Method for detecting ezetimibe and simvastatin tablets with distinguishing force dissolution curve

Abstract

The invention relates to the technical field of medicine detection, in particular to a method for detecting ezetimibe simvastatin tablets with a distinguishing force dissolution curve, which comprises the following steps: respectively using a buffer solution containing 0.2-0.3 wt% of lauryl sodium sulfate and having a pH value of 1-7 and a buffer solution containing 0.05-0.10 wt% of lauryl sodium sulfate and having a pH value of 4.5-7 as dissolution media, and performing dissolution by adopting a slurry method, so as to obtain the ezetimibe simvastatin tablets with the distinguishing force dissolution curve. And carrying out liquid phase analysis after sampling at regular time. The ezetimibe and simvastatin tablet is subjected to dissolution detection through the first dissolution medium and the second dissolution medium, so that the dissolution curve is established, the changes of the prescription and the process of the ezetimibe and simvastatin tablet are effectively distinguished, the ezetimibe and simvastatin tablet is rapidly detected, the dissolution and release rates of the ezetimibe and simvastatin tablet in a living body are predicted, and the detection accuracy of the ezetimibe and simvastatin tablet is improved. Therefore, the number of times of bioequivalence of the human body is reduced, and finally the purposes of reducing the input cost and improving the research and development efficiency are achieved.

Description

Technical Field

[0001] The present application relates to the technical field of drug detection, and in particular to a detection method for ezetimibe-simvastatin tablets having a differentiated intensity dissolution curve. Background Art

[0002] After oral administration of solid preparations, drug absorption depends on the dissolution or release of the drug from the preparation, the dissolution of the drug under physiological conditions, and the penetration of the gastrointestinal tract. In order to evaluate the degree of drug release, it is usually necessary to use human bodies as research subjects. After the drug is administered to the human body, human plasma is extracted at a specified time point and the drug concentration in the plasma is measured. This test is very expensive and has invisibly increased drug costs and social burdens.

[0003] Dissolution curves can be used to evaluate the dissolution and release rate of drugs in vivo. By establishing a differential dissolution curve, the pharmacokinetic behavior of drugs in vivo can be predicted, thereby reducing the number of human bioequivalence tests, and ultimately achieving the goal of reducing investment costs and improving R&D efficiency.

[0004] In the existing data, the dissolution method used for ezetimibe and simvastatin tablets is: dissolution medium 0.01 mol / L sodium dihydrogen phosphate buffer (pH 7.0) plus 0.5% SDSD; dissolution medium volume 900 mL; paddle method; 50 rpm.

[0005] The dissolution curve was established using the above method, and samples were taken at 5 / 10 / 15 / 20 / 30 / 45 / 60 min, respectively. The results are shown in Table 1.

[0006] Table 1 Existing dissolution curves

[0007] Sampling time (min) Ezetimibe Simvastatin 5 48％ 57％ 10 75％ 85％ 15 87％ 94％ 20 92％ 97％ 30 92％ 97％ 45 98％ 98％ 60 99％ 98％

[0008] The main drawback of this dissolution method is that the cumulative dissolution of the two components reached more than 85% at 15 minutes, which is a very rapid dissolution and cannot achieve the purpose of predicting the pharmacokinetic behavior of the drug in vivo.

[0009] Therefore, it is urgent to establish a dissolution curve with discriminating power to predict the pharmacokinetic behavior of ezetimibe and simvastatin tablets in vivo, so that the bioequivalence test can be passed in one time under the conditions of similar dissolution curves, thereby reducing the company's capital investment and reducing costs. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a detection method for a dissolution curve of ezetimibe-simvastatin tablets with a differentiated strength, thereby solving the defect that the existing dissolution curve of ezetimibe-simvastatin tablets has low differentiation.

