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After the drug preparation is administered, under the condition of the physiological medium in the human body, the preparation disintegrates into many small particles, the particles depolymerize, and the drug dissolves. The dissolved drug penetrates into the epithelial cells of the small intestine and is then absorbed into the blood circulation. Finally, it reaches the target organ, target tissue, and target cell to exert its curative effect. It is impossible to detect the distribution of the drug in the body and the concentration of the drug in the blood circulation every time. How to better predict the therapeutic effect in the body through in vitro research-the establishment of the method of in vitro dissolution has become a research and development worker to predict the in vivo release of the preparation. Favorable means of absorption and absorption, and then evaluate the bioavailability and clinical therapeutic effect of the preparation.
To a certain extent, the in vitro dissolution method has been used to evaluate the consistency of the quality of the preparation (when the production site, production equipment, production prescription and process changes occur during the development of the preparation, the consistency of the dissolution of the preparation can ensure the consistency of the treatment quality.), to ensure The quality does not change between batches, and even guides the development of innovative drug preparations (generally, in the process of innovative drug development, the dissolution rate is maximized as the pursuit, thereby improving the release and absorption of the drug in the body, increasing the exposure of the drug in the body, In turn, the efficacy of innovative drugs in patients can be investigated). How to develop a robust dissolution method plays a pivotal role in the development of innovative drugs.
There are countless articles introducing how to develop dissolution methods, but membrane adsorption, as a crucial step in dissolution development, is rarely introduced. The dissolution fluid at different time points dissolves different amounts of raw materials, which also contain difficult-to-dissolve excipients. The dissolution liquid containing insoluble particles cannot be directly detected by high-performance liquid chromatography. Even if the ultraviolet spectrophotometer is used for detection, the insoluble particles will cause the detection baseline to be unstable, which will affect the authenticity and reproducibility of the test results. sex. At this time, the dissolution solution is usually filtered with a membrane filter.
Then it involves the selectivity of the filter membrane. Generally, the filter membrane can be divided into water membrane system and organic membrane system. The water film system can filter the water-based medium, and the filter of the organic solvent is easy to cause the dissolution of the filter membrane, and unnecessary impurities will be added to the medium. The organic membrane system is used as a hydrophobic filter membrane, which generally filters organic solvents. Of course, it can also be used for the filtration of aqueous media, but it will feel difficult when filtering aqueous media. Therefore, if the water membrane meets the filtration requirements, it is recommended to use the water membrane.
Water membrane filter membranes have different pore sizes, generally 0.22 μm, 0.45 μm and 0.8 μm. When raising cells in school, I usually use a 0.22 μm membrane to filter PBS and cell culture fluid to prepare a sterile solution. 0.8μm is less used. At present, in the dissolution development of preparations, most of them are 0.45 μm, which can filter out insoluble particles and meet the needs of liquid phase and ultraviolet detection. For special detection instruments, the particle size in the solution may be more stringent, and the specific situation is analyzed in detail. . It is recommended to use membranes from the same manufacturer during the research and development process. After all, it cannot be determined whether the quality standards of each manufacturer are consistent or whether the quality of the membranes produced is different.
When we choose multiple 0.45μm water filter membranes of different materials, we can carry out the membrane adsorption research. Some preparation researchers prepare the solution of the raw material drug, and then pass the solution of the raw material drug through the membrane and centrifuge, and compare the difference between the two treatments to judge the adsorption of the drug. There are also R&D personnel who prepare a mixed solution of raw materials and blank complete excipients (all excipients that may be used in the preparation prescription), and process the mixed solution through filtration and centrifugation to compare the differences caused by these two treatments on the dissolution liquid, and then Determine the adsorption of drugs.
Regardless of whether the above operation method is right or wrong, we might as well explore it from the perspective of the principle of membrane filtration and its influencing factors. In general, the filter membrane mainly restricts the passage of the solution through the size of the pores. Insoluble particles are larger than the filter membrane control and will be rejected by the filter membrane. The interaction force between the surface chemical functional groups of the filter membrane and the API also affects the passage of the drug. When the drug and excipients are dispersed in the dissolution medium, the excipients, especially the acid-base excipients, will affect the pH of the dissolution medium, thereby affecting the charge of the raw drug in the solution, and finally affecting the force between the drug and the filter membrane, inhibiting The drug adsorbs the filter membrane or increases the force between the drug and the filter membrane. As introduced in USP1092, the selection of filters is based on the early stages of dissolution program development during the evaluation process, and may need to be reconsidered in later trials, such as changes in drug or ingredients and changes in the quality of excipients (microcrystalline cellulose particle size Change). This sentence also shows that the excipients have an important influence on the adsorption of the filter membrane. In the process of formulation development, attention should be paid to the change of the prescription, and at the same time, it is necessary to verify whether the filter membrane adsorption test matches the new prescription; The use of blank full excipients in the formulation does not seem to be able to replace the influence of the excipients in the prescription on the API. It is recommended that before the prescription is determined, the eluate can be centrifuged to avoid the trouble of multiple developments.
When we determine the formulation development prescription, we use the raw material drug and the prescribed amount of excipients to prepare a mixed solution. Of course, we can prepare the raw material drug solution in parallel. The two solutions were processed by centrifugation and filter membrane respectively. By comparing the adsorption of the two solutions, it was explored whether the excipients have an impact on the adsorption of the raw materials. Of course, in actual experiments, we can directly use raw materials and excipients in prescription quantities to prepare mixed solutions, and then centrifuge and pass through membranes respectively.
We usually compare the difference between the effluent of 0, 3, and 7ml through the filter membrane and the eluate treated by centrifugation, and then judge how much eluate passes through, and the filter membrane reaches saturation.
During the dissolution test, different sampling time points will be used. The preparations at the first few points are generally difficult to dissolve completely, and the drug concentration in the dissolution liquid is relatively low. In general, the higher the concentration of the eluate, the faster the filter membrane will be saturated. The eluate concentration used in the filter membrane adsorption experiment should include the eluate concentration corresponding to the lowest and highest dissolution amount. In general, the minimum dissolution amount and the maximum dissolution amount can be determined according to the previous research and the dissolution of the preparation, and the specific range can be slightly extended.
The development of dissolution methods cannot be replaced in the research of formulations. Although the filter membrane adsorption test is insignificant in the process of dissolution development, the scientific nature of the test also determines the accuracy and credibility of our dissolution data. Membrane adsorption test should not become a seriously neglected link in the development of dissolution. Gradually pay attention to the scientific nature of its test design, strengthen the exploration of the adsorption mechanism, know what it is, and know why it is so, it will be wonderful!