American Journal of Pharmacological Sciences
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American Journal of Pharmacological Sciences. 2015, 3(5), 110-119
DOI: 10.12691/ajps-3-5-2
Open AccessResearch Article

Nasal Drug Delivery Systems: An Overview

Muhammad U. Ghori1, Mohammed H. Mahdi1, Alan M. Smith1 and Barbara R. Conway1,

1Department of Pharmacy, University of Huddersfield, Huddersfield, UK

Pub. Date: December 18, 2015
(This article belongs to the Special Issue Recent Advances in Controlled Drug Delivery Systems)

Cite this paper:
Muhammad U. Ghori, Mohammed H. Mahdi, Alan M. Smith and Barbara R. Conway. Nasal Drug Delivery Systems: An Overview. American Journal of Pharmacological Sciences. 2015; 3(5):110-119. doi: 10.12691/ajps-3-5-2

Abstract

Since ancient times, drugs have been administered via the nasal route for therapeutic and recreational purposes. The interest in, and importance, of the systemic effects of drugs administered through the nasal route, have expanded over recent decades. Intra-nasal administration of drugs offers an interesting alternative for achieving systemic therapeutic effects of drugs that are comparable to the parenteral route, which can be inconvenient at times or oral administration, which can result in unacceptably low drug bioavailability. So, it is important to understand the potential and limitations of various nasal drug delivery systems. Therefore, the aim of this review article is to discuss the various pharmaceutical dosage forms that have the potential to be utilised for local or systemic drug administration. It is intuitively expected that this review will help to understand and further to develop suitable intra-nasal formulations to achieve specific therapeutic objectives.

Keywords:
nose intra-nasal bioavailability mucoadhesion drug delivery systems

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References:

[1]  CHIEN, Y.W., & CHANG, S.F., (1987). Intranasal drug delivery for systemic medications. Critical Reviews In Therapeutic Drug Carrier Systems. 4 (2), 67-194.
 
[2]  HARRIS, A.S., (1993). Review: Clinical opportunities provided by the nasal administration of peptides. Journal of Drug Targeting 1, 101-116.
 
[3]  CHIEN, Y.W., SU, K.S.E., & CHANG, S.F., (1989), Anatomy and physiology of the nose, in Y. W. Chen, K. S. E. Su, and S.-F. Chang, eds., Nasal systemic drug delivery: Drugs and the Pharmaceutical Sciences, v. 39: New York, Marcel Dekker Inc, p. 1-19.
 
[4]  DUQUESNOY, C., MAMET, J.P., SUMNER, D., & FUSEAU, E., (1998). Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration. European Journal of Pharmaceutical Sciences 6, 99-104.
 
[5]  ELLER, N., KOLLENZ, C.J., BAUER, P., & HITZENBERGER, G., (1998). The duration of antidiuretic response of two desmopressin nasal sprays. International Journal of Clinical Pharmacology and Therapeutics. 36 (9), 494-500.
 
[6]  SLOT, W.B., MERKUS, F.W.H.M., DEVENTER, S.J.H.V., & TYTGAT, G.N.J., (1997). Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients. Gastroenterology. 113, 430-433.
 
[7]  KNOESTER, P.D., JONKER, D.M., HOEVEN, R.T.M.V.D., VERMEIJ, T.A.C., EDELBROEK, P.M., BREKELMANS, G.J., & HAAN, G.J.D., (2002). Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers. British Journal of Clinical Pharmacology. 53, 501-507.
 
[8]  RATHBONE, M. J., HADGRAFT, J., & ROBERTS, M. S. (Eds.). (2002). Modified-release drug delivery technology. CRC Press.
 
[9]  CASETTARI, L & ILLUM. L (2014), Chitosan in nasal delivery systems for therapeutic drugs, Journal of Controlled Release. 190, 189-200.
 
