Method for optimizing dissolution curve and in-vivo bioequivalence of tablets

Abstract

The invention discloses a method for optimizing a dissolution curve and in-vivo bioequivalence of a tablet. The tablet comprises the following components in percentage by mass: 1-5% of amlodipine besylate (based on amlodipine), 55-65% of microcrystalline cellulose, 25-35% of anhydrous calcium hydrogen phosphate, 1-3% of carboxymethyl starch sodium and 0-2% of magnesium stearate. According to the invention, microcrystalline cellulose with an average particle size of 90-140 [mu] m, bulk density of 0.26-0.37 g / cm < 3 > and drying weight loss of not more than 1.5% is selected, and an optimized dissolution detection method is combined, so that dissolution curves of a self-made sample and a reference preparation in a plurality of media are similar, and in-vivo curative effects of the self-made sample and the reference preparation are ensured to be consistent.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation analysis technology, and particularly relates to a method for optimizing tablet dissolution profiles and in vivo bioequivalence. Background Technology

[0003] Currently, the standard dissolution testing method for amlodipine besylate tablets follows Method II—the paddle method—in the Chinese Pharmacopoeia. For example, patent CN103356497A discloses amlodipine besylate tablets and their manufacturing method, which uses Method III of Appendix XC, Part II of the 2010 edition of the Chinese Pharmacopoeia to determine dissolution. CN111110639B describes a pharmaceutical composition containing amlodipine besylate, which uses Method II of General Chapter 0931, Part IV of the 2015 edition of the Chinese Pharmacopoeia to determine dissolution. CN118490650A describes a method for preparing levamlodipine besylate tablets, which uses HPLC and General Chapter 0512 of ChP2020 to determine dissolution.

[0004] However, research has found that different types of microcrystalline cellulose on the market significantly affect the disintegration state of amlodipine besylate tablets during dissolution, thus affecting the dissolution profile results and their bioequivalence. Furthermore, no unified or standardized dissolution profile standard has been established for this formulation, and companies mostly develop their own testing methods based on their own needs. Therefore, to ensure consistent drug quality control and clinical efficacy, there is an urgent need for systematic optimization and standardization of the dissolution profile of amlodipine besylate tablets. This will help improve the accuracy and comparability of test results, further promoting the research and clinical application of this type of drug. Summary of the Invention

[0005] This invention provides a method for optimizing the dissolution curve and in vivo bioequivalence of amlodipine besylate tablets. The invention aims to improve the matching degree between existing amlodipine besylate tablet products and the original drug in multiple sets of dissolution curves, ensuring highly similar dissolution characteristics in vitro and in vivo. This application addresses the technical problems existing in the prior art by providing a method for optimizing the dissolution curve and in vivo bioequivalence of amlodipine besylate tablets. The amlodipine besylate tablets are composed of the following components by mass percentage: amlodipine besylate (calculated as amlodipine) 1-5%, microcrystalline cellulose 55-65%, anhydrous dicalcium phosphate 25-35%, sodium carboxymethyl starch 1-3%, and magnesium stearate 0-2%; more preferably, amlodipine besylate (calculated as amlodipine) 2-3%, microcrystalline cellulose 60-65%, anhydrous dicalcium phosphate 30-32%, sodium carboxymethyl starch 1-3%, and magnesium stearate 0-2%.

[0006] The microcrystalline cellulose has an average particle size of 90–140 μm and a bulk density of 0.26–0.37 g / cm³. 3The drying loss should not exceed 1.5%; slurry dissolution is adopted, and the control conditions include: pH of the dissolution medium is 1.0 to 7.0, and rotation speed is 50 to 100 rpm.

[0007] Furthermore, the slurry dissolution process includes: placing one amlodipine besylate tablet into 900 mL of dissolution medium, and then taking samples at fixed points for HPLC detection; the amlodipine besylate tablet is in the specification of 5 mg / tablet or 10 mg / tablet.

[0008] Furthermore, the fixed-point sampling time points are 5 min, 10 min, 15 min, 20 min, and 30 min.

