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Intranasal administration of acetylcholinesterase inhibitors
BMC Neuroscience volume 9, Article number: S6 (2008)
This short review outlines the rationale, challenges, and opportunities for intranasal acetylcholinesterases, in particular galantamine. An in vitro screening model facilitated the development of a therapeutically viable formulation. In vivo testing confirmed achievement of therapeutically relevant drug levels that matched or exceeded those for oral dosing, with a dramatic reduction in undesired emetic responses. Intranasal drug delivery is an effective option for the treatment of Alzheimer's disease and other central nervous system disorders.
Intranasal (IN) delivery provides a viable and attractive option for administering various therapeutic agents . Advantages of IN administration include a large surface area for delivery, rapid achievement of target drug levels, and avoidance of first pass metabolism; furthermore, this delivery route is noninvasive, maximizing patient comfort and compliance. In addition, IN dosing may facilitate transport of central nervous system (CNS) drugs into the brain [2–9], although this concept has not been universally established [10–14] and may depend on physicochemical properties of the drug [15–17]. Examples in the literature of CNS-related drugs given intranasally include opioids , benzodiazepines  and antimuscarinic agents , as well as acetylcholinesterase inhibitors [10, 21–23].
Acetylcholinesterase inhibitors for Alzheimer's disease
Acetylcholinesterase activity and inhibition have been the subject of studies for two decades, since the emergence of the cholinergic hypothesis, wherein deficits in learning, memory, and behavior are deemed to be associated with loss of cholinergic neurotransmission in the hippocampus and cortex . Although various promising new therapeutic options are being vigorously pursued , acetylcholinesterase inhibitors remain the current front-line therapeutic approach to treatment of mild-to-moderate Alzheimer's disease (AD) [24, 26]. AD is the most common form of disabling cognitive impairment in the elderly, and its increasing prevalence reflects a growing elderly population .
Examples of acetylcholinesterases used to treat AD include taurcine, rivastigmine, donepazil, and galantamine. Tacrine was the first acetylcholinesterase inhibitor approved for AD treatment , but this agent has been associated with some severe side effects, including hepatotoxicity, necessitating the research and development of newer inhibitors with greater specificity and higher potency. At present, commonly administered acetylcholinesterase inhibitors include rivastigmine, donepazil, and galantamine. Among these, galantamine possesses the dual mechanism of acetylcholinesterase inhibition and allosteric modulation of nicotinic acetylcholine receptors .
Rationale for intranasal delivery of acetylcholinesterase inhibitors
Currently marketed acetylcholinesterase inhibitors are found entirely in oral dosage form. However, alternative routes, in particular IN administration, may provide benefits relative to oral dosing. For instance, the relatively low bioavailability of oral tacrine  has generated interest in delivery via various epithelial tissues, including the nasal route . Similarly, the oral efficacy of physostigmine is limited because of low bioavailability, and investigations have focused on IN [10, 21] and transdermal  delivery as alternatives to intravenous infusion. Transdermal physostigmine provides a mean absolute bioavailability of 36% as compared with only 3% for oral delivery in humans , and IN physostigmine may provide essentially complete bioavailability .
In addition to the avoidance of first pass metabolism, IN dosing also provides the potential for ameliorating adverse effects specific to the gastrointestinal (GI) tract. In the case of galantamine, GI-related side effects (for example, nausea and vomiting) are the adverse events that most commonly lead to discontinuation of treatment . Moreover, the impact of galantamine on evacuative functions when it comes into contact with intestinal tissue has been described both in vivo and in vitro .
Development of intranasal galantamine
Because of solubility and dose volume limitations, the commercially available form of galantamine, namely the hydrobromide salt, is not suitable for IN dosing. Therefore, an alternative drug formulation with a different, pharmaceutically acceptable counter cation, lactate, was developed . The performance of galantamine-hydrobromide and galantamine-lactate was monitored using an in vitro epithelial tissue model and associated analyses . Based on its increased solubility, low cytotoxicity, and high cell viability in vitro, galantamine-lactate represents a viable candidate for IN delivery.
Having developed a strategy to suitably increase the concentration of galantamine for IN delivery, the next step was to optimize its transepithelial permeation while retaining low toxicity . Employing the same in vitro epithelial tissue model, various formulations containing permeation enhancers were screened via a design-of-experiments approach. Data collected during the in vitro screening phase included permeation, cytotoxicity, cell viability, and transepithelial electrical resistance (TER). The latter findings represent the integrity of the tight junctions between epithelial cells; reduction in TER corresponds with increased potential for paracellular, and hence overall, drug permeation. An optimal formulation was identified with low cytotoxicity, high cell viability, reduced TER, and enhanced permeation in vitro.
Various formulations were tested in vivo in rat [22, 23]. There was a good correlation between the in vitro permeation rate and in vivo drug levels achieved, validating the utility of the epithelial tissue model. In the absence of permeation enhancers, the absolute oral and nasal bioavailability was approximately 22% to 23%; the incorporation of permeation enhancers approximately doubled the IN bioavailability (41%).
