A review on factors affecting the design of nasal drug delivery system
Keywords:
Transmucosal nasal delivery, hepatic first-pass metabolism, non-invasive, microemulsions, microspheresAbstract
Transmucosal nasal delivery is a promising drug delivery option where common drug administrations (e.g., intravenous, intramuscular, or oral) are inapplicable. Recently, it has been shown that many drugs have better bioavailability by nasal route than by oral route. This has been attributed to rich vasculature and a highly permeable structure of the nasal mucosa coupled with avoidance of hepatic first-pass elimination, gut wall metabolism and/or destruction in the gastrointestinal tract. The physiology of the nose presents obstacles, but offers a promising route for non-invasive systemic delivery of numerous therapies and debatably drug delivery route to the brain. To overcoming problems in nasal drug delivery requires deep understanding of the various factors affecting nasal delivery. Thus present review focuses on various aspects of nasal drug delivery with special emphasis to factors affecting nasal drug administration.
References
Stoner CL, Cleton A, Johnson K, Oh DM,
Hallak H, Brodfuehrer J, Surendran N, Han
HK. Integrated oral bioavailability
projection using in vitro screening data as a
selection tool in drug discovery. Int J
Pharm. 2004;269:241-249.
Hou T, Wang J, Zhang W, Xu X. ADME
evaluation in drug discovery: Prediction of
oral absorption by correlation and
classification. J Chem Inf Model.
;47:208-218.
Dressman JB, Thelen K, Jantratid E.
Towards quantitative prediction of oral drug
absorption. Clin Pharmacokinet.
;47:655-667.
Davis SS. Further development in nasal
drug delivery. Pharmaceutical Science and
Technology Today. 1999;2:265-266.
D’Souza R, Mutalik S, Venkatesh M,
Vidyasagar S, Udupa N. Nasal Insulin Gel
as an Alternate to Parenteral Insulin:
Formulation, Preclinical, and Clinical
Studies. AAPS PharmSciTech.
;6:E184-E189.
Rathananand M, Kumar DS, Shirwaikar A,
Kumar R, Prasad RS .Preparation of
mucoadhesive microspheres for nasal
delivery by spray drying. Indian J
Pharmaceutical Sciences. 2007;69:651-657
Targeted liposomal drug delivery
system.United States Patent 7169410.
Waree Tiyaboonchai: Chitosan
Nanoparticles: A Promising System for
Drug Delivery. Naresuan University
Journal. 2003;11:51-66.
Illum L. Nasal drug delivery: possibilities,
problems and solutions. J Control Release.
;87:187-198.
Yamaya M, Finkbeiner WE, Chun SY,
Widdicombe JH. Differentiated structure
and function of cultures from human
tracheal epithelium. Am J Physiol.
;262:L713- L724.
Romeo VD, Meireles J, Sileno AP,
Pimplaskar HK, Behl CR. Effects of
physicochemical properties and other
factors on systemic nasal delivery. Adv
Drug Deliv Rev. 1998;29:89-116.
Illum L. Nasal drug delivery: new
developments and strategies. Drug Discov
Today. 2002;7:1184-1189.
Graff LC, Pollock GM. Nasal drug
administration: potential for targeted central
nervous system delivery. J Pharm Sci.
;94:1187-1195.
Leonard AK, Sileno AP, Brandt GC,
Foerder CA, Quay SC, Costantino HR. In
vitro formulation optimization of intranasal
galantamine leading to enhanced
bioavailability and reduced emetic response
in vivo. Int J Pharm. 2007;335:138-146.
Mygind N, Dahl R. Anatomy, physiology
and function of the nasal cavities in health
and disease. Adv Drug Deliv Rev.
;29:3-12.
Pires A, Fortuna A, Alves G, Falcao A.
Intranasal Drug Delivery: How, Why and
What for? J Pharm Pharmaceut Sci
(www.cspsCanada.org) 2009;12(3):288–
Chein YW and Chang S. In Transnasal
Systemic Medications: Fundamental
concepts and biomedical assessments,
Elsevier science publishers, Amsterdam.
;1-9.
Lewis JL, Nikula KJ, Novak R, Dahl AE.
Comparative localisation of
carboxylesterase in F344 rat, beagle dog
and human nasal tissue. Anat Rec.
;239:55-64.
Lewis DFV, Dickins M. Substrate SAR’s in
human P450s. Drug Discov Today.
