Khopade Shivani, Agnihotri Tejas Girish, Baviskar Shraddha, Pavar Bhaskar, Gomte Shyam Sudhakar, Maskar Tejas, Sharma Nitish, Kumar Hemant, Behera Santosh Kumar, Jain Aakanchha
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India.
AAPS PharmSciTech. 2025 Jun 3;26(5):155. doi: 10.1208/s12249-025-03152-1.
Type-2 diabetes mellitus (T2DM) is a chronic metabolic condition with more than 95% of the cases worldwide and can cause complications like retinopathy, nephropathy, cardiovascular problems, etc. Currently, major treatment protocols available for T2DM include oral hypoglycemic agents, insulin, and GLP-1 receptor agonists. Due to the unique mechanism of action, human glucagon-like peptide-1 (HuGLP-1) has been a focus for management of T2DM. Oral HuGLP-1 delivery is hindered by its hydrophilic nature, preventing intestinal absorption. Additionally, the unfavorable gut environment and hepatic metabolism significantly restrict its bioavailability. Sublingual administration offers a potential solution bypassing these obstacles. This route avoids first-pass metabolism and prevents enzymatic exposure of peptide thus enhancing its absorption. The goal of the present work is to design HuGLP-1 loaded hydrogel embedded with nanoliposomes that would protect it from systemic enzymes and extend the duration it spends in the bloodstream, improving its pharmacological activity. The particle size, polydispersity index, and entrapment efficiency of optimized HuGLP-1-NLs were found to be 179.2 ± 1.65 nm, 0.167 ± 0.01, and 47 ± 2.18%, respectively. Post sublingual delivery of HuGLP-1 NLs loaded hydrogel in T2DM induced SD rats, it showed significantly less reversal of hypoglycemia than the standard hydrogel (p < 0.001). In summary, extended sublingual administration of this formulation could boost T2DM management by improving patient compliance. This formulation could also be used for managing diabetes-related obesity and needs to be validated by preclinical testing on a large number of animal models.
2型糖尿病（T2DM）是一种慢性代谢疾病，全球超过95%的病例都受其影响，并且会引发视网膜病变、肾病、心血管问题等并发症。目前，T2DM的主要治疗方案包括口服降糖药、胰岛素和GLP-1受体激动剂。由于独特的作用机制，人胰高血糖素样肽-1（HuGLP-1）一直是T2DM治疗的焦点。口服HuGLP-1因其亲水性而阻碍肠道吸收。此外，不利的肠道环境和肝脏代谢显著限制了其生物利用度。舌下给药提供了一种绕过这些障碍的潜在解决方案。这种给药途径避免了首过代谢，防止肽受到酶的作用，从而提高其吸收。本研究的目的是设计一种负载HuGLP-1的水凝胶，其中嵌入纳米脂质体，以保护其免受全身酶的影响，并延长其在血液中的停留时间，提高其药理活性。优化后的HuGLP-1-NLs的粒径、多分散指数和包封率分别为179.2±1.65 nm、0.167±0.01和47±2.18%。在T2DM诱导的SD大鼠中舌下给药HuGLP-1 NLs负载的水凝胶后，与标准水凝胶相比，其低血糖逆转明显较少（p<0.001）。总之，延长这种制剂的舌下给药可以通过提高患者依从性来促进T2DM的管理。这种制剂也可用于治疗与糖尿病相关的肥胖症，需要通过对大量动物模型进行临床前测试来验证。
