Diltiazem hydrochloride sustained-release capsule and preparation method thereof

Abstract

The invention relates to a diltiazem hydrochloride sustained-release capsule, the content of the sustained-release capsule comprises a diltiazem hydrochloride sustained-release micro-tablet, and the diltiazem hydrochloride sustained-release micro-tablet comprises diltiazem hydrochloride, a release adjusting material and a hydrophilic gel material, the in-vitro release degree similarity factor f2 of the sustained-release capsule and a commercially available diltiazem hydrochloride sustained-release capsule produced by Mylan company is greater than 50. The diltiazem hydrochloride sustained-release capsule disclosed by the invention has an in-vitro release degree similar to that of a commercially available reference preparation, and is simple in production process, low in material cost and easy for industrial mass production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to a diltiazem hydrochloride sustained-release capsule and a preparation method thereof. Background Art

[0002] Diltiazem hydrochloride is a calcium ion antagonist. It dilates coronary arteries and collateral vessels and increases coronary flow by inhibiting the influx of calcium ions into coronary vessels and peripheral vascular smooth muscle cells, thereby improving myocardial ischemia and limiting the expansion of myocardial infarction. It can dilate peripheral blood vessels, lower blood pressure, reduce cardiac load, slow heart rate and reduce myocardial oxygen consumption. Diltiazem hydrochloride is suitable for the treatment of coronary heart disease, angina pectoris and mild to moderate hypertension, especially for hypertensive patients with coronary heart disease and angina pectoris.

[0003] The effective therapeutic concentration of diltiazem hydrochloride is 50-200ng / ml. The elimination half-life of single and multiple doses of ordinary tablets is 3.5 hours, and the half-life is slightly prolonged with increasing concentration. Its oral absorption rate can be as high as 80-90%, but due to the obvious first-pass effect, its bioavailability is only about 45%. Studies have reported that the sustained-release preparation of diltiazem hydrochloride can improve bioavailability and maintain effective therapeutic blood concentration from night to the critical early morning, making its efficacy safer and more reliable.

[0004] The commercially available diltiazem HCl Extended-Release Capsules (USP) produced by Mylan in the United States are taken once every 12 hours, and the capsule contents contain diltiazem HCl sustained-release micropellets, which are prepared by sequentially coating a drug-containing layer and a sustained-release layer on a sucrose pellet core. The above-mentioned sustained-release capsules have a complex prescription, a cumbersome process, a long preparation process, too many parameter controls, and a greater impact of process stability on equipment performance. In addition, a large amount of organic solvents are required when preparing the coated pellet core of the sustained-release capsule, and the environmental friendliness is poor.

[0005] At present, there is no literature report on diltiazem hydrochloride sustained-release capsules that have similar in vitro dissolution behavior to the commercially available diltiazem hydrochloride sustained-release capsules produced by Mylan, but with a simple preparation process and controllable product quality. Summary of the invention

[0006] To solve the above technical problems, the present invention includes the following aspects:

[0007] The first aspect of the present invention provides a diltiazem hydrochloride sustained-release capsule, wherein the content of the sustained-release capsule comprises a diltiazem hydrochloride sustained-release microtablet, wherein the diltiazem hydrochloride sustained-release microtablet comprises diltiazem hydrochloride, a release regulating material and a hydrophilic gel material, and the in vitro release similarity factor f2 of the sustained-release capsule and the commercially available diltiazem hydrochloride sustained-release capsule produced by Mylan is greater than 50.

[0008] Preferably, the weight percentage of diltiazem hydrochloride in the content of the sustained-release capsule is 40-60%. More preferably, the weight percentage of diltiazem hydrochloride in the content of the sustained-release capsule is 45-55%. Further preferably, the weight percentage of diltiazem hydrochloride in the content of the sustained-release capsule is 50%.

[0009] Preferably, the release regulating material is selected from one or more of Eudragit L100-55 (copolymer of methacrylic acid and ethyl acrylate (1:1)), Eudragit L100 (copolymer of methacrylic acid and methyl methacrylate (1:1)), Eudragit S100 (copolymer of methacrylic acid and methyl methacrylate (1:2)) and HPMCAS-LF (hydroxypropyl methylcellulose acetate succinate). More preferably, the release regulating material is selected from one or more of Eudragit L100-55, Eudragit L100 and Eudragit S100. Further preferably, the release regulating material is Eudragit L100-55.