[10]  KUBLIK, H., & VIDGREN, M. T., (1998). Nasal delivery systems and their effect on deposition and absorption. Advanced Drug Delivery Reviews, 29, 157-177.
 
[11]  CHATURVEDI, M., KUMAR. M., & PATHAK. K., (2011). A review on mucoadhesive polymer used in nasal drug delivery system. Journal of Advanced Pharmaceutical Technology and Research, 4, 215-222.
 
[12]  AULTON, M. E., TAYLOR, K., (2013). Aulton's Pharmaceutics: the design and manufacture of medicines, Edinburgh, Churchill Livingstone.
 
[13]  MAHDI, M. H., CONWAY, B. R., & SMITH, A. M. (2015). Development of mucoadhesive sprayable gellan gum fluid gels. International Journal of Pharmaceutics, 488(1), 12-19.
 
[14]  RHIDIAN, R., & GREATOREX, B., (2015). Chest pain in the recovery room, following topical intranasal cocaine solution use. British Medical Journal Case Reports doi: 10.1136/bcr-2015-20969
 
[15]  ANDRADE, C., (2015). Intranasal drug delivery in neuropsychiatry: Focus on intranasal ketamine for refractory depression. Journal of Clinical Psychiatry 76(5): 628-631.
 
[16]  HERMANN, N., (2015). Effectiveness of live attenuated influenza vaccines and trivalent inactivated influenza vaccines against confirmed influenza in children and adolescents in Saxony-Anhalt, 2012/13. Gesundheitswesen 77(7): 499-501
 
[17]  SINGH, L., & KHAN, A. D., Nasal drug delivery: a promising way for brain targeting. The Pharma Research 13.2, 1-12.
 
[18]  PRAJAPATI, S. T., Pathak, S.P., Thakkar, J. H., & Patel, C. N., (2015). Nanoemulsion based intranasal delivery of risperidone for nose to brain targeting. Bulletin of Pharmaceutical Research 5, 6-13.
 
[19]  MUNDLIA, J., & MUKESH, K. (2015). Nasal drug delivery: An overview. International Journal of Pharmaceutical Sciences and Research 6, 951-956.
 
[20]  UGWOKE, M. I., VERBEKE, N., & KINGET, R. (2001). The biopharmaceutical aspects of nasal mucoadhesive drug delivery. Journal of Pharmacy and Pharmacology, 53(1), 3-22.
 
[21]  OZSOY, Y., TUNCEL, T., CAN, A., AKEV, N., BIRTEKSOZ, S. & GERCEKER, A. (2000). In vivo studies on nasal preparations of ciprofloxacin hydrochloride. Pharmazie, 55, 607-609
 
[22]  Electronic Medicines Compendium (2015) [Database on the Internet]. Datapharm Communications Ltd. http://emc.medicines.org.uk.
 
[23]  UGWOKE, M. I., AGU, R. U., VERBEKE, N., & KINGET, R. (2005). Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives. Advanced Drug Delivery Reviews, 57(11), 1640-1665.
 
[24]  MERKUS, F. W. H. M., SCHIPPER, N. G. M., HERMENS, W. A. J. J., ROMEIJN, S. G., & VERHOEF, J. C. (1993). Absorption enhancers in nasal drug delivery: efficacy and safety. Journal of Controlled Release, 24(1), 201-208.
 
[25]  NATSUME, H., IWATA, S., MIYAMOTO, M., KAWAI, T., SUGIBAYASHI, K., MORIMOTO, Y., 1996. Screening of absorption enchancers for nasal peptide and protein delivery. Proceed. Internat. Symp. Control Release Bioactive Materials. 23, 481-482.
 
[26]  ZHOU, M., DONOVAN, M.D., 1996. Recovery of the nasal mucosa following laureth-9 induced damage. International Journal of Pharmaceutics.130, 93-102.
 
[27]  CHANDLER, S.G., ILLUM, L., THOMAS, N.W., 1991. Nasal absorption in rats. II. Effect of enhancers on insulin absorption and nasal histology. International Journal Pharmaceutics. 76, 61-70.
 
