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

该项目将评估一种用于药物鼻给药的新型吸收促进剂系统CriticalSorb。该项目将集中在四个关键领域：评估配方的物理化学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，确定与其他已知吸收促进剂的协同效应，项目的最后一部分将着眼于开发一个强大的体外细胞培养模型，以便在评估药物的鼻腔吸收时取代动物模型。研究背景：对于小分子量极性药物、多肽和蛋白质等不易通过注射途径给药的药物，鼻给药途径可用于全身给药。尽管鼻腔表面积大，血液供应广泛，极性分子、多肽和蛋白质的吸收率很低，但如果与吸收促进剂联合使用，吸收率可以大大提高。然而，增强系统通过许多机制起作用；动物研究表明，在大多数情况下，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，发现和评价新的吸收促进剂体系是很重要的。Critical Pharmaceuticals是一家小型专业制药公司，他们开发了一种基于吸收促进剂CriticalSorb的鼻腔给药平台，在重复给药剂量研究中显示，该平台对鼻膜无毒。项目的第一阶段将评估含有CriticalSorb和多肽或蛋白质形式的模型药物的配方的物理化学特性。CriticalSorb水溶液形成胶束，将进行实验以确定药物在这种胶束溶液中的位置，以及胶束性质。它将结合常规和最先进的“纳米技术”分析技术，包括：颗粒大小和分布，染料掺入，形态（冷冻透射电镜）。任务2。评价CriticalSorb的作用机理项目第二阶段将研究和描述CriticalSorb及其主要成分的增吸作用机理。这将集中于Calu-3细胞或HBEC（人支气管上皮）细胞系的细胞培养单层，并将评估跨粘膜运输的机制，可能是跨细胞或细胞旁途径。具体的作用机制将被研究，如紧密连接开放，网格蛋白或钙蛋白的细胞途径和对170 kDa膜结合p -糖蛋白的影响。任务3。CriticalSorb将与其他已知的具有替代作用模式的吸收促进剂（如通常研究的生物粘合剂多糖壳聚糖）结合使用，以确定增强剂之间的潜在协同效应。任务4。项目的最后阶段将包括比较体外细胞培养模型与体内现有数据的吸收增强效果，以及那些将由Critical Pharmaceuticals通过另一个项目在动物研究中创建的数据。将对数据进行Wagner-Nelson建模，以确定体外细胞培养模型的体内相关性和适用性。

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.