;7:918-925.
Krishna NSR, Getchell TV, Awasthi YC,
Dhooper N. Age and gender related trends
in the expression of glutathione Stransferases in human nasal mucosa. Ann
Otol Rhin Laryng. 1995;104:812-822.
Wearle LL, Crit. Rev. her.Drug carrier Sst.
;8,331-394.
Riddle D, Washington N and Wilson CD.
Drug delivery to the nasal and buccal
cavities, anatomical and physiological
considerations In, Duchene, D (eds.) Buccal
and nasal administration as an alternative to
parental administration, Editions de
SanteParis. 1992;29-39.
Druce HM, Ear Nose throat J. 1986;65:201.
Illum L. In: Mathiowitz E, Chickering DE,
Lehr CME, Bioadhesive formulations for
nasal peptide delivery: Fundamentals,
Novel Approaches and Development.
Marcel Dekker. New York. 1999;507-539.
Ingemann M; Frokjaer S; Hovgaard L;
Brøndsted H. Peptide and Protein Drug
Delivery Systems for Non-Parenteral
Routes of Administration. In
Pharmaceutical Formulation Development
of Peptides and Proteins; Frokjaer, S.,
Hovgaard, L., Eds.; Taylor & Francis:
Philadelphia, PA, USA, 2000;Chapter
:p.189.
Charlton S, Jones NS, Davis SS, Illum L.
Distribution and clearance of bioadhesive
formulations from the olfactory region in
man: Effect of polymer type and nasal
delivery device. Eur J Pharm Sci.
;30:295-302.
Arora P, Sharma S, Garg S. Permeability
issues in nasal drug delivery. Drug
DiscovToday. 2002;7:967-975.
Aulton ME. “Pharmaceutics – The science
of dosage form design” Churchill
Livingston. 2002;494.
Kadam SS, Mahadik KR, Pawar AP,
Paradkar AR. Transnasal delivery of
peptides – a review. The East. Pharm. July
;47–49.
Hirai S, Yashiki T, Mima H. Effect of
surfactants on nasal absorption of insulin in
rats. Int. J. Pharm. 1981;9:165-171.
Huang C, Kimura R, Nassar A, Hussain A.
Mechanism of nasal drug absorption of drug
II: absorption of L-tyrosine and the effect of
structural modification on its absorption. J
Pharm Sci. 1985;74:298-1301.
Pennington AK, Ratcliffe JH, Wilson CG,
Hardy JG. The influence of solution
viscosity on nasal spray deposition and
clearance. Int J Pharm. 1988;43:221-224.
Suzuki Y, Makino. Mucosal drug delivery
using cellulose derivatives as a functional
polymer. J Control Release. 1999;62:101-
Gattefosse bulletin. New lipidic systems
enhancing the bioavailability of problem
drugs. 1997;1-81.
Van De Donk HJM, Muller Plantema IP,
Zuidema J, Merkus FWHM. The effects of
preservatives on the cilliary beat frequency
of chicken embryo tracheas. Rhinology.
;18:119-130.
Merkus FW, Verhoef JC, Schipper NG,
Marttin E. Nasal mucociliary clearance as a
factor in nasal drug delivery. Adv Drug
Deliv Rev. 1998;29:13-38.
Aurora J. Development of Nasal Delivery
Systems: A Review. Drug Delivery
Technology. October 2002;Vol. 2:No. 7.
Margret chandira R, Debjit B, Chiranjib B,
Jayakar B, Recent advances in nasal drug
delivery systems-a review, Pharmavita.net
Kao HD, Traboulsi A, Itoh S, Dittert L,
Hussain A. Enhancement of the systemic
and CNS specific delivery of L-dopa by the
nasaladministration of its water soluble
prodrugs. Pharm Res. 2000;17:978-984.
Hussain AA, Al-Bayatti AA, Dakkuri A,
Okochi K, Hussain MA.Testosterone 17β-
N,N-Dimethylglycinate Hydrochloride: A
prodrug with a potential for nasal delivery
of testosterone. J Pharm Sci. 2002;91:785-
Wang H, Hussain AA, Wedlund PJ.
Nipecotic Acid: Systemic availability and
brain delivery after nasal administration of
nipecotic acid and n-Butyl nipecotate to
rats. Pharm Res. 2005;22:556-562.
