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<p>Clozapine is arguably the most effective antipsychotic in the treatment of schizophrenia. However, clozapine comes with a substantial and even sometimes lethal side-effect burden. The vast majority of side-effects are peripherally induced, requiring additional pharmacotherapy. An approach to diminishing such debilitating side-effects would be to minimize drug access to the periphery through consideration of other dosage forms and routes of administration. Although a number of intranasal formulations have been developed for clozapine, their antipsychotic potential and distribution across the brain remains unknown. We have developed a poloxamer-based clozapine-infused sol-gel engineered for sustained and controlled nose-to-brain drug delivery. Here in rats, we show that intranasal clozapine delivered via sol-gel achieves high concentrations in brain with minimal distribution to blood. Importantly, we also show that an industry-standard antipsychotic effect is achieved at a fraction (3.5%) of the dose required orally to achieve the same effect. These studies also show a greatly reduced potential of clozapine-infused sol-gel administered intranasally, to elevate blood glucose. The substantive reduction in dose achieved, through olfactory mucosa resident sol-gel restricts drug access to the periphery and therefore associated metabolic side-effects, making intranasal clozapine sol-gel an attractive option for further clinical investigation.</p>

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“Intranasal clozapine sol-gel formulation induces an antipsychotic effect at a fraction of a comparable oral therapeutic dose”

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • DW Eyles,
  • HS Parekh,
  • S. Alexander,
  • P. Pandey,
  • D. Siskind,
  • M. Ali,
  • M. Langguth,
  • R. Lohman,
  • X. Cui

摘要

Clozapine is arguably the most effective antipsychotic in the treatment of schizophrenia. However, clozapine comes with a substantial and even sometimes lethal side-effect burden. The vast majority of side-effects are peripherally induced, requiring additional pharmacotherapy. An approach to diminishing such debilitating side-effects would be to minimize drug access to the periphery through consideration of other dosage forms and routes of administration. Although a number of intranasal formulations have been developed for clozapine, their antipsychotic potential and distribution across the brain remains unknown. We have developed a poloxamer-based clozapine-infused sol-gel engineered for sustained and controlled nose-to-brain drug delivery. Here in rats, we show that intranasal clozapine delivered via sol-gel achieves high concentrations in brain with minimal distribution to blood. Importantly, we also show that an industry-standard antipsychotic effect is achieved at a fraction (3.5%) of the dose required orally to achieve the same effect. These studies also show a greatly reduced potential of clozapine-infused sol-gel administered intranasally, to elevate blood glucose. The substantive reduction in dose achieved, through olfactory mucosa resident sol-gel restricts drug access to the periphery and therefore associated metabolic side-effects, making intranasal clozapine sol-gel an attractive option for further clinical investigation.