A betaine composition with blood pressure lowering effect and its preparation method

Abstract

The present invention discloses a betaine composition having a blood pressure lowering effect and a preparation method thereof, belonging to the technical field of pharmaceutical compositions. The preparation method includes: preparing a tablet core, preparing a primary coating solution, preparing a secondary coating solution, primary coating, and secondary coating; the preparation of the primary coating solution includes: preparing a filler and primary mixing; the preparation of the secondary coating solution includes: preparing a supramolecular composition and secondary mixing; the betaine composition prepared by the present invention can avoid the problem of too low blood pressure after the use of the prepared betaine composition by controlling the release rate of the angiotensin converting enzyme inhibitor. The prepared betaine mixture has good storage stability, high qualified rate, and small difference in the content of the angiotensin converting enzyme inhibitor among the prepared betaine mixtures.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical compositions, and particularly relates to a betaine composition with antihypertensive effect and a preparation method thereof. Background Art

[0002] Betaine is an alkaloid, appearing as a white crystalline powder, odorless and sweet. Its chemical name is N,N,N-trimethylglycine. The chemical structure of betaine is similar to that of amino acids and belongs to the quaternary ammonium base substances. Betaine widely exists in animals, plants and microorganisms. Currently, the commonly used preparation methods of betaine are extraction from the roots, stems, leaves and fruits of natural plants and chemical synthesis using trimethylamine and chloroacetic acid as raw materials.

[0003] In mammalian bodies, betaine mainly plays the roles of maintaining the osmotic balance inside and outside cells and providing methyl groups. Specifically, first, as a natural compound, betaine has a bipolar structure, has extremely high solubility in water, and has a relatively low degree of interaction with enzymes and metabolic processes in cells. Therefore, betaine not only plays an important role in protecting cells, proteins and enzymes, but also can maintain cell functions under various environmental pressures such as low water, high salt and extreme temperatures; second, in the in vivo methylation reaction, betaine can promote the conversion of homocysteine to methionine by providing methyl groups.

[0004] Betaine also has the following pharmacological effects in mammalian bodies: first, anti-fatty liver, specifically, betaine can increase the phospholipid levels in blood and liver, thus playing an anti-fatty liver role; second, antihypertensive, specifically, betaine can dilate peripheral blood vessels and reduce peripheral vascular resistance, thus playing an antihypertensive role; third, anti-tumor, specifically, betaine can inhibit the mitosis of tumor cells in vitro, thus playing an anti-tumor role.

[0005] Hypertension is a phenomenon in which the pressure value of blood flowing on the blood vessel wall continuously exceeds the normal value. The causes of hypertension are mostly genetic factors and unhealthy lifestyles, such as high-salt diet, excessive alcohol consumption, long-term mental stress and lack of physical activity. The typical symptoms of hypertension include headache, fatigue or restlessness, arrhythmia and palpitations and tinnitus, etc. For hypertension patients, one of the commonly used treatment methods is drug treatment. The commonly used antihypertensive drugs mainly include calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, diuretics and β-blockers. Among them, the antihypertensive effect of angiotensin-converting enzyme inhibitors is clear. By reducing the generation of angiotensin II, it further reduces peripheral vasoconstriction, dilates peripheral blood vessels, reduces peripheral vascular resistance, and further plays a role in lowering blood pressure. Commonly used angiotensin-converting enzyme inhibitors include enalapril, captopril, benazepril hydrochloride, etc. However, angiotensin-converting enzyme inhibitors have the problem of slow onset.