[0009] Furthermore, the dissolution medium is selected from one of the following: an acidic solution with pH 1.2, an acidic solution with pH 4.0, a weakly acidic solution with pH 6.8, and water.

[0010] Furthermore, the acidic solution with pH 1.2 includes hydrochloride buffer, acetate buffer, phosphate buffer, or citrate buffer.

[0011] Furthermore, the acidic solution with pH 4.0 includes acetate buffer, phosphate buffer, or citrate buffer.

[0012] Furthermore, the weakly acidic solution with pH 6.8 includes acetate buffer, phosphate buffer, or citrate buffer.

[0013] Furthermore, the weakly acidic solution at pH 6.8 is a pH 6.8 phosphate buffer solution.

[0014] Furthermore, the rotational speed is 50 rpm, 75 rpm, or 100 rpm.

[0015] Furthermore, the rotational speed is 75 rpm.

[0016] The present invention selects microcrystalline cellulose with an average particle size of 90–140 μm and a bulk density of 0.26–0.37 g / cm³. 3 Using microcrystalline cellulose with a drying loss of no more than 1.5% as an excipient, combined with an optimized dissolution detection method, can ensure that the dissolution curves of the self-made sample and the reference preparation are similar in multiple media, and guarantee that the in vivo efficacy is consistent with that of the reference preparation. Attached Figure Description

[0017] Figure 1 These are the dissolution curves of amlodipine besylate tablets obtained in Examples 1-5 and the reference formulation at 100 rpm in the same medium.

[0018] Figure 2These are the dissolution curves of the amlodipine besylate tablets obtained in Examples 1-5 and the reference formulation at 75 rpm in the same medium.

[0019] Figure 3 The dissolution curves of amlodipine besylate tablets obtained in Examples 1-5 and the reference formulation at 50 rpm in the same medium are shown.

[0020] Figure 4 The dissolution curves of amlodipine besylate tablets obtained in Examples 1-5 and the reference formulation are shown in a medium at pH 6.8.

[0021] Figure 5 The dissolution curves of amlodipine besylate tablets obtained in Examples 1-5 and the reference formulation are shown in a medium at pH 4.0.

[0022] Figure 6 These are the dissolution curves of amlodipine besylate tablets obtained in Examples 1-5 and the reference formulation in aqueous medium. Detailed Implementation

[0023] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0024] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0025] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0026] In the embodiments of the present invention, dissolution detection is performed using HPLC, specifically referring to the detection methods and conditions in "General Chapter 0512 of the Chinese Pharmacopoeia, Part IV: High Performance Liquid Chromatography".

[0027] Table 1. Source and Model Information of Raw and Auxiliary Materials

[0028]

[0029]

[0030] Table 2 shows the prescription composition of amlodipine besylate in 5mg / tablet and 10mg / tablet strengths as follows:

[0031]

[0032] Preparation process of amlodipine besylate:

[0033] (1) Premixing: Add approximately 1 / 2 of the prescribed amount of microcrystalline cellulose, sodium carboxymethyl starch, amlodipine besylate, and anhydrous dicalcium phosphate to a laboratory hopper mixer and mix at 8 rpm for 5 min. Then, pass the mixture through a 1.0 mm circular sieve of a pulverizer and mix the sieved material in a laboratory hopper mixer at 8 rpm for 10 min.

[0034] (2) Total mixing: Add the remaining microcrystalline cellulose, magnesium stearate and premixed materials to the laboratory hopper mixer and mix at 8 rpm for 5 min.

[0035] (3) Tableting: For the 5mg tablet, use an 8.5mm round shallow concave punch. Calculate the tablet weight based on the theoretical tablet weight of 200mg and the intermediate particle content, controlling the hardness to 120-180N, with a weight difference of ±5%. For the 10mg tablet, use a 10.5mm round shallow concave punch. Calculate the tablet weight based on the theoretical tablet weight of 400mg and the intermediate particle content, controlling the hardness to 190-230N, with a weight difference of ±3%.

