Verapamil hydrochloride sustained-release capsule and preparation method thereof

Abstract

The invention relates to a verapamil hydrochloride sustained-release capsule, the content of the sustained-release capsule comprises a sustained-release coated pellet, and the sustained-release coated pellet comprises (a) a blank pellet core, (b) a drug coating layer wrapping the blank pellet core, and (c) a sustained-release coating layer wrapping the drug coating layer, the drug coating layer comprises verapamil hydrochloride and a release adjusting material, and the in-vitro release degree similarity factor f2 of the sustained-release capsule and a commercially available verapamil hydrochloride capsule # imgabs0 # is greater than 50. The release rate of the verapamil hydrochloride sustained-release capsule in an in-vitro dissolution medium with the pH value of 8.0 can reach 70% or above, the problem that the in-vitro release rate of verapamil hydrochloride is poor is effectively solved, and the in-vivo bioavailability of a medicine is greatly improved.

Description

Technical Field

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

[0002] Hypertension is one of the most common cardiovascular diseases and one of the major causes of death and disability in humans. Effective treatment of hypertension can significantly reduce the incidence, complication rate and mortality of cardiovascular events. It is estimated that by 2025, the prevalence of hypertension worldwide will reach 29%, which means that there will be 1.5 billion hypertensive patients in the world. In the case that the cause of hypertension is still unclear, treatment becomes the only effective means. Currently, the commonly used antihypertensive drugs in clinical practice include diuretics, renin-angiotensin system inhibitors (ACEI), angiotensin II receptor antagonists (ARB), calcium antagonists, α-receptor blockers and β-receptor blockers.

[0003] Calcium antagonists were proven to be effective in treating acute hypertension in 1962, and were widely studied and used to treat hypertension in the late 1970s. The antihypertensive mechanism of calcium antagonists is to block calcium ion channels on the myocardial and vascular smooth muscle cell membranes, inhibit the influx of extracellular calcium ions, reduce intracellular calcium ion levels, and cause changes in the functions of cardiovascular and other tissues and organs. Calcium antagonists are now widely used in the treatment of hypertension, coronary heart disease, arrhythmias, and cerebrovascular diseases. Half of the patients with hypertension and angina pectoris treated in China use calcium antagonists.

[0004] Verapamil hydrochloride, also known as isopamil and verapamil, has a trough-peak phenomenon in blood drug concentration due to the absorption characteristics of its ordinary preparations, which leads to excessive fluctuations in blood drug concentration and toxic side effects. Sustained-release preparations release drugs slowly, have stable blood drug concentrations, and have strong compliance, which are much superior to ordinary preparations. Therefore, verapamil hydrochloride is made into a sustained-release preparation that is administered 1-2 times a day, which is convenient for patients to take. While ensuring the effective therapeutic concentration, it reduces the toxic and side effects of the drug and avoids the development of drug resistance. In addition, low bioavailability has always been a problem that ordinary verapamil hydrochloride tablets are difficult to break through in scientific research, because its first-pass effect in the liver is significant, and its bioavailability is only about 10%-25%. At present, there are only studies on verapamil hydrochloride sustained-release tablets in China, but compared with the original preparation, Verapamil hydrochloride sustained-release capsules with similar in vitro release behavior and high release rate of active ingredients have not been reported so far. Summary of the invention

[0005] To solve the above technical problems, the present invention includes the following aspects:

[0006] The first aspect of the present invention provides a verapamil hydrochloride sustained-release capsule, wherein the content of the sustained-release capsule comprises sustained-release coated pellets, wherein the sustained-release coated pellets comprise: (a) a blank pellet core, (b) a drug coating layer wrapped outside the blank pellet core, and (c) a sustained-release coating layer wrapped outside the drug coating layer, wherein the drug coating layer comprises verapamil hydrochloride and a release regulating material, and the sustained-release capsule is similar to the commercially available verapamil hydrochloride capsule. The in vitro release similarity factor f2 is greater than 50.

