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    Home > Medical News > Latest Medical News > Imitation drug development weapon - an in vivo and external correlation assessment based on the comparison of pharmacodynamic parameters between different dosage forms of the same variety.

    Imitation drug development weapon - an in vivo and external correlation assessment based on the comparison of pharmacodynamic parameters between different dosage forms of the same variety.

    • Last Update: 2020-09-25
    • Source: Internet
    • Author: User
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    Introduction: This paper will propose an evaluation of in vivo and exterior correlation, through the same varieties, in vitro dissolution behavior between different dosage forms and the comparison of in vivo pharmacological parameters, the in vivo and exterior correlation of products to determine the necessity of in vitro dissolution curve fitting and conducive to biological equivalent experiments through the in vitro dissolution trend.
    . Since the state began to implement the consistent evaluation of the in vivo bioethics as the gold standard, industry colleagues have gradually accumulated knowledge and experience related to BE, with the continuous accumulation of theoretical learning and project practical experience, related research, thinking is also continuously in-depth, through BE and through consistent evaluation to obtain more and more varieties of production batches. The biological equivalent test of
    drug has certain complexity, the results are affected by many factors, the physical and chemical properties of the API, the disintegration and dissolution behavior of the preparation, the absorption site of the drug in the body and the mechanism, the differences between the subjects and the BE scheme design may have a decisive impact on the test results.
    At present, the industry basically uses the characteristic in-body dissolved curve to characterize the product's internal quality, through the characteristic in-body dissolved curve fitting method, to guide the development of imitation agent theory, to the greatest extent to ensure the success rate of BE test.
    the rational use of in-body dissolved curves has become the most advantageous weapon for the development of generic drugs.
    IVIVR theory, which is based on the association between in vitro dissolving curve and in vivo pharmacological parameters, is now more and more paid attention to by colleagues in the industry, and through the analysis and judgment of the in vivo correlation of the product, on the one hand, it can have a preliminary assessment and pre-judgment of the product BE risk, on the other hand, it also contributes to the determination of the technical objectives of imitation preparations.
    theory, BCS2 and BCS1 drugs with a relatively slow release trend are more likely to establish in vivo and off-body correlations because their absorption is not limited by absorption in the body.
    for these two species, we should pay more attention to the importance of in-body dissolved curve fitting.
    This paper will put forward an evaluation idea of in vivo and exterior correlation, through the same varieties, the in vitro dissolution behavior between different dosage forms and the comparison of in vivo pharmacological parameters, the in vivo and external correlation of the product to clarify the necessity of in vitro dissolution curve fitting and the trend of in vitro dissolution in favor of biological equivalent experiments.
    project case 1 variety 1 (dispersion tablets) the original research agent type has capsules and fine-grained agents, dispersion tablets belong to the domestic endearing dosage form, dispersion tablets can be dispersed in water after taking, can improve the compliance of patients with dysphagia, belong to the improvement of capsules, this product with the same specifications of the original research capsules as a competitive preparation.
    Due to the characteristics of the dosage form, the capsule agent and dispersion tablets of in-body solution has a large difference, the capsule agent dissolving behavior process, the capsule shell first rupture, rupture after the contents from the cystic shell scattered in the medium, API and then slowly dissolved, so the capsule solution has a certain slow release trend.
    of the dispersion sheet is rapid dispersion, relatively dissolved speed is also relatively fast.
    the actual development process, we also found that the dissolution of dispersed tablets is difficult to be consistent with the original capsule agent.
    this difference in in vitro dissolution is bound to increase the risk of biological equivalentity, so in the project stage, the feasibility of this variety of modified dosage form needs to be fully assessed before the research work can be started.
    evaluation idea: through the in vitro dissolution of the original research capsules and fine mitochondrials and the in vivo pharmacological parameters of the comparison, to assess the in vivo and external relevance of this product, to determine the feasibility of the development of the dispersion tablets.
