CN113109467A - Method for determining in-vitro dissolution of nifedipine sustained-release tablets - Google Patents
Method for determining in-vitro dissolution of nifedipine sustained-release tablets Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical analysis, and discloses a method for determining in-vitro dissolution of nifedipine sustained-release tablets, which comprises the following specific steps: placing the nifedipine sustained-release tablets in a rotating basket, dissolving out by using a two-chamber model experimental device, continuously extracting a dissolving-out liquid after dissolving out by using a dissolving-out medium and filtering by using a filter membrane, and measuring the concentration of nifedipine in the dissolving-out liquid at a fixed time point; wherein the extraction speed of the dissolution liquid is consistent with the supplement speed of a dissolution medium, and the dissolution medium is 0.1-0.5% of Tween80 phosphate buffer solution with the pH value of 6.8. The in vitro dissolution method ensures the accuracy of in vitro dissolution experiments by simulating in vivo absorption processes, realizes the consistency of dissolution curves measured by the in vitro dissolution experiments and in vivo absorption processes, and provides guarantee for realizing good prediction of human body bioequivalence.
Description
Technical Field
The invention relates to the technical field of pharmaceutical analysis, in particular to a method for determining in-vitro dissolution of nifedipine sustained-release tablets.
Background
At present, in-vitro dissolution experiments are considered to BE capable of estimating in-vivo dissolution behaviors and absorption conditions, but the in-vivo environment is complex, so that the phenomenon that the dissolution of preparation intermediates out of the body is similar and BE in the body is not equivalent is easily caused, the research and development progress of enterprises is hindered, and economic burden is also brought.
Nifedipine is a dihydropyridine calcium channel blocker, is a yellow crystal at normal temperature, is insoluble in water, is soluble in acetone or chloroform, is slightly soluble in ethanol, and is highly sensitive to light. Nifedipine has a logP of 2.20, has good lipid solubility, and is a BCS2 medicament. Nifedipine is not ionized in the pH value range of the gastrointestinal tract system, and the solubility is independent of pH. The nifedipine is absorbed by gastrointestinal tracts after being orally taken, the bioavailability of the nifedipine is low due to the first pass effect of the liver, the time to peak of the sustained-release tablet is 1.6-4h, and the drug-time curve is gentle. Nifedipine has wide tissue distribution, wherein the nifedipine has high concentration in liver, serum, kidney and lung, and has low concentration in brain and skeletal muscle. The binding rate of nifedipine to plasma protein in human body is up to 92-98%. 70-80% of the drug is excreted as water-soluble metabolite from urine, and only 0.1% of the original drug is excreted via urine, and has no accumulation in vivo.
The conventional dissolution mode of nifedipine is a basket method or a slurry method, has a plurality of defects in structure and performance, cannot comprehensively simulate the dissolution/absorption process of a medicament in vivo, so that the dissolution test is only used as a quality means for controlling the medicament in vitro and cannot be associated with the actual condition in vivo. Moreover, because the common nifedipine tablets have high release speed in vivo, need to be taken for many times every day and have large blood pressure fluctuation, on the basis, nifedipine sustained-release tablets and nifedipine controlled-release tablets are produced, the release period of the nifedipine sustained-release tablets is 12 hours, and the release period of the nifedipine controlled-release tablets is as long as 24 hours, so that stable pressure control can be realized. Based on nifedipine with different dosage forms and different specifications, in the in-vitro dissolution process, a proper method needs to be selected in order to properly simulate the dissolution/absorption mechanism of the drug and provide reference for well predicting the bioequivalence of the human body.
The Chinese patent application CN201710349978.2 discloses a method for measuring the dissolution curve of a nifedipine sustained-release tablet, which aims to overcome the defects of a pharmacopoeia method and has certain limitations by improving the structure of a polypropylene silk screen of an inner cylinder of a reciprocating cylinder dissolution instrument and combining the method of improving a dissolution medium.
Therefore, the development of an in vitro dissolution method that simulates in vivo absorption is of great significance to pharmaceutical companies.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a method for measuring the in-vitro dissolution of the nifedipine sustained-release tablet, which measures the dissolution concentration of the nifedipine sustained-release tablet by simulating the dynamic continuous process of in-vivo dissolution and absorption so as to realize good prediction of the bioequivalence of a human body.
