克服无形固体分散中的药物杂质挑战,合理开发生物相关的溶解-透方法
T Huzjak1, O Jakasanovski2, K Berginc2
1Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana 1000, Slovenia; Product Development, Lek Pharmaceuticals d.d., Verovškova 57, Ljubljana 1526, Slovenia.
概括
这项研究优化了无形固体分散的热挤出 (HME) 参数,建立了与患者生物可用性相关的药物释放的体外-体内相关性.
科学领域:
- 制药科学 制药科学
- 药物输送系统 药物输送系统
- 材料科学 材料科学 材料科学
背景情况:
- 热挤出 (HME) 对于创建无形固体分散 (ASD) 至关重要,以增强难溶药物的生物可用性 (BCS II/IV类).
- 优化HME过程参数 (温度,料速率,螺丝转速) 对于实现药物无形化和所需的释放形状至关重要.
- 药物的特性,包括其初始形式 (无水与水合物) 和杂质特征,显著影响ASD的表现.
研究的目的:
- 评估HME过程参数,药物形式和供应商对ASD生物相关药物释放的影响.
- 开发和验证用于评估ASD性能的体外溶解和溶解-透方法.
- 建立一个体外-体内相关性 (IVIVC),将体外超和沉行为与体内生物可用性联系起来.
主要方法:
- 使用BCS II/IV模型药物和PVP/VA聚合物通过HME制备ASD.
- 开发使用MicroFluxTM装置的小容量溶解方法和并排溶解-透方法.
- 在体内对狗进行研究和在患者进行临床研究,以确认生物相关性并确定IVIVC.
主要成果:
- 该研究确定了体外超和/沉和体内结果之间的关系.
- 开发的 in vitro 方法显示出高的分辨力和生物相关性.
- 证实了IVIVC,验证了体外模型对患者生物可用性的预测能力.
结论:
- 优化HME处理对于持续的ASD质量和性能至关重要.
- 试验室内测试必须考虑超和和体物种的形成,以准确预测ASD行为.
- 已建立的IVIVC支持使用这些体外方法用于仿制药产品开发和质量保证.
相关概念视频
01:27Factors Influencing Drug Absorption: Drug Dissolution
521
The pharmacokinetic journey of drugs from solid oral dosage forms into systemic circulation is multifaceted. It begins with disintegration, a prerequisite ensuring a solid dosage form's subdivision into minute particles. Dissolution occurs next as these granulated entities solubilize in gastrointestinal fluids. This solubilization is crucial for the succeeding stage, permeation, which describes the traversal of the drug across the intestinal membrane and its subsequent entry into the blood...
521
01:20Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
208
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...
208
01:23Factors Affecting Dissolution: Particle Size and Effective Surface Area
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Dissolution kinetics, an essential aspect of oral drug delivery, is significantly influenced by the drug's particle size. According to the Noyes-Whitney dissolution model, the dissolution rate correlates directly with the drug's surface area. The larger the surface area, the higher the drug's solubility in water, leading to a faster drug dissolution rate. Reducing particle size increases the effective surface area, enhancing the dissolution process. Micronization and nanosizing are...
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01:28Factors Influencing Drug Absorption: Pharmaceutical Parameters
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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...
134
01:21Factors Affecting Dissolution: Polymorphism, Amorphism and Pseudopolymorphism
311
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...
311
01:15Theories of Dissolution: Diffusion Layer Model
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Dissolution, the process by which drug particles dissolve in a solvent, is explained by the diffusion layer model, a theoretical framework that simulates the absorption of oral drugs and allows us to analyze experimental data.
This process starts with a thin layer, saturated with the drug, forming at the interface between the solid and liquid. The solute then diffuses from this layer into the main solution. The Noyes-Whitney equation suggests that the rate of dissolution relies on the diffusion...
This process starts with a thin layer, saturated with the drug, forming at the interface between the solid and liquid. The solute then diffuses from this layer into the main solution. The Noyes-Whitney equation suggests that the rate of dissolution relies on the diffusion...
773