[0011] In order to solve the above technical problems, the technical solution adopted by the present invention is: a detection method for ezetimibe simvastatin tablets with a differentiated strength dissolution curve, using a buffer solution with a pH of 1 to 7 containing 0.2 to 0.3 wt% of sodium dodecyl sulfate and a buffer solution with a pH of 4.5 to 7 containing 0.05 to 0.10 wt% of sodium dodecyl sulfate as dissolution media, respectively, using a slurry method for dissolution, and performing liquid phase analysis after regular sampling.

[0012] In some embodiments, the paddle speed of the paddle method is 40-60 rpm; and / or the dissolution temperature is 36.5-37.5°C.

[0013] In some embodiments, a buffer solution with a pH of 1 to 7 containing 0.2 to 0.3 wt % of sodium dodecyl sulfate is used as the first dissolution medium, and the ezetimibe component in the sample is dissolved using the first dissolution medium; a buffer solution with a pH of 4.5 to 7 containing 0.05 to 0.10 wt % of sodium dodecyl sulfate is used as the second dissolution medium, and the simvastatin component in the sample is dissolved using the second dissolution medium.

[0014] In some embodiments, the buffer of the first dissolution medium includes any one of 0.1N hydrochloric acid, 0.01N hydrochloric acid, 0.001N hydrochloric acid, pH 4.5 acetate buffer, pH 5.5 acetate buffer, pH 6.8 phosphate buffer or pH 7.0 phosphate buffer; and / or, the buffer of the second dissolution medium includes any one of pH 4.5 acetate buffer, pH 5.5 acetate buffer, pH 6.8 phosphate buffer or pH 7.0 phosphate buffer. Preferably, the buffer of the second dissolution medium is pH 7.0 phosphate buffer.

[0015] Specifically, the preparation process of the reference solution is as follows: respectively preparing reference substances of ezetimibe and simvastatin and dissolving them in acetonitrile, diluting to a fixed volume, and then diluting with the first dissolution medium or the second dissolution medium to obtain the reference substance solution;

[0016] The sample solution preparation process is as follows: take a sample of ezetimibe and simvastatin tablets, use 900 ml of each of the first dissolution medium and the second dissolution medium as the dissolution medium, and use the dissolution apparatus paddle method for dissolution, the paddle method speed is 50 rpm, and the temperature is 37±0.5°C; at different sampling time points, take out an appropriate amount of the dissolution solution, filter it and use it as the sample solution;

[0017] The determination process is: inject the sample solution and the reference solution into the high performance liquid analyzer respectively, and perform the detection under the set conditions. Specifically, the reference solution is stable within 12 hours at 25°C.

[0018] In some embodiments, the buffer of the first dissolution medium contains 0.25 wt % of sodium dodecyl sulfate; and the second dissolution medium contains 0.06 wt % of sodium dodecyl sulfate.

[0019] In some embodiments, the first dissolution medium is a phosphate buffer with a pH of 7.0, and the sodium dodecyl sulfate is 0.25 wt %;

[0020] And / or, the second dissolution medium is a phosphate buffer with a pH of 7.0, and the sodium dodecyl sulfate is 0.06 wt %.

[0021] In some embodiments, the preparation method of the first dissolution medium is: take 1.37g of sodium dihydrogen phosphate, add 900ml of water, adjust the pH to 7.0 with 50% sodium hydroxide solution, dilute to 1000ml with water, and then add 2.5g of sodium dodecyl sulfate to dissolve, and obtain;

[0022] The preparation method of the second dissolution medium is as follows: take 1.37g of sodium dihydrogen phosphate, add 900ml of water, adjust the pH to 7.0 with 50% sodium hydroxide solution, dilute to 1000ml with water, and then add 0.6g of sodium dodecyl sulfate to dissolve.

[0023] In some embodiments, the preparation method of the ezetimibe reference solution is: accurately weigh about 28 mg of the ezetimibe reference and place it in a 200 ml volumetric flask, add 10 ml of acetonitrile, sonicate until completely dissolved, dilute to the scale with a dissolution medium, shake well, transfer 4 ml of the above solution into a 50 ml volumetric flask, dilute to the scale with a dissolution medium, and shake well.

