Almutairy Bjad K, Khafagy El-Sayed, Aldawsari Mohammed F, Alshetaili Abdullah, Alotaibi Hadil Faris, Abu Lila Amr Selim
Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi Arabia.
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
ACS Omega. 2024 Apr 20;9(17):19536-19547. doi: 10.1021/acsomega.4c01133. eCollection 2024 Apr 30.
Pediatric pulmonary hypertension is a serious syndrome with significant morbidity and mortality. Sildenafil is widely used off-label in pediatric patients with pulmonary arterial hypertension. In this study, bile salt-stabilized nanovesicles (bilosomes) were screened for their efficacy to enhance the transdermal delivery of the phosphodiesterase type 5 inhibitor, sildenafil citrate, in an attempt to augment its therapeutic efficacy in pediatric pulmonary hypertension. A response surface methodology was implemented for fabricating and optimizing a bilosomal formulation of sildenafil (SDF-BS). The optimized SDF-BS formulation was characterized in terms of its entrapment efficiency (EE), zeta potential, vesicle size, and in vitro release profile. The optimized formula was then loaded onto hydroxypropyl methyl cellulose (HPMC) hydrogel and assessed for skin permeation, in vivo pharmacokinetics, and pharmacodynamic studies. The optimized SDF-BS showed the following characteristic features; EE of 88.7 ± 1.1%, vesicle size of 185.0 + 9.2 nm, zeta potential of -20.4 ± 1.1 mV, and efficiently sustained SDF release for 12 h. Skin permeation study revealed a remarkable improvement in SDF penetration from bilosomal gel compared to plain SDF gel. In addition, pharmacokinetic results revealed that encapsulating SDF within bilosomal vesicles significantly enhanced its systemic bioavailability (∼3 folds), compared to SDF oral suspension. In addition, pharmacodynamic investigation revealed that, compared to plain SDF gel or oral drug suspension, SDF-BS gel applied topically triggered a significant elevation ( < 0.05) in cGMP serum levels, underscoring the superior therapeutic efficacy of SDF-BS gel. Conclusively, bilosomes can be viewed as a promising nanocarrier for transdermal delivery of SDF that would grant higher therapeutic efficiency while alleviating the limitations encountered with SDF oral administration.
小儿肺动脉高压是一种具有显著发病率和死亡率的严重综合征。西地那非在患有肺动脉高压的儿科患者中被广泛超说明书使用。在本研究中，筛选了胆盐稳定的纳米囊泡（双分子层脂质体）增强5型磷酸二酯酶抑制剂枸橼酸西地那非经皮递送的效果，以试图提高其在小儿肺动脉高压中的治疗效果。采用响应面法制备并优化西地那非的双分子层脂质体制剂（SDF-BS）。对优化后的SDF-BS制剂进行包封率（EE）、ζ电位、囊泡大小和体外释放曲线等方面的表征。然后将优化后的制剂负载到羟丙基甲基纤维素（HPMC）水凝胶上，并进行皮肤渗透、体内药代动力学和药效学研究。优化后的SDF-BS具有以下特征：包封率为88.7±1.1%，囊泡大小为185.0 + 9.2 nm，ζ电位为-20.4±1.1 mV，并且能有效持续释放西地那非12小时。皮肤渗透研究表明，与普通西地那非凝胶相比，双分子层脂质体凝胶中西地那非的渗透有显著改善。此外，药代动力学结果显示，与西地那非口服混悬液相比，将西地那非包裹在双分子层脂质体囊泡中可显著提高其全身生物利用度（约3倍）。另外，药效学研究表明，与普通西地那非凝胶或口服药物混悬液相比，局部应用SDF-BS凝胶可使血清cGMP水平显著升高（<0.05），突出了SDF-BS凝胶的卓越治疗效果。总之，双分子层脂质体可被视为一种有前景的用于西地那非经皮递送的纳米载体，它将在提高治疗效率的同时减轻西地那非口服给药所遇到的局限性。