[28]  CHANDLER, S.G., ILLUM, L., THOMAS, N.W., 1994. Nasal absorption in rats. III. Effect on lysophospholipids on insulin absorption and nasal histology. Pharmaceutical Research. 11 (11), 1623-1630.
 
[29]  YAMAMOTO, A., MORITA, T., HASHIDA, M., SEZAKI, H., 1993. Effect of absorption promoters on nasal absorption of drugs with various molecular weights. International Journal of Pharmaceutics. 93, 91-99.
 
[30]  AUNGST, B.J., ROGERS, N.J., SHEFFER, E., 1988. Comparison of nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promotor. Journal of Pharmacology and Experimental Therapeutics. 244, 23-27.
 
[31]  BAGGER, M.A., NIELSEN, H.W., BECHGAARD, E., 2001. Nasal bioavailability of peptide T in rabbits: absorption enhancement by sodium glycolate and glycofurol. European Journal of Pharmaceutical Sciences. 14, 69-74.
 
[32]  MARTTIN, E., VERHOEF, J.C., MERKUS, F.W.H.M., 1998. Efficacy, safety and mechanism of cyclodextrins as absorption enhancers in nasal drug delivery of peptide and protein drugs. Journal of Drug Targeting. 6 (1), 17-36.
 
[33]  MATSUBARA, K., ABE, K., IRIE, T., UEKAMA, K., 1995. Improvement of nasal bioavailability of luteinizing hormone-releasing hormon agonist, buserelin, by cyclodextrin derivatives in rats. Journal of Pharmaceutical Sciences. 84 (11), 1295-1300.
 
[34]  TOUITOU, E., & BARRY, B. W. (Eds.). (2006). Enhancement in drug delivery. CRC Press.
 
[35]  DAVIS, S. S., & ILLUM, L. (2003). Absorption enhancers for nasal drug delivery. Clinical Pharmacokinetics, 42(13), 1107-1128.
 
[36]  VYAS, T. K., SHAHIWALA, A., MARATHE, S., & MISRA, A. (2005). Intranasal drug delivery for brain targeting. Current drug delivery, 2(2), 165-175.
 
[37]  HANSON, L. R., & FREY, W. H. (2008). Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. British Medical Journal Neuroscience, 9 (Suppl 3), S5.
 
[38]  BEHL, C. R., PIMPLASKAR, H. K., SILENO, A. P., DEMEIRELES, J. & ROMEO, V. D. (1998). Effects of physicochemical properties and other factors on systemic nasal drug delivery. Advanced Drug Delivery Reviews, 29, 89-116.
 
[39]  SINGH, A. K., SINGH, A. & MADHV, N. V., (2012). Nasal cavity, a promising transmucosal platform for drug delivery and research approaches from nasal to brain targeting. Journal of Drug Delivery and Therapeutics. 2(3), 22-33.
 
[40]  HARRIS, A. S., (1993). Review: clinical opportunities provided by the nasal administration of peptides. Journal of Drug Targeting, 1, 101-116.
 
[41]  HUSSEIN, N. R., (2014). Bioadhesive microparticles and liposomes of anti-Parkinson drugs for nasal delivery. PhD thesis, University of Central Lancashire.
 
[42]  JADHAV, K. R., GAMBHIRE, M. N., SHAIKH, I. M., KADAM, V. J., & PISAL, S. S. (2007). Nasal drug delivery system-factors affecting and applications. Current Drug Therapy, 2(1), 27-38.
 
[43]  SUMAN, J. D. (2003). Nasal drug delivery. Expert Opinion on Biological Therapy, 3(3), 519-523.
 
