23,081
Views
0
CrossRef citations to date
0
Altmetric
Review

The Nasal Approach to Delivering Treatment for Brain Diseases: An Anatomic, Physiologic, and Delivery Technology Overview

, &
Pages 709-733 | Published online: 04 Aug 2014

References

  • Nutt DJ Attridge J . CNS drug development in Europe – past progress and future challenges . Neurobiol. Dis.61 , 6 – 20 ( 2013 ).
  • Abbott A . Schizophrenia. The drug deadlock . Nature468 ( 7321 ), 158 – 159 ( 2010 ).
  • Pardridge WM . Drug transport across the blood–brain barrier . J. Cerebr. Blood F. Met.32 ( 11 ), 1959 – 1972 ( 2012 ).
  • Pinzon-Daza ML Campia I Kopecka J Garzon R Ghigo D Rigant C . Nanoparticle- and liposome-carried drugs: new strategies for active targeting and drug delivery across blood–brain barrier . Curr. Drug Metab.14 ( 6 ), 625 – 640 ( 2013 ).
  • Lochhead JJ Thorne RG . Intranasal delivery of biologics to the central nervous system . Adv. Drug Deliv. Rev.64 ( 7 ), 614 – 628 ( 2012 ).
  • Chapman CD Frey WH 2nd Craft S et al. Intranasal treatment of central nervous system dysfunction in humans . Pharm. Res.30 ( 10 ), 2475 – 2484 ( 2012 ).
  • Bastir M Rosas A Gunz P et al. Evolution of the base of the brain in highly encephalized human species . Nat. Commun.2 , 588 ( 2011 ).
  • Merkus FW Van Den Berg MP . Can nasal drug delivery bypass the blood-brain barrier?: questioning the direct transport theory . Drugs R. D.8 ( 3 ), 133 – 144 ( 2007 ).
  • Abbott NJ . Blood-brain barrier structure and function and the challenges for CNS drug delivery . J. Inherit. Metab. Dis.36 ( 3 ), 437 – 449 ( 2013 ).
  • Laterra J Keep R Betz LA Goldstein GW . Blood–cerebrospinal fluid barrier . In : Basic Neurochemistry: Molecular, Cellular and Medical Aspects.6th Edition . In : SiegelGJAgranoffBWAlbersRWet al. (Eds). Lippincott-Raven , PA, USA ( 1999 ).
  • Pardridge WM . Drug transport in brain via the cerebrospinal fluid . Fluids Barriers CNS8 ( 1 ), 7 ( 2011 ).
  • Landis MS Boyden T Pegg S . Nasal-to-CNS drug delivery: where are we now and where are we heading? An industrial perspective . Ther. Deliv.3 ( 2 ), 195 – 208 ( 2012 ).
  • De Lange EC Danhof M . Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain . Clin. Pharmacokinet.41 ( 10 ), 691 – 703 ( 2002 ).
  • Iliff JJ Wang M Liao Y et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta . Sci. Transl. Med.4 ( 147 ), 147ra111 ( 2012 ).
  • Chen Y Liu L . Modern methods for delivery of drugs across the blood–brain barrier . Adv. Drug Deliv. Rev.64 ( 7 ), 640 – 665 ( 2012 ).
  • Banks W . Drug transport into the central nervous system: using newer findings about the blood–brain barriers . Drug Deliv. Transl. Res.2 , 152 – 159 ( 2012 ).
  • Pardridge WM Boado RJ . Reengineering biopharmaceuticals for targeted delivery across the blood–brain barrier . Methods Enzymol.503 , 269 – 292 ( 2012 ).
  • Abdelbary GA Tadros MI . Brain targeting of olanzapine via intranasal delivery of core-shell difunctional block copolymer mixed nanomicellar carriers: in vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies . Int. J. Pharm.452 ( 1–2 ), 300 – 310 ( 2013 ).
  • Mistry A Stolnik S Illum L . Nanoparticles for direct nose-to-brain delivery of drugs . Int. J. Pharm.379 ( 1 ), 146 – 157 ( 2009 ).
  • Kanazawa T Akiyama F Kakizaki S Takashima Y Seta Y . Delivery of siRNA to the brain using a combination of nose-to-brain delivery and cell-penetrating peptide-modified nano-micelles . Biomaterials34 ( 36 ), 9220 – 9226 ( 2013 ).