[0010] Preferably, the weight percentage of the release regulating material in the sustained-release capsule content is 25%-50%. More preferably, the weight percentage of the release regulating material in the sustained-release capsule content is 30%-45%. Further preferably, the weight percentage of the release regulating material in the sustained-release capsule content is 35%-42.5%.

[0011] Preferably, the hydrophilic gel material is selected from one or more of hydroxypropyl methylcellulose K100LV, hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K100M, hydroxyethyl cellulose 250HX, hydroxypropyl cellulose HXF and hydroxyethyl cellulose 250HHX. More preferably, the hydrophilic gel material is selected from one or more of hydroxypropyl methylcellulose K100LV, hydroxypropyl methylcellulose K4M, hydroxypropyl cellulose HXF and hydroxyethyl cellulose 250HHX. Further preferably, the hydrophilic gel material is hydroxypropyl methylcellulose K4M.

[0012] Preferably, the weight percentage of the hydrophilic gel material in the sustained-release capsule content is 3%-20%. More preferably, the weight percentage of the hydrophilic gel material in the sustained-release capsule content is 5%-17%. Further preferably, the weight percentage of the hydrophilic gel material in the sustained-release capsule content is 7%-14.5%.

[0013] Preferably, the weight ratio of the release regulating material to the hydrophilic gel material is (2-10): 1. More preferably, the weight ratio of the release regulating material to the hydrophilic gel material is (2.2-8): 1. Further preferably, the weight ratio of the release regulating material to the hydrophilic gel material is (2.4-6): 1.

[0014] Preferably, the release regulating material is Eudragit L100-55, the hydrophilic gel material is hydroxypropyl methylcellulose K4M, and the weight ratio of the release regulating material to the hydrophilic gel material is (2.4-6):1.

[0015] Preferably, the diltiazem hydrochloride sustained-release microtablets further contain a lubricant.

[0016] Preferably, the lubricant is selected from one or more of magnesium stearate, silicon dioxide, and talc. More preferably, the lubricant is selected from one or more of magnesium stearate and silicon dioxide. Further preferably, the lubricant is selected from magnesium stearate or silicon dioxide.

[0017] Preferably, the diltiazem hydrochloride sustained-release microtablets contain 120 mg diltiazem hydrochloride, 102 mg Eudragit L100-55, 16.8 mg hypromellose K4M and 1.2 mg magnesium stearate.

[0018] Preferably, the diltiazem hydrochloride sustained-release microtablets contain 120 mg diltiazem hydrochloride, 93.6 mg Eudragit L100-55, 25.2 mg hypromellose K4M and 1.2 mg silicon dioxide.

[0019] Preferably, the diltiazem hydrochloride sustained-release microtablets contain 120 mg diltiazem hydrochloride, 84 mg Eudragit L100-55, 34.8 mg hypromellose K4M, 0.5 mg silicon dioxide and 0.7 mg magnesium stearate.

[0020] Preferably, the content of a unit dose of sustained-release capsule contains 1-6 diltiazem hydrochloride sustained-release microtablets. More preferably, the content of a unit dose of sustained-release capsule contains 2-5 diltiazem hydrochloride sustained-release microtablets. Further preferably, the content of a unit dose of sustained-release capsule contains 3-4 diltiazem hydrochloride sustained-release microtablets. Further preferably, the content of a unit dose of sustained-release capsule contains 4 diltiazem hydrochloride sustained-release microtablets.

[0021] Preferably, the content of diltiazem hydrochloride in each diltiazem hydrochloride sustained-release microtablet is 20-40 mg. More preferably, the content of diltiazem hydrochloride in each diltiazem hydrochloride sustained-release microtablet is 25-35 mg. Further preferably, the content of diltiazem hydrochloride in each diltiazem hydrochloride sustained-release microtablet is 30 mg.

[0022] Preferably, the content of diltiazem hydrochloride in each diltiazem hydrochloride sustained-release capsule is 60-120 mg. More preferably, the content of diltiazem hydrochloride in each diltiazem hydrochloride sustained-release capsule is 60 mg, 90 mg or 120 mg.

[0023] Preferably, the commercially available diltiazem hydrochloride sustained-release capsules produced by Mylan are called Diltiazem HCl Extended-Release Capsules, USP, with a specification of 60-120 mg. More preferably, the specification is 60 mg, 90 mg or 120 mg.

