Indapamide sustained-release pharmaceutical composition and preparation method thereof

Abstract

The invention relates to an indapamide sustained-release pharmaceutical composition which contains indapamide, fucoidin, a polyvinyl acetate povidone mixture kollidon SR, a disintegrating agent and a lubricant, and discloses a preparation method of the indapamide sustained-release pharmaceutical composition, and the indapamide sustained-release pharmaceutical composition provided by the invention has the advantages of drug dissolution meeting requirements, no burst release, simple process, and reduction of electrolyte flocculation and diabetes incidence.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a sustained-release indapamide pharmaceutical composition and a preparation method thereof. BACKGROUND

[0002] Indapamide is mainly used for the treatment of hypertension, is a kind of thiazide diuretics developed by the French Servier company, is a derivative of sulfonamides, has an indole ring structure, is pharmacologically related to thiazide diuretics, and is an antihypertensive drug with diuretic effect, calcium antagonism, and good influence on the prostaglandin system and blood phosphorus metabolism.

[0003] Indapamide is a new type of long-acting antihypertensive drug, which has diuretic and calcium antagonistic effects, has a good influence on the prostaglandin system, is convenient to take, and has good patient compliance, and is widely used in the treatment of hypertension in clinical practice.

[0004] However, it has been found in recent years that the drug has various adverse reactions, which are summarized as follows: 1. Influence on blood electrolytes. During clinical application, there are many reports of blood electrolyte disorders caused by the product; 2. Influence on glucose metabolism. It can inhibit the release of insulin, or antagonize the effect of insulin, or reduce the sensitivity of insulin, causing blood glucose to rise and glucose tolerance to decrease; 3. Allergic reactions.

[0005] Indapamide can reduce the serum APN level of patients with primary hypertension, and the APN level is closely related to anti-atherosclerosis and IS. Another study found that low potassium can activate the RAS and thus reduce the transport of glucose transporter-4 in skeletal muscle to the cell membrane, while hindering the intracellular insulin signal transduction to increase blood glucose, and indapamide as a thiazide diuretic can affect glucose metabolism by affecting the serum potassium concentration.

[0006] In view of the side effects of indapamide, CN201610175835.X discloses a pharmaceutical composition containing indapamide for treating hypertension and a preparation method thereof. The preparation is a rapid-release preparation, which contains indapamide 1.5-3.5 parts, Buxbaum 2000-4000 parts, white hook 2000-4000 parts, Fujian cypress 2000-4000 parts, and camphor 2000-4000 parts. The present application combines various traditional Chinese medicines with indapamide, which can avoid the common gastrointestinal reactions of indapamide. In the patent, various traditional Chinese medicine ingredients need to be decocted and extracted to obtain extract, which has a complex process and a long production cycle.

[0007] There are many patents for indapamide sustained-release preparations, mainly to solve the problems of unobvious sustained-release effect, burst phenomenon, low production efficiency, and complex preparation process.

[0008] Therefore, the prior art indapamide sustained-release preparation has the problems of unclear sustained-release effect, burst release, low production efficiency, complex preparation process, and the like, and the patient has the disadvantages of electrolyte flocculation and blood sugar increase after taking the preparation, and the like, and the person skilled in the art needs to study the above problems and find a better indapamide sustained-release preparation to meet the clinical needs.

[0009] The present inventors have developed an indapamide sustained-release pharmaceutical composition and a preparation method during the research process to solve the above problems, so that the present product is suitable for industrial production. SUMMARY

[0010] The present application aims at solving the above problems of the prior art and provides an indapamide sustained-release pharmaceutical composition and a preparation method thereof. The indapamide sustained-release pharmaceutical composition prepared by the present application has the advantages of meeting the dissolution requirements, no burst release, good stability, simple preparation process, and suitability for industrial production.

[0011] Specifically, the present application is realized by the following technical scheme:

[0012] An indapamide sustained-release pharmaceutical composition, which contains indapamide, fucoidan, a polyvinyl acetate povidone mixture kollidon SR, a disintegrant, and a lubricant.

[0013] The indapamide sustained-release pharmaceutical composition has a mass ratio of indapamide to fucoidan of 1:20-80 in the pharmaceutical composition per unit preparation.

[0014] Further, the indapamide sustained-release pharmaceutical composition has a mass ratio of indapamide to fucoidan of 1:30-70 in the pharmaceutical composition per unit preparation.

[0015] Further, the indapamide sustained-release pharmaceutical composition has a mass ratio of indapamide to fucoidan of 1:40-60 in the pharmaceutical composition per unit preparation.

[0016] The indapamide sustained-release pharmaceutical composition has a mass ratio of indapamide, fucoidan, a polyvinyl acetate povidone mixture kollidon SR, a disintegrant, and a lubricant of 1.5:(30-120):(50-200):(5-15):(0.1-5) in the pharmaceutical composition per unit preparation.