[0006] Through clinical trials, it was found that a betaine composition obtained by mixing betaine or its salt with an angiotensin-converting enzyme inhibitor can be used as an antihypertensive drug. Among them, the betaine salt is betaine hydrochloride, betaine phosphate, or betaine citrate. The betaine or its salt in the betaine composition can dilate peripheral blood vessels and reduce peripheral vascular resistance, thereby increasing the speed of onset and further overcoming the problem of slow onset when using an angiotensin-converting enzyme inhibitor alone as an antihypertensive drug. However, after further clinical trials, it was found that when betaine or its salt is mixed with an angiotensin-converting enzyme inhibitor and used, as the production amount of angiotensin II decreases, in synergy with the effect of betaine in dilating peripheral blood vessels, a blood pressure lowering peak appears, and further, the problem of excessively low blood pressure occurs.

[0007] To address the above problems, the most common methods are as follows: First, use betaine or its salt and an angiotensin-converting enzyme inhibitor separately and control the usage amount of betaine or its salt. However, it is difficult to control the usage amount. Second, after the angiotensin-converting enzyme inhibitor is sustained-release and then mixed with betaine or its salt and tableted to prepare a betaine mixture, thereby reducing the action speed of the angiotensin-converting enzyme inhibitor. Commonly used sustained-release methods include the coating method, microencapsulation method, and matrix sustained-release method. However, when the sustained-release angiotensin-converting enzyme inhibitor is mixed with betaine or its salt, due to different particle sizes, there is a problem of uneven dispersion, resulting in a large difference in the content of the angiotensin-converting enzyme inhibitor among the prepared betaine mixtures. In addition, for the sustained-release angiotensin-converting enzyme inhibitor prepared by the microencapsulation method, after being mixed with betaine or its salt, betaine or its salt adsorbs on the surface of the sustained-release angiotensin-converting enzyme inhibitor. Due to the strong hygroscopicity of betaine or its salt, the coating film or microcapsule film of betaine or its salt will be damaged during long-term storage, resulting in a decline in the sustained-release effect. Therefore, the sustained-release angiotensin-converting enzyme inhibitor prepared by the microencapsulation method has a problem of poor storage resistance. For the sustained-release angiotensin-converting enzyme inhibitor prepared by the coating method, not only does it have the same problems as the sustained-release angiotensin-converting enzyme inhibitor prepared by the microencapsulation method, but it also causes the coating film to rupture during tableting, further affecting the sustained-release effect. For the sustained-release angiotensin-converting enzyme inhibitor prepared by the matrix sustained-release method, after being mixed with betaine or its salt, betaine or its salt adsorbs in the sustained-release matrix of the sustained-release angiotensin-converting enzyme inhibitor. Due to the strong hygroscopicity of betaine or its salt, the sustained-release matrix will be damaged during long-term storage, affecting the sustained-release effect of the sustained-release matrix and resulting in an initial burst release problem in the prepared betaine mixture. Therefore, the sustained-release angiotensin-converting enzyme inhibitor prepared by the matrix sustained-release method also has a problem of poor storage resistance.

[0008] The inventors also tried to form a primary coating film by applying a coating solution containing betaine or its salt on the surface of the sustained-release angiotensin-converting enzyme inhibitor once, and then forming a secondary coating film by applying a hydrophobic coating material for secondary coating to prepare a betaine mixture. Although the storage stability of the prepared betaine mixture can be improved, there is a lack of hydrogen bond interaction between the primary coating film and the secondary coating film, resulting in poor bonding strength, which leads to problems such as powder shedding and pitted surface on the surface of the prepared betaine mixture, and a low qualified rate. Summary of the Invention

[0009] Aiming at the deficiencies of the prior art, the present invention provides a betaine composition with antihypertensive effects and a preparation method thereof. The prepared betaine composition can control the release rate of the angiotensin-converting enzyme inhibitor, avoid the problem of too low blood pressure after the prepared betaine composition is used, has good storage stability and a high qualified rate, and the content difference of the angiotensin-converting enzyme inhibitor between the prepared betaine mixtures is small.