[0024] In some embodiments, the preparation method of the simvastatin reference solution is as follows: accurately weigh about 27.5 mg of simvastatin reference substance and place it in a 100 ml volumetric flask, add 5 ml of acetonitrile, sonicate until completely dissolved, dilute to scale with dissolution medium, and shake well. Pipette 5 ml of the above solution into a 50 ml volumetric flask, dilute to scale with dissolution medium, and shake well.

[0025] In some embodiments, sampling is performed when the dissolution time is 5, 10, 15, 20, 30, 45, or 60 min, and the sample solution is prepared after filtration.

[0026] In some embodiments, the sample solution is prepared by filtering the dissolution solution in the corresponding time dissolution instrument through a 0.45 μm PTFE filter membrane.

[0027] In some embodiments, the system suitability solution is also prepared: take 1 ml of the reference solution, add 1 drop of hydrochloric acid, and shake well.

[0028] Preferably, in the system suitability solution, the separation between the ezetimibe peak and the simvastatin hydroxy acid peak, and between the simvastatin hydroxy acid peak and the simvastatin peak should be no less than 1.2.

[0029] Preferably, the tailing factor of the ezetimibe peak and the simvastatin peak in the reference solution should be ≤2.0; the RSD of the ezetimibe / simvastatin peak area in the reference solution should be ≤2.0%.

[0030] Preferably, the RSD of the peak area of ​​ezetimibe / simvastatin in the reference solution and the peak area of ​​ezetimibe / simvastatin in the back-standard solution should be ≤2.0%.

[0031] Preferably, the RSD of the peak area of ​​ezetimibe / simvastatin in the reference solution and the peak area of ​​ezetimibe / simvastatin in the back-standard solution should be ≤2.0%.

[0032] In some embodiments, liquid phase analysis is performed using a high performance liquid chromatograph, using a 0.025 mol / L phosphate buffer-acetonitrile solution in a volume ratio of 43-47:53-57 as the mobile phase. Preferably, the mobile phase uses a 0.025 mol / L phosphate buffer-acetonitrile solution in a volume ratio of 45:55.

[0033] In some embodiments, the setting conditions of the high performance liquid analyzer are as shown in Table 2:

[0034] Table 2

[0035]

[0036] In some embodiments, the mobile phase is sodium dihydrogen phosphate buffer-acetonitrile (mass ratio is 45:55). Specifically, the preparation method of sodium dihydrogen phosphate buffer is: accurately weigh 3g sodium dihydrogen phosphate (NaH2PO4) into a 1000ml beaker, add 900ml water, adjust the pH to 4.0±0.05 with phosphoric acid, dilute with water to a volume of 1000ml, and filter through a 0.22μm filter membrane to obtain.

[0037] The beneficial effects of the present invention are:

[0038] 1. The detection method of the ezetimibe-simvastatin tablets provided by the present invention has a distinguishing force dissolution curve, which can effectively distinguish the changes in the prescription and process of the ezetimibe-simvastatin tablets, thereby quickly detecting the ezetimibe-simvastatin tablets, predicting their dissolution and release rates in the organism, and understanding their pharmacokinetic behavior, thereby reducing the number of human bioequivalence tests, and ultimately achieving the purpose of reducing investment costs and improving research and development efficiency.

[0039] 2. The ezetimibe-simvastatin tablets provided by the present invention have a detection method for distinguishing the intensity dissolution curves, and ezetimibe and simvastatin are separately dissolved through two dissolution media. At the same time, the detection accuracy of the corresponding components is not affected in different dissolution media, thereby ensuring the accuracy of the final detection effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 is the dissolution curve of ezetimibe in Example 1;

[0041] Figure 2 is the dissolution curve of simvastatin in Example 1;

[0042] Figure 3 is the dissolution curve of ezetimibe in Example 2;

[0043] Figure 4 is the dissolution curve of simvastatin in Example 2;

[0044] Figure 5 is the dissolution curve of ezetimibe in Example 3;