[0007] Preferably, the blank pill core is selected from one or more of sucrose, starch, lactose, and microcrystalline cellulose. More preferably, the blank pill core material is selected from one or more of sucrose and starch. Further preferably, the blank pill core is a sucrose pill core. Further preferably, the blank pill core is a 30-35 mesh sucrose pill core.

[0008] Preferably, the weight percentage of the blank pill core in the sustained-release capsule content is 1-20%. More preferably, the weight percentage of the blank pill core in the sustained-release capsule content is 3-15%. Further preferably, the weight percentage of the blank pill core in the sustained-release capsule content is 5-10%. Further preferably, the weight percentage of the blank pill core in the sustained-release capsule content is 8-10%. Further preferably, the weight percentage of the blank pill core in the sustained-release capsule content is 8-9%. Further preferably, the weight percentage of the blank pill core in the sustained-release capsule content is 8.8%.

[0009] Preferably, the weight percentage of the verapamil hydrochloride in the sustained-release capsule content is 40-75%. More preferably, the weight percentage of the verapamil hydrochloride in the sustained-release capsule content is 50-70%. Further preferably, the weight percentage of the verapamil hydrochloride in the sustained-release capsule content is 55-65%. Further preferably, the weight percentage of the verapamil hydrochloride in the sustained-release capsule content is 60-65%. Further preferably, the weight percentage of the verapamil hydrochloride in the sustained-release capsule content is 62.4%.

[0010] Preferably, the release regulating material is selected from one or more of methacrylic acid and ethyl acrylate (1:1) copolymer Eudragit L100-55, methacrylic acid and methyl methacrylate (1:1) copolymer Eudragit L100, methacrylic acid and methyl methacrylate (1:2) copolymer Eudragit S100, and hydroxypropyl methylcellulose phthalate HPMCPHP-55. 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 selected from one or more of Eudragit L100-55 and Eudragit L100. Most preferably, the release regulating material is Eudragit L100-55.

[0011] Preferably, the weight percentage of the release regulating material in the sustained-release capsule content is 10-30%. More preferably, the weight percentage of the release regulating material in the sustained-release capsule content is 15-25%. Further preferably, the weight percentage of the release regulating material in the sustained-release capsule content is 15-20%. Further preferably, the weight percentage of the release regulating material in the sustained-release capsule content is 18-20%. Further preferably, the weight percentage of the release regulating material in the sustained-release capsule content is 18.7%.

[0012] Preferably, the sustained-release coating layer comprises a sustained-release material and a plasticizer.

[0013] Preferably, the sustained-release material is selected from one or more of ethyl cellulose, acrylic resin, and cellulose acetate. More preferably, the sustained-release material is selected from one or more of ethyl cellulose and acrylic resin. Further preferably, the sustained-release material is ethyl cellulose. Further preferably, the sustained-release material is ethyl cellulose with a viscosity of 7 mPa.s.

[0014] Preferably, the weight percentage of the sustained-release material in the sustained-release capsule content is 1-15%. More preferably, the weight percentage of the sustained-release material in the sustained-release capsule content is 3-12%. Further preferably, the weight percentage of the sustained-release material in the sustained-release capsule content is 5-10%. Further preferably, the weight percentage of the sustained-release material in the sustained-release capsule content is 7-8%. Further preferably, the weight percentage of the sustained-release material in the sustained-release capsule content is 7.5-8%. Further preferably, the weight percentage of the sustained-release material in the sustained-release capsule content is 7.9%.

[0015] Preferably, the plasticizer is selected from one or more of triethyl citrate, diethyl phthalate, and dibutyl sebacate. More preferably, the plasticizer is selected from one or more of triethyl citrate and diethyl phthalate. Further preferably, the plasticizer is triethyl citrate or diethyl phthalate.

[0016] Preferably, the weight percentage of the plasticizer in the sustained-release capsule content is 0.1-3%. More preferably, the weight percentage of the plasticizer in the sustained-release capsule content is 0.5-2%. Further preferably, the weight percentage of the plasticizer in the sustained-release capsule content is 1.0-1.5%. Further preferably, the weight percentage of the plasticizer in the sustained-release capsule content is 1.2%.