In order to achieve the purpose, the invention adopts the following technical scheme:
on one hand, the invention provides a method for determining in-vitro dissolution of nifedipine sustained release tablets, which comprises the following specific steps: placing the nifedipine sustained-release tablets in a rotating basket, utilizing a two-chamber model experimental device for simulating the in-vivo dissolution and transmembrane absorption processes of the insoluble oral pharmaceutical preparation for dissolution, continuously extracting a dissolution liquid after dissolution by a dissolution medium and filtration by a filter membrane, measuring the concentration of nifedipine in the dissolution liquid at a fixed time point to obtain an average differential dissolution curve chart between the concentration of nifedipine and the dissolution time, and obtaining an accumulated dissolution curve chart between the accumulated dissolution mass fraction and the dissolution time according to the differential dissolution relation;
wherein the extraction rate of the dissolution liquid is the same as the supplement rate of the dissolution medium.
Further, the dissolution medium is phosphate buffer solution with pH 6.8 of 0.1-0.5% Tween 80. Preferably, the dissolution medium is 0.1%, 0.3%, 0.5% Tween80 phosphate buffer pH 6.8. Wherein the pH 6.8 phosphate buffer solution of 0.1-0.5% Tween80 is 1000mL of phosphate buffer solution containing 1-5 g Tween 80. Experiments prove that the in vitro dissolution curve obtained by performing in vitro dissolution experiments by using low-concentration Tween80 (0.1%) has better discrimination, and the quality and the process difference of a tested preparation and a reference preparation can be moderately distinguished. High concentrations of Tween80 may mask the difference in actual dissolution capacity of the formulation. The pH 6.8 phosphate buffer solution of 0.1-0.5% Tween80 is used as a dissolution medium, the stability is high, the requirement is met, and the determination result can be reproduced when the dissolution curve is determined.
Further, the concentration of the nifedipine in the dissolution liquid is measured by adopting a high performance liquid chromatography, an average differential dissolution curve graph between the concentration of the nifedipine and the dissolution time is obtained after the corresponding time point and the concentration of the nifedipine are calculated, and an accumulated dissolution curve graph between the accumulated dissolution mass fraction and the dissolution time is obtained according to the differential dissolution relation. Precisely measuring 20 mu L of the dissolution liquid, injecting into a high performance liquid chromatograph, recording a chromatogram, and calculating the corresponding concentration of nifedipine. Chromatographic conditions of the high performance liquid chromatography: a C18 column; mobile phase: acetonitrile-0.1% phosphoric acid ultrapure water volume ratio (1: 1); flow rate: 1 mL/min; wavelength: 235 nm; sample introduction amount: 20 mu L of the solution; column temperature: 35 ℃ is carried out.
According to the differential dissolution data of the nifedipine sustained release tablets, the calculation formula of the cumulative dissolution relation between the cumulative dissolution fraction and the dissolution time is obtained as follows:
wherein, FdisIs the reference formulation or the test formulation at tiCumulative dissolution mass fraction at time, n is total number of samples, i is an integer between 1 and n, tiDissolution time, t, for the ith dissolution samplei-1Dissolution time corresponding to the i-1 th dissolution sample, CiConcentration of the i-th dissolution sample, Ci-1The concentration of the i-1 th dissolution sample, the Flowrate the flow rate of the vehicle and the dose of the pharmaceutical formulation.
Further, the nifedipine sustained-release tablet comprises a reference preparation and a tested preparation, a similarity factor f2 is calculated by using average dissolution concentration data of the reference preparation and the tested preparation of the nifedipine sustained-release tablet by using a similarity factor method, and the similarity factor f2 is used for comparing the similarity of the dissolution curve of the reference preparation and the dissolution curve of the tested preparation of the nifedipine sustained-release tablet; when the similarity is judged by using the value of the similarity factor f2, when the similarity factor f2 is greater than or equal to 50, the dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet are similar, and when the similarity factor f2 is less than 50, the dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet are not similar.