[0045] Figure 6 is the dissolution curve of simvastatin in Example 3;

[0046] Figure 7 is the dissolution curve of ezetimibe in Comparative Example 1;

[0047] Figure 8 is the dissolution curve of simvastatin in Comparative Example 1;

[0048] Fig. 9 is the dissolution curve of ezetimibe in Comparative Example 2;

[0049] Fig.10 is the dissolution curve of simvastatin in Comparative Example 2;

[0050] Fig.11 is the dissolution curve of ezetimibe in Comparative Example 3;

[0051] Fig.12 is the dissolution curve of simvastatin in Comparative Example 3;

[0052] Fig.13 is the dissolution curve of ezetimibe in Comparative Example 3;

[0053] Fig.14 This is the dissolution curve of simvastatin in Comparative Example 3. DETAILED DESCRIPTION

[0054] In order to explain the technical content, achieved objectives and effects of the present invention in detail, the following is an explanation in combination with the implementation modes and the accompanying drawings.

[0055] Example

[0056] Example 1

[0057] Example 1 uses the detection parameters shown in Table 3;

[0058] Table 3

[0059]

[0060]

[0061] In this embodiment, the detection method of the ezetimibe-simvastatin tablets with a differentiated intensity dissolution curve provided by the present invention is used to detect the ezetimibe-simvastatin tablets using different stirring paddle speeds during the granulation process. The stirring paddle speeds during the granulation process are respectively: 100 rpm and 300 rpm.

[0062] Specific data are shown in Tables 4 and 5, and the dissolution curves are shown in Figure 1 and Figure 2 shown.

[0063] Table 4 Example 1 Ezetimibe results

[0064]

[0065] Table 5 Simvastatin results of Example 1

[0066]

[0067] Example 2

[0068] The detection parameters used in this embodiment are the same as those in Example 1, except that the samples to be tested are ezetimibe and simvastatin tablets with different pressures in the tableting process, which are 80N and 100N respectively.

[0069] Specific data are shown in Tables 6 and 7, and the dissolution curves are shown in Figure 3 and Figure 4 shown.

[0070] Table 6 Example 2 Ezetimibe results

[0071]

[0072] Table 7 Example 2 Simvastatin results

[0073]

[0074] It can be seen from the results of Example 1 and Example 2 that the detection method for distinguishing the intensity dissolution curve of the ezetimibe simvastatin tablets provided by the present invention can detect the differences in the dissolution curves of the ezetimibe simvastatin tablets caused by different processes, so that the research and development personnel can adjust the process according to the dissolution curve obtained by the test, and ultimately make the pharmacokinetic behavior of the target preparation in the organism meet the expectations, thereby reducing the research and development costs.

[0075] Example 3

[0076] Based on the detection parameters of Example 1, the dissolution curves of the self-developed ezetimibe-simvastatin tablets with two different processes were tested. The specific results are shown in Table 8. Figure 5 and Figure 6 shown.

[0077] Table 8 Example 3 test results

[0078]

[0079]

[0080] Example 3 The dissolution curve of two self-made preparations with different processes was tested using the detection method of the dissolution curve of the ezetimibe and simvastatin tablets provided by the present invention, and compared with the reference preparation. It can be found that the dissolution curves of the two processes are different, the dissolution behaviors are greatly distinguished, and the dissolution behaviors of ezetimibe and simvastatin in process 1 are closer to the reference preparation. The dissolution behavior of ezetimibe in process 2 is significantly slower, and it is inconsistent with the dissolution behavior of the reference preparation (f2 <50), and the dissolution behavior of simvastatin is also slower. According to the comparison results of the dissolution curve, the R&D personnel analyzed from the perspective of product quality attributes and process feasibility, and the final prescription was selected as process 1. It can be found that the detection method of the ezetimibe and simvastatin tablets provided in this application with a distinguishing force dissolution curve can be actually applied to the research and development process, and has good application value.