[44]  ALAGUSUNDARAM, M., CHENGAIAH, B., GNANAPRAKASH, K., RAMKANTH, S., CHETTY, C. M., & DHACHINAMOORTHI, D. (2010). Nasal drug delivery system-an overview. International Journal of Research and Pharmaceutical Sciences, 1(4), 454-465.
 
[45]  SINTOV, A. C., LEVY, H. V., & BOTNER, S. (2010). Systemic delivery of insulin via the nasal route using a new microemulsion system: in vitro and in vivo studies. Journal of Controlled Release, 148(2), 168-176.
 
[46]  UPADHYAY, S., PARIKH, A., JOSHI, P., UPADHYAY, U. M., & CHOTAI, N. P. (2011). Intranasal drug delivery system-A glimpse to become maestro. Journal of Applied Pharmaceutical Science, 1(03), 34-44.
 
[47]  KARLA, P. K., KWATRA, D., GAUDANA, R., & MITRA, A. K. (2008). Nasal drug delivery; Modified-release drug delivery technology. 2nd ed. London, UK: Informa Healthcare.
 
[48]  HUANG, C. H., KIMURA, R., NASSAR, R. B., & HUSSAIN, A. (1985). Mechanism of nasal absorption of drugs I: Physicochemical parameters influencing the rate of in situ nasal absorption of drugs in rats. Journal of pharmaceutical sciences,74(6), 608-611.
 
[49]  SHINICHIRO, H., TAKATSUKA, Y., & HIROYUKI, M. (1981). Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. International Journal of Pharmaceutics, 9(2), 173-184.
 
[50]  DUVVURI, S., MAJUMDAR, S., & MITRA, A. K. (2003). Drug delivery to the retina: challenges and opportunities. Expert opinion on biological therapy, 3(1), 45-56.
 
[51]  WASHINGTON, N., WASHINGTON, C., WILSON, C.G., (2001). Physiological pharmaceutics: barriers to drug absorption. Taylor & Francis, New York.
 
[52]  DJUPESLAND, P.G. (2013). Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review. Drug Delivery and Translational Research 3, 42–62.
 
[53]  HANSEN, K., KIM, G., DESAI, K. G. H., PATEL, H., OLSEN, K. F., CURTIS-FISK, J., & SCHWENDEMAN, S. P. (2015). Feasibility investigation of cellulose polymers for mucoadhesive nasal drug delivery applications. Molecular Pharmaceutics, 12(8), 2732-2741.
 
[54]  RASSU, G., SODDU, E., COSSU, M., BRUNDU, A., CERRI, G., MARCHETTI, N., & DALPIAZ, A. (2015). Solid microparticles based on chitosan or methyl-β-cyclodextrin: A first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate. Journal of Controlled Release, 201, 68-77.
 
[55]  MENAKA, M., & PANDEY, V. P. Formulation development and evaluation of cinnarizine nasal spray. Pharma Health Sciences, 2(4), 339-346.
 
[56]  NAKAMURA, K., TANAKA, Y., & SAKURAI, M. (1996) Dynamic mechanical properties of aqueous gellan solutions in the sol–gel transition region Carbohydrate Polymers, 30. 101–108.
 
[57]  PATIL, S. B., & SAWANT, K. K. (2008). Mucoadhesive microspheres: a promising tool in drug delivery. Current drug delivery, 5(4), 312-318.
 
[58]  GAVINI, E., RASSU, G., FERRARO, L., GENEROSI, A., RAU, J. V., BRUNETTI, A., & DALPIAZ, A. (2011). Influence of chitosan glutamate on the in vivo intranasal absorption of rokitamycin from microspheres. Journal of Pharmaceutical Sciences, 100(4), 1488-1502.
 
[59]  SWAMY, N. G. N., & ABBAS, Z. (2012). Preparation and in vitro characterization of mucoadhesive polyvinyl alcohol microspheres containing amlodipine besylate for nasal administration. Indian Journal of Pharmaceutical Education and Research, 46(1), 55.
 