  • Pardeshi CV Belgamwar VS . Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting . Expert Opin. Drug Deliv.10 ( 7 ), 957 – 972 ( 2013 ).
  • Patel MM Goyal BR Bhadada SV Bhatt JS Amin AF . Getting into the brain: approaches to enhance brain drug delivery . CNS Drugs23 ( 1 ), 35 – 58 ( 2009 ).
  • Djupesland PG . Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review . Drug Deliv. Transl. Res.3 ( 1 ), 42 – 62 ( 2013 ).
  • Djupesland PG Mahmoud RA Messina JC . Accessing the brain: the nose may know the way . J. Cerebr. Blood F. Met.33 , 793 – 794 ( 2013 ).
  • Danielyan L Schafer R Von Ameln-Mayerhofer A et al. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease . Rejuvenation Res.14 ( 1 ), 3 – 16 ( 2011 ).
  • Johnson NJ Hanson LR Frey WH . Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures . Mol. Pharm.7 ( 3 ), 884 – 893 ( 2010 ).
  • Van Woensel M Wauthoz N Rosiere R et al. Formulations for intranasal delivery of pharmacological agents to combat brain disease: a new opportunity to tackle GBM? Cancers 5 ( 3 ), 1020 – 1048 ( 2013 ).
  • Freiherr J Hallschmid M Frey WH 2nd et al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence . CNS Drugs27 ( 7 ), 505 – 514 ( 2013 ).
  • Westin UE Bostrom E Grasjo J Hammarlund-Udenaes M Bjork E . Direct nose-to-brain transfer of morphine after nasal administration to rats . Pharm. Res.23 ( 3 ), 565 – 572 ( 2006 ).
  • Dhuria SV Hanson LR Frey WH 2nd. Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system . J. Pharm. Sci.98 ( 7 ), 2501 – 2515 ( 2009 ).
  • Stevens J Ploeger BA Van Der Graaf PH Danhof M De Lange EC . Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration . Drug Metab. Dispos.39 ( 12 ), 2275 – 2282 ( 2011 ).
  • Shingaki T Inoue D Furubayashi T et al. Transnasal delivery of methotrexate to brain tumors in rats: a new strategy for brain tumor chemotherapy . Mol. Pharm.7 ( 5 ), 1561 – 1568 ( 2010 ).
  • Lu W Jiang W Chen J Yin M Wang Z Jiang X . Modulation of brain delivery and copulation by intranasal apomorphine hydrochloride . Int. J. Pharm.349 ( 1–2 ), 196 – 205 ( 2008 ).
  • Wang D Gao Y Yun L . Study on brain targeting of raltitrexed following intranasal administration in rats . Cancer Chemother. Pharmacol.57 ( 1 ), 97 – 104 ( 2006 ).
  • Wang C Quan LH Guo Y Liu CY Liao YH . Uptake and biodistribution of rizatriptan to blood and brain following different routes of administration in rats . Int. J. Pharm.337 ( 1–2 ), 155 – 160 ( 2007 ).
  • Liu XF Fawcett JR Thorne RG Frey WH 2nd . Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion . Neurosci. Lett.308 ( 2 ), 91 – 94 ( 2001 ).
  • Liu XF Fawcett JR Thorne RG Defor TA Frey WH 2nd . Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage . J. Neurol. Sci.187 ( 1–2 ), 91 – 97 ( 2001 ).
  • Topkoru BC Altay O Duris K Krafft PR Yan J Zhang JH . Nasal administration of recombinant osteopontin attenuates early brain injury after subarachnoid hemorrhage . Stroke44 ( 11 ), 3189 – 3194 ( 2013 ).
  • Gomez D Martinez JA Hanson LR Frey WH 2nd Toth CC . Intranasal treatment of neurodegenerative diseases and stroke . Front. Biosci.4 , 74 – 89 ( 2012 ).
  • Thorne RG Hanson LR Ross TM Tung D Frey WH 2nd . Delivery of interferon-beta to the monkey nervous system following intranasal administration . Neuroscience152 ( 3 ), 785 – 797 ( 2008 ).
  • Thorne RG Pronk GJ Padmanabhan V Frey WH 2nd . Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration . Neuroscience127 ( 2 ), 481 – 496 ( 2004 ).