[0081] Comparative Example

[0082] In the existing detection methods, the dissolution method commonly used for ezetimibe simvastatin tablets is: the dissolution medium is 0.01 mol / L sodium dihydrogen phosphate buffer (pH7.0) plus 0.5% SDSD; at the same time, referring to the "Guidelines for the Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Preparations", the conventional dissolution medium is 0.1N HCl+0.5% SDS, pH4.5+0.5% SDS, and degassed water+0.5% SDS. A comparative experiment is now conducted on these four dissolution media.

[0083] Comparative Example 1

[0084] Comparative Example 1: Except that the dissolution medium is 0.1N HCl + 0.5% SDS, the other parameters and steps are the same as those of Example 3. The specific results are shown in Table 9. The dissolution curve is shown in Figure 7 and Figure 8 shown.

[0085] Table 9 Dissolution curve test results of 0.1N HCl + 0.5% SDS medium

[0086]

[0087] Comparative Example 2

[0088] Comparative Example 2: Except for the dissolution medium using pH 4.5 + 0.5% SDS, the other parameters and steps are the same as those of Example 3. The specific results are shown in Table 10. The dissolution curve is shown in Fig. 9 and Fig.10 shown.

[0089] Table 10 pH4.5+0.5% SDS medium dissolution curve test results

[0090]

[0091] Comparative Example 3

[0092] Comparative Example 3: Except that water + 0.5% SDS was used as the dissolution medium, the other parameters and steps were the same as those of Example 3. The specific results are shown in Table 11. The dissolution curve is shown in Fig.11 and Fig.12 shown.

[0093] Table 11 Water + 0.5% SDS medium dissolution curve test results

[0094]

[0095] Comparative Example 4

[0096] Comparative Example 4: Except for the dissolution medium using pH 7.0 + 0.5% SDS, the other parameters and steps were the same as those of Example 3. The specific results are shown in Table 12. The dissolution curve is shown in Fig.13 and Fig.14 shown.

[0097] Table 12 pH 7.0 + 0.5% SDS medium dissolution curve test results

[0098]

[0099] It can be seen from the results of Example 3 and Comparative Examples 1 to 4 that under the conditions of three dissolution media of pH 4.5 + 0.5% SDS, water + 0.5% SDS, and pH 7.0 + 0.5% SDS, the cumulative dissolution of the two components of each batch of samples from different processes at 15 minutes reached more than 85%, which is a very rapid dissolution and cannot achieve the purpose of predicting the pharmacokinetic behavior of the drug in vivo. In the 0.1N HCl + 0.5% SDS medium, the dissolution of simvastatin reached more than 85% at 15 minutes, which is a very rapid dissolution as above, and ezetimibe has no distinguishing strength in this medium. Therefore, the existing detection method cannot clearly distinguish the dissolution curves of ezetimibe and simvastatin, and the detection method of the ezetimibe simvastatin tablets provided by the present invention has a distinguishing strength dissolution curve, which can establish the dissolution curves of ezetimibe and simvastatin tablets prepared by different processes, can accurately distinguish, and has good application value.

[0100] It should be noted that the specific parameters or some commonly used reagents in the above embodiments are specific embodiments or preferred embodiments of the present invention, rather than limiting the present invention; those skilled in the art can make adaptive adjustments within the concept and protection scope of the present invention.

[0101] In addition, unless otherwise specified, the raw materials used may also be conventional commercial products in the art, or may be prepared by conventional methods in the art.

[0102] In addition, those skilled in the art should understand that, although there are many problems in the prior art, each embodiment or technical solution of the present invention can be improved in only one or several aspects, without having to solve all the technical problems listed in the prior art or background technology at the same time. Those skilled in the art should understand that the content not mentioned in a claim should not be used as a limitation on the claim.

[0103] Although the terms such as intermediate, solvent, etc. are used more frequently in this article, the possibility of using other terms is not excluded. These terms are used only to more conveniently describe and explain the essence of the present invention; interpreting them as any additional restrictions is contrary to the spirit of the present invention; the terms "first", "second", etc. (if any) in the description and claims of the embodiments of the present invention are used to distinguish similar objects, and are not necessarily used to describe a specific order or sequence.

