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Purpose <p>This study aimed to develop a thermoreversible in situ nasal gel of lithium citrate to achieve sustained release and improve nose-to-brain delivery potential for the treatment of bipolar disorder.</p> Method <p>Nine formulations of in <i>situ</i> gel of Tri-lithium citrate tetrahydrate were prepared by cold method using polymers carbopol 940 and poloxamer 407 based on 3<sup>2</sup> factorial design. The gel was characterized using gelation temperature and gel melting temperature, spread ability, mucoadhesion, in vitro permeability, in vitro diffusion, ex vivo permeability study. Histopathological and pharmacodynamic studies were performed only on the optimized formulation to assess nasal mucosal safety and behavioral efficacy in a ketamine-induced mania model.</p> Result <p>The optimized formulation exhibited a gelation temperature of 32–34&#xa0;°C, mucoadhesive strength of 5825–7074 dyne/cm², and gel strength of 5.3–6.4&#xa0;g. In vitro studies demonstrated 98–100% drug release within 7–8&#xa0;h, while ex vivo permeation through sheep nasal mucosa showed 90% release in 8&#xa0;h, following a Korsmeyer–Peppas model (R² = 0.9988; <i>n</i> = 0.67). Histopathological studies indicated that there was no indication of haemorrhage, necrosis, or ulceration in the nasal mucosa, whether it was treated with lithium citrate or left untreated. The trajectory data obtained by radial arm maze clearly showed higher movement of animals under study treated with controlled formulation (pseudo formulation without drug), entering almost every arm of the apparatus.</p> Conclusion <p>The optimized lithium citrate nasal gel exhibits favorable thermogelling, mucoadhesive, and sustained-release characteristics, along with acceptable mucosal safety. While pharmacodynamic outcomes suggest potential for enhanced nose-to-brain delivery, definitive evidence of brain targeting will require further pharmacokinetic quantification of lithium in brain tissues.</p>

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Targeted Lithium Delivery Via Nasal Gel: Improving Efficacy and Safety in Bipolar Disorder Therapy

  • 期刊论文

  • 发表日期：

    2026年1月16日

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  • Dhaval Bhavsar,
  • Atul Phatak,
  • Ujwala Desai

摘要

Purpose

This study aimed to develop a thermoreversible in situ nasal gel of lithium citrate to achieve sustained release and improve nose-to-brain delivery potential for the treatment of bipolar disorder.

Method

Nine formulations of in situ gel of Tri-lithium citrate tetrahydrate were prepared by cold method using polymers carbopol 940 and poloxamer 407 based on 32 factorial design. The gel was characterized using gelation temperature and gel melting temperature, spread ability, mucoadhesion, in vitro permeability, in vitro diffusion, ex vivo permeability study. Histopathological and pharmacodynamic studies were performed only on the optimized formulation to assess nasal mucosal safety and behavioral efficacy in a ketamine-induced mania model.

Result

The optimized formulation exhibited a gelation temperature of 32–34 °C, mucoadhesive strength of 5825–7074 dyne/cm², and gel strength of 5.3–6.4 g. In vitro studies demonstrated 98–100% drug release within 7–8 h, while ex vivo permeation through sheep nasal mucosa showed 90% release in 8 h, following a Korsmeyer–Peppas model (R² = 0.9988; n = 0.67). Histopathological studies indicated that there was no indication of haemorrhage, necrosis, or ulceration in the nasal mucosa, whether it was treated with lithium citrate or left untreated. The trajectory data obtained by radial arm maze clearly showed higher movement of animals under study treated with controlled formulation (pseudo formulation without drug), entering almost every arm of the apparatus.

Conclusion

The optimized lithium citrate nasal gel exhibits favorable thermogelling, mucoadhesive, and sustained-release characteristics, along with acceptable mucosal safety. While pharmacodynamic outcomes suggest potential for enhanced nose-to-brain delivery, definitive evidence of brain targeting will require further pharmacokinetic quantification of lithium in brain tissues.