  • Danielyan L Schafer R Von Ameln-Mayerhofer A et al. Intranasal delivery of cells to the brain . Eur. J. Cell Biol.88 ( 6 ), 315 – 324 ( 2009 ).
  • Deadwyler SA Porrino L Siegel JM Hampson RE . Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates . J. Neurosci.27 ( 52 ), 14239 – 14247 ( 2007 ).
  • Guastella AJ Macleod C . A critical review of the influence of oxytocin nasal spray on social cognition in humans: evidence and future directions . Horm. Behav.61 ( 3 ), 410 – 418 ( 2012 ).
  • Veening JG Olivier B . Intranasal administration of oxytocin: behavioral and clinical effects, a review . Neurosci. Biobehav. Rev.37 ( 8 ), 1445 – 1465 ( 2013 ).
  • Schioth HB Craft S Brooks SJ Frey WH 2nd Benedict C . Brain insulin signaling and Alzheimer's disease: current evidence and future directions . Mol. Neurobiol.46 ( 1 ), 4 – 10 ( 2012 ).
  • Born J Lange T Kern W Mcgregor GP Bickel U Fehm HL . Sniffing neuropeptides: a transnasal approach to the human brain . Nat. Neurosci.5 ( 6 ), 514 – 516 ( 2002 ).
  • Djupesland PG Skretting A . Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump . J. Aerosol Med. Pulm. Drug Deliv.25 ( 5 ), 280 – 289 ( 2012 ).
  • Djupesland PG Skretting A Winderen M Holand T . Breath actuated device improves delivery to target sites beyond the nasal valve . Laryngoscope116 ( 3 ), 466 – 472 ( 2006 ).
  • Van Den Berg MP Merkus P Romeijn SG Verhoef JC Merkus FW . Uptake of melatonin into the cerebrospinal fluid after nasal and intravenous delivery: studies in rats and comparison with a human study . Pharm. Res.21 ( 5 ), 799 – 802 ( 2004 ).
  • Merkus P Guchelaar HJ Bosch DA Merkus FW . Direct access of drugs to the human brain after intranasal drug administration?Neurology60 ( 10 ), 1669 – 1671 ( 2003 ).
  • Hashizume R Ozawa T Gryaznov SM et al. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163 . Neuro. Oncol.10 ( 2 ), 112 – 120 ( 2008 ).
  • Ozduman K Wollmann G Piepmeier JM Van Den Pol AN . Systemic vesicular stomatitis virus selectively destroys multifocal glioma and metastatic carcinoma in brain . J. Neurosci.28 ( 8 ), 1882 – 1893 ( 2008 ).
  • Balyasnikova IV Prasol MS Ferguson SD et al. Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors . Mol. Ther. doi:10.1038/mt.2013.199 ( 2013 ) (Epub ahead of print) .
  • Da Fonseca CO Schwartsmann G Fischer J et al. Preliminary results from a Phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas . Surg. Neurol.70 ( 3 ), 259 – 266 ; discussion266 – 257 ( 2008 ).
  • Da Fonseca CO Masini M Futuro D Caetano R Gattass CR Quirico-Santos T . Anaplastic oligodendroglioma responding favorably to intranasal delivery of perillyl alcohol: a case report and literature review . Surg. Neurol.66 ( 6 ), 611 – 615 ( 2006 ).
  • Reitz M Demestre M Sedlacik J et al. Intranasal delivery of neural stem/progenitor cells: a noninvasive passage to target intracerebral glioma . Stem Cells Transl. Med.1 ( 12 ), 866 – 873 ( 2012 ).
  • Aboody KS Najbauer J Metz MZ et al. Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies . Sci. Transl. Med.5 ( 184 ), 184ra159 ( 2013 ).
  • Wu S Li K Yan Y et al. Intranasal Delivery of Neural Stem Cells: A CNS-specific, non-invasive cell-based therapy for experimental autoimmune encephalomyelitis . J. Clin. Cell. Immunol.4 ( 3 ), ( 2013 ).
  • Aboody KS Najbauer J Danks MK . Stem and progenitor cell-mediated tumor selective gene therapy . Gene Ther.15 ( 10 ), 739 – 752 ( 2008 ).
  • Hadaczek P Yamashita Y Mirek H et al. The “perivascular pump” driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain . Mol. Ther.14 ( 1 ), 69 – 78 ( 2006 ).
