Benidipine hydrochloride tablet and preparation method thereof

Abstract

The invention provides a benidipine hydrochloride tablet as well as a preparation method and application thereof. The benidipine hydrochloride tablet comprises 2-10% of benidipine hydrochloride, 70-90% of a filler, 2-5% of an adhesive, 0.5-1% of a lubricant and 0.5-4% of a nonionic surfactant. The dissolution speed and the dissolution stability of the benidipine hydrochloride tablet in actual gastric juice containing salt and protease are improved, and the bioavailability and the drug effect are effectively improved.

Description

Technical Field

[0001] This application belongs to the fields of cardiovascular and cerebrovascular drugs and pharmaceutics. Specifically, this application provides a benidipine hydrochloride tablet and a preparation method thereof. Background Art

[0002] Benidipine hydrochloride was developed by Kyowa Hakko Kogyo Co., Ltd. in Japan and was first launched in Japan in the early 1990s. It has now become one of the most commonly used drugs for hypertension. Benidipine hydrochloride is a calcium channel blocker that mainly exerts its effect by inhibiting calcium channels on the vascular endothelial cell membrane, reducing myocardial contractility and peripheral resistance, and dilating the microcirculation of the coronary arteries, brain, and peritubular capillaries. In addition, benidipine hydrochloride also has an effect on improving renal function and preventing atherosclerosis.

[0003] Benidipine hydrochloride is basically insoluble in water and belongs to a low solubility and high osmotic pressure drug. The formulation prescription has a relatively obvious impact on the drug effect. Currently, the commercially available benidipine hydrochloride drugs are basically tablets. Summary of the Invention

[0004] In view of the above situation, on the one hand, this application provides a benidipine hydrochloride tablet, which contains 2-10% of benidipine hydrochloride, 70-90% of a filler, 2-5% of a binder, 0.5-1% of a lubricant, and 0.5-4% of a non-ionic surfactant.

[0005] Further, the filler is lactose and starch; the binder is polyvinyl alcohol; the non-ionic surfactant is polyethylene glycol 15 hydroxystearate, poloxamer 188, Myrij 52, or Brij 35; the lubricant is magnesium stearate.

[0006] Further, the benidipine hydrochloride tablet contains 3.5-4.5% of benidipine hydrochloride, 50-60% of lactose, 30-35% of starch, 8-10% of polyvinyl alcohol, 0.5-1% of magnesium stearate, and 1-2% of a non-ionic surfactant.

[0007] Further, the non-ionic surfactant is polyethylene glycol 15 hydroxystearate.

[0008] Further, the benidipine hydrochloride tablet also includes a gastric-soluble coating; preferably, a gastric-soluble Opadry coating.

[0009] Furthermore, the composition of each tablet core of the benidipine hydrochloride tablet is: 4 mg of benidipine hydrochloride, 55 mg of lactose, 31 mg of starch, 9 mg of polyvinyl alcohol, 0.8 mg of magnesium stearate, and 1 mg of polyethylene glycol 15 hydroxystearate; the coating is a gastric-soluble Opadry coating, and the coating weight gain is 3-5%.

[0010] The above components are expressed in terms of the content in 100 mg of the plain tablets. Those skilled in the art can understand that, on the one hand, when preparing tablets of different specifications, the content of each component can be enlarged or reduced proportionally; on the other hand, due to factors such as errors and moisture content during the preparation process, the content of each component may vary slightly.

[0011] On the other hand, the present application provides a method for preparing the above-mentioned benidipine hydrochloride tablets, and the method includes:

[0012] Placing benidipine hydrochloride, lactose and starch into a wet granulator, mixing; atomizing and adding an aqueous solution containing polyethylene glycol 15 hydroxystearate and polyvinyl alcohol; performing wet granulation; drying for 2 hours; sizing; adding magnesium stearate and mixing evenly; tabletting to obtain a tablet core; and coating the tablet core.

[0013] Further, an aqueous solution containing 3.33 w / v% polyethylene glycol 15 hydroxystearate and 30% w / v polyvinyl alcohol is atomized and added.

[0014] On the other hand, the present application provides the use of the above-mentioned benidipine hydrochloride tablets in the preparation of a medicament for treating hypertension.

[0015] On the other hand, the present application provides the use of the above-mentioned benidipine hydrochloride tablets in the preparation of a medicament for treating angina pectoris.

[0016] By spraying a part of non-ionic surfactant together with the binder during wet granulation, the present application effectively improves the problem of poor dissolution rate and stability of the existing benidipine hydrochloride tablets in actual gastric juice containing salt and protease, providing a basis for improving the drug efficacy. Description of the Drawings

[0017] Figure 1 Summary of the 30-minute cumulative dissolution of various tablets.

