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Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?

van Woensel M, Wauthoz N, Rosière R, Amighi K, Mathieu V, Lefranc F, van Gool SW, de Vleeschouwer S - Cancers (Basel) (2013)

Bottom Line: Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events.This route will bypass the blood-brain barrier and limit systemic side effects.Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven 3000, Belgium. matthias.vanwoensel@med.kuleuven.be.

ABSTRACT
Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma.

No MeSH data available.


Related in: MedlinePlus

Factors that can influence the efficacy of intranasally administrated substances, with the focus on indirect enhancers.
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cancers-05-01020-f003: Factors that can influence the efficacy of intranasally administrated substances, with the focus on indirect enhancers.

Mentions: From all the different polymers described in the previous sections, it is not only possible to make nanoparticles, but also mucoadhesive gels. Gels are three dimensional networks with a high viscosity, containing the active molecule. Charlton et al. demonstrated the gelling properties of chitosan and two low methylated pectins: LM-5 and LM-12 [129]. In a subsequent article, they published that the gel with 1% chitosan had a retention time on the human nasal mucosa that increased from 1.33 min to 12.58 min [88]. The potential of mucoadhesive gel formulations was also displayed by Perez et al. [89]. They coupled radioactive siRNA to PAMAM dendrimers to form dendriplexes, and formulated these particles into mucoadhesive gels containing either 1% (w/w) chitosan or 0.25% (w/w) carbopol 974P NFTM. These gels were prepared by blending the chitosan or carbopol with 23% (w/w) of thermosensible poloxamer to obtain in-situ gelation. Such a thermosetting gel has a phase transition below the temperature in the nasal cavity (32 °C to 35 °C) and above room temperature. Therefore it can be administered as a liquid. Different concentrations of the different gels were tested and no toxicity was observed. Two intranasal doses were necessary to achieve higher brain concentrations of radioactivity than achieved by intravenous administration of dendriplexes or intranasal administration of naked siRNA. Khan et al. prepared a gel with chitosan and hydroxyl propyl methyl cellulose and incorporated ropinirole, a dopamine D2 agonist [90]. Upon intranasal administration of the formulated ropinirole, concentrations in the brain were 8.5 times higher than after intravenous administration, and 3 times higher than after intranasal administration of non-formulated ropinirole. PEG, another popular polymer used for intranasal administration with or without mucoadhesive CS, was used by Zaki et al. to prepare a thermosetting gel with poloxamer conjugated with metoclopramide hydrochloride to enhance drug release [106]. Intranasal administration of the gel increased the bioavailability from 51.7%, for oral drug solution, to 69.1%. With similar gels, using carbopol, carboxymethyl cellulose and PEG, Babu et al. found an increased delivery of melatonin in the olfactory bulb [102]. Upon intranasal administrations of these gels, the increased delivery in the CSF was respectively 9.22-, 6.77- and 4.04-fold, as measured by microdialysis.


Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?

van Woensel M, Wauthoz N, Rosière R, Amighi K, Mathieu V, Lefranc F, van Gool SW, de Vleeschouwer S - Cancers (Basel) (2013)

Factors that can influence the efficacy of intranasally administrated substances, with the focus on indirect enhancers.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3795377&req=5

cancers-05-01020-f003: Factors that can influence the efficacy of intranasally administrated substances, with the focus on indirect enhancers.
Mentions: From all the different polymers described in the previous sections, it is not only possible to make nanoparticles, but also mucoadhesive gels. Gels are three dimensional networks with a high viscosity, containing the active molecule. Charlton et al. demonstrated the gelling properties of chitosan and two low methylated pectins: LM-5 and LM-12 [129]. In a subsequent article, they published that the gel with 1% chitosan had a retention time on the human nasal mucosa that increased from 1.33 min to 12.58 min [88]. The potential of mucoadhesive gel formulations was also displayed by Perez et al. [89]. They coupled radioactive siRNA to PAMAM dendrimers to form dendriplexes, and formulated these particles into mucoadhesive gels containing either 1% (w/w) chitosan or 0.25% (w/w) carbopol 974P NFTM. These gels were prepared by blending the chitosan or carbopol with 23% (w/w) of thermosensible poloxamer to obtain in-situ gelation. Such a thermosetting gel has a phase transition below the temperature in the nasal cavity (32 °C to 35 °C) and above room temperature. Therefore it can be administered as a liquid. Different concentrations of the different gels were tested and no toxicity was observed. Two intranasal doses were necessary to achieve higher brain concentrations of radioactivity than achieved by intravenous administration of dendriplexes or intranasal administration of naked siRNA. Khan et al. prepared a gel with chitosan and hydroxyl propyl methyl cellulose and incorporated ropinirole, a dopamine D2 agonist [90]. Upon intranasal administration of the formulated ropinirole, concentrations in the brain were 8.5 times higher than after intravenous administration, and 3 times higher than after intranasal administration of non-formulated ropinirole. PEG, another popular polymer used for intranasal administration with or without mucoadhesive CS, was used by Zaki et al. to prepare a thermosetting gel with poloxamer conjugated with metoclopramide hydrochloride to enhance drug release [106]. Intranasal administration of the gel increased the bioavailability from 51.7%, for oral drug solution, to 69.1%. With similar gels, using carbopol, carboxymethyl cellulose and PEG, Babu et al. found an increased delivery of melatonin in the olfactory bulb [102]. Upon intranasal administrations of these gels, the increased delivery in the CSF was respectively 9.22-, 6.77- and 4.04-fold, as measured by microdialysis.

Bottom Line: Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events.This route will bypass the blood-brain barrier and limit systemic side effects.Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven 3000, Belgium. matthias.vanwoensel@med.kuleuven.be.

ABSTRACT
Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma.

No MeSH data available.


Related in: MedlinePlus