[0024] Preferably, the in vitro release similarity factor f2 of the sustained-release capsule and the commercially available diltiazem hydrochloride sustained-release capsule produced by Mylan is greater than 55. More preferably, the in vitro release similarity factor f2 of the sustained-release capsule and the commercially available diltiazem hydrochloride sustained-release capsule produced by Mylan is greater than 60. Further preferably, the in vitro release similarity factor f2 of the sustained-release capsule and the commercially available diltiazem hydrochloride sustained-release capsule produced by Mylan is greater than 65.

[0025] The second aspect of the present invention provides a method for preparing the above-mentioned diltiazem hydrochloride sustained-release capsules, the preparation method comprising the following steps:

[0026] (1) mixing a prescribed amount of diltiazem hydrochloride, a release regulating material, a hydrophilic gel material and a lubricant;

[0027] (2) compressing the mixed powder into sustained-release microtablets in a tablet press;

[0028] (3) Fill the sustained-release microtablets directly into capsules to obtain the product.

[0029] Preferably, in step (1), the components are mixed in a mixer.

[0030] Preferably, in step (2), the powder is pressed into sustained-release microtablets using a punch with a diameter of 5 mm.

[0031] Preferably, the step (2) compresses to obtain a sustained-release microtablet with a tablet weight of 60 mg, which contains 30 mg of diltiazem hydrochloride.

[0032] Preferably, in step (3), the sustained-release microtablets are placed in a hopper of a capsule filling machine, and the capsule filling machine is used to fill the sustained-release microtablets into capsules.

[0033] Preferably, in step (3), 4 sustained-release microtablets are filled into each capsule.

[0034] The third aspect of the present invention provides the use of the above-mentioned diltiazem hydrochloride sustained-release capsules in the preparation of drugs for treating hypertension and angina pectoris.

[0035] The technical effects produced by the present invention are:

[0036] 1. The present invention unexpectedly discovered that the diltiazem hydrochloride sustained-release capsules prepared by mixing diltiazem hydrochloride with specific release regulating materials (e.g. Eudragit L100-55), hydrophilic gel materials (e.g. hydroxypropyl methylcellulose K4M), etc., and pressing them into sustained-release microtablets, which were then filled into capsule shells, had an in vitro release rate similar to that of the commercially available reference preparation, and were expected to achieve bioequivalence with the reference preparation.

[0037] 2. The diltiazem hydrochloride sustained-release capsules provided by the present invention have a simple production process, low material cost, and are easy to industrialize and mass-produce, thus saving the medication costs of patients. DETAILED DESCRIPTION

[0038] Test Example 1: In vitro dissolution test of diltiazem hydrochloride sustained-release capsules

[0039] 1. Test methods

[0040] 1.1. Preparation of Diltiazem Hydrochloride Sustained-Release Capsules

[0041] (1) Prescription

[0042] The prescriptions of Examples 1-3 of the present invention are shown in the following table (the drug content per unit dose is 120 mg, and the units of each excipient are all mg).

[0043] composition Example 1 Example 2 Example 3 Diltiazem hydrochloride 120 120 120 EudragitL100-55 102 93.6 84 Hydroxypropyl methylcellulose K4M 16.8 25.2 34.8 Silicon dioxide — 1.2 0.5 Magnesium Stearate 1.2 — 0.7 total 240 240 240

[0044] The prescriptions of comparative examples 1-7 of the present invention are shown in the following table (the drug content per unit dose is 120 mg, and the units of each auxiliary material are all mg).

[0045] composition Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Diltiazem hydrochloride 120 120 120 120 120 120 120 EudragitL100-55 118.8 — — — — — — EudragitL100 — 118.8 — — — — — Eudragit S100 — — 118.8 — — — — Hydroxypropyl methylcellulose K100LV — — — 118.8 — — — Hydroxypropyl methylcellulose K4M — — — — 118.8 — — Hydroxyethyl Cellulose 250HHX — — — — — 118.8 — Hydroxypropylcellulose HXF — — — — — — 118.8 Magnesium Stearate 1.2 1.2 1.2 1.2 1.2 1.2 1.2 total 240 240 240 240 240 240 240

[0046] The prescriptions of comparative examples 8-13 of the present invention are shown in the following table (the drug content per unit dose is 120 mg, and the units of each auxiliary material are all mg).