[0017] The disintegrant is selected from one or a mixture of two or more proportions of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked povidone, and sodium carboxymethyl starch. Preferably, the disintegrant is cross-linked povidone.

[0018] The lubricant is one or more of magnesium stearate, calcium stearate, talc, and sodium stearyl fumarate. Preferably, the lubricant is magnesium stearate.

[0019] The indapamide sustained-release pharmaceutical composition contains the following components per unit of pharmaceutical composition: indapamide 1.5 mg, fucoidan 30 mg-120 mg, polyvinyl acetate povidone mixture kollidon SR 50-200 mg, cross-linked povidone 5-15 mg, and magnesium stearate 0.1 mg-5 mg.

[0020] The indapamide sustained-release pharmaceutical composition contains the following components per unit of pharmaceutical composition: indapamide 1.5 mg, fucoidan 75 mg, polyvinyl acetate povidone mixture kollidon SR 125 mg, cross-linked povidone 10 mg, and magnesium stearate 2.5 mg.

[0021] The indapamide sustained-release pharmaceutical composition is preferably a solid preparation, such as a capsule, a tablet, granules, powder, sustained-release agent, or a dripping pill.

[0022] Further preferably, the solid preparation of the indapamide sustained-release pharmaceutical composition of the present application is a tablet.

[0023] The present application also provides a preparation method of the pharmaceutical composition, which comprises the following steps:

[0024] The prescribed amount of indapamide, fucoidan, polyvinyl acetate povidone mixture kollidon SR, and disintegrant are weighed, mixed, and sieved, and then mixed again. A lubricant is added to the mixed granules, and the granules are compressed into tablets.

[0025] Advantages: The present application provides an indapamide sustained-release pharmaceutical composition, which has a required drug dissolution and no burst release, and a simple process, thereby reducing the occurrence of electrolyte flocculation. DETAILED DESCRIPTION

[0026] The advantages of the present application are further described by the following examples, which are only for illustrative purposes and should not be construed as limiting the present application. The modifications and improvements of the present application that are obvious to those skilled in the art are also within the scope of the present application.

[0027] The following examples are indapamide sustained-release tablets and a preparation method thereof. The described operations are conventional preparation operations.

[0028] Example 1

[0029]

[0030] Preparation process:

[0031] Take the prescription amount of indapamide, fucoidan, polyvinyl acetate povidone mixture kollidon SR, cross-linked povidone, and mix with a lifting mixer for 10 min, then sieve with a swing granulator, screen aperture 1.0 mm, mix the sieved powder for another 15 min, add magnesium stearate to the mixed granules, mix for 5 min, and press the tablets with a rotary tablet press.

[0032] Example 2

[0033]

[0034] Preparation process: same as Example 1.

[0035] Example 3

[0036]

[0037] Preparation process:

[0038] Preparation process: same as Example 1.

[0039] Comparative Example 1

[0040]

[0041] Preparation process:

[0042] Take the prescription amount of indapamide, fucoidan, cross-linked povidone, and mix with a lifting mixer for 10 min, then sieve with a swing granulator, screen aperture 1.0 mm, mix the sieved powder for another 15 min, add magnesium stearate to the mixed granules, mix for 5 min, and press the tablets with a rotary tablet press.

[0043] Comparative Example 2

[0044]

[0045] Preparation process:

[0046] Take the prescription amount of indapamide, fucoidan, cross-linked povidone, and mix with a lifting mixer for 10 min, then sieve with a swing granulator, screen aperture 1.0 mm, mix the sieved powder for another 15 min, add magnesium stearate to the mixed granules, mix for 5 min, and press the tablets with a rotary tablet press.

[0047] Verification Example

[0048] I. Release rate determination of indapamide sustained-release tablets

[0049] Release determination: Take the samples of Example 1-3 and Comparative Example 1-2, and determine according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 edition fourth part general rule 0931 second method), using the dissolution determination method second device, 0.01 mol / L hydrochloric acid 500 ml as the dissolution medium, the speed is 50 revolutions per minute, and the operation is according to the law. After 4, 8 and 16 hours, take the solution appropriately, and immediately supplement the same volume of solvent preheated to 37±0.5℃. Take the removed solution through a 0.45μm filter membrane, and take the filtrate as the test sample solution. Take an appropriate amount of indapamide reference substance, accurately weigh, add ethanol, shake thoroughly to dissolve, and dilute to prepare a solution containing 1μg of indapamine per 1ml, shake well, and use as the reference substance solution. According to the chromatographic conditions under the content determination of indapamine sustained-release tablets (State Food and Drug Administration State Drug Standard WS1-(X-006)-2007Z-2011), accurately measure 20μl of the above test sample solution and the reference substance solution, respectively, inject into the liquid chromatograph, record the chromatogram, and calculate the release amount at different times by external standard method. The results are shown in Table 1.

