Tao Ning, Yan Zihui, Wang Xin, Wang Yuhui, Ji Li, Qiu Lin, Cui Pengfei, Wang Jianhao
School of Pharmacy, Changzhou University, Changzhou, 213164, P. R. China.
Department of Otolaryngology, The Affiliated Changzhou No. 2 People'S Hospital of Nanjing Medical University, Changzhou, 213003, P. R. China.
AAPS J. 2025 Mar 14;27(2):63. doi: 10.1208/s12248-025-01046-5.
Approximately 40% of marketed drugs and 75% of invested drugs in the pharmaceutical field are poorly soluble hydrophobic drugs with minimal solubility in water which make them difficult to be absorbed by the body and significantly limiting their applications. Among chemotherapeutic agents, numerous antitumor drugs such as platinum compounds, camptothecin, paclitaxel and others are also restricted in processing and preparation due to solubility issues. Therefore, improving the solubility and enhancing the therapeutic efficacy of drugs have always been significant research topics in current pharmaceutics. Herein, we propose an amorphous solid dispersion system PRTA-DOX, involving the protein drug protamine sulphate and hydrophobic doxorubicin as the model hydrophobic drug. In previous studies, ASD (Amorphous Solid Dispersion) has been demonstrated to enhance the solubility of hydrophobic drugs and result in a storage-stable system. Protamine sulphate as a marketed drug is reliable in safety and conveniently obtained. Doxorubicin, an antitumor drug with a broad antitumor spectrum, is commonly used in the treatment of breast cancer. Typically, doxorubicin is prepared in the form of a hydrochloride salt to increase its solubility. However, the utilization of doxorubicin hydrochloride is reduced due to drug resistance issues in biological cells and it exhibits higher toxicity to the body. In this system, protamine sulphate which is rich in arginine guanidino hydrophobic planes physically mixes with doxorubicin which is a hydrophobic molecule with aromatic rings and they are connected through weak interactions: π-π conjugation. They constitute an amorphous solid dispersion system which increases the solubility of hydrophobic doxorubicin, enhances cellular uptake, mitigate some cellular drug resistance and thereby achieves the purpose of improving therapeutic efficacy.
在制药领域，约40%的上市药物和75%的在研药物是难溶性疏水药物，在水中的溶解度极低，这使得它们难以被人体吸收，并严重限制了其应用。在化疗药物中，许多抗肿瘤药物，如铂类化合物、喜树碱、紫杉醇等，也因溶解度问题在加工制备方面受到限制。因此，提高药物的溶解度并增强其治疗效果一直是当前药剂学中的重要研究课题。在此，我们提出一种无定形固体分散体系统PRTA-DOX，它包含蛋白质药物硫酸鱼精蛋白和作为模型疏水药物的疏水性阿霉素。在先前的研究中，已证明无定形固体分散体（ASD）可提高疏水药物的溶解度，并形成一种储存稳定的系统。硫酸鱼精蛋白作为一种上市药物，安全性可靠且易于获得。阿霉素是一种具有广泛抗肿瘤谱的抗肿瘤药物，常用于治疗乳腺癌。通常，阿霉素以盐酸盐的形式制备以增加其溶解度。然而，由于生物细胞中的耐药性问题，盐酸阿霉素的利用率降低，并且它对人体表现出更高的毒性。在该系统中，富含精氨酸胍基疏水平面的硫酸鱼精蛋白与具有芳香环的疏水分子阿霉素物理混合，它们通过弱相互作用：π-π共轭相连。它们构成了一个无定形固体分散体系统，该系统增加了疏水性阿霉素的溶解度，增强了细胞摄取，减轻了一些细胞耐药性，从而达到提高治疗效果的目的。
