Intranasal delivery of insulin via the olfactory nerve pathway

Renner, Dan B.; Svitak, Aleta L.; Gallus, Nathan J.; Ericson, Marna E.; Frey, William H.; Hanson, Leah R.

doi:10.1111/j.2042-7158.2012.01555.x

Cited by 98 publications

(79 citation statements)

References 22 publications

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“…Numerous previous studies regarding protein and peptide delivery to the CNS have indicated that proteins such as NGF (Chen et al, 1998;De Rosa et al, 2005), insulin (Francis et al, 2008;Renner et al, 2012;Shemesh et al, 2012), and IGF-1 (Fletcher et al, 2009;Liu et al, 2001;Thorne et al, 2004) preferentially enter the CNS through extracellular channels between the olfactory receptor neuron (ORN) axons and the olfactory ensheathing cells protecting them from the cribiform plate (Dhuria et al, 2010;Wu et al, 2008). As a result, it is probable that preferentially depositing substances onto the olfactory epithelium where ORN axons originate would increase the amount of D1-D2 interfering peptide delivered to the CNS while minimizing loss to the periphery.…”

Section: Discussionmentioning

confidence: 99%

“…In some cases, IN drug delivery can result in 100-fold increases in protein drug concentration in multiple brain regions (Dhuria et al, 2010). A number of proteins including insulin and nerve growth factor have been delivered effectively to the central nervous system (CNS) IN in both animals and humans (De Rosa et al, 2005;Renner et al, 2012;Shemesh et al, 2012). Some of the other advantages of IN drug delivery include the possibility for at-home use, multiple dosings a day, and its cost effectiveness.…”

Section: Introductionmentioning

confidence: 99%

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Intranasal Delivery of a Peptide with Antidepressant-Like Effect

Brown

Liu

2014

Neuropsychopharmacol

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A critical issue in drug development is developing effective, noninvasive delivery routes to the central nervous system (CNS). Major depressive disorder (MDD) is an illness associated with significant morbidity. Even with multiple antidepressant trials, 10-15% of patients continue to experience persistent depressive symptoms. We previously developed an interfering peptide that has antidepressant-like effects in rats when injected directly into the brain. To be clinically viable, it must demonstrate efficacy via a noninvasive administration route. We report here that the interfering peptide designed to disrupt the interaction between the D1 and D2 dopamine receptors can be delivered to relevant brain areas using the Pressurized Olfactory Device (POD), a novel intranasal delivery system developed by Impel NeuroPharma. We validate this delivery method by demonstrating that, at doses X1.67 nmol/g, the D1-D2 interfering peptide has a significant antidepressant-like effect comparable to that of imipramine in the forced swimming test (FST), a common test for antidepressant efficacy. The antidepressant-like effect of the interfering peptide can be detected for 2 h after intranasal administration. Furthermore, we show that the interfering peptide disrupts the D1-D2 interaction and it can be detected in the prefrontal cortex after intranasal administration. This study provides strong preclinical support for intranasal administration of the D1-D2 interfering peptide as a new treatment option for patients suffering from MDD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intranasal Delivery of a Peptide with Antidepressant-Like Effect

Brown

Liu

2014

Neuropsychopharmacol

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“…This has been shown for insulin (Renner et al, 2012), Andrews et al, 2011 No hypoglycemic effect after removal of stratum corneum Peptide Delivery Systems orexin-A (Dhuria et al, 2009), and exendin (Banks et al, 2004). Hexarelin, a growth hormone-releasing peptide, was delivered to the brain using a cosolvent and n-tridecyl-b-D-maltoside for improving the peptide permeation and enabling 1.6-fold greater plasma concentrations compared with intravenous administration (Yu and Kim, 2009).…”

Section: A Development Challenges Of Peptide Delivery Formulationsmentioning

confidence: 99%

Novel Delivery Systems for Improving the Clinical Use of Peptides

et al. 2015

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“…After nasal delivery, drugs are taken up by the olfactory cell through the olfactory mucosa and transported into the brain, including the olfactory bulb, nucleus, amygdale, and hippocampus, along the olfactory beam, avoiding the obstruction of BBB and making it relatively easier to enter the brain. 7,8 Serralheiro et al 9 found that the bioavailability of lamotrigine (LTG) in brain was 116.5% comparing intranasal administration with intravenous administration in mice. Through the nasal route, drugs can avoid the obstruction of the BBB and enter the brain relatively easily.…”

Section: Introductionmentioning

confidence: 99%

mPEG-PLA/TPGS mixed micelles via intranasal administration improved the bioavailability of lamotrigine in the hippocampus

Yu¹,

Lv²,

Yuan³

et al. 2017

IJN

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Purpose This study aimed to develop a novel methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA)/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) mixed micelle drug delivery system to improve lamotrigine (LTG) distribution in the hippocampus. Methods LTG-loaded mPEG-PLA/TPGS mixed micelles and LTG-loaded mPEG-PLA micelles were formulated, and their characteristics, particle size, surface morphology, and release behavior in vitro were researched. Then, a microdialysis sampling technique coupled with two validated chromatographic systems was developed for the continuous measurement of the protein-unbound form of LTG in the rat plasma and hippocampus after administering two kinds of micelles and LTG solution intranasally. Results The drug loading and mean size of LTG-loaded micelles and LTG-loaded mixed micelles prepared with optimal formulation were 36.44%±0.14%, 39.28%±0.26%, 122.9, and 183.5 nm, respectively, with a core–shell structure. The cumulative release rate in vivo of LTG-loaded mixed micelles was 84.21% at 24 hours and showed more sustained release while that of LTG-loaded micelles was 80.61% at 6 hours. The T max and area under concentration-time curve from zero to time of last quantifiable concentration of LTG solution, LTG-loaded micelles, and LTG-loaded mixed micelles were 55, 35, and 15 minutes and about 5,384, 16,500, and 25,245 (min⋅μg)/L in the hippocampus, respectively. Conclusion The results revealed that LTG-loaded mPEG-PLA/TPGS mixed micelles enhanced the absorption of LTG at the nasal cavity and reduced the efflux of LTG in the brain, suggesting that the function of TPGS inhibited P-glycoprotein and LTG-loaded mPEG-PLA/TPGS mixed micelles had the potential to overcome refractory epilepsy.

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Intranasal delivery of insulin via the olfactory nerve pathway

Abstract: These results demonstrated that intranasal administration of labelled insulin targeted the CNS through the olfactory nerve pathway in mice.

Cited by 98 publications

References 22 publications

Intranasal Delivery of a Peptide with Antidepressant-Like Effect

Intranasal Delivery of a Peptide with Antidepressant-Like Effect

Novel Delivery Systems for Improving the Clinical Use of Peptides

mPEG-PLA/TPGS mixed micelles via intranasal administration improved the bioavailability of lamotrigine in the hippocampus

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