  • Thorne RG Emory CR Ala TA Frey WH 2nd . Quantitative analysis of the olfactory pathway for drug delivery to the brain . Brain Res.692 ( 1–2 ), 278 – 282 ( 1995 ).
  • Leopold DA Hummel T Schwob JE Hong SC Knecht M Kobal G . Anterior distribution of human olfactory epithelium . Laryngoscope110 ( 3 Pt 1 ), 417 – 421 ( 2000 ).
  • Kaur P Kim K . Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits . Int. J. Pharm.364 ( 1 ), 27 – 35 ( 2008 ).
  • Forbes AR Gamsu G . Lung mucociliary clearance after anesthesia with spontaneous and controlled ventilation . Am. Rev. Respir. Dis.120 ( 4 ), 857 – 862 ( 1979 ).
  • Cervin A Lindberg S Mercke U . Effects of halothane on mucociliary activity in vivo . Otolaryngol. Head Neck Surg.112 ( 6 ), 714 – 722 ( 1995 ).
  • Kesimci E Bercin S Kutluhan A Ural A Yamanturk B Kanbak O . Volatile anesthetics and mucociliary clearance . Minerva Anestesiol.74 ( 4 ), 107 – 111 ( 2008 ).
  • Catani M Dell’acqua F Thiebaut De Schotten M . A revised limbic system model for memory, emotion and behaviour . Neurosci. Biobehav. Rev.37 ( 8 ), 1724 – 1737 ( 2013 ).
  • Hummel T Livermore A . Intranasal chemosensory function of the trigeminal nerve and aspects of its relation to olfaction . Int. Arch. Occup. Environ. Health.75 ( 5 ), 305 – 313 ( 2002 ).
  • Ivanusic JJ Kwok MM Jennings EA . Peripheral targets of 5-HT(1D) receptor immunoreactive trigeminal ganglion neurons . Headache51 ( 5 ), 744 – 751 ( 2011 ).
  • Ivanusic JJ Kwok MM Ahn AH Jennings EA . 5-HT(1D) receptor immunoreactivity in the sphenopalatine ganglion: implications for the efficacy of triptans in the treatment of autonomic signs associated with cluster headache . Headache51 ( 3 ), 392 – 402 ( 2011 ).
  • Shemesh E Rudich A Harman-Boehm I Cukierman-Yaffe T . Effect of intranasal insulin on cognitive function: a systematic review . J. Clin. Endocrinol. Metab.97 ( 2 ), 366 – 376 ( 2012 ).
  • Hollander E Bartz J Chaplin W et al. Oxytocin increases retention of social cognition in autism . Biol. Psychiatry61 ( 4 ), 498 – 503 ( 2007 ).
  • Hollander E Novotny S Hanratty M et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger's disorders . Neuropsychopharmacology28 ( 1 ), 193 – 198 ( 2003 ).
  • Guastella AJ Hickie IB Mcguinness MM et al. Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research . Psychoneuroendocrinology38 ( 5 ), 612 – 625 ( 2013 ).
  • Cole P Savard P Miljeteig H Haight JS . Resistance to respiratory airflow of the extrapulmonary airways . Laryngoscope103 ( 4 Pt 1 ), 447 – 450 ( 1993 ).
  • Sahin-Yilmaz A Naclerio RM . Anatomy and physiology of the upper airway . Proc. Am. Thorac. Soc.8 ( 1 ), 31 – 39 ( 2011 ).
  • Cole P . The four components of the nasal valve . Am. J. Rhinol.17 ( 2 ), 107 – 110 ( 2003 ).
  • Haight JS Cole P . The site and function of the nasal valve . Laryngoscope93 ( 1 ), 49 – 55 ( 1983 ).
  • Nodelman V Ultman JS . Longitudinal distribution of chlorine absorption in human airways: comparison of nasal and oral quiet breathing . J. Appl. Physiol.86 ( 6 ), 1984 – 1993 ( 1999 ).
  • Schroeter JD Garcia GJ Kimbell JS . A computational fluid dynamics approach to assess interhuman variability in hydrogen sulfide nasal dosimetry . Inhal. Toxicol.22 ( 4 ), 277 – 286 ( 2010 ).
  • Mann DG Sasaki CT Fukuda H Mann DG Suzuki M Hernandez JR . Dilator naris muscle . Ann. Otol. Rhinol. Laryngol.86 ( 3 Pt 1 ), 362 – 370 ( 1977 ).