[0017] Preferably, the sustained-release coating layer further comprises an anti-adhesive agent.

[0018] Preferably, the anti-adherent is selected from one or more of magnesium stearate, glyceryl monostearate, and talc. More preferably, the anti-adherent is selected from one or more of magnesium stearate and glyceryl monostearate. Further preferably, the anti-adherent is magnesium stearate or glyceryl monostearate.

[0019] Preferably, the weight percentage of the anti-adhesive agent in the sustained-release capsule content is 0.1-3%. More preferably, the weight percentage of the anti-adhesive agent in the sustained-release capsule content is 0.2-2%. Further preferably, the weight percentage of the anti-adhesive agent in the sustained-release capsule content is 0.5-1%. Further preferably, the weight percentage of the anti-adhesive agent in the sustained-release capsule content is 0.8%.

[0020] Preferably, the content of the sustained-release capsule further comprises a lubricant.

[0021] Preferably, the lubricant is selected from one or more of talc, micropowdered silica gel and magnesium stearate. More preferably, the lubricant is selected from one or more of talc and magnesium stearate. Further preferably, the lubricant is talc.

[0022] Preferably, the weight percentage of the lubricant in the sustained-release capsule content is 0.1-3%. More preferably, the weight percentage of the lubricant in the sustained-release capsule content is 0.5-2%. Further preferably, the weight percentage of the lubricant in the sustained-release capsule content is 0.8-1.5%. Further preferably, the weight percentage of the lubricant in the sustained-release capsule content is 1.0%.

[0023] Preferably, the verapamil hydrochloride sustained-release capsule comprises 50.8 mg sucrose pellet core, 360 mg verapamil hydrochloride, 107.9 mg Eudragit L100-55, 45.6 mg ethyl cellulose, 6.9 mg triethyl citrate and 5.8 mg talc.

[0024] Preferably, the verapamil hydrochloride sustained-release capsule comprises 50.8 mg sucrose pellet core, 360 mg verapamil hydrochloride, 107.9 mg Eudragit L100, 45.6 mg ethyl cellulose, 6.9 mg triethyl citrate and 5.8 mg talc.

[0025] Preferably, the verapamil hydrochloride sustained-release capsule comprises 50.8 mg sucrose pellet core, 360 mg verapamil hydrochloride, 107.9 mg Eudragit S100, 45.6 mg ethyl cellulose, 6.9 mg triethyl citrate and 5.8 mg talc.

[0026] Preferably, the verapamil hydrochloride sustained-release capsule comprises 50.8 mg sucrose pellet core, 360 mg verapamil hydrochloride, 107.9 mg HPMCP HP-55, 41.0 mg ethyl cellulose, 6.9 mg triethyl citrate, 4.6 mg magnesium stearate and 5.8 mg talc.

[0027] Preferably, the verapamil hydrochloride sustained-release capsule comprises 51.3 mg sucrose pellet core, 360 mg verapamil hydrochloride, 91.3 mg Eudragit L100-55, 43.9 mg Eudragit RS, 6.8 mg diethyl phthalate, 4.5 mg glyceryl monostearate and 5.6 mg talc.

[0028] Preferably, the verapamil hydrochloride sustained-release capsule comprises 54.1 mg sucrose pellet core, 360 mg verapamil hydrochloride, 153.3 mg Eudragit L100-55, 49.6 mg Eudragit RS, 7.6 mg diethyl phthalate, 5.1 mg glyceryl monostearate and 6.4 mg talc.

[0029] Preferably, the sustained-release capsules are similar to commercially available verapamil hydrochloride capsules. The in vitro release similarity factor f2 is greater than 60. More preferably, the sustained-release capsule is similar to the commercially available verapamil hydrochloride capsule. The in vitro release similarity factor f2 is greater than 70. Further preferably, the sustained-release capsule is similar to the commercially available verapamil hydrochloride capsule. The in vitro release similarity factor f2 is greater than 75. Further preferably, the sustained-release capsule is similar to the commercially available verapamil hydrochloride capsule. The in vitro release similarity factor f2 is greater than 80. Further preferably, the sustained-release capsule is similar to the commercially available verapamil hydrochloride capsule. The in vitro release similarity factor f2 is greater than 85.