[60]  CASETTARI, L., & ILLUM, L. (2014). Chitosan in nasal delivery systems for therapeutic drugs. Journal of Controlled Release, 190, 189-200.
 
[61]  RATHANANAND, M., KUMAR, D. S., SHIRWAIKAR, A., KUMAR, R., SAMPATH KUMAR, D., & PRASAD, R. S. (2007). Preparation of mucoadhesive microspheres for nasal delivery by spray drying. Indian Journal of Pharmaceutical Sciences, 69(5), 651.
 
[62]  DYER, A. M., WATTS, P., CASTILE, J., JABBAL-GILL, I., NANKERVIS, R., SMITH, A., ILLUM. L. (2002). Nasal delivery of insulin using novel chitosan based formulations: a comparative study in two animal models between simple chitosan formulations and chitosan nanoparticles. Pharmaceutical Research. 19, 998-1008.
 
[63]  CAO, S. L., ZHANG, Q. Z., & JIANG, X. G. (2007). Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy. Acta Pharmacological Sinica, 28(4), 584-590.
 
[64]  ZITT, M., KOSOGLOU, T., & HUBBELL, J. (2007). Mometasone furoate nasal spray. Drug Safety, 30(4), 317-326.
 
[65]  NILESH, S. (2013). Nanosuspension based in situ gelling nasal spray of carvedilol: development, in vitro and in vivo characterization. AAPS PharmSciTech 14(1): 189-199
 
[66]  GALGATTE, U. C., KUMBHAR, A. B., & CHAUDHARI, P. D. (2014). Development of in situ gel for nasal delivery: design, optimization, in vitro and in vivo evaluation. Drug Delivery, 21(1), 62-73.
 
[67]  VILA, A., SANCHEZ, A., TOBIO, M., CALVO, P., & ALONSO, M. J. (2002). Design of biodegradable particles for protein delivery. Journal of Controlled Release, 78(1), 15-24.
 
[68]  DAVIS, S. S. (2001). Nasal vaccines. Advanced Drug Delivery Reviews, 51(1), 21-42.
 
[69]  MADAN, M., LEWIS, M. B., UDUPA, S., BAIG, N. (2009). In situ forming polymeric drug delivery systems. Indian Journal Pharmaceutical Sciences, 71, 242-51.
 
[70]  SWORN, G., SANDERSON, G. R., & GIBSON, W. (1995). Gellan gum fluid gels. Food Hydrocolloids, 9(4), 265-271.
 
[71]  DOI, K. (2002). U.S. Patent No. 6,368,616. Washington, DC: U.S. Patent and Trademark Office.
 
[72]  ANDO, T., MAITANI, Y., YAMAMOTO, T., TAKAYAMA, K., & NAGAI, T. (1998). Nasal insulin delivery in rabbits using soybean-derived sterylglucoside and sterol mixtures as novel enhancers in suspension dosage forms. Biological and Pharmaceutical Bulletin, 21(8), 862-865.
 
[73]  AIKAWA, K., MATSUMOTO, K., UDA, H., TANAKA, S., SHIMAMURA, H., ARAMAKI, Y., & TSUCHIYA, S. (1998). Prolonged release of drug from o/w emulsion and residence in rat nasal cavity. Pharmaceutical Development & Technology, 3(4), 461-469.
 
[74]  TAMILVANAN, S. (2008). Oil-in-Water nanosized emulsions: Medical Applications. Pharmaceutical Sciences Encyclopedia. John Wiley & Sons, Inc.
 
[75]  KARARLI, T. T., NEEDHAM, T. E., GRIFFIN, M., SCHOENHARD, G., FERRO, L. J., & ALCORN, L. (1992). Oral delivery of a renin inhibitor compound using emulsion formulations. Pharmaceutical Research, 9(7), 888-893.
 
