Evaluation of a novel absorption promoter - criticalsorb for the nasal delivery of drugs.

用于鼻腔给药的新型吸收促进剂 Criticalsorb 的评估。

• 批准号: BB/H016538/1
• 金额: $ 9.59万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Training Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH016538%2F1
• 关键词: Evaluation; novel; absorption; promoter; criticalsorb

The project will evaluate a novel absorption promoter system - CriticalSorb for the nasal delivery of drugs. The project will focus on four key areas: evaluation of the physico-chemical properties of the formulations and identify essential characteristics, investigate its mechanisms of action using appropriate cell culture models, identify synergistic effects with other known absorption promoters and the final part of the project will look at developing a robust in vitro cell culture model in order to replace animal models when evaluating the nasal absorption of drugs. Background The nasal route of delivery can be exploited for the systemic delivery of drugs such as small molecular weight polar drug, peptides and proteins that are not easily administered via other routes than by injection. Despite the large surface area of the nasal cavity and extensive blood supply absorption of polar molecules, peptides and proteins is low but can be greatly improved if administered in conjunction with an absorption promoting agent. The enhancer systems work by a number of mechanisms however; animal studies have shown that most often there is a direct correlation between the absorption enhancing effect obtained and the damage caused to the nasal membrane. It is therefore important to discover and evaluate new absorption promoter systems. Critical Pharmaceuticals is a small specialty pharmaceutical company and have developed a nasal drug delivery platform based on an absorption promoter called CriticalSorb which has shown to be non-toxic to the nasal membrane in repeat dosing studies Task1. Physico-chemical characterisation of the formulations The first stage of the project will evaluate at the physico-chemical characterization of formulations containing CriticalSorb and a model drug in the form of a peptides or a protein. The CriticalSorb aqueous solutions form micelles and experiments will be carried out to determine the position of drug within such the micellar solutions, as well as the micellar properties. It will apply a combination of routine and state of the art 'nanotechnology' analytical techniques including: particle size and distribution, dye incorporation, morphology (cryo-TEM). Task 2. Evaluation of CriticalSorb mechanism of action The second stage of the project will study and describe the mechanism of action of the absorption enhancing effect of CriticalSorb and its principal components. This will focus on cell culture monolayers of either Calu-3 cells or HBEC (human bronchial epithelial) cells lines and will assess the mechanism of transport across the mucosal membrane, potentially transcellular or paracellular route. Specific mechanism of action will be investigated, such as the tight junction opening, clathrin or calveolin cellular pathway and effect on the 170 kDa membrane bound P-glycoprotein. Task 3. Potential synergistic effects of CriticalSorb with other known absorption enhancers CriticalSorb will be combined with other known absorption enhancers with alternative modes of action such as the typically investigated bioadhesive polysaccharide Chitosan to determine potential synergistic effects between the enhancers. Task 4. In vitro - in vivo correlation of absorption enhancing effect The final stage of the project will include comparisons of absorption enhancing effect from in vitro cell culture models with the in vivo data presently available, and those that will be created in animal studies by Critical Pharmaceuticals through another project. Wagner-Nelson modeling of the data will be carried out to determine the in vitro-in vivo correlation and the suitability of the in vitro cell culture model.

该项目将评估一种新的吸收促进系统-用于鼻腔给药的CriticalSorb。该项目将侧重于四个关键领域：评价制剂的理化性质并确定基本特征，使用适当的细胞培养模型研究其作用机制，确定与其他已知的吸收促进剂的协同效应，该项目的最后部分将着眼于开发一种稳健的体外细胞培养模型，以便在评估鼻吸收时取代动物模型。毒品鼻递送途径可用于全身递送药物，例如小分子量极性药物、肽和蛋白质，这些药物不容易通过注射以外的其它途径给药。尽管鼻腔的表面积大，并且极性分子、肽和蛋白质的广泛血液供应吸收低，但是如果与吸收促进剂联合施用，则可以大大改善。然而，增强剂系统通过多种机制起作用;动物研究表明，最常见的是，所获得的吸收增强效果与对鼻膜造成的损伤之间存在直接相关性。因此，重要的是发现和评估新的吸收促进剂系统。Critical Pharmaceuticals是一家小型专业制药公司，开发了一种基于吸收促进剂CriticalSorb的鼻腔给药平台，该平台在重复给药研究任务1中显示对鼻膜无毒。制剂的物理化学表征该项目的第一阶段将评价含有CriticalSorb和肽或蛋白质形式的模型药物的制剂的物理化学表征。CriticalSorb水溶液形成胶束，将进行实验以确定药物在此类胶束溶液中的位置以及胶束性质。它将应用常规和最先进的“纳米技术”分析技术的组合，包括：粒度和分布，染料掺入，形态（低温TEM）。任务2.评价CriticalSorb的作用机制该项目的第二阶段将研究和描述CriticalSorb及其主要成分的吸收增强作用的作用机制。这将侧重于Calu-3细胞或HBEC（人支气管上皮）细胞系的细胞培养单层，并将评估跨粘膜转运机制，可能是跨细胞或细胞旁途径。将研究具体的作用机制，如紧密连接开放、网格蛋白或钙蛋白细胞通路以及对170 kDa膜结合P-糖蛋白的影响。任务3. CriticalSorb与其他已知吸收促进剂的潜在协同效应CriticalSorb将与具有替代作用模式的其他已知吸收促进剂（例如通常研究的生物粘附性多糖壳聚糖）组合，以确定促进剂之间的潜在协同效应。任务4.吸收增强效应的体外-体内相关性该项目的最后阶段将包括将体外细胞培养模型的吸收增强效应与目前可用的体内数据以及Critical Pharmaceuticals通过另一个项目在动物研究中创建的数据进行比较。将对数据进行Wagner-Nelson建模，以确定体外-体内相关性和体外细胞培养模型的适用性。