Yang C, Gao H, Mitra AK. Chemical
stability, enzymatic hydrolysis, and nasal
uptake of amino acid ester prodrugs of
acyclovir. J Pharm Sci. 2001;90:617-624..
Costantino HR, Illum L, Brandt G, Johnson
PH, Quay SC. Intranasal delivery:
Physicochemical and therapeutic aspects.
Int J Pharm. 2007;337:1-24.
Morimoto K, Miyazaki M, Kakemi M.
Effects of proteolytic enzyme inhibitors on
nasal absorption of salmon calcitonin in
rats. Int J Pharm. 1995;113:1-8.
Machida M. Effects of surfactants and
protease inhibitors on nasal absorption of
recombinant human granulocyte
colonystimulating factor (rhG-CSF) in rats.
Biol Pharm Bull. 1994;17:1375-1378.
Bernkop-Schnurch A. Use of inhibitory
agents to overcome the enzymatic barrier to
perorally administered therapeutic peptides
and proteins. J Control Release. 1998;52:1-
Hussain MA. The use of alphaaminoboronic acid derivatives to stabilize
peptide drugs during their intranasal
absorption. Pharm Res. 1989;6:186-189.
Hoang VD, Uchenna AR, Mark J, Renaat
K, Norbert V. Characterization of human
nasal primary culture systems to investigate
peptide metabolism. Int J Pharm.
;238:247-256.
O’Hagan DT. Nasal absorption enhancers
for biosynthetic human growth hormone in
rats. Pharm Res. 1990;7:772-776.
Greimel A, Bernkop-Schnürch A, Del Curto
MD, D'Antonio M. Transport
characteristicsof a beta sheet breaker
peptide across excised bovine nasal mucosa.
Drug Dev Ind Pharm. 2007;33:71-77.
Karasulu E, Yavasoğlu A, Evrensanal Z,
Uyanikgil Y, Karasulu HY. Permeation
studies and histological examination of
sheep nasal mucosa following
administration of different nasal
formulations with or without absorption
enhancers. Drug Delivery. 2008;15:219-
Sinswat P, Tengamnuay P. Enhancing
effect of chitosan on nasal absorption of
salmon calcitonin in rats: comparison with
hydroxypropyl- and dimethyl-β-
cyclodextrins. Int J Pharm. 2003;257:15-22.
Zaki NM, Mortada ND, Awad GA, Abd
ElHady SS. Rapid-onset intranasal delivery
of metoclopramide hydrochloride Part II:
Safety of various absorption enhancers and
pharmacokinetic evaluation. Int J Pharm.
;327:97-103.
Illum L. Nanoparticulate systems for nasal
delivery of drugs: A real improvement over
simple systems? J Pharm Sci. 2007;96:473-
Giunchedi P, Juliano C, Gavini E, Cossu M,
Sorrenti M. Formulation and in vivo
evaluation of chlorhexidine buccal tablets
prepared using drug loaded chitosan
microspheres. Eur J Pharm Biopharm.
;53:233-239.
Maestrelli F, Zerrouk N, Chemto C, Mura
P. Influence of chitosan and its glutamate
and hydrochloride salts on naproxen
dissolution rate and permeation across
Caco-2 cells. Int J Pharm. 2004;271:257-
Ravi Kumar MNV, Muzzarelli RAA,
Muzzarelli C, Sashiwa H, Domb AJ.
Chitosan chemistry and pharmaceutical
perspectives. Chem Rev. 2004;104:6017-
Washington N, Steele RJ, Jackson SJ, Bush
D, Mason J, Gill DA, Pitt K, Rawlins DA.
Determination of baseline human nasal pH
and the effect of intranasally administered
buffers. Int J Pharm. 2003;198:139-146.
Pujara CP, Shao Z, Duncan MR, Mitra AK.
Effects of formulation variables on nasal
epithelial cell integrity: Biochemical
evaluations. Int J Pharm. 1995;114:197-
Sankar C: Rani M: Srivastava AK: Mishra
B. Chitosan based pentazocine
microspheres for intranasal systemic
delivery: development and
biopharmaceutical evaluation. Pharmazie.
;56(3):223-6.