And according to the accumulative dissolution relation of the reference preparation and the accumulative dissolution relation of the tested preparation, obtaining a calculation formula of a similarity factor between the accumulative dissolution relation of the reference preparation and the accumulative dissolution relation of the tested preparation, wherein the calculation formula comprises the following steps:
wherein f is2 TIs a similarity factor between the cumulative dissolution relation of the reference preparation and the cumulative dissolution relation of the tested preparation, n is the total sampling number, i is an integer between 1 and n, FTdisIs the cumulative dissolution mass fraction of the test preparation at the dissolution time corresponding to the i-th dissolution sample, FRdisThe cumulative dissolution mass fraction of the reference preparation at the dissolution time corresponding to the i-th dissolution sample is used.
Further, the temperature of the dissolution medium is controlled at (37. + -. 0.5) DEG C. Experiments prove that the temperature of the dissolution medium enables nifedipine to have higher stability, and simultaneously, the method is beneficial to simulating the temperature in human bodies, and the measured dissolution curve is closer to the trend of in-vivo absorption.
Furthermore, the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are 1-15 mL/min. Preferably, the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are 5-12 mL/min. Preferably, the extraction rate of the dissolution liquid and the supplement rate of the dissolution medium are both 5mL/min, 6mL/min, 8mL/min, 10mL/min or 12 mL/min.
Furthermore, the rotating speed of the rotating basket is 10-150 rpm. Preferably, the rotating speed of the rotating basket is 50-100 rpm. Preferably, the rotational speed of the spin basket is 75 rpm. Under the condition of the rotating speed, the dissolution rate is high, and hydrodynamic disturbance can not occur.
Further, the fixed time points are 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150, 180min and the like until the nifedipine sustained-release tablets are dissolved out.
Further, the specific structure of the two-chamber model experimental device for simulating the in vivo dissolution and transmembrane absorption processes of the insoluble oral drug preparation is disclosed in patent CN 201920858418.4.
Further, the specification of the nifedipine sustained-release tablet is 10 mg.
On one hand, the invention provides a method for determining in-vitro dissolution of a nifedipine sustained-release tablet, which is to perform dissolution on the nifedipine sustained-release tablet by using a two-chamber model experimental device for simulating in-vivo dissolution and transmembrane absorption processes of an insoluble oral pharmaceutical preparation, and comprises the following specific steps:
1) dissolving media enter the porous filter membrane cup through the action of the liquid inlet pump, when the volumes of the dissolving media in the porous filter membrane cup and the dissolving cup in the outer chamber are the same, the liquid outlet pump is started, the working frequencies of the liquid inlet pump and the liquid outlet pump are consistent, and the total volume of the dissolving media is kept unchanged; the dissolution medium is 0.1% Tween80 phosphate buffer solution with pH of 6.8, and the aperture of the filter membrane coated outside the porous filter membrane cup is 0.45 μm;
2) placing the nifedipine sustained-release tablets in a rotating basket, wherein the rotating speed of the rotating basket is 75rpm, continuously extracting the dissolution liquid after the dissolution liquid is filtered by a filter membrane, wherein the extraction speed of the dissolution liquid and the supplement speed of a dissolution medium are both 6mL/min, and measuring the concentration of nifedipine in the dissolution liquid at a fixed time point;
the fixed time points are 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150 and 180min until the nifedipine sustained-release tablets are dissolved out;
3) the method comprises the steps of measuring average dissolution concentrations of nifedipine at different time points in a dissolution liquid by adopting a high-performance liquid phase, obtaining an average differential dissolution curve graph between the average dissolution concentration and the dissolution time of the nifedipine according to corresponding time points and the average dissolution concentration of the nifedipine, and obtaining an accumulated dissolution curve graph between accumulated dissolution mass fraction and dissolution time according to a differential dissolution relation.
Further, calculating a similarity factor f2 by using average dissolution concentration data of a reference preparation and a tested preparation of the nifedipine sustained release tablet by using a similarity factor method, wherein the similarity factor f2 is used for comparing the similarity of the dissolution curve of the reference preparation and the dissolution curve of the tested preparation of the nifedipine sustained release tablet; when the similarity is judged by using the value of the similarity factor f2, when the similarity factor f2 is greater than or equal to 50, the dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet are similar, and when the similarity factor f2 is less than 50, the dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet are not similar.