[0047] composition Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 Diltiazem hydrochloride 120 120 120 120 120 120 EudragitL100-55 72 — — 96 96 96 EudragitL100 — 96 — — — — Eudragit S100 — — 96 — — — Hydroxypropyl methylcellulose K100LV — — — 22.8 — — Hydroxypropyl methylcellulose K4M 46.8 22.8 22.8 — — — Hydroxyethyl Cellulose 250HHX — — — — 22.8 — Hydroxypropylcellulose HXF — — — — — 22.8 Silicon dioxide — 1.2 — 0.5 0.5 0.5 Magnesium Stearate 1.2 — 1.2 0.7 0.7 0.7 total 240 240 240 240 240 240

[0048] (2) Preparation process

[0049] The preparation methods of Examples 1-3 and Comparative Examples 1-13 are as follows:

[0050] 1) mixing the prescribed amount of diltiazem hydrochloride, the release regulating material, the hydrophilic gel material and the lubricant in a mixer;

[0051] 2) The mixed powder is placed in a tablet press hopper, and the mixed powder is pressed into a round sustained-release microtablet with a diameter of 5 mm and a tablet weight of 60 mg using the tablet press, each sustained-release microtablet containing 30 mg of diltiazem hydrochloride;

[0052] 3) Place the sustained-release micro-tablets in the hopper of a capsule filling machine, and use the capsule filling machine to fill four micro-tablets into one capsule to obtain diltiazem hydrochloride sustained-release capsules with a specification of 120 mg.

[0053] The total amount of diltiazem hydrochloride and auxiliary materials in each batch is 1000 g.

[0054] 1.2. Dissolution Determination of Diltiazem Hydrochloride Sustained-Release Capsules

[0055] The diltiazem hydrochloride sustained-release capsules prepared in Examples 1-3 and Comparative Examples 1-13 and the diltiazem hydrochloride sustained-release capsules as a reference preparation (produced by Mylan, USA, the product name is Diltiazem HCl Extended-Release Capsules, USP, specification is 120 mg) were taken respectively, and the in vitro release of each prescription was determined by the paddle method, the rotation speed was 100 rpm, the dissolution medium was pH 1.2 hydrochloric acid solution, the dissolution medium temperature was 37°C ± 0.5°C, the dissolution medium volume was 900 mL, and the release of diltiazem hydrochloride (%) was determined by sampling at 2h, 4h, 6h, 8h, and 12h, respectively, and the detection wavelength was UV 270nm, and the dissolution similarity factor f2 of each embodiment and comparative example and the reference preparation was calculated.

[0056] 2. Test results

[0057] The release results of the diltiazem hydrochloride sustained-release capsules of Examples 1-3 of the present invention at different time points are shown in Table 1 below.

[0058] Table 1 Release data of the prescriptions of Examples 1-3 of the present invention

[0059] Sampling time Reference preparation Example 1 Example 2 Example 3 2 hours 5 9 12 14 4 hours 20 25 31 30 6 hours 35 39 41 43 8 hours 48 46 52 54 12 hours 72 65 70 70 Similarity factor f2 — 66 58 56

[0060] The release results of the diltiazem hydrochloride sustained-release capsules of Comparative Examples 1-7 of the present invention at different time points are shown in Table 2 below.

[0061] Table 2 Release data of comparative examples 1-7 of the present invention

[0062]

[0063]

[0064] The release results of the diltiazem hydrochloride sustained-release capsules of Comparative Examples 8-13 of the present invention at different time points are shown in Table 3 below.

[0065] Table 3 Release data of comparative examples 8-13 of the present invention

[0066] Sampling time Reference preparation Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 2 hours 5 20 47 44 17 16 17 4 hours 20 40 69 66 39 35 36 6 hours 35 54 88 82 48 45 45 8 hours 48 61 92 93 54 50 51 12 hours 72 76 100 99 62 56 59 Similarity factor f2 — 41 18 19 45 46 47

[0067] It can be seen from the test results of Examples 1-3 in Table 1 that when the amount of the release regulating material Eudragit L100-55 is 35%-42.5% and the amount of the hydrophilic gel material hydroxypropyl methylcellulose K4M is 7%-14.5%, the release similarity factor of the prepared sustained-release capsules and the reference preparation can reach more than 50, confirming that the combination of the release regulating material Eudragit L100-55 and the hydrophilic gel material hydroxypropyl methylcellulose K4M can make the diltiazem hydrochloride sustained-release capsules achieve an in vitro release similar to that of the reference preparation, and it is expected to achieve bioequivalence with the reference preparation.