    Literature Information: In the Japanese Orange Book, the dissolution curve in the 100mg medium of the capsule is retrieved as follows: Under the same solubility conditions, the dissolution curve in each medium of the fine particle agent 100mg is as follows: the capsule is shown in addition to pH1. 2 hydrochloric acid dissolved relatively quickly outside, in other media are the trend of slow release, 360min did not fully dissolve, and fine particles in each medium, 5min that reached a relatively high amount of dissolved, 5min to 120min dissolved a small slow rise.
    the trend of in-body dissolution between the two dosage forms was significant.
    we need to look at what pharmacodynamics are in both.
    From the Japanese IF file, we did not directly obtain the pharmacological parameters of capsules and fine gels, but we obtained from a Japanese company's generic IF file, respectively, imitation capsules and original capsule pharmacological comparison, as well as imitation fine gels and original The pharmacodynamic comparison of fine-grained agents is as follows: The comparison of capsules: Experimental scheme: pharmacodynamic data, wherein the data in the red box is the pharmacological parameters of the capsule standard preparation: the comparison of fine-grained agents: the pharmacological data, wherein the data in the red box Pharmacodynamic parameters for standard preparations for fine-grained agents: The number of subjects varied between the two groups of experiments, but the dosage and blood point were the same, and we put the data of the two groups of standard preparations together for a rough comparison, as follows: After a rough comparison We can see that there is a high similarity between Cmax and AAUC between the two dosage forms, and there are some differences in Tmax, which should be related to the difference in the speed at which the two dosage forms dissolve and release in the body, and the fine particles dissolve faster, so there is a shorter Tmax.
    So we boldly speculate that there is no significant in vitro-in vivo correlation with in vivo absorption in the range of in vitro dissolution trends presented by capsules and fine lattices.
    At the same dose, such as dissolved faster than the capsule, there is also a chance to achieve biological equivalents with the capsule agent, therefore, the development of the dispersion tablets is highly feasible, this variety can be modified imitation! BE batch of reagents and parameter preparations in-body solubility curve: Results: This variety in accordance with the relevant technical requirements to ensure dispersion tablets for development, the prescribing process determined compared with the comparison preparation capsules, the dissolution in each medium is significantly faster than the comparison preparation, but successfully passed the BE experiment, dispersion tablets and capsules biological equivalent.
    To obtain the pharmaceutical dynamics parameters comparison between the different dosage forms of the original study, in addition to supporting the evaluation of the development of modified dosage form varieties, will also provide strong support for the imitation of the same dosage form, adequate literature research and in vivo correlation assessment, will give the preparation research and development personnel a more conducive to biological equivalent direction. Project
    case 2 for varieties two (capsules), based on the above analysis and demonstration of the conclusions obtained, we can boldly give the following conclusions: in the development process of generic drugs, dissolved faster than the parameter preparation is for the biological equivalent of the body has a relatively low risk, such as the prescription process development process, multi-media dissolution curve is difficult to fit all with the compared preparation, then the generic in vitro solution to achieve faster than the competitive preparation trend.
    The process of the development of generic drugs of this variety, after step-by-step amplification, the process verified that three batches of samples dissolved slightly faster than the BE batch of the parameter preparation in the pH1.2 medium, three batches of samples and the similar factors of the parameters did not reach 50, the graph is as follows: Dissolve conditions: basket Method, 75 turn, 900 ml media volume according to the above assessment, the process verified that although the three batches of dissolved and BE batch parameter preparation similar factors can not reach 50, but the product dissolved too fast is the direction of low risk, so choose one batch of normal biological equivalent research.
    results: Biological equivalents passed successfully.
    Aposage: As a preparation research and development personnel, well aware of the difficulty of multi-media curve fitting with the participating preparations, sometimes in order to fit a curve needs to take a month to two months, but in the willow time, found that other media against their own.