  • Hairfield WM Warren DW Hinton VA Seaton DL . Inspiratory and expiratory effects of nasal breathing . Cleft Palate J.24 ( 3 ), 183 – 189 ( 1987 ).
  • Djupesland PG Skatvedt O Borgersen AK . Dichotomous physiological effects of nocturnal external nasal dilation in heavy snorers: the answer to a rhinologic controversy?Am. J. Rhinol.15 ( 2 ), 95 – 103 ( 2001 ).
  • Cole P . Stability of nasal airflow resistance . Clin. Otolaryngol. Allied Sci.14 ( 2 ), 177 – 182 ( 1989 ).
  • Dahl R Mygind N . Anatomy, physiology and function of the nasal cavities in health and disease . Adv. Drug Deliv. Rev.29 ( 1–2 ), 3 – 12 ( 1998 ).
  • Halama AR Decreton S Bijloos JM Clement PA . Density of epithelial cells in the normal human nose and the paranasal sinus mucosa. A scanning electron microscopic study . Rhinology28 ( 1 ), 25 – 32 ( 1990 ).
  • Jones N . The nose and paranasal sinuses physiology and anatomy . Adv. Drug Deliv. Rev.51 ( 1–3 ), 5 – 19 ( 2001 ).
  • Einer-Jensen N Larsen L . Local transfer of diazepam, but not of cocaine, from the nasal cavities to the brain arterial blood in rats . Pharmacol. Toxicol.87 ( 6 ), 276 – 278 ( 2000 ).
  • Einer-Jensen N Larsen L Deprez S Starns E Schwartz S . Intranasal absorption of sumatriptan and naratriptan: no evidence of local transfer from the nasal cavities to the brain arterial blood in male rats . Biopharm. Drug Dispos.22 ( 5 ), 213 – 219 ( 2001 ).
  • Dhuria SV Hanson LR Frey WH 2nd . Intranasal delivery to the central nervous system: mechanisms and experimental considerations . J. Pharm. Sci.99 ( 4 ), 1654 – 1673 ( 2010 ).
  • Daiber P Genovese F Schriever VA Hummel T Mohrlen F Frings S . Neuropeptide receptors provide a signalling pathway for trigeminal modulation of olfactory transduction . Eur. J. Neurosci.37 ( 4 ), 572 – 582 ( 2013 ).
  • Husner A Frasnelli J Welge-Lussen A Reiss G Zahnert T Hummel T . Loss of trigeminal sensitivity reduces olfactory function . Laryngoscope116 ( 8 ), 1520 – 1522 ( 2006 ).
  • Feron F Perry C Mcgrath JJ Mackay-Sim A . New techniques for biopsy and culture of human olfactory epithelial neurons . Arch. Otolaryngol. Head Neck Surg.124 ( 8 ), 861 – 866 ( 1998 ).
  • Waddell AN Patel SK Toma AG Maw AR . Intranasal steroid sprays in the treatment of rhinitis: is one better than another?J. Laryngol. Otol.117 ( 11 ), 843 – 845 ( 2003 ).
  • Suman JD Laube BL Dalby R . Validity of in vitro tests on aqueous spray pumps as surrogates for nasal deposition, absorption, and biologic response . J. Aerosol. Med.19 ( 4 ), 510 – 521 ( 2006 ).
  • Si XA Xi J Kim J Zhou Y Zhong H . Modeling of release position and ventilation effects on olfactory aerosol drug delivery . Respir. Physiol. Neurobiol.186 ( 1 ), 22 – 32 ( 2013 ).
  • Kundoor V Dalby RN . Effect of formulation- and administration-related variables on deposition pattern of nasal spray pumps evaluated using a nasal cast . Pharm. Res.28 ( 8 ), 1895 – 1904 ( 2011 ).
  • Kundoor V Dalby RN . Assessment of nasal spray deposition pattern in a silicone human nose model using a color-based method . Pharm. Res.27 ( 1 ), 30 – 36 ( 2010 ).
  • Guo Y Laube B Dalby R . The effect of formulation variables and breathing patterns on the site of nasal deposition in an anatomically correct model . Pharm. Res.22 ( 11 ), 1871 – 1878 ( 2005 ).