[0036] Table 3. Prescription composition of Examples 1-5

[0037]

[0038] (NMT, Not More Than; component dosage unit is mg)

[0039] Amlodipine besylate tablets of different microcrystalline cellulose grades were prepared according to the formulation composition and preparation process of amlodipine besylate in Table 3 (Examples 1-5). The dissolution rates of the obtained amlodipine besylate tablets and the reference formulation under different dissolution conditions were further investigated. The reference formulation was... Batch number: EP4079, certified by Pfizer Pharmaceuticals Ltd.

[0040] Table 4 Information on dissolution media

[0041]

[0042] The amlodipine besylate tablets obtained in Examples 1 to 5 were dissolved at 100 rpm, 75 rpm, and 50 rpm in pH 1.2 buffer solution, and three parallel batches were tested respectively. The results are shown in Tables 5 to 7. Figures 1-3 As shown.

[0043] (When f2 ≥ 50, it indicates that the dissolution curves are similar. The larger the f2, the better. When the dissolution rate of both the reference and the self-made product is > 85% at 15 min, there is no need to calculate f2, and the dissolution curves are directly determined to be similar.)

[0044] Table 5. Dissolution results of amlodipine besylate tablets and reference formulation obtained in Examples 1-5 at 100 rpm.

[0045]

[0046] Table 6. Dissolution results of amlodipine besylate tablets and reference formulation obtained in Examples 1-5 at 75 rpm.

[0047]

[0048] Table 7. Dissolution results of amlodipine besylate tablets and reference formulation obtained in Examples 1-5 at 50 rpm.

[0049]

[0050]

[0051] Through Tables 5-7 and Figures 1-3 The results show that the ability to distinguish the types of microcrystalline cellulose varies at different speeds. The ability to distinguish is stronger at 50 rpm and 100 rpm, and the ability to distinguish is strongest at 75 rpm.

[0052] The dissolution results of the self-made sample and the reference preparation were further compared in three media: pH 6.8 buffer, pH 4.0 buffer and water.

[0053] Table 8 shows the dissolution results of amlodipine besylate tablets obtained in Examples 1–5 and the reference formulation in pH 6.8 buffer solution.

[0054]

[0055] Table 9 shows the dissolution results of amlodipine besylate tablets obtained in Examples 1–5 and the reference formulation in pH 4.0 buffer solution.

[0056]

[0057] Table 10 Dissolution results of amlodipine besylate tablets and reference formulation obtained in water in Examples 1-5

[0058]

[0059]

[0060] From Tables 8-10 and Appendix Figures 4-6 It can be seen that the dissolution curves of the amlodipine besylate tablets obtained in Examples 3 and 4 and the reference formulation are very similar in the three media at 75 rpm.

[0061] Bioequivalence studies

[0062] In vivo absorption assay: Refer to the Guidelines for Bioavailability and Bioequivalence Studies of Drug Formulations (Chinese Pharmacopoeia 2020 Edition, Part IV, Guideline 9011). The 90% confidence intervals of the ratio of Cmax, AUC(0→t), and AUC(0→∞) of the logarithmic transformation values ​​of the development formulation and the reference formulation falling between 80% and 125% indicate that the development formulation is bioequivalent to the reference formulation. The inventors compared the bioequivalence studies of amlodipine besylate tablets (Examples 3 and 4) obtained using M112 and PH-112, and the specific test results are as follows:

[0063] Table 11 Drug absorption in Examples 3 and 4

[0064]

[0065] As shown in Table 11, the 90% confidence intervals of the ratios of Cmax, AUC(0→t), and AUC(0→∞) of the logarithmic transformation values ​​of Examples 3 and 4 to the reference formulation fall between 80% and 125%, indicating that they are equivalent to the reference formulation.

[0066] The above dissolution and bioequivalence studies show that:

[0067] (1) The amlodipine besylate tablets obtained using M102 in Example 1 had a high moisture content (large loss on drying). In a pH 1.2 medium, the dissolution curves were similar to the reference formulation at 100 rpm and 75 rpm. However, at 50 rpm, f2 < 50, which did not meet the requirement that the dissolution curves were similar to the reference formulation.

[0068] (2) The amlodipine besylate tablets obtained using M302 in Example 2 have a high moisture content (large loss on drying) and a high bulk density. In a pH 1.2 medium, at 75 rpm, the dissolution curve is similar to that of the reference formulation; at 100 rpm and 50 rpm, f2 is less than 50, which does not meet the requirement that the dissolution curve is similar to that of the reference formulation.

