Improved Brain Uptake of Therapeutic Peptide QBP1 via Intranasal Administration of its In-situ Gel Formulation in Rats
Refereed conference paper presented and published in conference proceedings

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QBP1 (amino acids sequence: SNWKWWPGIFD) has been identified as a therapeutic peptide for the polyglutamine neurodegenerative diseases, but its brain uptake and pharmacokinetics profile is not known yet. The current study aims to 1) compare the brain uptake and pharmacokinetics profile of QBP1 after intravenous administration versus that from intranasal administration, and 2) develop an in-situ gel formulation to enhance the brain uptake for intranasally delivered QBP1.
To compare the brain uptake and pharmacokinetics profiles after intravenous and intranasal administrations of 12.5 mg/kg QBP1 water solution in rats, plasma samples were collected at 2, 5, 10, 15, 20 and 30 min post-dosing and brain were also collected at 30 min post-dosing. In addition, to evaluate its stability in biological matrix, QBP1 at 2 μg/mL were incubated in rat plasma and brain homogenate at 37 °C for 60 min followed by monitoring of its remaining by LC/MS/MS analyses. To enhance brain uptake and retention of the intranasally administered QBP1, an in-situ gel formulation of QBP1 was developed and optimized by MODDE Pro (MKS Instruments AB, Umea, Sweden) followed by its in vivo brain uptake evaluation in comparison to that of water solution and water solution with 0.5% chitosan, Briefly, after intranasal administration of 12.5 mg/kg QBP1 in different formulations (water solution, water solution with 0.5% chitosan, and in-situ gel), rats were sacrificed at 15 min and 30 min and the plasma and brain samples was collected. All the collected plasma and brain samples were extracted by protein precipitation using 2-fold volume of acetonitrile and subjected to LC/MS/MS analyses for content of QBP1.
After intravenous administration, QBP1 was quickly eliminated in plasma with a short t1/2 of 11.3 ± 4.6 min and area under the plasma concentration vs time curve (AUC0-30min) was 13.2 ± 5.0 μg×min/mL. Brain uptake of QBP1 after intravenous administration was very limited, and only 5.7 ± 2.7 ng/g of QBP1 was detected in the brain at 30 min post-dosing. In order to increase the brain uptake of QBP1, intranasal delivery was exploited as a non-invasive method that might provide more efficient brain uptake. After intranasal administration of QBP1, decreased systemic exposure was observed with low bioavailability (0.13%), and the brain uptake level was detected at 12.2 ± 8.6 ng/g at 30 min post-dosing, similar to that of the intravenous route. The in-vitro stability test showed that under physiological condition (37 °C, pH 7.4), QBP1 was not stable in plasma and brain with only 19.3 % and 0.6 % of QBP1 remained in rat plasma and in brain homogenate after 60-min incubation at 2 μg/mL, respectively.
To further improve the brain uptake of the QBP1, in-situ gel system was applied for intranasal delivery of QBP1. The sol-gel transition temperature of the in-situ gel was optimized to 28 °C, close to the temperature in the nasal cavity. The optimized in-situ gel formulation via MODDE Pro consisted 36% Pluronic F-127, 1.5% Pluronic F-68, 12.5 % QBP1, and 0.5% chitosan. Although the in-situ gel of QBP1 did not significantly increase the plasma concentrations of QBP1, it achieved 6-fold and 10-fold higher brain concentration at 15 min and 30 min respectively compared to that of the water solution group. Moreover, compared to those treated with 0.5% chitosan and QBP1 in water solution, in-situ gel of QBP1 demonstrated significantly higher brain concentration at 15 min post-dosing, suggesting the in-situ gel formulation with 0.5% chitosan achieved the best brain uptake of QBP1.
The pharmacokinetic and brain uptake study of QBP1 after intravenous administration demonstrated its quick elimination, low systemic exposure, and low brain uptake, which might partially attribute to its extensive degradation in plasma and brain. Intranasal administration using the in-situ gel formulation could be an effective intranasal formulation for the brain-targeting delivery of the therapeutic peptide QBP1.
All Author(s) ListMengbi Yang, Qianwen Wang, Ho Yin Edwin Chan, Zhong Zuo
Name of Conference2017 AAPS (American Association of Pharmaceutical Sciences) Annual Meeting
Start Date of Conference12/11/2017
End Date of Conference15/11/2017
Place of ConferenceSan Diego
Country/Region of ConferenceUnited States of America
LanguagesEnglish-United States

Last updated on 2018-02-10 at 12:24