[0018] Figure 2 Summary of the 30-minute cumulative dissolution of tablets with different dosages of polyethylene glycol 15 hydroxystearate. Detailed Description of the Invention

[0019] Raw materials:

[0020] The raw material of benidipine hydrochloride (particle size D90 15 μm) and the reference substance are purchased from Shandong Xinhua Pharmaceutical; excipients such as lactose, starch, polyvinyl alcohol, magnesium stearate, polyethylene glycol 15 hydroxystearate, poloxamer 188, tween 80, Brij 35, and gastric-soluble Opadry are purchased from manufacturers such as Shanhe Pharmaceutical Excipients, Xidian Pharmaceutical Excipients, and Merck, and are all of pharmaceutical grade.

[0021] Artificial gastric juice was purchased from Shanghai Yuanye. According to the manufacturer's records, it contains 0.3% w / v sodium chloride and 0.3% w / v pepsin, with an HCl concentration of approximately 0.07 M and a pH of 1.2 - 1.4.

[0022] Reference preparation 1: Concorde Kirin Benidipine Hydrochloride Tablets (Coniel), 4 mg.

[0023] Reference preparation 2: Benidipine Hydrochloride Tablets from a domestic manufacturer, 4 mg.

[0024] All other reagents were either domestic products or self - prepared.

[0025] Instruments:

[0026] High - shear wet granulator: Xinyite G30.

[0027] Spectrophotometer: Shimadzu uv1800.

[0028] Dissolution tester: Haineng DT08 equipped with an automatic sampling system.

[0029] Example 1 Dissolution performance of existing benidipine hydrochloride tablets

[0030] Referring to the provisions of the Chinese Pharmacopoeia, the paddle method was used to detect the dissolution performance of various existing benidipine hydrochloride tablets (dissolution medium 150 mL, 50 revolutions per minute). The ultraviolet spectrophotometry was used to measure the light absorption at 359 nm for detection. A standard curve was plotted using the standard product, and the content of benidipine hydrochloride in the solution and the cumulative dissolution were calculated (5 parallel tests for each sample). The results are shown in Table 1 and Table 2.

[0031] Table 1 Dissolution performance of existing benidipine hydrochloride tablets (0.1 M hydrochloric acid medium)

[0032]

[0033] Table 2 Dissolution performance of existing benidipine hydrochloride tablets (artificial gastric juice medium)

[0034]

[0035]

[0036] As shown in Table 1, existing benidipine hydrochloride tablets have good dissolution performance in a low pH environment similar to gastric juice and constructed with dilute hydrochloric acid. However, when using an actual simulated gastric juice containing sodium chloride and protein, the dissolution performance significantly decreases. On the one hand, it is manifested in a slower dissolution rate, with the cumulative dissolution decreasing by about 20% within the gastric emptying time of about 30 minutes in normal liquid. On the other hand, the dissolution deviation between parallel tests increases. According to existing research, the near-neutral pH environment and complex conditions in the intestine are not conducive to the stable dissolution and absorption of benidipine hydrochloride. Therefore, such a decrease in gastric dissolution performance is likely to affect the bioavailability and efficacy of the drug.

[0037] Example 2: Adding a non-ionic surfactant to improve the dissolution performance of benidipine hydrochloride tablets

[0038] In the prior art, 0.1M hydrochloric acid with a pH of about 1.2 or PBS containing SDS with a pH of about 7 is generally used to detect the dissolution effect of benidipine hydrochloride. Therefore, the above problems have not been fully reflected and solved. The inventor considered that the increase in deviation and the decrease in dissolution performance might be due to the uneven disintegration of local adhesion during the wetting and dissolution processes of the tablets in the presence of sodium chloride. It was considered to add some non-ionic surfactants to adjust the existence mode of hydrophobic groups such as hydrocarbon groups in polyvinyl alcohol, benidipine hydrochloride, and pepsin to solve this problem.

[0039] The applicant selected lactose, starch, polyvinyl alcohol, and magnesium stearate as fillers, binders, and lubricants with reference to existing benidipine hydrochloride tablets, and mixed a non-ionic surfactant when spraying the binder.

[0040] The composition and preparation method of Tablet 1 are as follows:

[0041] Table 3 Composition of Tablet 1

[0042]

[0043]

[0044] Place benidipine hydrochloride, lactose, and starch in a wet granulator and mix for 5 minutes at a stirring speed of 100 rpm; atomize and add an aqueous solution containing 6.67 w / v% polyethylene glycol 15 hydroxystearate and 30% w / v polyvinyl alcohol; perform wet granulation for 2 minutes; dry at 45 degrees Celsius for 2 hours; screen the granules; add magnesium stearate and mix evenly; press to obtain a plain tablet. Coating with a 10% suspension of Opadry gastric-soluble type, with a coating weight gain of 4%.

[0045] The composition and preparation method of Tablet 2 are the same as those of Tablet 1, except that 2 mg of poloxamer 188 is used to replace polyethylene glycol 15 hydroxystearate.

[0046] The composition and preparation method of tablet 3 are the same as those of tablet 1, except that 2 mg of Tween 80 is used instead of polyethylene glycol 15 hydroxystearate.