[0104] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for detecting the dissolution curve of ezetimibe and simvastatin tablets having a differentiated strength, characterized in that: A buffer solution with a pH value of 1 to 7 and containing 0.2 to 0.3 wt % of sodium dodecyl sulfate and a buffer solution with a pH value of 4.5 to 7 and containing 0.05 to 0.10 wt % of sodium dodecyl sulfate were used as dissolution media, respectively. The paddle method was used for dissolution, and liquid phase analysis was performed after regular sampling.

2. The method for detecting the dissolution curve of ezetimibe and simvastatin tablets according to claim 1, characterized in that: The stirring speed of the paddle method is 40-60 rpm; and / or the dissolution temperature is 36.5-37.5°C.

3. The detection method of ezetimibe-simvastatin tablets having a differentiated strength dissolution curve according to claim 2, characterized in that: A buffer solution with a pH value of 1 to 7 and containing 0.2 to 0.3 wt % of sodium dodecyl sulfate is used as the first dissolution medium, and the ezetimibe component in the sample is dissolved using the first dissolution medium; a buffer solution with a pH value of 4.5 to 7 and containing 0.05 to 0.10 wt % of sodium dodecyl sulfate is used as the second dissolution medium, and the simvastatin component in the sample is dissolved using the second dissolution medium.

4. The detection method of ezetimibe-simvastatin tablets having a differentiated strength dissolution curve according to claim 3, characterized in that: The buffer of the first dissolution medium includes any one of 0.1N hydrochloric acid, 0.01N hydrochloric acid, 0.001N hydrochloric acid, pH 4.5 acetate buffer, pH 5.5 acetate buffer, pH 6.8 phosphate buffer or pH 7.0 phosphate buffer; and / or, the buffer of the second dissolution medium includes any one of pH 4.5 acetate buffer, pH 5.5 acetate buffer, pH 6.8 phosphate buffer or pH 7.0 phosphate buffer.

5. The method for detecting the dissolution curve of ezetimibe and simvastatin tablets according to claim 4, characterized in that: The buffer of the first dissolution medium contains 0.25 wt % of sodium dodecyl sulfate; and the second dissolution medium contains 0.06 wt % of sodium dodecyl sulfate.

6. The detection method of ezetimibe-simvastatin tablets having a differentiated strength dissolution curve according to claim 4, characterized in that: The first dissolution medium is a phosphate buffer with a pH of 7.0, and the sodium dodecyl sulfate is 0.25wt%; And / or, the second dissolution medium is a phosphate buffer with a pH of 7.0, and the sodium dodecyl sulfate is 0.06 wt %.

7. The detection method of ezetimibe-simvastatin tablets having a differentiated strength dissolution curve according to claim 6, characterized in that: The preparation method of the first dissolution medium is as follows: take 1.37g of sodium dihydrogen phosphate, add 900ml of water, adjust the pH to 7.0 with 50% sodium hydroxide solution, dilute to 1000ml with water, and then add 2.5g of sodium dodecyl sulfate to dissolve, and obtain; The preparation method of the second dissolution medium is as follows: take 1.37g of sodium dihydrogen phosphate, add 900ml of water, adjust the pH to 7.0 with 50% sodium hydroxide solution, dilute to 1000ml with water, and then add 0.6g of sodium dodecyl sulfate to dissolve.

8. The method for detecting the dissolution curve of ezetimibe and simvastatin tablets according to claim 1, characterized in that: Sampling was performed at the dissolution time of 5, 10, 15, 20, 30, 45, and 60 min, and the sample solution was prepared after filtration.

9. The detection method of ezetimibe-simvastatin tablets having a differentiated intensity dissolution curve according to claim 8, characterized in that: Liquid phase analysis was performed using a high performance liquid chromatograph, using a 0.025 mol / L phosphate buffer-acetonitrile solution with a volume ratio of 43-47:53-57 as the mobile phase.

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