The invention keeps the total volume of the dissolution medium unchanged by maintaining the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium, so that the periphery of the nifedipine sustained-release tablet reaches the leakage groove condition, and the medicine can be released continuously. Because the porous filter membrane cup and the outer chamber dissolution cup have the drug concentration difference, the free drugs released from the porous filter membrane cup enter the outer chamber dissolution cup, and the undissolved drugs or auxiliary material powder are blocked in the porous filter membrane cup by the filter membrane, so that the drug loss in the sampling process is prevented. The medicine-containing medium in the outer-chamber dissolving-out cup is continuously pumped away by the sampling tube, samples are collected at different time points respectively, and other media are stored in a waste liquid collecting bottle. Therefore, the method of the invention keeps the leakage groove condition of the nifedipine sustained release tablet medicament preparation by continuously inputting the fresh medium and outputting the medicament-containing medium, and effectively simulates the in vivo absorption state by forming an open dissolution model. The dissolution capacity of the nifedipine sustained release tablet in unit time is distinguished by detecting the drug concentration at different sampling points, so that the absorption capacity of the nifedipine sustained release tablet in a human body is predicted.
Compared with the prior art, the invention has the following beneficial effects:
the embodiment of the invention proves that the method simulates the in vivo absorption process, ensures the accuracy of the in vitro dissolution test, realizes the consistency of the dissolution curve trend measured by the in vitro dissolution test and the in vivo drug absorption-time curve trend of the BE test, can evaluate the advantages and disadvantages of the nifedipine sustained-release tablets, also makes a prediction for bioequivalence, improves the success rate of the bioequivalence test, and ensures the bioavailability of the drugs after being marketed.
In comparative example 1, example 3 and example 4, the dissolution curves of the reference formulations are similar (both the line shape and the trend are the same), further illustrating that the method provided by the present invention has good reproducibility, good stability of the dissolution method and high accuracy.
In comparative example 1, example 3 and example 4, the dissolution curves and dissolution rates of the test preparations are different, and the test preparations and the reference preparations have better discrimination, so that the quality and the process difference between the reference preparations and the test preparations can be effectively distinguished, and the similarity and the quality consistency of the reference preparations can be evaluated.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without creative efforts.
FIG. 1 is a graph of the mean differential dissolution of a reference formulation of the 10mg extended release nifedipine tablet of example 1.
FIG. 2 is a graph showing the mean cumulative dissolution of a reference formulation of the sustained release tablet of nifedipine 10mg in example 1.
FIG. 3 mean in vivo time-course graph of reference and tested nifedipine sustained release tablets in example 2
FIG. 4 mean cumulative absorption curve of nifedipine sustained release tablet reference preparation in example 2
FIG. 5 is the mean differential dissolution curve of the reference preparation and the tested preparation of the 10mg nifedipine sustained release tablet in example 3.
FIG. 6 is the average cumulative dissolution curve of the reference preparation and the tested preparation of the 10mg nifedipine sustained release tablet in example 3.
FIG. 7 is the average cumulative dissolution curve of the reference preparation and the tested preparation of the sustained release tablet of nifedipine 10mg in example 4.
FIG. 8 is the mean differential dissolution curve of the reference preparation and the tested preparation of the 10mg nifedipine sustained release tablet in example 4.
Fig. 9 predicted drug-time curves for the reference and test formulations of the 10mg nifedipine extended release tablet of example 4.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
Example 1 conditional screening
The method for determining the in-vitro dissolution of the nifedipine sustained release tablet comprises the following specific steps:
1) dissolving media enter the porous filter membrane cup through the action of the liquid inlet pump, when the volumes of the dissolving media in the porous filter membrane cup and the outer chamber dissolving cup are 75mL, the liquid outlet pump is started, the working frequencies of the liquid inlet pump and the liquid outlet pump are consistent, and the total volume of the dissolving media in the device is kept unchanged at 150 mL; the temperature of the dissolution medium is kept at 37 ℃, and the aperture of the filter membrane coated outside the porous filter membrane cup is 0.45 mu m;
2) placing the nifedipine sustained-release tablets in a rotating basket, wherein the rotating speed of the rotating basket is 75rpm, filtering the dissolution liquid by a filter membrane, continuously extracting the dissolution liquid, and measuring the concentration of nifedipine in the dissolution liquid at a fixed time point;
the fixed time points are 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150 and 180min until the nifedipine sustained-release tablets are dissolved out;
3) measuring the content of nifedipine at different time points in the dissolution liquid by adopting a high performance liquid, calculating corresponding time points and the concentration of nifedipine to obtain an average differential dissolution curve graph between the concentration of nifedipine and the dissolution time, and obtaining an accumulated dissolution curve graph between the accumulated dissolution mass fraction and the dissolution time according to the differential dissolution relation.
