CN108007826B - Method for measuring in-vitro accumulated release rate of long-acting liquid preparation - Google Patents
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Abstract
The invention provides a method for measuring in-vitro accumulated release rate of a long-acting liquid preparation, belonging to the technical field of drug analysis. The method comprises the following steps: sample loading: placing the release medium and the long-acting liquid preparation in a sealable container in a certain ratio; rotating and mixing: placing the sealed container after sample loading in a rotary mixer, wherein the temperature of the rotary mixer is maintained at 35-40 ℃, and the angle of a rotating shaft of the rotary mixer is 0-30 degrees from the horizontal plane; sampling and detecting: respectively taking out the sealable containers at different time points after the containers are placed in the rotary mixer, respectively centrifuging the mixed liquid in the sealable containers, taking the supernatant, filtering the supernatant through a microporous filter membrane to obtain a sample solution, carrying out content determination on the free or encapsulated main drug components in the sample solution, and calculating the cumulative release degrees at different time points. The method avoids the influence of external factors such as gravity on the release of the long-acting liquid preparation, meets the requirements of methodology and has small deviation.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and particularly relates to a method for measuring in-vitro accumulated release rate of a long-acting liquid preparation.
Background
The method for measuring the in vitro accumulated release rate is designed for long-acting solid preparations or semisolid preparations, and usually a dissolution instrument is used for measuring different dosage forms, and different dissolution methods are adopted, such as a paddle method, a rotary basket method, a small cup method and the like. With the development of new dosage form pharmaceutical technology, some long-acting liquid preparations are developed, and how to measure the in vitro cumulative release rate becomes more critical.
The existing methods for the in vitro accumulative release rate of the long-acting liquid preparation mainly comprise a dialysis membrane method and a mixed centrifugation method. The dialysis membrane method comprises a forward dialysis method and a reverse dialysis method, wherein a sample and a release medium are separated through a dialysis membrane, the release medium and free medicines can freely pass through the dialysis membrane, but the sample cannot pass through the dialysis membrane, so that the method is suitable for samples with uniform particle size distribution and small particle size, but the leakage condition of the sample with large particle size is difficult to achieve, and the phenomenon of membrane blockage of the sample often occurs; the mixed centrifugation method is to mix the release medium and the sample together according to a certain proportion, and the conventional mixing mode is mixing in a horizontal plane, such as water bath constant temperature oscillation and gas bath shaking table oscillation, and then the free drug is separated from the sample by centrifugation, but the accuracy, precision and repeatability of the method can not meet the methodological requirements, or the method can meet the methodological requirements but has larger deviation.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a method for measuring the in-vitro cumulative release rate of a long-acting liquid preparation. Through the rotation mixing of vertical plane (the rotation axis angle of rotary mixer personally submits 0 ~ 30 degrees with the horizontal plane), make but the long-acting liquid preparation in the sealed container realize the periodic upset from top to bottom with the release medium, change the fluid dynamics among the mixing process, be favorable to intensive mixing between them, avoided following situation: the long acting liquid formulation is accumulated to the bottom of the container under the influence of gravity to slow down the release, or the long acting liquid formulation is accelerated by destroying the structure thereof, so that the accuracy, precision and repeatability of the determination method cannot meet the requirements of methodology, or meet the requirements of methodology but have larger deviation.
The invention provides a method for measuring in-vitro accumulated release rate of a long-acting liquid preparation, which comprises the following steps:
s1 sample loading: placing the release medium and the long-acting liquid preparation in a sealable container in a certain ratio;
s2 rotary mixing: placing the sealed container after sample loading in a rotary mixer, wherein the temperature of the rotary mixer is maintained at 35-40 ℃, and the angle of a rotating shaft of the rotary mixer is 0-30 degrees from the horizontal plane;
s3 sampling detection: respectively taking out the sealable containers at different time points after the containers are placed in the rotary mixer, centrifuging the mixed solution in the sealable containers, taking the supernatant, filtering the supernatant through a microporous filter membrane to obtain a sample solution, performing content determination on free or encapsulated main drug components in the sample solution by adopting a high performance liquid chromatography method or an ultraviolet spectroscopy method, and calculating the cumulative release degrees at different time points.