  • Fung MC Inthavong K Yang W Lappas P Tu J . External characteristics of unsteady spray atomization from a nasal spray device . J. Pharm. Sci.102 ( 3 ), 1024 – 1035 ( 2013 ).
  • Inthavong K Tian ZF Tu JY Yang W Xue C . Optimising nasal spray parameters for efficient drug delivery using computational fluid dynamics . Comput. Biol. Med.38 ( 6 ), 713 – 726 ( 2008 ).
  • Scheibe M Bethge C Witt M Hummel T . Intranasal administration of drugs . Otolaryngol. Head Neck Surg.134 ( 6 ), 643 – 646 ( 2008 ).
  • Al-Ghananeem AM Sandefer EP Doll WJ Page RC Chang Y Digenis GA . Gamma scintigraphy for testing bioequivalence: a case study on two cromolyn sodium nasal spray preparations . Int. J. Pharm.357 ( 1–2 ), 70 – 76 ( 2008 ).
  • Mcinnes FJ O’mahony B Lindsay B et al. Nasal residence of insulin containing lyophilised nasal insert formulations, using gamma scintigraphy . Eur. J. Pharm. Sci.31 ( 1 ), 25 – 31 ( 2007 ).
  • Bleier BS Debnath I Harvey RJ Schlosser RJ . Temporospatial quantification of fluorescein-labeled sinonasal irrigation delivery . Int. Forum Allergy Rhinol.1 ( 5 ), 361 – 365 ( 2011 ).
  • Rudman KL O’brien EK Leopold DA . Radiographic distribution of drops and sprays within the sinonasal cavities . Am. J. Rhinol. Allergy25 ( 2 ), 94 – 97 ( 2011 ).
  • Aggarwal R Cardozo A Homer JJ . The assessment of topical nasal drug distribution . Clin. Otolaryngol. Allied Sci.29 ( 3 ), 201 – 205 ( 2004 ).
  • Suman JD Laube BL Dalby R . Comparison of nasal deposition and clearance of aerosol generated by nebulizer and an aqueous spray pump . Pharm. Res.16 ( 10 ), 1648 – 1652 ( 1999 ).
  • Moller W Saba GK Haussinger K Becker S Keller M Schuschnig U . Nasally inhaled pulsating aerosols: lung, sinus and nose deposition . Rhinology49 ( 3 ), 286 – 291 ( 2011 ).
  • Vecellio L De Gersem R Le Guellec S et al. Deposition of aerosols delivered by nasal route with jet and mesh nebulizers . Int. J. Pharm.407 ( 1–2 ), 87 – 94 ( 2011 ).
  • Laube BL . Devices for aerosol delivery to treat sinusitis . J. Aerosol Med.20 ( Suppl. 1 ), S5 – S17 ; discussionS17 – S18 ( 2007 ).
  • Giroux M . Controlled Particle Dispersion: Effective Nasal Delivery from a Versatile, Flexible Delivery Platform.ON drug Delivery Ltd , East Sussex, UK , 13 – 15 ( 2005 )
  • Craft S Baker LD Montine TJ et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial . Arch. Neurol.69 ( 1 ), 29 – 38 ( 2012 ).
  • Reger MA Watson GS Green PS et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD . Neurology70 ( 6 ), 440 – 448 ( 2008 ).
  • Djupesland PG . Intranasal insulin improves cognition and modulates beta-amyloid in early AD . Neurology71 ( 11 ), 864 ; author reply864 ( 2008 ).
  • Kurve Technology . www.kurvetech.com
  • Hankin CS Cox L Lang D et al. Medical costs and adherence in patients receiving aqueous versus pressurized aerosol formulations of intranasal corticosteroids . 33 ( 3 ), 258 – 264 ( 2012 ).
  • Suman J . Current understanding of nasal morphology and physiology as a drug delivery target . Drug Deliv. Transl. Res.3 ( 1 ), 4 – 15 ( 2013 ).
  • Berger WE Mohar DE Laforce C et al. A 26-week tolerability study of ciclesonide nasal aerosol in patients with perennial allergic rhinitis . Am. J. Rhinol. Allergy26 ( 4 ), 302 – 307 ( 2012 ).
  • Mohar D Berger WE Laforce C et al. Efficacy and tolerability study of ciclesonide nasal aerosol in patients with perennial allergic rhinitis . Allergy Asthma Proc.33 ( 1 ), 19 – 26 ( 2012 ).