Sankar C, Mishra B. Development and in
vitro evaluation of gelatin A microspheres
of Ketorolac tromethamine for intranasal
administration. Acta Pharm. 2003;53:101-
Shah V, Sharma M, Parmar V, Upadhyay
U. Formulation of sildenafil citrate loaded
nasal microsphers: An in vitro, ex vivo
characterization. International Journal of
Drug Delivery. 2010;2:213-220.
Gavini E, Rassu G, Sanna V, Cossu M and
Giunchedi M. Mucoadhesive microspheres
for nasal administration of an antiemetic
drug, metoclopramide: in-vitro/ex-vivo
studies Journal of Pharmacy and
Pharmacology. 2004;57(3):287 – 294.
Harikarnpakdee S, Lipipun V,
Sutanthavibul N, and Ritthidej GC. Spray
dried mucoadhesive microspheres:
preparation and transport through nasal cell
monolayer AAPS PharmSciTech. 2005
november accepted.
Dalpiaz A, Giunchedi P, Gavini E,
Colombo G, Bortolotti F. Brain targeting of
an antiischemic agent by nasal
administration of microparticles, 15th
international symposium on
microencapsulation, Parma (Italy). 2005;18-
Dandagi PM, Mastiholimath VS, Gadad
AP, Iliger SR. Mucoadhesive Microspheres
of Propranolol Hydrochloride for Nasal
Delivery. Indian J Pharm Sci. 2007;69:402.
Mahajan H, Gattani S and Surana S. Spray
Dried Mucoadhesive Microspheres of
Ondansetron for Nasal Administration,
International Journal of Pharmaceutical
Sciences and Nanotechnology. 1(3):267-
Mahajan HS, Gattani SG 2009. Nasal
administration of ondansetron using a novel
microspheres delivery system,
Pharmaceutical Development and
Technology. 2008;14(2):226-232.
Yadav AV, Mote HH. Development of
starch microspheres for intranasal delivery,
Indian J Pharm Sci. 2008;70-74.
Jain SA, Chauk DS, Mahajan HS, Tekade
AR, Gattani SG. Formulation and
evaluation of nasal mucoadhesive
microspheres of Sumatriptan succinate,
Journal of Microencapsulation.
;26(8):711-721.
Shaji J, Poddar A, Iyer S. Brain-targeted
nasal clonazepam microspheres, Indian J
Pharm Sci. 2009;7(6):715-718.
Vyas TK, Babbar AK, Sharma RK, Singh
S, Misra, A. Intranasal mucoadhesive
microemulsions of clonazepam: Preliminary
studies on brain targeting. J Pharm Sci
;95:570-580.
kwatikar PS, kulkarni NP, yadav SP and
sakarkar DM, formulation and evaluation of
an anti-epileptic drug loaded microemulsion
for nose to brain delivery, asian J.
Pharmaceutics, april-june, 2009.
Florence K, Agrawal HG and Misra A.
Intranasal delivery of clobazam for
treatment of status epileptics.
Shende AJ, Patil RR and Devarajan PV,
Microemulsion of lomotrigone for nasal
delivery, Ind.J.Pharm. Sci., 2007;69(5):721-
Holvoet C, Heyden YV, and PlaizierVercammen J. Inclusion complexation of
lorazepam with different cyclodextrins
suitable for parenteral use. Drug Dev. Ind.
Pharm. 2005:31:567–575.
Date AA and Nagarsenker MS. Parenteral
microemulsions: an overview. Int. J. Pharm.
;355:19–30.
Yalin M, Öner F, Öner L and Hincal AA.
Preparation and properties of a stable
intravenous lorazepam emulsion. J. Clin.
Pharm. Ther.1997;22:39–44.
Amit AK and Vandana BP. Development
and Evaluation of Lorazepam
Microemulsions for Parenteral Delivery.
AAPS PharmSciTech, 2008:9(3):966-971.
Pakalnis A, Kring D, Paolicchi J. Parenteral
satisfaction with sumatriptan nasal spray in
childhood migraine. J Child Neurol.
;18:772-775.
Villalon CM, Centurion D, Valdivia LF, de
Vries P, Saxena PR. Migraine:
pathophysiology, pharmacology, treatment
and future trends. Curr Vasc Pharmacol.
;1:71Y84.
Martindale PK. The Complete Drug
Reference. London, UK: Pharmaceutical
Press; 1999:450Y452.
Gladstone JP, Gawel M. Newer
formulations of the triptans: advances in
migraine treatment. Drugs.
;63:2285Y2305.