[76]  Kararli, T. T., Needham, T. E., Schoenhard, G., Baron, D. A., Schmidt, R. E., Katz, B., & Belonio, B. (1992). Enhancement of nasal delivery of a renin inhibitor in the rat using emulsion formulations. Pharmaceutical Research, 9(8), 1024-1028.
 
[77]  LI, L., NANDI, I., & KIM, K. H. (2002). Development of an ethyl laurate-based microemulsion for rapid-onset intranasal delivery of diazepam. International Journal of Pharmaceutics, 237(1), 77-85.
 
[78]  KO, K. T., NEEDHAM, T. E., & ZIA, H. (1998). Emulsion formulations of testosterone for nasal administration. Journal of Microencapsulation, 15(2), 197-205.
 
[79]  KLANG, V., SCHWARZ, J. C., & VALENTA, C. (2015). Nanoemulsions in Dermal Drug Delivery. In Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement (pp. 255-266). Springer Berlin Heidelberg.
 
[80]  ZHANG, X., & WU, B. (2015). Submicron lipid emulsions: a versatile platform for drug delivery. Current Drug Metabolism, 16(3), 211-220.
 
[81]  SHINDE, R. L., BHARKAD, G. P., & DEVARAJAN, P. V. (2015). Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: role of docosahexaenoic acid. European Journal of Pharmaceutics and Biopharmaceutics, 96, 363-379.
 
[82]  YADAV, S., GATTACCECA, F., PANICUCCI, R., & AMIJI, M. M. (2015). Comparative biodistribution and pharmacokinetic analysis of cyclosporine-a in the brain upon intranasal or intravenous administration in an oil-in-water nanoemulsion formulation. Molecular Pharmaceutics, 12(5), 1523-1533.
 
[83]  DE PONTI, R., & LARDINI, E. (1991). Use of chemical enhancers for nasal drug delivery. Drug Development & Industrial Pharmacy, 17(11), 1419-1436.
 
[84]  MERKUS, F. W. H. M., SCHIPPER, N. G. M., HERMENS, W. A. J. J., ROMEIJN, S. G., & VERHOEF, J. C. (1993). Absorption enhancers in nasal drug delivery: efficacy and safety. Journal of Controlled Release, 24(1), 201-208.
 
[85]  NATSUME, H., IWATA, S., OHTAKE, K., MIYAMOTO, M., YAMAGUCHI, M., HOSOYA, K. I & MORIMOTO, Y. (1999). Screening of cationic compounds as an absorption enhancer for nasal drug delivery. International Journal of Pharmaceutics, 185(1), 1-12.
 
[86]  TENGAMNUAY, P., & MITRA, A. K. (1990). Bile salt–fatty acid mixed micelles as nasal absorption promoters of peptides. I. Effects of ionic strength, adjuvant composition, and lipid structure on the nasal absorption of [D-Arg2] kyotorphin. Pharmaceutical Research, 7(2), 127-133.
 
[87]  TENGAMNUAY, P., & MITRA, A. K. (1990). Bile salt–fatty acid mixed micelles as nasal absorption promoters of peptides. II. In vivo nasal absorption of insulin in rats and effects of mixed micelles on the morphological integrity of the nasal mucosa. Pharmaceutical Research, 7(4), 370-375.
 
[88]  SHAO, Z., & MITRA, A. K. (1994). Bile salt–fatty acid mixed micelles as nasal absorption promoters. III. Effects on nasal transport and enzymatic degradation of acyclovir prodrugs. Pharmaceutical Research, 11(2), 243-250.
 
[89]  LAW, S. L., & SHIH, C. L. (2001). Characterization of calcitonin-containing liposome formulations for intranasal delivery. Journal of Microencapsulation, 18(2), 211-221.
 
[90]  LAW, S. L., HUANG, K. J., & CHOU, H. Y. (2001). Preparation of desmopressin-containing liposomes for intranasal delivery. Journal of Controlled Release, 70(3), 375-382.
 