Intranasal galantamine alleviates GI-related side effects.
In order to explore the hypothesis that IN dosing reduces GI-related side effects when compared with oral dosing, emetic responses were monitored for the oral versus IN galantamine formulations in a ferret model. The ferret was previously established to be a good model for emetic sensitivity . The emetic study revealed a dramatic decrease in GI-related side effects when galantamine was administered by the IN route. During the first 4 hours after IN administration, only three emeses (retching events) were observed as compared with 34 with oral administration. The near absence of nausea, achieved despite similar or higher systemic exposure due to IN administration, further confirms that the observed emetic side effects associated with oral galantamine are caused by interactions in the GI tract and not systemic exposure to the drug.
As shown using IN galantamine, IN delivery provides a viable and attractive option for administering various therapeutic drugs. An in vitro screening model facilitated the development of a therapeutically viable formulation, whereas in vivo testing confirmed achievement of therapeutically relevant drug levels that matched or exceeded those for oral dosing, with a dramatic reduction in undesired emetic responses. The screening methods used show that IN drug delivery is an effective option for the treatment of AD and other CNS disorders.
central nervous system
transepithelial electrical resistance.
Costantino HR, Illum L, Brandt G, Johnson PH, Quay SC: Intranasal delivery: Physicochemical and therapeutic aspects. Int J Pharm. 2007, 337: 1-24. 10.1016/j.ijpharm.2007.03.025.
Wang Y, Aun R, Tse FL: Brain uptake of dihydroergotamine after intravenous and nasal administration in the rat. Biopharm Drug Dispos. 1998, 19: 571-575. 10.1002/(SICI)1099-081X(199812)19:9<571::AID-BDD142>3.0.CO;2-O.
Chow HS, Chen Z, Matsuura GT: Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats. J Pharm Sci. 1999, 88: 754-758. 10.1021/js9900295.
Chow HH, Anavy N, Villalobos A: Direct nose-brain transport of benzoylecgonine following intranasal administration in rats. J Pharm Sci. 2001, 90: 1729-1735. 10.1002/jps.1122.
Liu XF, Fawcett JR, Throne RG, DeFor TA, Frey WH: Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage. J Neurol Sci. 2001, 187: 91-97. 10.1016/S0022-510X(01)00532-9.
Zhang QZ, Jiang XG, Wu CH: Distribution of nimodipine in brain following intranasal administration in rats. Acta Pharmacol Sin. 2004, 25: 522-527.
Westin U, Piras E, Jansson B, Bergstrom U, Dahlin M, Brittebo E, Bjork E: Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents. Eur J Pharm Sci. 2005, 24: 565-573. 10.1016/j.ejps.2005.01.009.
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. 2006, 23: 565-572. 10.1007/s11095-006-9534-z.
Wang D, Gao Y, Yun L: Study on brain targeting of raltitrexed following intranasal administration in rats. Cancer Chemother Pharmacol. 2006, 57: 97-104. 10.1007/s00280-005-0018-3.
Dahlin M, Bjork E: Nasal administration of a physostigmine analogue (NXX-066) for Alzheimer's disease to rats. Int J Pharm. 2001, 212: 267-274. 10.1016/S0378-5173(00)00612-8.
Berg Van den MP, Merkus P, Romeijn SG, Verhoef JC, Merkus FW: Hydroxocobalamin uptake into the cerebrospinal fluid after nasal and intravenous delivery in rats and humans. J Drug Target. 2003, 11: 325-331. 10.1080/10611860310001640075.
Berg van den 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. 2004, 21: 799-802. 10.1023/B:PHAM.0000026431.55383.69.
Berg van den MP, Verhoef JC, Romeijn SG, Merkus FW: Uptake of estradiol or progesterone into the CSF following intranasal and intravenous delivery in rats. Eur J Pharm Biopharm. 2004, 58: 131-135. 10.1016/j.ejpb.2004.02.010.
Yang Z, Huang Y, Gan G, Sawchuk RJ: Microdialysis evaluation of the brain distribution of stavudine following intranasal and intravenous administration to rats. J Pharm Sci. 2005, 94: 1577-1588. 10.1002/jps.20334.
Sakane T, Akizuki M, Yamashita S, Nadai T, Hashida M, Sezaki H: The transport of a drug to the cerebrospinal fluid directly from the nasal cavity: the relation to the lipophilicity of the drug. Chem Pharm Bull (Tokyo). 1991, 39: 2456-2458.
Sakane T, Akizuki M, Yamashita S, Sezaki H, Nadai T: Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the dissociation of the drug. J Pharm Pharmacol. 1994, 46: 378-379.
Sakane T, Akizuki M, Taki Y, Yamashita S, Sezaki H, Nadai T: Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the molecular weight of drugs. J Pharm Pharmacol. 1995, 47: 379-381.
