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Title:
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Nose-to-Brain Delivery of Diazepam from an Intranasal Aqua-Triggered In-Situ (ATIS) Gelling Microemulsion: Monitoring Brain Uptake by Microdialysis.
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Authors:
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Bachhav SS; Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P. Marg, Matunga (E), Mumbai, Maharashtra, 400019, India.
Dighe V; National Center for Preclinical Reproductive and Genetic Toxicology, National Institute for Research in Reproductive Health (NIRRH), ICMR, J. M. Street, Parel, Mumbai, 400012, India.
Mali N; Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India.
Gogtay NJ; Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India.
Thatte UM; Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India.
Devarajan PV; Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P. Marg, Matunga (E), Mumbai, Maharashtra, 400019, India. .
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Source:
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European journal of drug metabolism and pharmacokinetics [Eur J Drug Metab Pharmacokinet] 2020 Dec; Vol. 45 (6), pp. 785-799.
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Publication Type:
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Journal Article
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Language:
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English
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Imprint Name(s):
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Publication: <2010- >: Paris : Springer France
Original Publication: Paris, Edifor.
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MeSH Terms:
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Anticonvulsants/*administration & dosage
Anticonvulsants/*pharmacokinetics
Brain/*metabolism
Diazepam/*administration & dosage
Diazepam/*pharmacokinetics
Adhesiveness ; Administration, Intranasal ; Animals ; Anticonvulsants/adverse effects ; Diazepam/adverse effects ; Drug Compounding ; Drug Delivery Systems ; Emulsions ; Extracellular Fluid/metabolism ; Gels ; Irritants ; Male ; Microdialysis ; Nasal Mucosa ; Rats
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Substance Nomenclature:
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0 (Anticonvulsants)
0 (Emulsions)
0 (Gels)
0 (Irritants)
Q3JTX2Q7TU (Diazepam)
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Entry Date(s):
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Date Created: 20200820 Date Completed: 20201127 Latest Revision: 20201127
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Update Code:
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20240105
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DOI:
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10.1007/s13318-020-00641-5
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PMID:
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32813265
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Background and Objectives: An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling microemulsion which gels instantaneously on contact with minute quantities of water to form a mucoadhesive gel. The objective of the study was to develop ATIS diazepam (ATIS-diazepam) as an alternative to the injection for epileptic emergencies and evaluate its brain uptake and nose-to-brain targeting efficiency in rats.
Methods: ATIS-diazepam (1 mg/100 µL) was prepared and characterized for in vitro formulation characteristics. An LC-MS/MS method was developed and validated for the bioanalysis of diazepam. In vivo studies for pharmacokinetics, brain uptake and nasal irritation of intranasal ATIS-diazepam were conducted in rats. Brain uptake was investigated with brain microdialysis, a highly sensitive technique enabling quantification of free drug, which correlates to efficacy.
Results: ATIS-diazepam exhibited globule size < 200 nm, low viscosity, negative zeta potential and good stability. A significant increase in mucoadhesion was exhibited by ATIS-diazepam following the addition of a small quantity of water. ATIS-diazepam showed burst release in pH 6.4 with 50% diazepam release in ~ 10 min, which was sustained over 1 h. The absolute bioavailability was ~ 50% with both intranasal free-diazepam and ATIS-diazepam. Intranasal administration of ATIS-diazepam revealed immediate absorption with rapid and high brain extracellular fluid concentration compared to intravenous free-diazepam solution. The estimated direct transport potential and drug targeting efficiency of intranasal ATIS-diazepam was significantly higher (2-fold) than intranasal free-diazepam solution, which was attributed to the mucoadhesive and microemulsion properties of ATIS-diazepam. The nasal irritation study revealed the safety of ATIS-diazepam compared to free-diazepam solution.
Conclusion: Intranasal ATIS-diazepam showed promise of higher direct nose-to-brain targeting, better safety and hence has an immense implication in the treatment of epileptic emergencies.
