intranasal administration, and protects against cerebral ischemia/reperfusion in adult rats (Ma et al., 2008).

Neuroprotection with erythropoietin (EPO) plays a significant role in neural survival and functional recovery of acute ischemic stroke. EPO, given intravenously, has limited access to the brain through the blood brain barrier (BBB), and high dosages are needed to obtain a protective effect in this condition. A promising approach has been developed with a nonerythropoietic variant of EPO, Neuro-EPO. It is similar to endogenous brain EPO but without erythropoietic activity. Researchers have demonstrated nasal administration of these agents to be a potential, novel, neurotherapeutic approach that could revolutionize the treatment of neurodegenerative disorders in the 21st century (Garcia-Rodriguez and Sosa-Teste, 2009).

Targeting of interferon-β to the CNS was possible following intranasal administration in monkey. In a study, the macromolecules bypassed the BBB and rapidly entered the primate CNS along olfactory and trigeminal extracellular pathways (Thorne et al., 2008). The same result was also reported in targeting of recombinant human VEGF 165 directly into the CNS following intranasal administration in adult Sprague-Dawley rats (Yang et al., 2008).

Another breakthrough in nose-to-brain targeting is in the brain tumor therapy. A fundamental limitation in the treatment of brain tumors is that only less than 1% of most therapeutic agents administered systemically are able to cross the BBB. Telomerase, a reverse transcriptase that is expressed in the vast majority of malignant gliomas can be inhibited by GRN-163, a telomerase inhibitor, that was successfully delivered intranasally into intracerebral tumors and selectively killed brain tumor cells in rats with no apparent toxicity (Hashizume and Gupta, 2010).

Delivery of Genes

A major clinical challenge for delivery of genes to the CNS results from the limitations of the currently available vectors. Most of the viral vectors are too big, and have to be injected directly into brain tissues. Therefore, nasal administration for delivery of plasmid DNA encoding therapeutic or antigenic genes is gaining attention in recent years as an alternative method due to its non-invasive administration.

The beta-galactosidase protein encoded by the recombinant plasmids was significantly expressed in brain tissues following intranasal administration. Over 1 hour after dosing, the brain targeting efficiencies were shown consistently higher for plasmid DNA administered intranasally than that administered intravenously. The authors concluded that intranasally applied plasmid DNA may reach the brain through a direct route, possibly via the olfactory bulb, and that the nasal route might be an alternative method to deliver plasmid DNA to the brain (Han et al., 2007).

The advantage of the vectors based on herpes simplex virus is that they are neurotropic. However, previous study has reported that vectors based on the type 1 herpes simplex virus (HSV-1) induced apoptosis in CNS neurons, causing severe and often fatal encephalitis in immunocompetent humans (Perkins et al., 2003). However, vectors based on herpes simplex type 2 virus, ΔRR, is less virulent in the CNS than HSV-1, and it does not trigger apoptosis in CNS neurons (Perkins et al., 2003). A study showed that ΔRR delivered by intranasal route protected rats and mice from seizures and neuronal loss, granting it as a promising therapeutic platform for the treatment of chronic neurodegenerative diseases (Laing et al., 2006).

One study investigated the intranasal delivery of Calcitonin gene-related peptide (CGRP), a potent vasodilator, to the brain. The data suggested that intranasal CGRP significantly relieved vasospasm, improved cerebral blood flow, and reduced cortical and endothelial cell death. Intranasal route was shown to be an effective way to deliver CGRP for brain targeting (Sun et al., 2010).

Delivery of polynucleotide agents (e.g., naked DNA, RNA, and antisense) has already been granted patent for directly transporting along the olfactory or trigeminal neural pathways to the CNS to achieve either the controlled expression of a polypeptide or the in vivo production of an antisense polynucleotide sequence (Reinhard and Frey, US Patent 12419999).


The feasibility of intranasal brain targeting was encouraging although most of the results were based on animal models. Advanced technology applied in study design of brain research will assist to clarify the unknown of the correlation between these animal models and humans. With the enormous research achievements in this direction, several investigational drugs via intranasal delivery to the brain are currently in clinical trials for the treatment of Alzheimer’s disease (Gozes and Divinski, 2007; Reger et al., 2008) and obesity (Johnson and Quay, 2005).

Whatever the on-going debate on the validity of data interpreted, olfactory pathway is standing strong on the clinical ground in its position as a potential route to deliver drugs directly into the human brain. The exciting developments for biotechnology products to be delivered to the brain through nasal cavity offer optimism.


The author reports no conflicts of interest.


Al-Ghananeem AM, Saeed H, Florence R, Yokel RA, Malkawi AH. Intranasal drug delivery of didanosine-loaded chitosan nanoparticles for brain targeting; an attractive route against infections caused by AIDS viruses. J Drug Target 18(5):381-388, 2010.