[0068] In contrast, it can be seen from the test results of Comparative Examples 1-7 in Table 2 that when different release regulating materials or hydrophilic gel materials are used alone in the formulation, the release similarity factor of the prepared sustained-release capsules and the reference preparation cannot reach 50. It can be seen from the test results of Comparative Examples 9-13 in Table 3 that when the hydrophilic gel material hydroxypropyl methylcellulose K4M is used in combination with different release regulating materials (Eudragit L100 and Eudragit S100) in the formulation, or when the release regulating material Eudragit L100-55 is used in combination with different hydrophilic gel materials (hydroxypropyl methylcellulose K100LV, hydroxypropyl cellulose HXF and hydroxyethyl cellulose 250HHX), the release similarity factor of the prepared sustained-release capsules and the reference preparation cannot reach 50. It can be seen from the test results of Comparative Example 8 in Table 3 that when the mixing ratio of the release regulating material Eudragit L100-55 and the hydrophilic gel material hydroxypropyl methylcellulose K4M in the prescription is less than 2:1, the release similarity factor of the prepared sustained-release capsule and the reference preparation cannot reach 50. The above test results show that other common release regulating materials and hydrophilic gel materials used alone or in combination cannot obtain a dissolution similar to that of the reference preparation, and thus it is expected that bioequivalence with the reference preparation cannot be achieved.

[0069] Although specific embodiments of the present invention have been described, it will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the scope or spirit of the present invention. Therefore, the present invention is intended to cover all such changes and modifications that fall within the scope of the appended claims and their equivalents.

Claims

1. A diltiazem hydrochloride sustained-release capsule, characterized in that: The content of the sustained-release capsule comprises diltiazem hydrochloride sustained-release microtablets, which comprise diltiazem hydrochloride, a release regulating material and a hydrophilic gel material. The in vitro release similarity factor f2 of the sustained-release capsule and the commercially available diltiazem hydrochloride sustained-release capsule produced by Mylan is greater than 50.

2. The diltiazem hydrochloride sustained-release capsule according to claim 1, characterized in that: The release regulating material is selected from one or more of Eudragit L100-55, Eudragit L100, Eudragit S100 and HPMCAS-LF.

3. The diltiazem hydrochloride sustained-release capsule according to claim 1, characterized in that: The release regulating material is Eudragit L100-55.

4. The diltiazem hydrochloride sustained-release capsule according to any one of claims 1 to 3, characterized in that: The hydrophilic gel material is selected from one or more of hydroxypropyl methylcellulose K100LV, hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K100M, hydroxyethyl cellulose 250HX, hydroxypropyl cellulose HXF and hydroxyethyl cellulose 250HHX.

5. The diltiazem hydrochloride sustained-release capsule according to claim 4, characterized in that: The hydrophilic gel material is hydroxypropyl methylcellulose K4M.

6. The diltiazem hydrochloride sustained-release capsule according to claim 1, characterized in that: The weight ratio of the release regulating material to the hydrophilic gel material is (2-10):

1.

7. The diltiazem hydrochloride sustained-release capsule according to claim 1, characterized in that: The diltiazem hydrochloride sustained-release microtablets further comprise a lubricant.

8. The diltiazem hydrochloride sustained-release capsule according to claim 7, characterized in that: The lubricant is selected from one or more of magnesium stearate, silicon dioxide and talc.

9. The method for preparing the diltiazem hydrochloride sustained-release capsules according to any one of claims 1 to 8, characterized in that: The preparation method comprises the following steps: (1) mixing a prescribed amount of diltiazem hydrochloride, a release regulating material, a hydrophilic gel material and a lubricant; (2) compressing the mixed powder into sustained-release microtablets in a tablet press; (3) Fill the sustained-release microtablets directly into capsules to obtain the product.

10. Use of the diltiazem hydrochloride sustained-release capsule according to any one of claims 1 to 8 in the preparation of a medicament for treating hypertension and angina pectoris.

Images