[0030] The second aspect of the present invention provides a method for preparing the above-mentioned verapamil hydrochloride sustained-release capsules, the method comprising the following steps:

[0031] (1) dissolving a prescribed amount of verapamil hydrochloride and a release regulating material in a solvent to prepare a drug-containing coating solution;

[0032] (2) slowly spraying the drug-containing coating solution prepared in step (1) onto the prescribed amount of blank pellets in a fluidized bed coating machine to coat the blank pellets with a drug coating layer, thereby preparing drug-containing pellets;

[0033] (3) dissolving a prescribed amount of sustained-release material, a plasticizer, and an optional anti-adhesive agent in a solvent to prepare a sustained-release coating solution;

[0034] (4) slowly spraying the sustained-release coating solution prepared in step (3) onto the drug-containing micropellets prepared in step (2) in a fluidized bed coating machine, so that the drug-containing micropellets are coated with a sustained-release coating layer, thereby preparing sustained-release coated micropellets;

[0035] (5) Mixing the sustained-release coated pellets obtained in step (4) with a lubricant and filling them into capsules to obtain the product.

[0036] Preferably, the solvent in step (1) is a mixed solvent of ethanol and water. More preferably, the solvent in step (1) is a mixed solvent of ethanol and water in a volume ratio of 8:2.

[0037] Preferably, the weight ratio of the release regulating material to the solvent in step (1) is (1-10): 100. More preferably, the weight ratio of the release regulating material to the solvent in step (1) is 6:100.

[0038] Preferably, the solvent in step (3) is ethanol.

[0039] Preferably, in step (3), the weight ratio of the sustained-release material, the plasticizer and the optional anti-adherent agent to the solvent is (1-10): 100. More preferably, in step (3), the weight ratio of the sustained-release material, the plasticizer and the optional anti-adherent agent to the solvent is 8:100.

[0040] Preferably, the fluidized bed coating parameters in step (2) are set as follows: air inlet temperature is 30-50°C, material temperature is 30-40°C, air outlet temperature is 30-40°C, atomization pressure is 1.0-2.0 bar, air volume is 80-150 cfm, humidity is not more than 35%, and flow rate is 5-40 g / min. More preferably, the fluidized bed coating parameters in step (3) are set as follows: air inlet temperature is 40°C, material temperature is 34°C, air outlet temperature is 33°C, atomization pressure is 1.5 bar, air volume is 110 cfm, humidity is not more than 30%, and flow rate is 10-30 g / min.

[0041] Preferably, the fluidized bed coating parameters in step (4) are set as follows: inlet air temperature is 30-40°C, material temperature is 30-40°C, outlet air temperature is 25-35°C, atomization pressure is 1.0-2.0 bar, air volume is 80-150 cfm, humidity is not more than 35%, and flow rate is 5-20 g / min. More preferably, the fluidized bed coating parameters in step (4) are set as follows: inlet air temperature is 38°C, material temperature is 32°C, outlet air temperature is 31°C, atomization pressure is 1.5 bar, air volume is 110 cfm, humidity is not more than 30%, and flow rate is 10-15 g / min.

[0042] The third aspect of the present invention provides the use of the above-mentioned verapamil hydrochloride sustained-release capsules in the preparation of a medicament for treating essential hypertension, angina pectoris or arrhythmia.

[0043] The technical effects produced by the present invention are:

[0044] 1. The contents of the verapamil hydrochloride sustained-release capsule of the present invention are sustained-release coated pellets, wherein a blank pellet core is sequentially coated with a drug-containing coating layer containing verapamil hydrochloride and a specific release regulating material (e.g., Eudragit L100-55, Eudragit L100, Eudragit S100, HPMCP HP-55) and a sustained-release coating layer. The sustained-release capsule has a release rate of more than 70% in a dissolution medium at pH 8.0 in vitro, which effectively solves the problem of poor in vitro release of verapamil hydrochloride and greatly improves the bioavailability of the drug in vivo.

