School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
Department of Pharmaceutics, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia.
Eur J Pharm Biopharm. 2021 Jan;158:294-312. doi: 10.1016/j.ejpb.2020.12.003. Epub 2020 Dec 9.
Current therapy of tuberculosis (TB) has several limitations, such as risk of liver injury and intestinal dysbiosis due to frequent oral administration of antibiotics. Transdermal administration could be used to improve antibiotic delivery for treatment of Mycobacterium tuberculosis infection. Therefore, we developed a novel approach, using hydrogel-forming microneedle (MN) arrays to transdermally deliver TB drugs, namely rifampicin, isoniazid, pyrazinamide and ethambutol, which have different physicochemical properties. These drugs were individually prepared into three types of drug reservoirs, including lyophilised tablets, directly compressed tablets and poly(ethylene glycol) tablets. Formulations of each drug reservoir type were optimised to achieve a rapidly dissolving tablet, and further integrated with hydrogel-forming MN arrays for in vitro permeation studies. Three types of hydrogel formulation were manufactured using different type of polymers and crosslinking processes. These MN arrays were then evaluated in terms of swelling ability, morphology and physical properties. Results of solute diffusion studies showed that drug permeation across the swollen hydrogel membrane was affected mostly by physiochemical properties and functional groups of each drug. In the in vitro studies, the amount of permeated drug through the hydrogel-forming MN arrays across the dermatomed neonatal porcine skin was affected by the drug solubility and reservoir design. The highest permeation of rifampicin (3.64 mg) and ethambutol (46.99 mg) were achieved using MN arrays combined with the poly(ethylene glycol) tablets and directly compressed tablet, respectively. For isoniazid and pyrazinamide, the highest drug permeation was attained using lyophilised reservoir with the amount of drug delivered approximately 58.45 mg and 20.08 mg, respectively. These equate to transdermal delivery of approximately 75% (rifampicin), 79% (isoniazid), 20% (pyrazinamide) and 47% (ethambutol) of the drugs loaded into the reservoirs on average. Importantly, the results of this work have demonstrated the versatility of hydrogel formulations to deliver a TB drug regime using MN arrays. Accordingly, this is a promising approach to deliver high dose of TB drugs.
目前的结核病（TB）治疗存在诸多局限，例如频繁口服抗生素可能导致肝损伤和肠道菌群失调。经皮给药可以改善抗生素的递送，从而治疗分枝杆菌感染。因此，我们开发了一种新方法，使用水凝胶形成的微针（MN）阵列经皮递药，治疗分枝杆菌感染。所用药物包括利福平、异烟肼、吡嗪酰胺和乙胺丁醇，它们具有不同的理化性质。这些药物分别制成三种药物储库，包括冻干片、直接压片和聚乙二醇（PEG）片。我们优化了每种药物储库类型的配方，以实现快速溶解的片剂，并将其与水凝胶形成的 MN 阵列进一步整合，用于体外渗透研究。使用不同类型的聚合物和交联工艺制造了三种类型的水凝胶制剂。然后评估了这些 MN 阵列的溶胀能力、形态和物理性质。溶质扩散研究结果表明，药物在肿胀水凝胶膜中的渗透主要受药物的理化性质和官能团的影响。在体外研究中，药物通过水凝胶形成 MN 阵列渗透到去皮新生猪皮中的量受药物溶解度和储库设计的影响。使用 MN 阵列与聚乙二醇片和直接压片相结合，利福平（3.64mg）和乙胺丁醇（46.99mg）的渗透量最高。对于异烟肼和吡嗪酰胺，使用冻干储库的药物渗透量最高，分别约为 58.45mg 和 20.08mg。这相当于经皮递送储库中加载药物的约 75%（利福平）、79%（异烟肼）、20%（吡嗪酰胺）和 47%（乙胺丁醇）。重要的是，这项工作的结果表明了水凝胶制剂的多功能性，可以使用 MN 阵列递送结核病药物方案。因此，这是一种很有前途的高剂量结核病药物递送方法。