    The opening stage to carry out a full in vivo correlation assessment, in the development process, anchoring the low-risk in vitro dissolution trend for prescription process groping, can maximize the efficiency of research and development, improve the success rate of BE, if the literature is sufficient, perhaps we do not have to put too much effort into the f2 watershed.
    above is an example of simplified research and development, of course, there are varieties, through the in vitro data comparison between different dosage forms, the preparation research and development personnel need to pay more attention to the fit of the in vitro dissolved curve.
    project case 3 varieties three (capsules) and varieties two have very similar characteristics, in the filling process, capsule shell models, content weight and even accessories composition have a high similarity, the development of this variety, we also refer to the same ideas as the above varieties, carried out an assessment of internal and external correlation.
    This variety of original research capsules and fine granules on the market, we first look at the situation of in-body dissolution: the Japanese Orange Book published in the original research capsule agent 50 mg of in-body dissolved curve as follows: the same specifications of the original study of fine particles in-body solubility The curve is as follows: As can be known from the results, similar to the above-mentioned capsules, there is also a large difference in in-body dissolution behavior between the two dosage forms of the variety, affected by the solubility of the API, the dissolution of the capsule is slower than the above-mentioned varieties of capsules, and shows a more significant pH dependence.
    Due to the very small number of imitations of this variety in Japan, it is not possible to obtain the comparison data of pharmacological parameters between different dosage forms from the Japanese IF file, but we obtain the following information from the FDA database: The above table gives the pharmacological parameters comparison between tablets, syrups, dry suspensions, due to syrup Dosage form is more complex, affected by syrup viscosity, may affect the absorption of the body, do not consider, simply compare tablets and dry suspension of pharmacological parameters, as follows: by the results, tablets and dry suspension Cmax and AUC have a large difference, especially AUC, the ratio of the two has been close to falling below 80%.
    Although it was not available to obtain the tablets and the in-body dissolution data of the dry suspension, but from the dosage form characteristics and the Japanese capsule agent and fine particles of the dissolution of the situation, it is speculated that there should be a greater difference between the in-body dissolution between the two, and the release rate of the dry suspension should be significantly faster than the tablet.
    After analysis, we believe that the inside and outside of this product has a certain correlation, the speed of dissolution and pharmacokological parameters into a certain regularity, the in vitro dissolved curve fitting needs to spend more time and energy to overcome.
    : This product has passed the official BE.
    Conclusion: Due to the complexity of the role of drugs in the body, the evaluation of in vivo and external correlation provided in this paper is not absolutely rigorous, but the comparison of pharmacodynamic parameters between different dosage forms can indeed reveal to some extent some characteristics of the variety itself.
    In the course of our development, there are many more such cases, such as the nabilor tablet instructions show that its tablets and oral solution biological equivalents, meaning that the disintegration of tablets should not become an absorption of the speed limit step, prescription process development process attention to ensure the speed of tablet dissolution.
    cephalosporine dry suspension is equivalent to tablets on an empty stomach and the post-meal biopsy is not effective, meaning we need to put more effort into curved ratios under high pH media.
    biological equivalents of zocarditin tablets and oral fluids, meaning that tablets develop faster and have a relatively low risk in the body.
    project opening preparation phase, we put more effort into the analysis of internal and external correlation, through the information obtained to guide the development of preparations, can minimize the difficulty of research and development, improve research and development efficiency, save research and development costs.
    only this article, throw bricks to lead jade, hope that the industry preparation research and development colleagues to discuss together, jointly enhance.
    Author's introduction Liu Xiaoming, general manager of the oral solids and intestinally soluble special agents division of Beijing New Leading Pharmaceutical Technology Development Co., Ltd., has more than ten years of experience in the research and development and management of oral solids preparations, is familiar with the various dosage forms and process characteristics of solid preparations, has accumulated many varieties of prescription process development and industrialization amplification theory and practical experience, good at guiding prescription process development through the evaluation and analysis of in vivo correlation, the division's pre-BE and BE maintain a very high success rate.
    .
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