[91]  MURAMATSU, K., MAITANI, Y., TAKAYAMA, K., & NAGAI, T. (1999). The relationship between the rigidity of the liposomal membrane and the absorption of insulin after nasal administration of liposomes modified with an enhancer containing insulin in rabbits. Drug Development & Industrial Pharmacy, 25(10), 1099-1105.
 
[92]  JUNG, B. H., CHUNG, B. C., CHUNG, S. J., LEE, M. H., & SHIM, C. K. (2000). Prolonged delivery of nicotine in rats via nasal administration of proliposomes. Journal of Controlled Release, 66(1), 73-79.
 
[93]  JUNG, B. H., CHUNG, S. J., & SHIM, C. K. (2002). Proliposomes as prolonged intranasal drug delivery systems. STP Pharma sciences, 12(1), 33-38.
 
[94]  TAKENAGA, M., SERIZAWA, Y., AZECHI, Y., OCHIAI, A., KOSAKA, Y., IGARASHI, R., & MIZUSHIMA, Y. (1998). Microparticle resins as a potential nasal drug delivery system for insulin. Journal of Controlled Release, 52(1), 81-87.
 
[95]  ISHIKAWA, E., YANAKA, K., SUGIMOTO, K., AYUZAWA, S., & NOSE, T. (2002). Reversible dementia in patients with chronic subdural hematomas. Journal of Neurosurgery, 96(4), 680-683.
 
[96]  ILLUM, L., FARRAJ, N. F., & DAVIS, S. S. (1994). Chitosan as a novel nasal delivery system for peptide drugs. Pharmaceutical Research, 11(8), 1186-1189.
 
[97]  UGWOKE, M. I., AGU, R. U., VANBILLOEN, H., BAETENS, J., AUGUSTIJNS, P., VERBEKE, N., & BORMANS, G. (2000). Scintigraphic evaluation in rabbits of nasal drug delivery systems based on carbopol 971P® and carboxymethylcellulose. Journal of Controlled Release, 68(2), 207-214.
 
[98]  CALLENS, C., & REMON, J. P. (2000). Evaluation of starch–maltodextrin-Carbopol® 974 P mixtures for the nasal delivery of insulin in rabbits. Journal of Controlled Release, 66(2), 215-220.
 
[99]  HASÇIÇEK, C., GÖNÜL, N., & ERK, N. (2003). Mucoadhesive microspheres containing gentamicin sulfate for nasal administration: preparation and in vitro characterization. Il Farmaco, 58(1), 11-16.
 
[100]  FERNANDEZ-URRUSUNO, R., CALVO, P., REMUÑÁN-LÓPEZ, C., VILA-JATO, J. L., & ALONSO, M. J. (1999). Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharmaceutical Research, 16(10), 1576-1581.
 
[101]  NAGAI, K., & THØGERSEN, H. C. (1984). Generation of β-globin by sequence-specific proteolysis of a hybrid protein produced in Escherichia coli. Nature. 309(5971), 810-812
 
[102]  OECHSLEIN, C. R., FRICKER, G., & KISSEL, T. (1996). Nasal delivery of octreotide: Absorption enhancement by particulate carrier systems. International Journal of Pharmaceutics, 139(1), 25-32.
 
[103]  TESHIMA, D., YAMAUCHI, A., MAKINO, K., KATAOKA, Y., ARITA, Y., NAWATA, H., & OISHI, R. (2002). Nasal glucagon delivery using microcrystalline cellulose in healthy volunteers. International Journal of Pharmaceutics, 233(1), 61-66.
 
[104]  SUZUKI, Y., & MAKINO, Y. (1999). Mucosal drug delivery using cellulose derivatives as a functional polymer. Journal of Controlled Release, 62(1), 101-107.
 
[105]  UGWOKE, M. I., SAM, E., VAN DEN MOOTER, G., VERBEKE, N., & KINGET, R. (1999). Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits. International Journal of Pharmaceutics, 181(1), 125-138.
 