Bigal ME, Bordini CA, Antoniazzi AL,
Speciali JG. The triptan formulations: a
critical evaluation. Arq Neuropsiquiatr.
;61:313Y320.
Shelke RR and Devrajan PV, Aqua
triggered In Situ Gelling Microemulsion for
Nasal Delivery; Indian J Pharm Sci
;Sep-Oct:pp-726-727.
Shelke RR and Devrajan PV, Aqua
triggered In Situ Gelling Microemulsion for
Nasal Delivery; Indian J Pharm Sci
;Sep-Oct:pp-726-727.
Tushar K Vyas AK Babbar R, Sharma K
and Misra A. Intranasal mucoadhesive
microemulsions of zolmitriptan:
Preliminary studies on brain-targeting.
Journal of Drug Targeting 2005;13:(5):317-
Tiwari NG and Bajaj AN. formulation
development of eucalyptuss oil
microemulsion for intranasal delivery.
Indian J Pharm Sci 2007;Sep-Oct:pp-731-
Zhang Q, Jiang X, Jiang W, Lu W, Su L
and Shi Z, Preparation of nimodipineloaded microemulsion for intranasal
delivery and evaluation on the targeting
efficiency to the brain International Journal
of Pharmaceutics. 2004;275:1-2(4):85-96.
Jing Y, Jian PZ, Qi NP, Yun L and Liang C.
Distribution of nobiletin chitosan-based
microemulsions in brain following i.v.
injection in mice International Journal of
Pharmaceutics. March 2008;352:1-
(20):256-262.
Jogani V, Shah P, Mishra P, and Misra AN.
Intranasal mucoadhesive microemulsion of
tacrine to improve brain targeting.
Alzheimer Dis Assoc Disord.
;22(2):116-124.
Vyas TK, Babbar AK, Sharma RK, Misra
AN. Intranasal mucoadhesive
microemulsion of zolmitriptan: preliminary
studies on brain targeting. J Drug Target
;13(5):317-324.
Lianly IL, Nandi I, Kim KH. Development
of an ethyl laurate based microemulsion for
rapid onset of intranasal delivery of
diazepam. Int J Pharm 2002;237:77-85.
Dongxing Wang1, Yongliang Gao1 and
Liuhong Yun1 Study on brain targeting of
raltitrexed following intranasal
administration in rats cancer Chemotherapy
and Pharmacology. 2006;57(1);97-104.
Elshafeey A, Bendas E and Mohamed O.
Intranasal Microemulsion of Sildenafil
Citrate: in vitro evaluation and in vivo
pharmacokinetic study in Rabbits,. AAPS
PharmSciTech 2009;10(2):361-367.
Botner S, Levy HV, Sintov AC. Intranasal
Delivery of Insulin via Microemulsion
based Formulation; Nanotech 2008;Abstract
no 559.
P D Knoester, D M Jonker, R T M van der
Hoeven, T A C Vermeij, P M Edelbroek, G
J Brekelmans, and G J de Haan,
Pharmacokinetics and pharmacodynamics
of midazolam administered as a
concentrated intranasal spray. A study in
healthy volunteers, Br J Clin Pharmacol.
May;53(5):501–507.
Alpar HO, Bowen JC, Brown MRW.
Effectiveness of liposomes as adjuvants of
orally and nasally administered tetanus
toxoid. Int J Pharm 1992;88:335–44.
Maitani Y, Asano S, Takahashi S, Nakagaki
M, Nagai T. Permeability of insulin
entrapped in liposome through the nasal
mucosa of rabbits. Chem Pharm Bull
;40:1569–72.
Law SL, Huang K J, Chou HY. Preparation
of desmopressin-containing liposomes for
intranasal delivery. J Control Rel
;70:375–82.
Iwanaga K, Matsumoto S, Morimoto K,
Kakemi M, Yamashita S, Kimura T.
Usefulness of liposomes as an intranasal
dosage formulation for topical drug
application. Biol Pharm Bull 2000;23:323–
Morimoto K, Morisaka K, Kamada A.
Enhancement of nasal absorption of insulin
and calcitonin using polyacrylic acid gel. J
Pharm Pharmacol 1985;37:134–6.
Callens C. Pringels E. Remon JP. Influence
of multiple nasal administrations of
bioadhesive powders on the insulin
bioavailability. Int. J. Pharm.
;250:415-422.