[0045] 2. The material cost of preparing the verapamil hydrochloride sustained-release capsules of the present invention is low, the process is simple and controllable, and it is easy to industrialize and mass-produce. DETAILED DESCRIPTION

[0046] Test Example 1: In vitro dissolution screening test of verapamil hydrochloride sustained-release capsules with different prescriptions

[0047] 1. Test methods

[0048] 1.1. Preparation of sustained-release capsules

[0049] (1) Prescription

[0050] The prescriptions of Examples 1-6 of the present invention are shown in the following table (the drug content per unit dose is 360 mg, and the units of each auxiliary material are all mg).

[0051]

[0052] The prescriptions of comparative examples 1-4 of the present invention are shown in the following table (the drug content per unit dose is 360 mg, and the units of each auxiliary material are all mg).

[0053]

[0054] (2) Preparation process

[0055] The preparation methods of Examples 1-6 and Comparative Examples 1-4 are as follows:

[0056] 1) dissolving the prescribed amount of verapamil hydrochloride and the release regulating material in a mixed solvent of ethanol and water in a volume ratio of 8:2 to prepare a drug-containing coating solution, wherein the weight ratio of the release regulating material to the mixed solvent is 6:100;

[0057] 2) placing the prescribed amount of sucrose pellets in a fluidized bed coating machine, and slowly spraying the drug-containing coating solution prepared in step 1) into the fluidized bed to coat the sucrose pellets with a drug coating layer, thereby preparing drug-containing micropellets; the fluidized bed coating parameters of this step are set as follows: inlet air temperature is 40° C., material temperature is 34° C., outlet air temperature is 33° C., atomization pressure is 1.5 bar, air volume is 110 cfm, humidity is not more than 30%, and flow rate is 10-30 g / min;

[0058] 3) dissolving the prescribed amount of sustained-release material, plasticizer and anti-adherent (if any) in ethanol to prepare a sustained-release coating solution, wherein the weight ratio of the sustained-release material, plasticizer and anti-adherent (if any) to ethanol is 8:100;

[0059] 4) slowly spraying the sustained-release coating solution prepared in step 3) into the fluidized bed to coat the drug-containing pellets obtained in step 2) with a sustained-release coating layer, thereby preparing sustained-release coated pellets; the fluidized bed coating parameters of this step are set as follows: inlet air temperature is 38° C., material temperature is 32° C., outlet air temperature is 31° C., atomization pressure is 1.5 bar, air volume is 110 cfm, humidity is not more than 30%, and flow rate is 10-15 g / min;

[0060] 5) mixing the sustained-release micropellets prepared in step 4) with a lubricant and filling them into capsules to obtain the product.

[0061] The amount of verapamil hydrochloride added in each batch is 2000 g, and the amounts of other auxiliary materials added are converted according to the unit dose of the prescription.

[0062] 1.2. Dissolution test of sustained-release capsules

[0063] The Verapamil Hydrochloride Sustained Release Capsules prepared in Examples 1-6 and Comparative Examples 1-4 and the Verapamil Hydrochloride Capsules as a reference preparation were respectively taken. (produced by RECRO GAINESVILLE, USA), the in vitro release of each formulation was determined by the paddle method, the rotation speed was 100 rpm, the dissolution medium was pH 8.0 phosphate buffer, the dissolution medium temperature was 37°C ± 0.5°C, the dissolution medium volume was 900 mL, and the release of verapamil hydrochloride (%) was determined by sampling at 2h, 4h, 6h, 8h, 12h, 16h, and 22h, respectively, the detection wavelength was UV 278nm, and the release of each embodiment and comparative example and the reference preparation was calculated. The dissolution similarity factor f2.

[0064] 2. Test results

[0065] Verapamil hydrochloride sustained-release capsules and reference preparations described in Examples 1-6 and Comparative Examples 1-4 The release results and similarity factor f2 are shown in Table 1 below.

