凯托可纳-富马里克酸制药晶:从改善生物可用性的配方设计到生物相容性测试和抗真菌有效性评估
Ioana Baldea1, Remus Moldovan1, Andras-Laszlo Nagy2
1Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania.
International journal of molecular sciences
|January 8, 2025
概括
这项研究开发了一个Ketoconazole-Fumaric酸共晶体,增强抗真菌药物的生物可用性和有效性. 晶体在体外和体内表现有所改善,为难溶性药物提供了有前途的配方策略.
科学领域:
- 制药科学 制药科学
- 晶体工程 晶体工程
- 药物运输 药物运输 药物运输
背景情况:
- 像Ketoconazole这样的水溶性较差的药物存在配方挑战.
- 晶形成是一种提高溶解度和生物可用性的策略.
- 晶体工程提供了一条通往具有增强性质的稳定固体形式的途径.
研究的目的:
- 开发一种可控的共结晶过程,用于1:1的凯托可纳-富马里酸共结晶.
- 为了评估开发的共晶体的物理化学,体外和体内性能.
- 为了研究共晶与其目标酶的分子相互作用.
主要方法:
- 通过冷却控制的共结晶,使用元稳定区域宽度的确定.
- 使用粉末X射线衍射进行实验室扩展和表征.
- 在细胞系上进行体外生物测定,在老鼠体内药理动力学研究,以及分子对接模拟.
主要成果:
- 一个稳定的,单相 1:1 基托可纳-酸共晶体成功地产生了高产率 (高达 90%).
- 在实验室中,cocrystal对人类皮肤纤维细胞和肝癌细胞的疗效有所改善.
- 在体内研究表明,从老鼠的晶中提升了Ketoconazole的口服生物可用性,在小鼠中没有显著的肝毒性或皮肤敏感性.
结论:
- 结晶形成是一种有效的策略,可以提高Ketoconazole的生物可用性和疗效.
- 酸辅制剂改善了凯托可纳与点酶CYP51.1的结合亲和力.
- 这种协同晶体配方代表了一种有前途的方法来治疗由不溶性药物引起的真菌感染.
相关概念视频
Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
173
Orally administered drugs primarily enter the systemic circulation via passive diffusion through the intestinal membranes. The drug's absorption is influenced by drug stability in the gastrointestinal GI tract, membrane permeability, the surface area available for absorption, luminal drug concentration, and residence time in the lumen. Drug permeability can be enhanced by adjusting the lipophilicity, polarity, or molecular size of the drug, promoting its passive transport across intestinal...
173
Factors Influencing Drug Absorption: Pharmaceutical Parameters
114
Solid dosage forms such as tablets and capsules undergo rigorous manufacturing processes to ensure stability and effectiveness. Their dissolution and absorption properties are influenced significantly by the choice of excipients (inactive ingredients that serve various roles in the formulation), and the methodology applied during production. The manufacturing parameters, such as compression force and granulation techniques, significantly affect dissolution rates. Elevated compression forces...
114
Factors Influencing Drug Absorption: Physicochemical Parameters
214
The physicochemical characteristics of drugs play a crucial role in formulating stable and bioavailable drug products. The solubility of a drug, governed by the varying pH along the GI tract and its dissociation constant (pKa), is pivotal in determining its ionization state and absorption rate. Notably, weak acids and bases remain unionized and are absorbed more rapidly.
Enhanced drug absorption can be achieved by reducing particle sizes and increasing surface areas, thereby facilitating...
Enhanced drug absorption can be achieved by reducing particle sizes and increasing surface areas, thereby facilitating...
214
Factors Affecting Dissolution: Polymorphism, Amorphism and Pseudopolymorphism
281
Polymorphism refers to the existence of a drug substance in multiple crystalline forms, known as polymorphs. Recently, this term has been expanded to include solvates (forms containing a solvent), amorphous forms (non-crystalline forms), and desolvated solvates (forms from which the solvent has been removed).
Some polymorphic crystals possess lower aqueous solubility than their amorphous counterparts, leading to incomplete absorption. For instance, the oral suspension of Chloramphenicol, which...
Some polymorphic crystals possess lower aqueous solubility than their amorphous counterparts, leading to incomplete absorption. For instance, the oral suspension of Chloramphenicol, which...
281
Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH
1.0K
Drug absorption within the gastrointestinal (GI) tract is a complex process influenced by several critical factors, including the site pH, the drug's dissociation constant (pKa), and the drug's lipophilicity. The GI tract exhibits a pH gradient, with an acidic environment in the stomach and a more alkaline environment in the small intestine. This pH variation directly affects the ionization state of drugs.
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
1.0K
Preclinical Development: Overview
4.2K
Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the...
4.2K