[106]  CALLENS, C., CEULEMANS, J., LUDWIG, A., FOREMAN, P., & REMON, J. P. (2003). Rheological study on mucoadhesivity of some nasal powder formulations. European Journal of Pharmaceutics and Biopharmaceutics, 55(3), 323-328.
 
[107]  CALLENS, C., PRINGELS, E., & REMON, J. P. (2003). Influence of multiple nasal administrations of bioadhesive powders on the insulin bioavailability. International Journal of Pharmaceutics, 250(2), 415-422.
 
[108]  ISHIKAWA, F., KATSURA, M., TAMAI, I., & TSUJI, A. (2001). Improved nasal bioavailability of elcatonin by insoluble powder formulation. International Journal of Pharmaceutics, 224(1), 105-114.
 
[109]  ILLUM, L. H. H. O. N., JØRGENSEN, H., BISGAARD, H., KROGSGAARD, O., & ROSSING, N. (1987). Bioadhesive microspheres as a potential nasal drug delivery system. International Journal of Pharmaceutics, 39(3), 189-199.
 
[110]  ILLUM, L., FARRAJ, N. F., DAVIS, S. S., JOHANSEN, B. R., & O'HAGAN, D. T. (1990). Investigation of the nasal absorption of biosynthetic human growth hormone in sheep-use of a bioadhesive microsphere delivery system. International Journal of Pharmaceutics, 63(3), 207-211.
 
[111]  BJÖRK, E., & EDMAN, P. (1990). Characterization of degradable starch microspheres as a nasal delivery system for drugs. International Journal of Pharmaceutics, 62(2), 187-192.
 
[112]  EDMAN, P., BJÖRK, E., & RYDEN, L. (1992). Microspheres as a nasal delivery system for peptide drugs. Journal of Controlled Release, 21(1), 165-172.
 
[113]  RYDEN, L., & EDMAN, P. (1992). Effect of polymers and microspheres on the nasal absorption of insulin in rats. International Journal of Pharmaceutics, 83(1), 1-10.
 
[114]  PERESWETOFF-MORATH, L., & EDMAN, P. (1995). Dextran microspheres as a potential nasal drug delivery system for insulin-in vitro and in vivo properties. International journal of pharmaceutics, 124(1), 37-44.
 
[115]  PERESWETOFF-MORATH, L. (1998). Microspheres as nasal drug delivery systems. Advanced Drug Delivery Reviews, 29(1), 185-194.
 
[116]  SOANE, R. J., HINCHCLIFFE, M., DAVIS, S. S., & ILLUM, L. (2001). Clearance characteristics of chitosan based formulations in the sheep nasal cavity. International Journal of Pharmaceutics, 217(1), 183-191.
 
[117]  ILLUM, L. (2003). Nasal drug delivery: possibilities, problems and solutions. Journal of Controlled Release, 87(1), 187-198.
 
[118]  KRAULAND, A. H., GUGGI, D., & BERNKOP-SCHNÜRCH, A. (2006). Thiolated chitosan microparticles: a vehicle for nasal peptide drug delivery. International Journal of Pharmaceutics, 307(2), 270-277.
 
[119]  SCALIA, S., YOUNG, P. M., & TRAINI, D. (2015). Solid lipid microparticles as an approach to drug delivery. Expert Opinion on Drug Delivery, 12(4), 583-599.
 
[120]  OTTO, D. P., OTTO, A., & DE VILLIERS, M. M. (2015). Differences in physicochemical properties to consider in the design, evaluation and choice between microparticles and nanoparticles for drug delivery. Expert Opinion in Drug Delivery. 12(5):763-777
 
[121]  BHATT, R., SINGH, D., PRAKASH, A., MISHRA, N. (2015) Development, characterization and nasal delivery of rosmarinic acid-loaded solid lipid nanoparticles for the effective management of Huntington's disease. Drug Delivery. 22(7), 931-939.