[0066] Table 1 In vitro release data of Examples 1-6 and Comparative Examples 1-4 of the present invention

[0067]

[0068] As can be seen from Table 1, using Eudragit L100-55, Eudragit L100, Eudragit S100 or HPMCP HP-55 as the release regulating material in the drug-containing layer in the formulation can make the final release amount of verapamil hydrochloride in the pH 8.0 dissolution medium reach more than 70%, and the overall release rate is similar to that of the reference preparation, and f2 is more than 70, which is expected to achieve bioequivalence with the reference preparation.

[0069] In comparison, when other release regulating materials (e.g., Eudragit RL and hydroxypropyl methylcellulose E5 in Comparative Examples 1-2) are selected, or when the content of Eudragit L100-55 is too low (e.g., the content of Eudragit L100-55 in Comparative Example 3 is only 7.2%), the final release of verapamil hydrochloride is below 61%, which is significantly lower than the reference preparation. When the content of Eudragit L100-55 is too high (e.g., the content of Eudragit L100-55 in Comparative Example 4 is as high as 31.2%), the similarity factor f2 of its release rate with the reference preparation is less than 50, so it is impossible to obtain a dissolution rate similar to that of the reference preparation, and it is expected that it will not be able to achieve bioequivalence with the reference preparation.

[0070] 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 verapamil hydrochloride sustained-release capsule, characterized in that: The content of the sustained-release capsule comprises sustained-release coated pellets, wherein the sustained-release coated pellets comprise: (a) a blank pellet core, (b) a drug coating layer wrapped around the blank pellet core, and (c) a sustained-release coating layer wrapped around the drug coating layer, wherein the drug coating layer comprises verapamil hydrochloride and a release regulating material. The sustained-release capsule is similar to the commercially available verapamil hydrochloride capsule. The in vitro release similarity factor f2 is greater than 50.

2. The verapamil 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 HPMCPHP-55.

3. The verapamil hydrochloride sustained-release capsule according to claim 1, characterized in that: The weight percentage of the release regulating material in the sustained-release capsule content is 10-30%.

4. The verapamil hydrochloride sustained-release capsule according to claim 1, characterized in that: The sustained-release coating layer comprises a sustained-release material and a plasticizer.

5. The verapamil hydrochloride sustained-release capsule according to claim 4, characterized in that: The sustained-release material is selected from one or more of ethyl cellulose, acrylic resin, and cellulose acetate.

6. The verapamil hydrochloride sustained-release capsule according to claim 4, characterized in that: The plasticizer is selected from one or more of triethyl citrate, diethyl phthalate, and dibutyl sebacate.

7. The verapamil hydrochloride sustained-release capsule according to claim 1, characterized in that: The sustained-release coating layer also contains an anti-adherent agent.

8. The verapamil hydrochloride sustained-release capsule according to claim 1, characterized in that: The contents of the sustained-release capsule also include a lubricant.

9. The method for preparing the verapamil hydrochloride sustained-release capsules according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: (1) dissolving a prescribed amount of verapamil hydrochloride and a release regulating material in a solvent to prepare a drug-containing coating solution; (2) slowly spraying the drug-containing coating solution prepared in step (1) onto the prescribed amount of blank pellets in a fluidized bed coating machine to coat the blank pellets with a drug coating layer, thereby preparing drug-containing pellets; (3) dissolving a prescribed amount of sustained-release material, a plasticizer, and an optional anti-adhesive agent in a solvent to prepare a sustained-release coating solution; (4) slowly spraying the sustained-release coating solution prepared in step (3) onto the drug-containing micropellets prepared in step (2) in a fluidized bed coating machine, so that the drug-containing micropellets are coated with a sustained-release coating layer, thereby preparing sustained-release coated micropellets; (5) Mixing the sustained-release coated pellets obtained in step (4) with a lubricant and filling them into capsules to obtain the product.

10. Use of the verapamil hydrochloride sustained-release capsule according to any one of claims 1 to 8 in the preparation of a medicament for treating essential hypertension, angina pectoris or arrhythmia.

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