Injectable PLGA-based In Situ Forming Subconjunctival Implant for Sustained Ocular Delivery of Ketotifen Fumarate: Formulation, Drug Release, and Biocompatibility Studies.

IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Nur Mita, Xuejia Kang, Pengyu Chen, Oladiran Fasina, Shenise Howard, Anna-Catherine Bowden, Richard J McMullen, Amol Suryawanshi, R Jayachandra Babu
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Abstract

Ketotifen fumarate is very effective in treating ocular conditions like allergic conjunctivitis. However, its clinical effectiveness is limited by rapid washout, frequent dosing, and poor bioavailability. This study developed a ketotifen fumarate-loaded in situ forming subconjunctival injectable implant (ISFSI) for use in large animal species such as horses and alpacas. ISFSIs were formulated by dispersing ketotifen fumarate in polylactide-co-glycolide (PLGA) combined with different release retarders (Kolliphor® RH 40, Labrasol®, and Maisine®), then characterized for visual appearance, viscosity, solidification time, and in vitro drug release. The changes in the release medium pH and the solidified ISFSI wet weight were monitored for up to 4 weeks. The selected ISFSI, KFM5, was further characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and rheological behavior. The injectability of KFM5 was predicted using the power law for five different syringe and needle dimensions. Cytotoxicity was tested using the Alamar Blue assay and Calcein AM/PI staining on a human corneal epithelial cell line (HCE-T). Results showed that all ISFSI formulations were clear yellowish, with drug recoveries exceeding 95%, varying viscosities, and solidified upon contact with the release medium. KFM5 exhibited a triphasic drug release profile with the lowest burst release (4.91 ± 0.55%) and followed Higuchi kinetics. SEM imaging revealed a "hollow and sponge-like" structure, while DSC confirmed the crystallinity and thermal transitions of ketotifen fumarate within the solidified implant. Rheological analysis indicated shear-thinning fluid behavior with acceptable injection forces. Cytotoxicity assays confirmed > 90% cell viability, confirming biocompatibility in the ocular tissue.

可注射的基于plga的原位形成结膜下植入物用于富马酸酮替芬的持续眼部递送:配方、药物释放和生物相容性研究。
富马酸酮替芬在治疗过敏性结膜炎等眼部疾病方面非常有效。然而,其临床效果受到快速冲洗、频繁给药和生物利用度差的限制。本研究开发了一种负载富马酸酮替芬的原位形成结膜下注射植入物(ISFSI),用于马和羊驼等大型动物。将富马酸酮替芬分散于聚乳酸-共聚物(PLGA)中,并与不同的缓释剂(Kolliphor®RH 40、Labrasol®和Maisine®)联合配制isfsi,然后对其视觉外观、粘度、凝固时间和体外药物释放进行表征。监测释放介质pH和凝固后ISFSI湿重的变化长达4周。所选择的ISFSI, KFM5,通过扫描电镜(SEM),差示扫描量热法(DSC)和流变学行为进一步表征。KFM5的可注射性采用幂律对五种不同的注射器和针头尺寸进行预测。采用Alamar Blue法和钙黄蛋白AM/PI染色法检测人角膜上皮细胞系(HCE-T)的细胞毒性。结果表明:所有制剂均呈淡黄色,药物回收率超过95%,粘度变化,与释放介质接触后固化。KFM5具有三相释药特性,释药量最小(4.91±0.55%),符合Higuchi动力学。扫描电镜成像显示“中空海绵状”结构,而DSC证实了固化种植体内富马酸酮替芬的结晶度和热转变。流变学分析表明,在可接受的注入力下,流体表现为剪切减薄。细胞毒性试验证实> 90%的细胞活力,证实了眼组织的生物相容性。
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来源期刊
AAPS PharmSciTech
AAPS PharmSciTech 医学-药学
CiteScore
6.80
自引率
3.00%
发文量
264
审稿时长
2.4 months
期刊介绍: AAPS PharmSciTech is a peer-reviewed, online-only journal committed to serving those pharmaceutical scientists and engineers interested in the research, development, and evaluation of pharmaceutical dosage forms and delivery systems, including drugs derived from biotechnology and the manufacturing science pertaining to the commercialization of such dosage forms. Because of its electronic nature, AAPS PharmSciTech aspires to utilize evolving electronic technology to enable faster and diverse mechanisms of information delivery to its readership. Submission of uninvited expert reviews and research articles are welcomed.
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