The inventor finds out through a large number of experiments that: the conventional mixing methods are mixing in a horizontal plane, such as constant temperature oscillation of a water bath and oscillation of a gas bath shaker, and the mixing method directly influences the release of the medicine, slow release due to accumulation of a sample to the bottom of a container under the action of gravity or fast release due to damage to the structure of the sample due to long-time mixing in the horizontal plane, so that the accuracy, precision and repeatability of the determination method cannot meet the methodological requirements, or the accuracy, precision and repeatability of the determination method meet the methodological requirements but have larger deviation. In contrast, the inventor unexpectedly thinks that the long-acting liquid preparation is mixed by adopting a vertical plane rotary mixing mode, and the specific rotating angle, the rotating radius, the rotating time and the like are screened and optimized, so that the fluid dynamics in the mixing process is changed, the long-acting liquid preparation and the release medium are quickly and fully mixed, the release of the long-acting liquid preparation is prevented from being influenced by external factors such as gravity, the methodological requirement is met, and the deviation is small.
Preferably, the rotating speed of the rotating mixer is 10-15 rpm, and the rotating radius is 12-18 cm.
More preferably, the rotating mixer has a rotating axis angle of 0 degree from the horizontal plane, a rotating speed of 12rpm, and a rotating radius of 15 cm. Under the rotating condition, the influence of gravity is avoided, and the structure of the long-acting liquid preparation cannot be damaged.
Preferably, the temperature of the impeller is maintained at 37 degrees. More preferably, the rotary mixer may be placed in an incubator at a temperature of 37 ℃.
Preferably, the different time points include 0 th, 4 th, 24 th, 48 th, 72 th and 96 th.
Preferably, the number of the sealable containers is multiple and is an integral multiple of the number of different time points, and the rotating shaft angle, the rotating speed and the rotating radius of each sealable container are kept consistent.
Preferably, the sealable container comprises a volumetric flask, a conical flask, a stoppered test tube, a centrifuge tube and a cuvette.
Preferably, the release medium consists of 1mol/l KH2PO4 15.6ml、1mol/l K2HPO4 34.4ml、5mol/l NaCl 30ml、0.5g NaN35g BSA is dissolved by adding distilled water, then the pH is adjusted to 7.4, and the volume is adjusted to 1L.
Preferably, the long-acting liquid preparation is propofol long-acting liquid preparation or doxorubicin hydrochloride liposome injection.
Preferably, the long-acting liquid preparation is in the form of injection, microsphere preparation, targeted emulsion, microcapsule and liposome.
Preferably, the certain proportion is 8-12 ml: 0.2-0.5 ml. More preferably, said certain proportion is 10 ml: 0.2 ml.
Preferably, the rotating speed of the centrifugation is 8000-12000 rpm, and the time is 12-16 min.
More preferably, the centrifugation is performed at 10000rpm for 15 min.
Preferably, the particle size of the microfiltration membrane is 0.22 μm.
Compared with the prior art, the invention has the beneficial effects that:
(1) the mixing degree of the long-acting liquid preparation and the release medium can be finely adjusted by applying a vertical plane rotary mixing mode, namely, the long-acting liquid preparation and the release medium are periodically turned up and down in the mixing process by changing the rotating speed, the rotating angle and the rotating radius, so that the fluid dynamics in the mixing process is changed, and finally, the mixing degree of the long-acting liquid preparation and the release medium is changed. The oscillatory mixing on the reverse horizontal plane cannot effectively change the fluid dynamics of the sample and the release medium in the mixing process due to no overturning effect, and the mixing degree of the sample and the release medium is difficult to finely adjust.
(2) By applying the rotary mixing mode of the vertical plane, through fine adjustment of the mixing degree of the sample and the release medium, proper mixing conditions are easily found, so that the sample and the release medium can achieve the uniform mixing effect, the sample can be ensured not to be damaged, and the influence of external factors such as gravity is avoided.
