Response Surface Methodology Assisted Development and Optimization of DB213 In Situ Thermosensitive Gel for Intranasal Delivery to the Central Nervous System
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DB213 is an HIV-1 replication inhibitor targeting the Central Nervous System (CNS) in treatment of HIV-associated neurocognitive disorders. The objective of this study is to use the response surface methodology to develop and optimize an in situ thermosensitive gel of DB213 for its intranasal delivery.

The experiments were designed with the help of Design Expert® Software (Version 9.0). A 3-level factorial design was chosen to evaluate the effects of three independent variables [amount of Pluronic F-127 (X1), amount of Pluronic F-68 (X2) and amount of Chitosan (X3)] on the following responses: gelation temperature (T sol-gel), consistency index, in vitro release at 1 h, in vitro release at 6 h, in vivo nasal mucociliary clearance time.
Both of the final optimized in situ thermosensitive gel formulation and water solution of DB213 were intranasally administered (IN) at a dose of 1 mg/kg in Sprague-Dawley rats. To compare the in vivo CNS uptake of DB213 from different formulations, DB213 water solution and in situ gel were administered via IN in SD rats with a catheter fixed to the cisterna magna (n=3 per group) for cerebrospinal fluid (CSF) samples collection at 5, 8, 10, 15, 20, 30, 45, 60, 90, 120 min post-dosing. To estimate the relative bioavailability of DB213, another batch of SD rats were used to collect plasma samples at 5, 10, 15, 20, 30, 45, 60, 90, 120, 240, 360 and 540 min post-dosing (n=3 per group). Samples collected from in vitro release study, plasma and CSF were analyzed by an established LC/MS/MS method.

A total of 17 runs were generated by the Design Expert® Software using Box-Behnken design. Mathematical equations and response surface plots were generated to analyze the effects of independent variables on the response. In specific, both variable X1 (amount of Pluronic F-127) and X2 (amount of Pluronic F-68) demonstrated significant influence on T sol-gel, in vitro release and mucociliary clearance time. The increase of X1 would lead to the increase of T sol-gel , decrease in the total amount of drug released in vitro and mucociliary clearance time. On the contrary, the increase of X2 would cause the decrease of T sol-gel and increase of total amount of drug released in vitro and mucociliary clearance time. In addition, variable X2 and X3 (amount of chitosan) had significant influence on consistency index, resulting in the increase of consistency index value at both solution form and gel form with the increase of variable X2 and X3. The final optimized formulation, consisting of 25 % Pluronic F-127 (w/v%), 2% Pluroinc F-68(w/v%), and 0.5 % Chitosan (w/v%), had a T sol-gel of 32 ±1℃ (n=3) with 82 ± 1% of the drug released after 6 h in vitro (n=3) and a mucociliary clearance time of 31±4 min (n=3) to the nasopalatine.
AUC0→120 min, CSF obtained from the optimized in situ gel was 2.23 times higher than that from DB213 water solution, indicating significant improvement in the brain targeting delivery of DB213 by the optimized in situ gel formulation. Based on the area under the curve of plasma concentration-time of DB213 from 0 to 540 min from water solution (17072.43 ± 10022.71 ng•min/ml) and the in situ gel (20915.76 ± 13817.16 ng•min/ml), the relative bioavailability of DB213 optimized in situ gel formulation was calculated to be 122.51%.
An in situ thermosensitive gel of DB213 for intranasal delivery targeting the CNS system was developed and optimized by a multifactorial response surface methodology. The optimized in situ gel formulation demonstrated more than 2 times increase in the CNS uptake and an 1.2 times greater systemic bioavailability of DB213 than its water solution.

This work was generously supported by the Lui Che Woo Institute of Innovative Medicine BRAIN Initiative, Faculty of Medicine, The Chinese University of Hong Kong (Project Number 8303404).
All Author(s) ListQianwen Wang, Shaohong Peng, Qian Zhang, Chun-Ho Wong, H.Y. Edwin Chan, Zhong Zuo
Name of ConferenceAAPS Annual Meeting and Exposition 2016
Start Date of Conference13/11/2016
End Date of Conference17/11/2016
Place of ConferenceDenver
Country/Region of ConferenceUnited States of America
LanguagesEnglish-United States

Last updated on 2018-18-01 at 11:20