Quality by Design Approach for the Development of Cariprazine Hydrochloride Loaded Lipid-Based Formulation for Brain Delivery via Intranasal Route.

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Current drug metabolism Pub Date : 2024-10-03 DOI:10.2174/0113892002327148240924071717

Pallavi Chiprikar, Prakash Biradar, Vinayak Mastiholimath, Nisha Shirkoli

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Abstract

Background: Cariprazine (CPZ) is a third-generation antipsychotic medication that has been approved for treating schizophrenia. This study aimed to develop a cariprazine-loaded nanostructured lipid carrier (CPZ-NLCs) to prevent first-pass metabolism and improve bioavailability and site-specific delivery from the nose to the brain.

Method: The CPZ-NLCs were prepared using melt emulsification. The formulation was optimized using the Box-Behnken design (BBD); where the influence of independent variables on critical quality attributes, such as particle size and entrapment efficiency, was studied.

Result: The optimized batch (F6) had a particle size of 173.3 ± 0.6 nm and an entrapment efficiency of 96.1 ± 0.57%, respectively. The in vitro release showed >96% release of CPZ from NLC within 30 min. The optimized formulation's ex vivo studies revealed significantly increased CPZ permeability (>75%) in sheep nasal mucosa compared to the CPZ suspension (~26%). The ciliotoxicity study of the nasal mucosa revealed that the CPZ-NLC formulation did not affect the nasal epithelium. The intranasal administration of the formulation achieved 76.14±6.23 μg/ml concentration in the brain which was significantly higher than the oral CPZ suspension administration (30.46±7.24 μg/ml). The developed formulation was stable for 3 months.

Conclusion: The study concluded that the developed CPZ-NLC could significantly improve the bioavailability with quick delivery to the brain.

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通过设计提高质量的方法开发经鼻内途径脑部给药的盐酸卡哌嗪负载脂基制剂

背景介绍卡哌嗪（CPZ）是第三代抗精神病药物，已被批准用于治疗精神分裂症。本研究旨在开发一种Cariprazine负载的纳米结构脂质载体（CPZ-NLCs），以防止首过代谢，提高生物利用度和从鼻腔到大脑的特异性给药：方法：采用熔融乳化法制备CPZ-NLCs。方法：采用熔融乳化法制备 CPZ-NLCs，并采用盒-贝肯设计（BBD）对配方进行优化，研究自变量对粒度和包埋效率等关键质量属性的影响：结果：优化批次（F6）的粒度为 173.3 ± 0.6 nm，包埋效率为 96.1 ± 0.57%。体外释放试验表明，30 分钟内 CPZ 从 NLC 中的释放率大于 96%。优化制剂的体内外研究显示，与 CPZ 悬浮液（约 26%）相比，CPZ 在绵羊鼻粘膜中的渗透性明显增加（>75%）。鼻粘膜纤毛毒性研究表明，CPZ-NLC 制剂不会影响鼻腔上皮细胞。该制剂在脑内的浓度为 76.14±6.23 μg/ml，明显高于口服 CPZ 悬浮液的浓度（30.46±7.24 μg/ml）。所开发的制剂在 3 个月内稳定：该研究得出结论，所开发的 CPZ-NLC 能显著提高生物利用度，并能快速输送到大脑。

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来源期刊

Current drug metabolism 医学-生化与分子生物学

CiteScore

4.30

自引率

4.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism. More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.