Balazs DA, Godbey W. Liposomes for use in gene delivery. J Drug Deliv 2011:326497, 2011.

Brasnjevic I, Steinbusch HWM, Schmitz C, Martinez-Martinez P. Delivery of peptide and protein drugs over the blood-brain barrier. Prog Neurobiol 87:212-251, 2009.

Bulychev LE, Poryvaev VD, Ryzhikov AB, Karpyshev NN, Alekseeva AG, Goncharova EP, Pliasunov IV. An intensification of antiviral and interferon effects of ridostin (an interferon inducer) by cationic liposomes in vitro and in intranasal administration. Vopr Virusol 48(4):45-47, 2003.

Charlton ST, Davis SS, Illum L. Evaluation of bioadhesive polymers as delivery systems for nose to brain delivery: in vitro characterisation studies. J Control Release 118(2):225-234, 2007.

Chen XQ, Fawcett JR, Rahman YE, Ala TA, Frey II WH. Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimers Dis 1(1):35-44, 1998.

Deli MA, Abraham CS, Kataoka Y, Niwa M. Permeability studies on in vitro blood-brain barrier models: physiology, pathology and pharmacology. Cell Mol Neurobiol 25:59-127, 2005.

Dhuria SV, Hanson LR, Frey II WH. Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther 328(1):312-320, 2009a.

Dhuria SV, Hanson LR, Frey II WH. Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system. J Pharm Sci 98(7):2501-2515, 2009b.

Ding X, Dahl AR. Olfactory mucosa: composition, enzymatic localization, and metabolism (chapter 3). In: Handbook of Olfaction and Gustation, 2nd edition. Doty RL (ed.). pp. 33-52. Marcel Dekker, New York, New York, USA, 2003.

Frey II WH (inventor); Chiron Corporation (assignee). Method for administering a cytokine to the central nervous system and the lymphatic system. United States Patent 6991785. Mar. 20, 2002.

Garcia-Rodriguez JC, Sosa-Teste I. The nasal route as a potential pathway for delivery of erythropoietin in the treatment of acute ischemic stroke in humans. ScientificWorldJournal 9:970-981, 2009.

Gonzalez AM, Leadbeater WE, Burg M, Sims K, Terasaki T, Johanson CE, Stopa EG, Eliceiri BP, Baird A. Targeting choroid plexus epithelia and ventricular ependyma for drug delivery to the central nervous system. BMC Neurosci 12:4, 2011.

Gozes I, Divinski I. NAP, a neuroprotective drug candidate in clinical trials, stimulates microtubule assembly in the living cell. Curr Alzheimer Res 4:507-509, 2007.

Greco MAK, Frey II WH, DeRose J, Matthews RB, Hanson LRB (inventors); SRI International and Health Partners Research Foundation (assignees). Intranasal delivery of modafinil. United States Patent 20100204334. Feb. 6, 2009.

Han IK, Kim MY, Byun HM, Hwang TS, Kim JM, Hwang KW, Park TG, Jung WW, Chun T, Jeong GJ, Oh YK. Enhanced brain targeting efficiency of intranasally administered plasmid DNA: an alternative route for brain gene therapy. J Mol Med 85(1):75-83, 2007.

Hashizume R, Gupta N. Telomerase inhibitors for the treatment of brain tumors and the potential of intranasal delivery. Curr Opin Mol Ther 12(2):168-175, 2010.

Heydel JM, Holsztynska EJ, Legendre A, Thiebaud N, Artur Y, Le Bon AM. UDP-glucuronosyltransferases (UGTs) in neuro-olfactory tissues: expression, regulation, and function. Drug Metab Rev 42(1):71-94, 2010.

Horvát S, Fehér A, Wolburg H, Sipos P, Veszelka S, Tóth A, Kis L, Kurunczi A, Balogh G, Kürti L, Eros I, Szabó-Révész P, Deli MA. Sodium hyauronate as a mucoadhesive component in nasal formulation enhances delivery of molecules to brain tissue. Eur J Pharm Biopharm 72(1):252-259, 2009.

Illum L. Is nose-to-brain transport of drugs in man a reality? J Pharm Pharmacol 56:3-17, 2004.

Illum L. Transport of drugs from the nasal cavity to central nervous system. Eur J Pharm Sci 11:1-18, 2000.

Johnson PH, Quay SC. Advances in nasal drug delivery through tight junction technology. Expert Opin Drug Deliv 2(2):281-298, 2005.

Khan S, Patil K, Bobade N, Yeole P, Gaikwad R. Formulation of intranasal mucoadhesive temperature-mediated in situ gel containing ropinirole and evaluation of brain targeting efficiency in rats. J Drug Target 18(3):223-234, 2010.

Khan S, Patil K, Yeole P, Gaikwad R. Brain targeting studies on buspirone hydrochloride after intranasal administration of mucoadhesive formulation in rats. J Pharm Pharmacol 61(5):669-675, 2009.