The conditions were changed as follows:
condition 1: the dissolution medium is 0.1% Tween80 phosphate buffer solution with pH of 6.8, and the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are both 6 mL/min;
condition 2: the dissolution medium is 0.1% Tween80 phosphate buffer solution with pH of 6.8, and the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are both 12 mL/min;
condition 3: the dissolution medium is 0.3% Tween80 phosphate buffer solution with pH of 6.8, and the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are both 12 mL/min;
the results of experiments carried out with the nifedipine sustained release tablet reference preparation are shown in fig. 1-2; the dissolution capacity of the nifedipine sustained-release tablets at different time is shown by an average differential dissolution curve diagram, and the dissolution amount of the nifedipine sustained-release tablets at different time is shown by an accumulated dissolution curve. The concentration of the nifedipine can be easily diluted when the supplement speed (12mL/min) of the dissolution medium is too high, the supplement speed (6mL/min) of the dissolution medium is low and meets the dissolution rate of the nifedipine in vivo, and the simulation in vivo absorption mode is more accurate. Experiments prove that the obtained in-vitro dissolution curve has better discrimination by using low-concentration Tween80 (0.1%) to perform in-vitro dissolution experiments, and the quality and the process difference of a tested preparation and a reference preparation can be moderately distinguished. High concentrations of Tween80 may mask the difference in actual dissolution capacity of the formulation.
Example 2
The method is characterized in that 12 healthy volunteers are subjected to postprandial bioequivalence research by adopting random, open, three-cycle and cross experimental design, the elution period among cycles is 7 days, the volunteers take the nifedipine sustained-release tablet reference preparation or the tested preparation 20 mg/time per week and 1 time per day, and the blood sampling time is designed to be 4mL of upper limb venous blood collected respectively before administration (0h) and 10min, 20min, 30min, 45min, 1.0h, 1.25h, 1.5h, 1.75h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 15h, 24h and 36h after administration. The samples were centrifuged (3,500rpm, 10min), and plasma was separated and stored in an ultra-low temperature freezer at-80 ℃. Specifically, 100 μ L of plasma sample is taken, 600 μ L of anhydrous methanol (containing internal standard) is added, vortexed for 5min, fully and uniformly mixed, centrifuged at 12,000rpm for 10min, and the supernatant is taken to enter an HPLC-MS (high performance liquid chromatography-tandem mass spectrometer) for analyzing the content of nifedipine in plasma.
Reference formulation: nifedipine sustained release tablets, BAYER, specification 10 mg;
test formulations: nifedipine sustained release tablets (T1), with the specification of 10 mg;
nifedipine sustained release tablets (T2), with the specification of 10 mg;
the results show that the peak time of the reference formulation is about 2.67h, AUC and CmaxSignificantly higher than the two tested formulations (FIG. 3), the BE results showed that the two tested formulations were compared to the reference formulationAUC and C of the formulationmaxAre not equivalent.
TABLE 1 pharmacokinetic parameters of nifedipine sustained-release tablets
The percentage in vivo absorption (Fabs%) of nifedipine following oral administration of the reference formulation was analyzed by the Wagner-Nelson method and the results showed that the formulation was completely absorbed about 3h after oral administration (FIG. 4) and the absorption rate constant k was calculateda＝0.8664h-1。
Example 3
The method for determining the in-vitro dissolution of the nifedipine sustained release tablet comprises the following specific steps:
1) dissolving media enter the porous filter membrane cup through the action of the liquid inlet pump, when the volumes of the dissolving media in the porous filter membrane cup and the outer chamber dissolving cup are 75mL, the liquid outlet pump is started, the working frequencies of the liquid inlet pump and the liquid outlet pump are consistent, and the total volume of the dissolving media in the device is kept unchanged at 150 mL; the dissolution medium is 0.1% Tween80 phosphate buffer solution with pH 6.8, the temperature of the dissolution medium is kept at 37 ℃, and the aperture of the filter membrane coated outside the porous filter membrane cup is 0.45 μm;
2) placing the nifedipine sustained-release tablets in a rotating basket, wherein the rotating speed of the rotating basket is 75rpm, filtering the dissolution liquid by a filter membrane, continuously extracting the dissolution liquid, and measuring the concentration of nifedipine in the dissolution liquid at a fixed time point;
the fixed time points are 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150 and 180min until the nifedipine sustained-release tablets are dissolved out;
the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are both 6 mL/min;
3) measuring the content of nifedipine at different time points in the dissolution liquid by adopting a high performance liquid, calculating corresponding time points and the concentration of nifedipine to obtain an average differential dissolution curve graph between the concentration of nifedipine and the dissolution time, and obtaining an accumulated dissolution curve graph between the accumulated dissolution mass fraction and the dissolution time according to the differential dissolution relation.