(3) The determination method provided by the invention has the advantages of simple operation, low cost and good reproducibility of test results, can truly reflect the in-vitro accumulated release trend of the sample, meets the methodological requirements, has small deviation, and can be suitable for the consistency evaluation of the in-vitro accumulated release degree of the long-acting liquid preparation.
Drawings
FIG. 1 is a graph showing the results of the effect of different rotation axis angles on the release rate of propofol long acting liquid formulations.
Figure 2 is a graph of the results of the effect of different rotational speeds on the rate of release of propofol long acting liquid formulation.
Fig. 3 is a graph showing the results of the effect of different radii of rotation on the release rate of propofol long acting liquid formulations.
Fig. 4 is a graph showing the results of comparison of the release rates of propofol long-acting liquid formulations measured by different methods.
FIG. 5 is a graph showing the results of comparing the release rates of doxorubicin hydrochloride liposome injection measured by different methods.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples.
The instrument in the embodiment of the invention comprises: analytical balance (Sartorius 125D), high-speed centrifuge (Cence TG16-W), mixing rotator (DRAGON MX-RD-Pro), high performance liquid chromatograph (Agilent 1260UV), constant temperature drying oven (Shanghai-constant BPH-9162), pH meter (Raynaud's PHSJ-3F), and osmotic pressure tester (Shanghai medical science FM-8P). A water bath constant temperature oscillator, a gas bath constant temperature shaking table (Changzhou guohua), a dissolution instrument (Tianda tianfa), and a microporous filter membrane (Shibi pure).
The reagents in the examples of the present invention include: acetonitrile (SINENCE), ethanol (SIGMA), potassium dihydrogen phosphate, sodium hydroxide, dipotassium hydrogen phosphate, sodium chloride (Guangzhou chemical reagent factory), bovine serum albumin (Calbiochem), sodium azide (Ciya chemical), propofol reference Substance (SIGMA), propofol long-acting liquid preparation (Guangdong Jiabo pharmaceutical Co., Ltd., batch number: 201604200102), doxorubicin hydrochloride liposome injection (Shiyao Takara Shuzo), and doxorubicin hydrochloride reference substance (China food and drug testing institute).
Solution preparation in the embodiment of the invention:
(1) formulation of release media
1mol/l KH2PO4Solution: 13.61mg KH was weighed out2PO4Put into a 100ml measuring flask, dissolved by adding water and diluted to the scale mark.
1mol/l K2HPO4Solution: weighing 22.82mg K2HPO4Put into a 100ml measuring flask, dissolved by adding water and diluted to the scale mark.
5mol/l NaCl solution: 29.22mg NaCl was weighed into a 100ml measuring flask, dissolved in water and diluted to the mark.
Release medium PBB solution: taking 1mol/l KH2PO4 15.6ml，1mol/l K2HPO4 34.4ml，5mol/l NaCl 30ml，0.5g NaN35g BSA, dissolved in distilled water, adjusted to pH 7.4 and made to volume of 1L.
(2) Preparation of mobile phase
Mobile phase A: weighing KH2PO43.42g, NaOH 0.70g, and water to 1000mL to make phosphate buffer solution.
Mobile phase B: and (3) acetonitrile.
(3) Preparation of control solutions
And (3) placing a proper amount of the propofol reference substance into a 50ml measuring flask, and adding acetonitrile to fix the volume to a scale to obtain a reference substance solution.
Example a examination of mixing conditions
1) Different rotation axis angles
Examination of the results of the tests at rotation axis angles of 0, 30, 60, 90 degrees (i.e., horizontal plane of the prior art) respectively, as shown in fig. 1, it can be seen that the release rate is significantly slowed down as the rotation axis angle increases.
