Application of IVIVR in dosage form design

Guide: This paper is pushed from the modified dosage type project to the clinical feasibility assessmentTry to compare an approved cephalosporine form with a modified drug to establish an invivia correlationAssess the feasibility of the modification form, control the initial development risk of the project, guide the clinical development, and reduce the risk of reviewIntroduction
the demand for new technologies has been growing over the past decade as the demand for drug compliance has increasedcan adjust solid dosage forms (e.godor preparations and dispersants) to meet patient needs, design liquids, syrups, granules and suspensions for children, and granules and dispersants for older patients with difficulty swallowingHow to prove the safety and effectiveness of modified dosage forms and determine in vitro and in vivo targets is a common problem for us in the process ofdosage form designour company successfully changed a spore variety from capsule to dispersalLet's take this as an example to detail the application of IVIVR in dosage form designthe process of evaluating the varieties of modified dosage forms is as:(1) collecting prescription composition of different dosage forms, dissolving curves in different media, pharmacokinetics;(2) establishing invivia and external correlation;(3) predicting inviviable behavior of different dosage forms, determining the risk of changing dosage forms,(4) control having key differential dissolved behavior, and determining the necessity of clinical trialscase introduction
a cephalosporin is the third generation of cephalosporins, antibacterial spectrum, used to treat a variety of sensitive bacteria caused by infection, especially suitable for light and moderate infections This product is available in the United States in 300mg capsules and 125mg/5ml of suspension Japanese marketed in tablets, capsules and granules in sizes of 50mg and 100mg the above-mentioned dissolved curves indicate that the solute behavior of tablets and capsules is similar However, in pH3.0 media, the dissolving behavior of tablets is faster than capsules, in pH6.8 media, tablets, capsules and fine granules are quickly dissolved Fine granules have a faster dissolving behavior under various pH conditions, which is related to the design of its prescription composition conclusion: By comparing the in vitro solute behavior of different dosage forms, it was found that the variety had the same pharmacokinetics, i.e the difference of in vitro behavior between different dosage forms, and did not show the behavioral differences in the body For example, fine granules dissolve faster in vitro, but Cmax and AUC values are not high relative to tablets and capsules Analysis of the reasons: API is BCSIV class, low permeability, resulting in limited gastrointestinal absorption in vivo prediction using Gastroplus modeling, the physical and chemical properties of this product and in vivo behavior are linked, different dosage forms are simulated to ensure the rationality and scientific nature of the modified dosage form, the model prediction values are tabled below tablets and capsules by different dosage forms dissolved curvecan can be seen, the dosage forms in the pH3.0 medium of large differences, with a clear differentiation force, the use of the medium dissolved data, to predict the absorption rate and degree Each dosage form dissolves the curve in the pH3.0 medium as follows: the different dosage forms dissolved curve into the software, using the biochemical parameters of the API in Table 3, and combined with the ACAT model in Gastroplus, to predict the absorption curve in the capsule and tablet body, as follows: conclusion: by the above absorption curve, using pH3.0 media, predicting the absorption curve of the body, tablet and capsule absorption curve a predictive value for ADMET for modeling The effects of pharmacokinetics and enzyme expression of high perfusion organs such as liver and kidneycane can be accurately simulated set pharmacokinetic parameters according to the predicted parameters of enzymes and transport-in-proteins in the above-mentioned tissues The PK data in the literature were extracted, based on the pharmacokinetics predicted by the room model, and the following data were obtained, the following table was obtained: modeling using the two-room model, using in vitro data, using convolution method to calculate, and predicting inviviable pharmacokinetics Simulated 12h in vivo absorption metabolism, as follows: conclusion: The above data show that the model predicts that the values of the species of tablet Cmax, AUC, Tmax and if literature are basically the same, proving that the developed model predicts well capsules and fine granules the same theory, using Gastroplus software, the capsule and granules different in vitro solute behavior, modeling prediction, the results are as follows: conclusion: the prediction results show that although the dosage form is different, in vitro behavior, but 50mg specificationcapsules and fine granule pharmacokinetics (such as Cmax, AUC) similar The Tmax value of the fine granule is lower than the capsule dosage form, which is due to the rapid release of the fine granule, but the absorption rate and degree of the fine granule are not significantly different from the capsule The difference between the two doses of Tmax is also reported in the literature, indicating that the results of the Gastroplus calculation are accurate results analysis
the above study suggests that the cephalospora can be designed without affecting safety and effectiveness Tablets and granules are biologically equivalent to approved capsule dosage forms The model results show that the API is BCSIV, and its absorption is not affected by prescription composition and in vitro solute, which is one of the reasons why many dosage forms are approved in this variety early in the study, by comparing the different dosage forms listed in Japan, it was shown that tablets, fine granules and capsules may be biologically equivalent The prescription composition of the granule is designed differently from the capsule, which releases faster Therefore, we can safely speculate that the dispersion tablets (rapid in vitro behavior) are biologically equivalent to the capsule dispersed tablets are tablets that can quickly disintegrate evenly dispersed in water, and due to the dosage form characteristics, the prescription design and dissolved curve are different from the capsule design Based on the above-mentioned research, it is shown that the faster dissolving curve (fine granules) does not affect the absorption of the body, which also provides a scientific basis for the change of the capsule for this variety to a dispersed tablet concluding evaluate the feasibility of the modified dosage type project, the model simulation can be used to bridge different dosage forms, establish an in vitro/in vitro (IVIVR) relationship, and control the initial development risk of the project In the process of prescription development, the medium with invivity and external relevance is determined, and the pharmaceutical goal of self-product development is clarified In vitro evaluation of self-products developed for BE testing, based on in vitro data of self-products, virtual BE tests using models, and the necessity of clinical trials are determined For the modified type varieties, the calculation of model simulation is far-reaching, and it can predict the risk of the modified type earlier, guide the clinical development and reduce the review risk