[0050] Table 1 Determination results of release of samples of Example 1-3 and Comparative Example 1-2

[0051]

[0052] According to the standard, as indapamine sustained-release tablets, the release amount of each tablet at 4, 8 and 16 hours should be equivalent to 17-27%, 35-55% and more than 75% of the labeled amount. As can be seen from Table 1, the release amount of Example 1-3 at 4 hours reaches about 23%, the release amount at 8 hours reaches about 40%, and the release amount at 16 hours is more than 75%, which meets the quality standard requirements of indapamine sustained-release tablets. Among them, Example 1 group is better than Example 2-3 group, the release is more stable and complete, which shows that when the mass ratio of indapamine, fucoidan, polyvinyl acetate povidone mixture kollidon SR, disintegrant and lubricant is 1.5:75:125:10:2.5, the release of indapamine is the most stable and complete; Compared with Comparative Example 1-2, since Comparative Example 1 does not use polyvinyl acetate povidone mixture kollidon SR as an excipient, the release amount at 4 hours exceeds 30%, the release amount at 8 hours exceeds 75%, and the release amount at 16 hours exceeds 95%, which has a burst release phenomenon and does not achieve the effect of sustained release; Comparative Example 2 does not add fucoidan, and the release amount at 16 hours is less than 75%, which does not meet the requirements. It is analyzed that the selection of excipients, the ratio and the addition of fucoidan may have a certain influence on the release of indapamine.

[0053] II. Pharmacodynamic study

[0054] 1. Source of experimental samples

[0055] The sample prepared in Example 1 above and an indapamide sustained-release tablet control group (Guojin Yinhua Pharmaceutical Co., Ltd. production, State Drug Code H20052001).

[0056] 2. Animals and materials

[0057] Animals: Spontaneous hypertensive rats (SHR) rats, number 30, half male and half female, body weight 190-220g; Wistar rats, half male and half female, body weight 190-220g; all from Jiangsu Qinglongshan Biotechnology Co., Ltd., Production License No. SCXK (Su) 2024-0001.

[0058] Reagents: Heparin sodium is produced by Xuzhou Wanbang Biochemical Pharmaceutical Factory, diluted with distilled water to 1*10 6 Unit / L, take 50ul to wet the test tube wall, 37℃ oven dry for standby.

[0059] Blood pressure meter: BP-2010A type small animal intelligent non-invasive blood pressure meter (softron, Japan).

[0060] 3. Grouping and administration

[0061] At least three dose groups should be set for in vivo pharmacokinetic study, and the high dose is preferably close to the maximum tolerated dose, and the medium and small doses are selected according to the upper and lower limit range of the effective dose of the animal. After feeding the spontaneous hypertensive rat (SHR) model for 1 week, whether the rat model is qualified is judged by detecting blood pressure. 30 SHR rats are randomly divided into model group, indapamide sustained-release tablet control group (indapamide, 0.09mg·kg -1 ), and Example 1 sample low, medium and high dose groups (0.06mg / kg, 0.09mg / kg, 0.12mg / kg), and Wistar rats are selected as blank group, 6 in each group. The dosing dose is calculated according to the body surface area conversion formula of human and animal, and the dosing group is given intragastrically according to the set dose (10mL·kg-1), and the blank group and the model group are given distilled water, once a day, for 8 weeks.

[0062] 4. Effect of the present application on blood pressure of hypertension

[0063] According to the operation instruction of Japan Softlon / BP-2010A non-invasive tonometer, the non-invasive rat tail tonometer system is preheated for half an hour, the temperature is 45℃, the rats are fixed in a specific rat box in a quiet environment with a room temperature of 20-28℃, the rat tail is placed in a circulating heated pressurizable channel, the rat tail artery waveform is stable after the rat is in a quiet state, and the tail artery pressure is measured by inflation and pressurization. The average value is obtained by measuring three times. The blood pressure of the SHR rats in the sample administration group, the model group, the indapamide sustained-release tablet control group and the Wistar rat blank group is measured before and after administration for 8 weeks, and the data is sorted and recorded. The results are shown in Table 2.

[0064] Table 2 Effect of the present application on systolic pressure of rats

[0065]

[0066] Note: compared with the blank group, *P<0.05, **P<0.01; compared with the model group, △ P<0.05, △△ P<0.01; compared with the indapamide sustained-release tablet control group, ▲ P<0.05, ▲▲ P<0.01.