2) Different rotation speeds
The results of the tests at rotational speeds of 6, 12 and 24 revolutions per minute were examined, respectively, as shown in fig. 2. It can be seen that the release speed is obviously increased along with the increase of the rotating speed, but when the rotating speed is 24 revolutions, the cumulative release rate of 96 hours is close to 100 percent and exceeds the range of 85-95 percent, and the release is accelerated probably because the structure of a propofol long-acting liquid preparation sample is damaged to a certain extent.
3) Different radius of rotation
The results of the tests were examined for radii of rotation of 10cm, 15cm and 20cm, respectively, as shown in FIG. 3. It can be seen that the release rate increases slightly with increasing rotational speed.
Therefore, the following mixing conditions are finally selected as the optimum conditions: the rotating shaft angle is 0 degree, the rotating speed is 12 revolutions per minute, and the rotating radius is 15 cm.
EXAMPLE II determination of cumulative in vitro Release of Long-acting liquid formulations
The method for measuring the in-vitro cumulative release rate of the long-acting liquid preparation comprises the following steps:
s1 sample loading: placing 10mL of release medium and 0.2mL of propofol long-acting liquid preparation in a sealable container;
s2 rotary mixing: placing the sealed container after sample loading in a rotary mixer, placing the rotary mixer in a 37 ℃ constant temperature incubator, wherein the angle of a rotating shaft of the rotary mixer is 0 degree to the horizontal plane, the rotating speed is 12rpm, and the rotating radius is 15 cm;
s3 sampling detection: taking out the sealable containers at 0, 4, 24, 48, 72 and 96h after the rotary mixer, respectively, taking 6 sealable containers at each time point, respectively centrifuging the mixed solution in the sealable containers, taking the supernatant, filtering with a 0.22 mu m microporous filter membrane to obtain a sample solution, performing content determination on the free main drug components by adopting high performance liquid chromatography, and calculating the cumulative release degrees of 0, 4, 24, 48, 72 and 96 h. The results are shown in Table 1. The detection result of the method is compared with the detection result of the agent 400DS, and the result is shown in Table 2.
The chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent, phosphate buffer solution-acetonitrile (30: 70) is used as a mobile phase, the detection wavelength is 272nm, the column temperature is 30 ℃, and the flow rate is 1.6 ml/min.
TABLE 1 cumulative release test results at different time points
Table 2 comparison with detection results by Aglient 400DS
As can be seen from Table 1, the reproducibility and repeatability of the determination method provided by the invention are good, and the RSD% of each sampling point is within 2%. As can be seen from Table 2, f was obtained by comparing the detection results of Agilent 400DS2The factor is 63.6, which shows that the method has high reliability of the measured result, low test cost and simple and convenient operation.
EXAMPLE three comparison of the Process of the invention with the conventional Process
The in vitro cumulative release degree of the propofol long-acting liquid preparation is examined under the same conditions by respectively applying a dissolution instrument paddle method, a water bath oscillation method, a gas bath oscillation method and the method (the method is simply referred to as the method), and the test result is shown in figure 4. As can be seen from FIG. 4, the cumulative release degree of the conventional method does not change much after 48h, and the actual change cannot be reflected. The reason is presumed to be as follows: in the dissolving-out instrument paddle method, a dialysis membrane is fixed on a stirring paddle, a small cup method is used for testing, and in the testing process, the accumulated release degree is not changed greatly after 48 hours because a sample blocks the dialysis membrane. For the water bath shaking and the gas bath shaking methods, since the samples were slowly piled up to the bottom of the container due to the gravity by shaking for a long time in the horizontal plane, the cumulative release degree did not change much after 48 hours.
EXAMPLE four in vitro cumulative Release measurements on commercially available Long-acting liquid formulations
The mixing conditions and the sampling post-treatment method in the second embodiment of the invention are applied to the commercial doxorubicin hydrochloride liposome injection, the content of the free main drug component (adriamycin) in the injection is measured by adopting a high performance liquid chromatography, and finally the in vitro cumulative release degree of the preparation at different time is calculated. The chromatographic conditions are that octadecylsilane chemically bonded silica is used as a filler, methanol-sodium acetate buffer (7:3) is used as a mobile phase, the pH value of the sodium acetate buffer is adjusted to 3.4 by glacial acetic acid, the detection wavelength is 233nm, the column temperature is 30 ℃, and the flow rate is 1.0 ml/min.