Reference formulation: nifedipine sustained release tablets, BAYER, specification 10 mg;
test formulations: nifedipine sustained release tablets (T1), with the specification of 10 mg;
nifedipine sustained release tablets (T2), with the specification of 10 mg;
under the dissolution conditions, in-vitro dissolution results of a nifedipine sustained-release tablet reference and two tested preparations are shown in figures 5-6, and the cumulative dissolution rate within 3h is R > T2 > T1.
As can be seen from the average differential dissolution curves of the reference preparation and the tested preparation of the 10mg nifedipine sustained release tablet (figure 5), the dissolution behaviors of the three preparations within 30min are similar, but after 30min, obvious distinction appears, the dissolution rate of the reference preparation is fast, T2 times is fast, T1 is slow, and the cumulative dissolution curves are different. Comparing the area under the differential dissolution curves of reference formulation R with T1, T2 within 40min from the onset of dissolution, the results show that the area under the differential dissolution curves of T1, T2 is significantly lower than reference formulation R. Therefore, the dissolution behavior of the two test formulations is not consistent with that of the reference formulation.
In vitro dissolution experiments were performed using low concentrations of 0.1% Tween8, and the in vitro dissolution results obtained were in line with the trends of the in vivo test results. The in vitro dissolution profile of example 3 is similar to the in vivo drug-time profile trend of example 2, and the cumulative release ratio T2/R (0.83), T1/R (0.59) at 3h of the in vitro dissolution profile of example 3 is close to the AUC ratio of the three formulations tested in vivo in example 2. The in vitro dissolution profile of example 3 also compares with C of T1, T2 in the in vivo test of example 2maxThe result is obviously lower than that of a reference preparation, and the result shows that the in vitro dissolution curve detected by the method is consistent with the in vivo absorption trend, and has certain in vivo and in vitro correlation.
Example 4
The method for determining the in-vitro dissolution of the nifedipine sustained release tablet comprises the following specific steps:
1) dissolving media enter the porous filter membrane cup through the action of the liquid inlet pump, when the volumes of the dissolving media in the porous filter membrane cup and the outer chamber dissolving cup are 75mL, the liquid outlet pump is started, the working frequencies of the liquid inlet pump and the liquid outlet pump are consistent, and the total volume of the dissolving media in the device is kept unchanged at 150 mL; the dissolution medium is 0.1% Tween80 phosphate buffer solution with pH 6.8, the temperature of the dissolution medium is kept at 37 ℃, and the aperture of the filter membrane coated outside the porous filter membrane cup is 0.45 μm;
2) placing the nifedipine sustained-release tablets in a rotating basket, wherein the rotating speed of the rotating basket is 75rpm, filtering the dissolution liquid by a filter membrane, continuously extracting the dissolution liquid, and measuring the concentration of nifedipine in the dissolution liquid at a fixed time point;
the fixed time points are 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150 and 180min until the nifedipine sustained-release tablets are dissolved out;
the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are both 6 mL/min;
3) measuring the content of nifedipine at different time points in the dissolution liquid by adopting a high performance liquid, calculating corresponding time points and the concentration of nifedipine to obtain an average differential dissolution curve graph between the concentration of nifedipine and the dissolution time, and obtaining an accumulated dissolution curve graph between the accumulated dissolution mass fraction and the dissolution time according to the differential dissolution relation.