Laing JM, Gober MD, Golembewski EK, Thompson SM, Gyure KA, Yarowsky PJ, Aurelian L. Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice. Mol Ther 13(5):870-881, 2006.

Lemiale F, Kong WP, Akyürek LM, Ling X, Huang Y, Chakrabarti BK, Eckhaus M, Nabel GJ. Enhanced mucosal immunoglobulin A response of intranasal adenoviral vector human immunodeficiency virus vaccine and localization in the central nervous system. J Virol 77(18):10078-10087, 2003.

Liu XF, Fawcett JR, Hanson LR, Frey II WH. The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats. J Stroke Cerebrovasc Dis 13:16-23, 2004.

Ma YP, Ma MM, Cheng SM, Ma HH, Yi XM, Xu GL, Liu XF. Intranasal bFGF-induced progenitor cell proliferation and neuroprotection after transient focal cerebral ischemia. Neurosci Lett 437(2):93-97, 2008.

Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm 379(1):146-157, 2009.

Morrison EE, Costanzo RM. Morphology of the human olfactory epithelium. J Comp Neurol 297(1):1-13, 1990.

Mygind N, Dahl R. Anatomy, physiology and function of the nasal cavities in health and disease. Adv Drug Deliv Rev 29:3-12, 1998.

Nathanson D, Mischel PS. Charting the course across the blood-brain barrier. J Clin Invest 121(1):31-33, 2011.

Pardridge WM. Drug and gene delivery to the brain: The vascular route. Neuron 36:555-558, 2002.

Pardridge WM. The blood-brain barrier: bottleneck in brain drugs development. NeuroRx 2:3-14, 2005.

Pardridge WM. Preparation of Trojan horse liposomes (THLs) for gene transfer across the blood-brain barrier. Cold Spring Harb Protoc 4:pdb.prot5407, 2010.

Perkins D, Gyure KA, Pereira EF, Aurelian L. Herpes simplex virus type 1-induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase. J Neurovirol 9:101-111, 2003.

Perkins D, Pereira EF, Aurelian L. The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) functions as a dominant regulator of apoptosis in hippocampal neurons involving activation of the ERK survival pathway and upregulation of the antiapoptotic protein Bag-1. J Virol 77:1292-1305, 2003.

Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, Mehta P, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70:440-448, 2008.

Reinhard C, Frey II WH (inventors). Delivery of polynucleotide agents to the central nervous system. United States Patent 12419999. Apr. 7, 2009.

Sun BL, Shen FP, Wu QJ, Chi SM, Yang MF, Yuan H, Xie FM, Zhang YB, Chen J, Zhang F. Intranasal delivery of calcitonin gene-related peptide reduces cerebral vasospasm in rats. Front Biosci (Elite Ed) 2:1502-1513, 2010.

Thorne RG, Hanson LR, Ross TM, Tung D, Frey WHII. Delivery of interferon-beta to the monkey nervous system following intranasal administration. Neuroscience 152(3):785-797, 2008.

Thorne RG, Pronk GJ, Padmanabhan V, Frey II WH. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127:481-496, 2004.

Ugwoke MI, Kaufmann G, Verbeke N, Kinget R. Intranasal bioavailability of apomorphine from carboxymethylcellulose-based drug delivery systems. Int J Pharm 202:125-131, 2000.

Ugwoke MI, Sam E, Mooter GVD, Verbeke N, Kinget R. Bioavailability of apomorphine following intranasal administration of mucoadhesive drug delivery systems in rabbits, Eur J Pharm Sci 9:213-219, 1999.

Ugwoke MI, Verbeke N, Kinget R. The biopharmaceutical aspects of nasal mucoadhesive drug delivery. J Pharm Pharmacol 53:3-21, 2001.

Vaka SR, Murthy SN. Enhancement of nose-brain delivery of therapeutic agents for treating neurodegenerative diseases using peppermint oil. Pharmazie 65(9):690-692, 2010.

Vaka SR, Sammeta SM, Day LB, Murthy SN. Delivery of nerve growth factor to brain via intranasal administration and enhancement of brain uptake. J Pharm Sci 98(10):3640-3646, 2009.

Vyas TK, Shahiwala A, Marathe S, Misra A. Intranasal drug delivery for brain targeting. Curr Drug Deliv 2:165-175, 2005.

Yang JP, Liu HJ, Cheng SM, Wang ZL, Cheng X, Yu HX, Liu XF. Direct transport of VEGF from the nasal cavity to brain. Neurosci Lett 449(2):108-111, 2009.

Yu H, Kim K. Direct nose-to-brain transfer of a growth hormone releasing neuropeptide, hexarelin after intranasal administration to rabbits. Int J Pharm 378(1-2):73-79, 2009.

[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(61):497-503, June 2011.]

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