Meanwhile, the in vitro accumulated release degree is measured by using a water bath oscillation method and a dissolution instrument paddle method, but from 24 hours, the release result of the existing water bath oscillation and dissolution instrument paddle method is obviously low, the in vitro accumulated release degree of the doxorubicin hydrochloride liposome injection cannot be truly reflected, and the specific test result is shown in table 3 and fig. 5.
TABLE 3 comparison of the results of the tests for determining the extraliposomal cumulative release of doxorubicin hydrochloride by different methods
In conclusion, the method provided by the invention can realize the determination of the in vitro accumulative release rate of the long-acting liquid preparation, and has the advantages of high result reliability, low test cost, simple and convenient operation and the like.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (5)
1. A method for measuring the in vitro accumulative release rate of a long-acting liquid preparation is characterized by comprising the following steps: the method comprises the following steps:
s1 sample loading: placing the release medium and the long-acting liquid preparation in a sealable container in a certain ratio;
s2 rotary mixing: placing the sealed container after sample loading in a rotary mixer, wherein the temperature of the rotary mixer is maintained at 35-40 ℃, and the angle of a rotating shaft of the rotary mixer is 0-30 degrees from the horizontal plane; the rotating speed of the rotating mixer is 10-15 rpm, and the rotating radius is 12-18 cm;
s3 sampling detection: respectively taking out the sealable containers at different time points after the containers are placed in the rotary mixer, respectively centrifuging the mixed solution in the sealable containers, taking the supernatant, filtering the supernatant through a microporous filter membrane to obtain a sample solution, performing content determination on free or encapsulated main drug components in the sample solution by adopting a high performance liquid chromatography method or an ultraviolet spectroscopy method, and calculating the cumulative release degrees at different time points;
the different time points include 0 th, 4 th, 24 th, 48 th, 72 th and 96 th;
the release medium is prepared from 1mol/l KH2PO4 15.6ml、1mol/l K2HPO4 34.4ml、5mol/l NaCl 30ml、0.5g NaN35g of BSA is dissolved by adding distilled water, then the pH value is adjusted to 7.4, and the volume is fixed to 1L to obtain the BSA-soluble emulsion;
the long-acting liquid preparation is a propofol long-acting liquid preparation or doxorubicin hydrochloride liposome injection;
the certain proportion is 8-12 ml: 0.2-0.5 ml; the rotating speed of the centrifugation is 8000-12000 rpm, and the time is 12-16 min.
2. The method for determining the in vitro cumulative release of a long-acting liquid formulation according to claim 1, wherein: the angle of the rotating shaft of the rotating mixer is 0 degree to the horizontal plane, the rotating speed is 12rpm, and the rotating radius is 15 cm.
3. The method for determining the in vitro cumulative release of a long-acting liquid formulation according to claim 1, wherein: the temperature of the impeller was maintained at 37 ℃.
4. The method for determining the in vitro cumulative release of a long-acting liquid formulation according to claim 1, wherein: the sealable container comprises a volumetric flask, a conical flask, a test tube with a plug, a centrifuge tube and a colorimetric tube.
5. The method for determining the in vitro cumulative release of a long-acting liquid formulation according to claim 1, wherein: the long-acting liquid preparation comprises injection, microsphere preparation, targeted emulsion, microcapsule and liposome.
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| CN110824122B (en) * | 2019-10-29 | 2021-05-25 | 江苏盈科生物制药有限公司 | In-vitro release model and in-vitro release method of propofol fat emulsion injection |
| CN111122802A (en) * | 2019-12-30 | 2020-05-08 | 广东嘉博制药有限公司 | Method for measuring release curve of propofol fat emulsion injection |
| CN112881239B (en) * | 2020-12-30 | 2022-03-04 | 清华大学 | Method for determining tritium diffusion coefficient based on accumulated release share |
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