Reference formulation: nifedipine sustained release tablets, BAYER, batch number JPS2392, specification 10 mg;
test formulations: nifedipine sustained release tablets are prepared by self, and the specification is 10 mg;
under the dissolution conditions, in-vitro dissolution results of the nifedipine sustained-release tablet reference preparation and the tested preparation are shown in figures 7 to 8, and the accumulative dissolution rate of the reference preparation (29.3%) is slightly higher than that of the tested preparation (27.1%) within 3 h. As can be seen from the average differential dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet of 10mg (figure 7), the release rate of the reference preparation is lower than that of the tested preparation within 30min after the dissolution of the reference preparation, and is higher than that of the tested preparation within 40-120min, and the release rates of the two preparations are basically consistent within 150-180 min.
The in vitro dissolution results of figures 7-8 of the present invention show that the reference formulation has an average cumulative dissolution of 2.2% higher than the test formulation, and both formulations are considered to have similar dissolution (f2 ═ 90.9) if operational and instrumental errors are excluded. In the average differential dissolution curves of the reference preparation and the tested preparation of the 10mg nifedipine sustained release tablet, the release rate of the tested preparation is slightly higher than that of the reference preparation at the point of 180min, and the cumulative dissolution rates of the two preparations are gradually close according to the trend. Since nifedipine is a BCS2 drug, dissolution is a rate-limiting step, and when the cumulative release rates of the two preparations are consistent, the probability of AUC equivalence is high. On the other hand, the average differential dissolution curves of the reference preparation and the test preparation of the 10mg nifedipine sustained release tablet show that the area under the differential dissolution curve of the test preparation within 40min from the start of dissolution is significantly higher than that of the reference preparation (fig. 7).
Analyzing the dissolution rate constant k of the reference preparation and the test preparation based on their differential dissolution curvesd. K before the dissolution rate of the formulation reaches the peakdGreater than the rate (k) of the drug being carried away by the dissolution mediume) Resulting in a sustained increase in the concentration of the drug in the dissolution cup. For nifedipine sustained-release tablets, it is assumed that k is within 40 minutes from the start of dissolution of the preparationd＞＞keThen k isdCan be approximated as the slope of the differential dissolution rate for that segment. K for the reference formulation is obtained by logarithmic conversion of the differential dissolution ratedIs 2.32h-1K of the test preparationdIs 2.52h-1. Further suppose that the in vitro dissolution rate constant k of a pharmaceutical preparationdIs equal to the absorption rate constant k of the drug in vivoaAccording to the formula for calculating the blood concentration of the unicompartmental model (
C is the in vivo drug concentration, K is the elimination rate constant, KaIs the absorption number rate constant, F is the bioavailability; v is apparent distribution volume; t is time, X0Is dosage), and parameters such as V/F, k and the like in the formula select data obtained by a nifedipine in-vivo pre-BE test to predict the blood concentration of the nifedipine in a test preparation and a reference preparation. The predicted results are shown in FIG. 9, where the predicted time-course curves for the two preparations substantially overlap, and C for the test preparationmax(72.60ng/mL) was slightly higher than the reference formulation (71.92ng/mL), but the difference was small, indicating that the test formulation is biologically equivalent to the reference formulation.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for determining in-vitro dissolution of nifedipine sustained release tablets is characterized by comprising the following specific steps: placing the nifedipine sustained-release tablets in a rotating basket, utilizing a two-chamber model experimental device for simulating the in-vivo dissolution and transmembrane absorption processes of the insoluble oral pharmaceutical preparation for dissolution, continuously extracting a dissolution liquid after dissolution by a dissolution medium and filtration by a filter membrane, measuring the concentration of nifedipine in the dissolution liquid at a fixed time point to obtain an average differential dissolution curve chart between the concentration of nifedipine and the dissolution time, and obtaining an accumulated dissolution curve chart between the accumulated dissolution mass fraction and the dissolution time according to the differential dissolution relation;
the dissolution medium is phosphate buffer solution with pH 6.8 of 0.1-0.5% Tween 80;
the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are respectively and independently 1-15 mL/min.
2. The method for determining in vitro dissolution of nifedipine sustained release tablets according to claim 1, characterized in that: the concentration of nifedipine in the dissolution liquid is measured by adopting a high performance liquid chromatography;
the specification of the nifedipine sustained release tablet is 10 mg.
3. The method for determining in vitro dissolution of nifedipine sustained release tablets according to claim 1, wherein the dissolution medium is 0.1% Tween80 pH 6.8 phosphate buffer, 0.3% Tween80 pH 6.8 phosphate buffer or 0.5% Tween80 pH 6.8 phosphate buffer.
