Clozapine-Encapsulated Binary Mixed Micelles in Thermosensitive Sol–Gels for Intranasal Administration

Abstract

(1) Background: Clozapine is the most effective antipsychotic. It is, however, associated with many adverse drug reactions. Nose-to-brain (N2B) delivery offers a promising approach. This study aims to develop clozapine-encapsulated thermosensitive sol–gels for N2B delivery. (2) Methods: Poloxamer 407 and hydroxypropyl methylcellulose were mixed and hydrated with water. Glycerin and carbopol solutions were added to the mixture and stirred overnight at 2–8 °C. Clozapine 0.1% w/w was stirred with polysorbate 20 (PS20) or polysorbate 80 (PS80) at RT (25 °C) before being added to the polymer solution. The final formulation was made to 10 g with water, stirred overnight at 2–8 °C and then adjusted to pH 5.5. (3) Results: Formulations F3 (3% PS20) and F4 (3% PS80) were selected for further evaluation, as their gelation temperatures were near 28 °C. The hydrodynamic particle diameter of clozapine was 18.7 ± 0.2 nm in F3 and 20.0 ± 0.4 nm in F4. The results show a crystallinity change in clozapine to amorphous. Drug release studies showed a 59.1 ± 3.0% (F3) and 53.1 ± 2.7% (F4) clozapine release after 72 h. Clozapine permeated after 8 h was 20.8 ± 3.0% (F3) and 17.8 ± 3.1% (F4). The drug deposition was higher with F4 (144.8 ± 1.4 µg/g) than F3 (110.7 ± 2.7 µg/g). Both sol–gels showed no phase separation after 3 months. (4) Conclusions: Binary PS80-P407 mixed micelles were more thermodynamically stable and rigid due to the higher synergism of both surfactants. However, binary mixed PS20-P407 micelles showed better drug permeation across the nasal mucosa tissue and may be a preferable carrier system for the intranasal administration of clozapine.

Response to Letter to the Editors From Prof D. Taylor

“…This is in part the reasoning behind the suggested use of intranasal clozapine. 5,6 Whether the presence of PEG 400 in a liquid formulation might affect matters is a further consideration, as of course is the wider topic of the widespread use of PEG-containing laxatives. We are not aware of any studies on these topics.…”

“…However, this would be expected to give improved bioavailability if anything because the first-pass effect would be bypassed. This is in part the reasoning behind the suggested use of intranasal clozapine 5,6 . Whether the presence of PEG 400 in a liquid formulation might affect matters is a further consideration, as of course is the wider topic of the widespread use of PEG-containing laxatives.…”

Self-Assembling Lecithin-Based Mixed Polymeric Micelles for Nose to Brain Delivery of Clozapine: In-vivo Assessment of Drug Efficacy via Radiobiological Evaluation

“…11 Recently many nasal CLZ nano preparations have been developed; nanosized binary mixed micelles intranasal gel was developed using poloxamer/polysorbate which improved both drug permeation rate through nasal sheep mucosa and system stability. 12 Patel et al formulated CLZ nanosuspension for nose to brain delivery which demonstrated higher CLZ concentration and faster absorption in the brain compared with CLZ suspension. 13 Another approach for intranasal CLZ appeared in the formulation of polymeric nanomixed micelles using Tetronic® 904/Synperonic® PE/F127, the optimized formula was radiolabeled by 99m Tc to ensure the direct delivery of CLZ from nose to brain and high bioavailability of the drug in the central nervous system (CNS).…”

LA67 Liposome-Loaded Thermo-Sensitive Hydrogel with Active Targeting for Efficient Treatment of Keloid via Peritumoral Injection

“…Local delivery of therapeutic agents through hydrogels can provide more sustained release and high doses of medicinal drugs directly at the site of tumor tissue, reducing dosing frequency, preventing prolonged blood circulation, reducing side effects on normal tissue, and improving therapeutic outcomes of patients. Poloxamer hydrogel is a classical thermo-sensitive hydrogel system that has enabled the injectable [ 18 ], transdermal [ 19 ], mucosal adhesion [ 20 ], nasal [ 21 ], and ophthalmic [ 22 ] delivery of a variety of drugs such as curcumin [ 23 ], quercetin [ 24 ], resveratrol [ 25 ], and tannic acid [ 26 ]. Thermo-sensitive hydrogels remain liquid at room temperature to improve their injectability and diffusivity.…”