[0047] The composition and preparation method of tablet 4 are the same as those of tablet 1, except that 2 mg of Brij 35 is used instead of polyethylene glycol 15 hydroxystearate.

[0048] The composition and preparation method of tablet 5 are the same as those of tablet 1, except that 2 mg of Myrij 52 is used instead of polyethylene glycol 15 hydroxystearate.

[0049] The composition and preparation method of the control tablet 3 are the same as those of tablet 1, except that the polyethylene glycol 15 hydroxystearate component is removed.

[0050] The dissolution effects of the above tablets were detected using the method described in Example 1, and the results are shown in Table 4.

[0051] Table 4 Dissolution performance of existing benidipine hydrochloride tablets (artificial gastric juice medium)

[0052]

[0053]

[0054] The results show that the formulation of tablet 1 is helpful for the dissolution performance in artificial gastric juice medium, and the dissolution rate reaches about 85% in about 30 minutes, showing obvious progress compared with other tablets and the control tablet (see Figure 1 ).

[0055] Example 4 Optimization of the dosage of non-ionic surfactant

[0056] With other components fixed to ensure the basic tableting and strength and other properties of the tablets, different dosages of polyethylene glycol 15 hydroxystearate were selected: tablet 1-1: 0.5 mg, tablet 1-2: 1 mg, tablet 1-3: 4 mg, tablet 1-4: 8 mg, tablet 1: 2 mg (data cited from Example 3).

[0057] Table 5 Dissolution effects of tablets with different dosages of polyethylene glycol 15 hydroxystearate

[0058]

[0059] The results show that the dosage of 1 mg of polyethylene glycol 15 hydroxystearate not only further improves the dissolution effect, but also further reduces the standard deviation among various samples, which is better than other dosages (see Figure 2 ).

[0060] Example 5 Basic properties of tablets

[0061] Prepare the product according to the formulation of tablet 1-2 in Example 4. The tablet weight is 100 mg, the diameter is 6 mm, the hardness is 54 N, and each tablet contains 4 mg of benidipine hydrochloride. Use the C18 column liquid phase method to accurately detect the content and uniformity, both of which meet the requirements of the pharmacopoeia. The preliminary accelerated stability test shows that the addition of polyethylene glycol 15 hydroxystearate has no adverse effect on the content stability of benidipine hydrochloride and the amount of related substances.

Claims

1. A benidipine hydrochloride tablet, characterized in that: The benidipine hydrochloride tablets contain 2-10% of benidipine hydrochloride, 70-90% of a filler, 2-5% of a binder, 0.5-1% of a lubricant, and 0.5-4% of a nonionic surfactant.

2. The benidipine hydrochloride tablets according to claim 1, wherein the filler is lactose and starch; the binder is polyvinyl alcohol; the nonionic surfactant is polyethylene glycol 15 hydroxystearate, poloxamer 188, Myrij52 or Brij35; and the lubricant is magnesium stearate.

3. The benidipine hydrochloride tablets according to claim 2, wherein the benidipine hydrochloride tablets comprise 3.5-4.5% benidipine hydrochloride, 50-60% lactose, 30-35% starch, 8-10% polyvinyl alcohol, 0.5-1% magnesium stearate, and 1-2% nonionic surfactant.

4. The benidipine hydrochloride tablets according to claim 3, wherein the nonionic surfactant is polyethylene glycol 15 hydroxystearate.

5. The benidipine hydrochloride tablet according to any one of claims 1 to 4, further comprising a gastric soluble coating.

6. The benidipine hydrochloride tablets according to claim 5, wherein the ingredients of the core portion of each benidipine hydrochloride tablet are: 4 mg benidipine hydrochloride, 55 mg lactose, 31 mg starch, 9 mg polyvinyl alcohol, 0.8 mg magnesium stearate, and 1 mg polyethylene glycol 15-hydroxystearate; the gastric soluble coating is a gastric soluble Opadry coating, and the coating weight gain is 3-5%.

7. The method for preparing benidipine hydrochloride tablets according to claim 5 or 6, characterized in that: The method comprises: Put benidipine hydrochloride, lactose and starch in a wet granulator and mix; add an aqueous solution containing polyethylene glycol 15-hydroxystearate and polyvinyl alcohol by atomization; wet granulate; dry for 2 hours; granulate; add magnesium stearate and mix well; tablet press to obtain tablet core; and coat the tablet core.

8. The method according to claim 7, wherein an aqueous solution containing 3.33 w / v% polyethylene glycol 15 hydroxystearate and 30% w / v polyvinyl alcohol is added by atomization.

9. Use of the benidipine hydrochloride tablets according to any one of claims 1 to 6 in the preparation of a medicament for treating hypertension.

10. Use of the benidipine hydrochloride tablets according to any one of claims 1 to 6 in the preparation of a medicament for treating angina pectoris.

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