  • Impelpharma . www.impelpharma.com
  • Hoekman JD Ho RJ . Enhanced analgesic responses after preferential delivery of morphine and fentanyl to the olfactory epithelium in rats . Anesth. Analg.113 ( 3 ), 641 – 651 ( 2011 ).
  • University TechWATCH . http://utechwatch.com/2013/05/impel-neuropharma-succeeds-in-nose-to-brain-drug-delivery-clinical-trial
  • Obaidi M Offman E Messina J Carothers J Djupesland PG Mahmoud RA . Improved pharmacokinetics of sumatriptan with breath powered nasal delivery of sumatriptan powder . Headache53 ( 8 ), 1323 – 1333 ( 2013 ).
  • Hansen FS Djupesland PG Fokkens WJ . Preliminary efficacy of fluticasone delivered by a novel device in recalcitrant chronic rhinosinusitis . Rhinology48 ( 3 ), 292 – 299 ( 2010 ).
  • Djupesland PG Docekal P . Intranasal sumatriptan powder delivered by a novel breath-actuated bi-directional device for the acute treatment of migraine: a randomised, placebo-controlled study . Cephalalgia30 ( 8 ), 933 – 942 ( 2010 ).
  • Vlckova I Navratil P Kana R Pavlicek P Chrbolka P Djupesland PG . Effective treatment of mild-to-moderate nasal polyposis with fluticasone delivered by a novel device . Rhinology47 ( 4 ), 419 – 426 ( 2009 ).
  • Luthringer R Djupesland PG Sheldrake CD et al. Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device . J. Pharm. Pharmacol.61 ( 9 ), 1219 – 1228 ( 2009 ).
  • Djupesland PG Skretting A Winderen M Holand T . Bi-directional nasal delivery of aerosols can prevent lung deposition . J. Aerosol Med.17 ( 3 ), 249 – 259 ( 2004 ).
  • Dale O Nilsen T Loftsson T et al. Intranasal midazolam: a comparison of two delivery devices in human volunteers . J. Pharm. Pharmacol.58 ( 10 ), 1311 – 1318 ( 2006 ).
  • Djupesland PG Messina JC Mahmoud RA . Breath powered nasal delivery: a new route to rapid headache relief . Headache53 ( Suppl. 2 ), 72 – 84 ( 2013 ).
  • Moller W Lubbers C Munzing W Canis M . Pulsating airflow and drug delivery to paranasal sinuses . Curr. Opin. Otolaryngol Head Neck Surg.19 ( 1 ), 48 – 53 ( 2011 ).
  • Skretting A Djupesland PG . A new method for scintigraphic quantification of deposition and clearance in anatomical regions of the human nose . Nucl. Med. Commun.30 ( 8 ), 629 – 638 ( 2009 ).
  • Charlton ST Whetstone J Fayinka ST Read KD Illum L Davis SS . Evaluation of direct transport pathways of glycine receptor antagonists and an angiotensin antagonist from the nasal cavity to the central nervous system in the rat model . Pharm. Res.25 ( 7 ), 1531 – 1543 ( 2008 ).
  • Charlton ST Davis SS Illum L . Nasal administration of an angiotensin antagonist in the rat model: effect of bioadhesive formulations on the distribution of drugs to the systemic and central nervous systems . Int. J. Pharm.338 ( 1–2 ), 94 – 103 ( 2007 ).
  • Alexander TH Davidson TM . Intranasal zinc and anosmia: the zinc-induced anosmia syndrome . Laryngoscope116 ( 2 ), 217 – 220 ( 2006 ).
  • Graf PM . Rhinitis medicamentosa . J. Allergy Clin. Immunol.19 , 295 – 304 ( 2007 ).
  • Illum L . Nasal drug delivery – recent developments and future prospects . J. Control. Release161 ( 2 ), 254 – 263 ( 2012 ).
  • Dhuria SV Hanson LR Frey WH 2nd . Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system . J. Pharmacol. Exp. Ther.328 ( 1 ), 312 – 320 ( 2009 ).
  • Charlton ST Davis SS Illum L . Evaluation of effect of ephedrine on the transport of drugs from the nasal cavity to the systemic circulation and the central nervous system . J. Drug Target.15 ( 5 ), 370 – 377 ( 2007 ).