4. The method for determining in vitro dissolution of nifedipine sustained release tablets according to claim 1, wherein the temperature of the dissolution medium is controlled to (37 ± 0.5) ° c.
5. The method for determining in vitro dissolution of nifedipine sustained release tablets according to claim 1, wherein the extraction rate of the dissolution liquid is in accordance with the supplement rate of the dissolution medium; the extraction speed of the dissolution liquid and the supplement speed of the dissolution medium are 5-12 mL/min.
6. The method for determining in vitro dissolution of nifedipine sustained release tablets according to claim 5, wherein the extraction rate of the dissolution liquid and the supplement rate of the dissolution medium are both 5mL/min, 6mL/min, 8mL/min, 10mL/min or 12 mL/min.
7. The method for determining in-vitro dissolution of the nifedipine sustained-release tablet according to claim 1, wherein the rotating basket rotates at 10-150 rpm.
8. The method for determining in vitro dissolution of nifedipine sustained release tablets according to claim 1, wherein the fixed time points are 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150, 180min until the dissolution of nifedipine sustained release tablets is completed.
9. The method for determining in vitro dissolution of nifedipine sustained release tablets according to claim 1, wherein the nifedipine sustained release tablets comprise a reference preparation and a test preparation;
calculating a similarity factor f2 by using average dissolution concentration data of a reference preparation and a tested preparation of the nifedipine sustained-release tablet by adopting a similarity factor method, wherein the similarity factor f2 is used for comparing the similarity of the dissolution curve of the reference preparation and the dissolution curve of the tested preparation of the nifedipine sustained-release tablet; when the similarity is judged by using the value of the similarity factor f2, when the similarity factor f2 is greater than or equal to 50, the dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet are similar, and when the similarity factor f2 is less than 50, the dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet are not similar.
10. A method for determining in-vitro dissolution of a nifedipine sustained-release tablet is characterized in that the nifedipine sustained-release tablet is dissolved by a two-chamber model experimental device for simulating the in-vivo dissolution and transmembrane absorption processes of an insoluble oral pharmaceutical preparation, and the method comprises the following specific steps:
1) dissolving media enter the porous filter membrane cup through the action of the liquid inlet pump, when the volumes of the dissolving media in the porous filter membrane cup and the dissolving cup in the outer chamber are the same, the liquid outlet pump is started, the working frequencies of the liquid inlet pump and the liquid outlet pump are consistent, and the total volume of the dissolving media is kept unchanged; the dissolution medium is 0.1% Tween80 phosphate buffer solution with pH of 6.8, and the aperture of the filter membrane coated outside the porous filter membrane cup is 0.45 μm;
2) placing the nifedipine sustained-release tablets in a rotating basket, wherein the rotating speed of the rotating basket is 75rpm, continuously extracting the dissolution liquid after the dissolution liquid is filtered by a filter membrane, wherein the extraction speed of the dissolution liquid and the supplement speed of a dissolution medium are both 6mL/min, and measuring the concentration of nifedipine in the dissolution liquid at a fixed time point;
the fixed time points are 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150 and 180min until the nifedipine sustained-release tablets are dissolved out;
3) measuring the average dissolution concentration of nifedipine at different time points in the dissolution liquid by adopting a high performance liquid, obtaining an average differential dissolution curve graph between the average dissolution concentration and the dissolution time of nifedipine according to the corresponding time points and the average dissolution concentration of nifedipine, and obtaining an accumulated dissolution curve graph between the accumulated dissolution mass fraction and the dissolution time according to the differential dissolution relation;
calculating a similarity factor f2 by using average dissolution concentration data of a reference preparation and a tested preparation of the nifedipine sustained-release tablet by adopting a similarity factor method, wherein the similarity factor f2 is used for comparing the similarity of the dissolution curve of the reference preparation and the dissolution curve of the tested preparation of the nifedipine sustained-release tablet; when the similarity is judged by using the value of the similarity factor f2, when the similarity factor f2 is greater than or equal to 50, the dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet are similar, and when the similarity factor f2 is less than 50, the dissolution curves of the reference preparation and the tested preparation of the nifedipine sustained release tablet are not similar.
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