Illum L, Watts P, Fisher AN, Hinchcliffe M, Norbury H, Jabbal-Gill I, Nankervis R, Davis SS: Intranasal delivery of morphine. J Pharmacol Exp Ther. 2002, 301: 391-400. 10.1124/jpet.301.1.391.
Olivier JC, Djilani M, Fahmy S, Couet W: In situ nasal absorption of midazolam in rats. Int J Pharm. 2001, 213: 187-192. 10.1016/S0378-5173(00)00668-2.
Ahmed S, Sileno AP, deMeireles JC, Dua R, Pimplaskar HK, Xia WJ, Marinaro J, Langenback E, Matos FJ, Putcha L, Romeo VD, Behl CR: Effects of pH and dose on nasal absorption of scopolamine hydrobromide in human subjects. Pharm Res. 2000, 17: 974-977. 10.1023/A:1007551927177.
Hussain MA, Mollica JA: Intranasal absorption of physostigmine and arecoline. J Pharm Sci. 1991, 80: 750-751. 10.1002/jps.2600800808.
Leonard AK, Sileno AP, MacEvilly C, Foerder CA, Quay SC, Costantino HR: Development of a novel high-concentration galantamine formulation suitable for intranasal delivery. J Pharm Sci. 2005, 94: 1736-1746. 10.1002/jps.20389.
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. 10.1016/j.ijpharm.2006.11.013.
Ballard CG, Greig NH, Guillozet-Bongaarts AL, Enz A, Darvesh S: Cholinesterases: roles in the brain during health and disease. Curr Alzheimer Res. 2005, 2: 307-318. 10.2174/1567205054367838.
Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J: Therapeutic approaches to Alzheimer's disease. Brain. 2006, 129: 2840-2855. 10.1093/brain/awl280.
Geldmacher DS, Frolich L, Doody RS, Erkinjuntti T, Vellas B, Jones RW, Banerjee S, Lin P, Sano M: Realistic expectations for treatment success in Alzheimer's disease. J Nutr Health Aging. 2006, 10: 417-429.
Caselli RJ, Beach TG, Yaari R, Reiman EM: Alzheimer's disease a century later. J Clin Psychiatry. 2006, 67: 1784-1800.
Crismon ML: Tacrine: first drug approved for Alzheimer's disease. Ann Pharmacother. 1994, 28: 744-751.
Samochocki M, Höffle A, Fehrenbacher A, Jostock R, Ludwig J, Christner C, Radina M, Zerlin M, Ullmer C, Pereira EF, Lubbert H, Albuquerque WX, Maelicke A: Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not muscarinic acetylcholine receptors. J Pharmacol Exp Ther. 2003, 305: 10254-1036. 10.1124/jpet.102.045773.
Lou G, Montgomery PR, Sitar DS: Bioavailability and pharmacokinetic disposition of tacrine in elderly patients with Alzheimer's disease. J Psychiatry Neurosci. 1996, 21: 334-339.
Gore AV, Liang AC, Chien YW: Comparative biomembrane permeation of tacrine using Yucatan minipigs and domestic pigs as the animal model. J Pharm Sci. 1998, 87: 441-447. 10.1021/js970359u.
Walter K, Muller M, Barkworth MF, Nieciecki AV, Stanislaus F: Pharmacokinetics of physostigmine in man following a single application of a transdermal system. Br J Clin Pharmacol. 1995, 39: 59-63.
Sramek JJ, Frackiewicz EJ, Cutler NR: Review of the acetylcholinesterase inhibitor galantamine. Expert Opin Investig Drugs. 2000, 9: 2393-2402. 10.1517/13543718.104.22.1683.
Turiiski VI, Krustev AD, Sirakov VN, Getova DP: In vivo and in vitro study of the influence of the anticholinesterase drug galantamine on motor and evacuative functions of rat gastrointestinal tract. Eur J Pharmacol. 2004, 49: 233-239. 10.1016/j.ejphar.2004.07.054.
Johnson PH, Quay SC: Advances in nasal drug delivery through tight junction technology. Expert Opin Drug Deliv. 2005, 2: 281-98. 10.1517/17425247.2.2.281.
Yamashita M, Yamashita M, Tanaka J, Chagi K, Takeda S, Kurihara T, Takeda Y, Fujii Y: Vomiting induction by ipecac syrup in dogs and ferrets. J Toxicol Sci. 1997, 22: 409-412.
The authors would like to thank Heather Culley for editorial assistance with this manuscript.
This article has been published as part of BMC Neuroscience Volume 9 Supplement 3, 2008: Proceedings of the 2007 and 2008 Drug Discovery for Neurodegeneration Conference. The full contents of the supplement are available online at http://0-www.biomedcentral.com.brum.beds.ac.uk/1471-2202/9?issue=S3.
The authors declare that they have no competing interests.
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Costantino, H.R., Leonard, A.K., Brandt, G. et al. Intranasal administration of acetylcholinesterase inhibitors. BMC Neurosci 9, S6 (2008) doi:10.1186/1471-2202-9-S3-S6
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