时间:
The main evaluation indexes of solid preparation quality are content, content uniformity, related substance and dissolution. In terms of content/uniformity, the current domestic production situation is that after granulation and before tablet pressing, samples are extracted from representative places in the intermediate container which is considered to have been fully mixed, mixed evenly and sent to the quality inspection department to determine the average tablet weight (or pack size) of the main drug content of 100%. The production department adjusts the filling amount according to the value and then presses the tablet. As long as the mechanical properties of the preparation are good, the tablet pressing error is controlled within A certain range, the content/content uniformity will not appear in general, not to mention the content range is generally 90% ~ 110%, and the uniformity of A+1.8S is required to be within 15.0. From the above process, we can see that there is almost no "technical content" in this, just make an object into a uniform shape and make it according to a certain specification. This has nothing to do with the intrinsic quality of the drug or how much it is absorbed in the body. Therefore, there is no correlation with respect to content/uniformity in terms of the intrinsic quality of solid preparations. Because even if the amount is more accurate, if there is no absorption or effective absorption into the body, the amount is meaningless! Therefore, we should firmly establish the scientific concept of "taking medicine is not eating content, but eating bioavailability"! As for the substance concerned, the ability to establish a test for the accurate determination of impurities is important, but it is insignificant compared with the importance of absorption of the drug in the body. Because if the main drug has not been effectively absorbed, the main body absorption, even the presence of 2% impurity is not important. Unless some specific, more toxic impurities, such as dicyanguanidine in metformin hydrochloride, paraminophen in acetaminophen, etc., need special attention.
The technology of dissolution is "the soul and core of the evaluation of solid preparation". With the continuous research and deepening of dissolution, the understanding and understanding of dissolution are also developing and changing. Today, the assay is not only designed to establish in vitro and in vivo correlations, but has also become a simple, inexpensive and rigorous laboratory test to demonstrate in vivo release properties of drugs. It is a scientific evaluation means and method for "analyzing" and "dismembering" the intrinsic quality of the original solid preparation. Moreover, it has become the mapping and carrier of the external appearance of the internal quality of solid preparation. Therefore, the in-depth study of this detection technology can play a pivotal role in a series of situations such as drug research and development, quality control, production, circulation and alteration More and more attention and expectations from all aspects!
The application aspects of this technology are listed as follows
(1) For innovative drugs or new dosage forms, this test is helpful for the screening of excipients and prescriptions and the dissolution evaluation of active ingredients (apis) in the drug development stage. For new preparations, factors that affect biological characteristics such as formulation, process or excipients should be screened with high dissolution amount in multi-pH dissolution medium or slow release property in multi-pH dissolution medium as far as possible as the starting point, and dissolution test conditions that can distinguish the advantages and demerits of these factors should be found. And then gradually through animal, human/clinical trials to prove this in vitro differentiation in human bioavailability differences, so as to establish in vivo and in vitro correlation, and finally scientific, reasonable, systematic development of the product quality standards.
(2) Optimize the characteristics of apis that may affect bioavailability. For insoluble drugs, salt-forming form, crystal type (available crystal, crystal shape, etc.), particle size (size distribution range and specific surface area), pKa value, solubility in different pH values or different dissolution media should be studied. And in the study of API quality, dissolution degree should be considered, so as to expect better drug properties. The thickness of the diffusion layer is related to the drug particle size, and the specific surface dissolution rate of particles below 5um is significantly increased. It was reported that the specific surface dissolution rate of particles with particle size less than 5um was not significantly affected by stirring intensity, while the same drug particles with particle size ranging from 25 to 35um were significantly affected by stirring. Particle size reduction is beneficial to drug dissolution, but smaller is not better. The effective surface area plays an important role in the size of the specific surface area. If the drug is hydrophobic and the leaching medium has poor wettability, the "effective surface area" will be reduced, and the reduction of particle size will slow the dissolution rate. Therefore, the study of API with different particle size distribution should be carried out.
(3) As a favorable evidence method to predict the success of generic drug bioequivalence test (hereinafter referred to as BE test), it can greatly reduce R&D costs and expenditure.
(4) It becomes an effective means to evaluate which preparation process can make the intrinsic quality of generic drugs infinitely close to that of original drugs. Because preparation technology is the core technology of drugs, its high confidentiality in the original research plant makes it particularly important for the generic drug factory to make in-depth technological breakthroughs in the process of imitation. In order to understand the specific situation of the inner quality of the original agent and the high-tech content contained therein, it is necessary to use a measurable objective, scientific and easy to reproduce evaluation means to analyze, express and map, so as to guide the R&D personnel to develop and solve the key problems in a correct direction. At this time, dissolution detection means is an effective weapon!
(5) It is also very important to evaluate all kinds of changes that may affect the biological characteristics of drugs (such as process changes, production scale-up, source changes of auxiliary materials, prescription changes, production site changes, etc.), which can prove whether it is necessary to conduct bioavailability or bioequivalence studies before and after the changes;
(6) It also plays an important role in evaluating the quality difference of the same preparation from different sources.
(7) As a routine quality control step of drug manufacturing quality management practice (GMP), this test has become an important means to examine whether the physical properties of drugs are uniform and stable, whether the internal quality of the drug within the validity period has changed, and an important evaluation method to strictly control the production process.
(8) It becomes one of the important means to investigate the uniformity and internal quality stability of drugs between batches/within batches.
(9) In vitro dissolution test is also helpful to evaluate and predict potential risks, especially for some indicators of sudden release of drugs for treatment of window stenosis.
For example, Chinese pharmacopoeia Gliclazide tablets (II) should not exceed 50% of 60 minutes and 75% of 180 minutes, respectively. In the Japanese Book of Orange, Camasipine films should be no longer than 60 percent of 5 minutes and no less than 70 percent of 30 minutes. The list of these drugs is as follows: Aplendine hydrochloride, isoproterenol hydrochloride, ethinylestrel, Ethylsuccinate, carbmazepine, Quinidine sulfate, guanethidine sulfate, Clindamycin hydrochloride, Clonazepam hydrochloride, digoxin, propiamide phosphate, Zonisacin, cyclosporine, digoxin, Propiamide phosphate, Zonisamide, Tacrolimus, Sirolimus, mantecophenolate, valproic acid (sodium), phenytoin, phenobarbital, piperidol hydrochloride Zolazin, pramidone, procainamine hydrochloride, methotrexate, lithium carbonate, warfarin (sodium), gliburide, toluentobuliurea, glifenuride, hexurea acetate, tolutamide, Gliclazide, theophylline, dihydroxypropylline, aminophylline, choltheophylline.
(10) Dissolution test can also be used to study the quality of (insoluble drug) granules, (insoluble drug) dry suspension, chewable tablets, dispersible tablets, particles, scaffolds, liposomes, nanospheres and embedding agents. At the same time, for some novel special preparations, it can also be used as one of the means to investigate the biological characteristics of the preparations.
To sum up, compared with other detection technologies, dissolution technology is more and more able to reflect the future development direction of drugs, and its application and deepening has attracted much attention and expectation.