[0067] From Table 2, compared with the blank group, the systolic pressure of the rats in the model group after modeling is significantly increased, which indicates that the hypertensive rat model is established. Compared with the model group, after continuous administration of the sample of Example 1 for 8 days, the systolic pressure of each dose group of Example 1 and the indapamide sustained-release tablet control group after treatment is significantly lower than that of the model group, which has a significant difference, indicating that each dose group of Example 1 has a blood pressure lowering effect on the hypertensive rat model and has a dose-dependent effect; compared with the indapamide sustained-release tablet control group, the systolic pressure of the high-dose group of the indapamide sustained-release tablet of Example 1 after treatment is significantly lower than that of the indapamide sustained-release tablet control group, which indicates that the effect of the high-dose group of the indapamide sustained-release tablet of Example 1 is significantly better than that of the indapamide sustained-release tablet control group. It is speculated that the fucoidan added in the Example 1 group has a synergistic blood pressure lowering effect with indapamide.

[0068] 5, Effect of the present application on plasma potassium K + of hypertensive rats

[0069] Collect 1 ml of blood sample from the retro-orbital plexus, place it in a heparin-treated test tube, centrifuge as soon as possible, and take the plasma for determination of potassium level. The results are shown in Table 3.

[0070] Table 3 Effect of the present application on plasma potassium K + of rats

[0071]

[0072] Note: compared with the blank group, *P < 0.05, **P < 0.01; compared with the model group, △ P < 0.05, △△ P < 0.01; compared with the indapamide sustained-release tablet control group, ▲ P < 0.05, ▲▲ P < 0.01.

[0073] As shown in Table 3, compared with the blank group, the model group had no significant difference in blood potassium. Compared with the model group, the indapamide sustained-release tablet control group could reduce the plasma potassium K + concentration, and had a significant difference, indicating that the indapamide sustained-release tablet control group could cause electrolyte disorder; compared with the indapamide sustained-release tablet control group, after 8 days of continuous administration of the sample of Example 1, the Example 1 dose groups could increase the plasma potassium K + concentration, and had a significant difference with the indapamide sustained-release tablet control group, indicating that the doses of Example 1 had an improvement effect on electrolyte disorder, and there was no significant difference between the dose groups, it was speculated that the indapamine sustained-release tablets prepared by the Example 1 group could improve the low blood potassium after indapamine treatment alone, which might be related to the addition of fucoidan.

[0074] Although the embodiments of the present application have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the present application, and the scope of the present application is defined by the appended claims and their equivalents.

Claims

1. An indapamide sustained release pharmaceutical composition, characterized by, The composition contains indapamide, fucoidan, polyvinyl acetate povidone mixture kollidon SR, disintegrant, lubricant.

2. The sustained release pharmaceutical composition of indapamide according to claim 1, characterized in that, The mass ratio of indapamide to fucoidan in the pharmaceutical composition per unit preparation is 1:20-80.

3. The sustained release pharmaceutical composition of indapamide according to claim 1, characterized in that, The mass ratio of indapamide to fucoidan in the pharmaceutical composition per unit preparation is 1:30-70.

4. The sustained release pharmaceutical composition of indapamide according to claim 1, characterized in that, The mass ratio of indapamide to fucoidan in the pharmaceutical composition per unit preparation is 1:40-60.

5. The sustained release pharmaceutical composition of indapamide according to claim 1, wherein The mass ratio of indapamide, fucoidan, polyvinyl acetate povidone mixture kollidon SR, disintegrant, lubricant in the pharmaceutical composition per unit preparation is 1.5: (30-120): (50-200): (5-15): (0.1-5).

6. The sustained release pharmaceutical composition of indapamide according to claim 1, wherein The disintegrant is selected from one or more than two proportions of mixture of sodium croscarmellose, low-substituted hydroxypropyl cellulose, cross-linked povidone and sodium carboxymethyl starch.

7. The sustained release pharmaceutical composition of indapamide according to claim 1, wherein The lubricant is one or more of magnesium stearate, calcium stearate, talc, sodium stearyl fumarate.

8. The sustained release pharmaceutical composition of indapamide according to claim 1, wherein The pharmaceutical composition per unit preparation contains the following components: indapamide 1.5 mg, fucoidan 30 mg-120 mg, polyvinyl acetate povidone mixture kollidon SR 50-200 mg, cross-linked povidone 5-15 mg, magnesium stearate 0.1 mg-5 mg.

9. The sustained release pharmaceutical composition of indapamide according to claim 1, wherein The pharmaceutical composition per unit preparation contains the following components: indapamide 1.5 mg, fucoidan 75 mg, polyvinyl acetate povidone mixture kollidon SR 125 mg, cross-linked povidone 10 mg, magnesium stearate 2.5 mg.

10. The sustained release pharmaceutical composition of indapamide according to claim 1, wherein The preparation method of the pharmaceutical composition comprises the following steps: weighing the prescribed amount of indapamide, fucoidan, polyvinyl acetate povidone mixture kollidon SR, disintegrant, mixing preliminarily, sieving, mixing again, adding lubricant to the mixed granules, and tabletting.

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