[0069] (3) The amlodipine besylate tablets obtained using PH-200LM in Example 5 had a large bulk density and average particle size. In pH 1.2 medium, at 75 rpm, the dissolution curve was similar to that of the reference formulation. However, at 100 rpm and 50 rpm, f2 was less than 50, which did not meet the requirement that the dissolution curve was similar to that of the reference formulation.

[0070] (4) The amlodipine besylate tablets obtained using M112 and PH-112 (Examples 3 and 4) had suitable moisture content, bulk density, and particle size. In pH 1.2 medium, at 75 rpm, the dissolution profile was similar to the reference formulation; at 100 rpm and 50 rpm, f2 > 50, satisfying the requirement that the dissolution profile was similar to the reference formulation. In addition, in pH 6.8 buffer, pH 4.0 buffer, and water medium, at 75 rpm, f2 > 50, satisfying the requirement that the dissolution profile was similar to the reference formulation.

[0071] (5) The amlodipine besylate tablets obtained in Examples 3 and 4 were finally compared with the reference preparation in an in vivo bioequivalence study. The results showed that they were equivalent and met the requirements for in vivo efficacy.

[0072] Therefore, amlodipine besylate tablets can be selected with an average particle size of 90–140 μm and a bulk density of 0.26–0.37 g / cm³. 3 The microcrystalline cellulose used has a drying loss of no more than 1.5%. Preferably, microcrystalline cellulose with a median particle size of 100 μm and a bulk density of 0.26–0.36 g / mL is selected. A specific dissolution detection method is employed to ensure that the dissolution curves of the self-made sample and the reference formulation are similar in multiple media, and to guarantee consistency with the in vivo efficacy of the reference formulation.

[0073] The embodiments of this application have been described above with reference to the accompanying drawings. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method for optimizing the dissolution profile and in vivo bioequivalence of tablets, wherein the tablets are composed of the following components by weight percentage: amlodipine besylate (calculated as amlodipine) 1-5%, microcrystalline cellulose 55-65%, anhydrous dicalcium phosphate 25-35%, sodium carboxymethyl starch 1-3%, and magnesium stearate 0-2%; characterized in that, The microcrystalline cellulose has an average particle size of 90–140 μm and a bulk density of 0.26–0.37 g / cm³. 3 The loss on drying should not exceed 1.5%. The slurry dissolution method was adopted, and the controlled conditions included: the pH of the dissolution medium was 1.0 to 7.0, and the rotation speed was 50 to 100 rpm.

2. The method according to claim 1, characterized in that, The slurry dissolution process includes: placing one amlodipine besylate tablet into 900 mL of dissolution medium, and then taking samples at fixed points for HPLC detection; the amlodipine besylate tablets are in the form of 5 mg / tablet or 10 mg / tablet.

3. The method according to claim 2, characterized in that, The fixed-point sampling time points are 5 min, 10 min, 15 min, 20 min, and 30 min.

4. The method according to claim 3, characterized in that, The leaching medium is selected from one of the following: an acidic solution with pH 1.2, an acidic solution with pH 4.0, a weakly acidic solution with pH 6.8, and water.

5. The method according to claim 4, characterized in that, The acidic solution with pH 1.2 includes hydrochloride buffer, acetate buffer, phosphate buffer, or citrate buffer.

6. The method according to claim 5, characterized in that, The acidic solution with pH 4.0 includes acetate buffer, phosphate buffer, or citrate buffer.

7. The method according to claim 6, characterized in that, The weakly acidic solution with pH 6.8 includes acetate buffer, phosphate buffer, or citrate buffer.

8. The method according to claim 7, characterized in that, The weakly acidic solution with pH 6.8 is a pH 6.8 phosphate buffer solution.

9. The method according to any one of claims 1 to 8, characterized in that, The rotational speed is 50 rpm, 75 rpm, or 100 rpm.

10. The method according to claim 9, characterized in that, The rotational speed is 75 rpm.

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