[0010] To solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0011] A preparation method of a betaine composition with antihypertensive effects, comprising: preparing a tablet core, preparing a primary coating solution, preparing a secondary coating solution, primary coating, and secondary coating;

[0012] In the preparation of the tablet core, the angiotensin-converting enzyme inhibitor, microcrystalline cellulose, hydroxypropyl methylcellulose mixture, cross-linked polyvinylpyrrolidone, and magnesium stearate are respectively pulverized and sieved through a 100-mesh sieve to obtain the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized cross-linked polyvinylpyrrolidone, and pulverized magnesium stearate. The pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized cross-linked polyvinylpyrrolidone, and ultrapure water are mixed and sieved through a 24-mesh sieve to make wet granules, dried at 50-60 °C for 55-60 min, sieved through a 24-mesh sieve for sizing, and then mixed with the pulverized magnesium stearate and pressed to obtain the tablet core;

[0013] In the preparation of the tablet core, the angiotensin-converting enzyme inhibitor is one of enalapril, captopril, and benazepril hydrochloride;

[0014] The hydroxypropyl methylcellulose composition is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M, wherein the mass ratio of the mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M is 1:1-1.2;

[0015] The mass ratio of the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, ultrapure water, and pulverized magnesium stearate is 40 - 45:100 - 110:45 - 55:3 - 4:50 - 60:24 - 27;

[0016] The pressure during tabletting is 30 - 35 N;

[0017] The preparation of the primary coating solution includes: preparing the filler and performing primary mixing;

[0018] For the preparation of the filler, hydroxypropyl-β-cyclodextrin and the first portion of ultrapure water are mixed and then stirred. The temperature during stirring is controlled at 25 - 40 °C, the stirring speed is 100 - 300 rpm. After stirring for 20 - 30 min, while keeping the temperature and stirring speed unchanged, silica micropowder is added and stirred for 2 - 3 h. Then centrifugation is carried out, with the rotation speed during centrifugation controlled at 2500 - 3000 rpm for 10 - 15 min. The precipitate is mixed with the second portion of ultrapure water and stirred. The temperature during stirring is controlled at 25 - 40 °C, the stirring speed is 100 - 300 rpm, and it is stirred for 5 - 10 min. Then the temperature is raised to 85 - 95 °C, while keeping the stirring speed unchanged, and stirring reflux is carried out. An aqueous citric acid solution is added and stirred refluxed for 3.5 - 4 h. Then centrifugation is carried out, with the rotation speed during centrifugation controlled at 2500 - 3000 rpm for 10 - 15 min. The precipitate is washed 4 - 6 times with ultrapure water and then dried at 110 - 130 °C to obtain the filler;

[0019] In the preparation of the filler, the dosage ratio of hydroxypropyl-β-cyclodextrin, the first portion of ultrapure water, silica micropowder, the second portion of ultrapure water, and the aqueous citric acid solution is 50 - 60 g:1000 - 1100 mL:100 - 110 g:1000 - 1100 mL:550 - 650 mL;

[0020] The particle size of the silica micropowder is 5 μm;

[0021] The mass concentration of the aqueous citric acid solution is 20%;

[0022] For the primary mixing, the filler and ultrapure water are mixed and then stirred. The temperature during stirring is controlled at 30 - 50 °C, the stirring speed is 100 - 300 rpm. After stirring for 20 - 30 min, while keeping the temperature and stirring speed unchanged, betaine or its salt is added and stirred for 2 - 2.5 h. Then, while still keeping the temperature and stirring speed unchanged, hydroxypropyl methylcellulose is added and stirred for 1 - 1.5 h to obtain the primary coating solution;

[0023] In the first mixing, the dosage ratio of the filler, ultrapure water, betaine or its salt, and hydroxypropyl methylcellulose is 120 - 130 g: 1000 - 1100 mL: 45 - 50 g: 50 - 55 g;

[0024] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0025] The betaine or its salt is one of betaine, betaine hydrochloride, betaine phosphate, and betaine citrate;

[0026] The preparation of the secondary coating solution includes: preparing a supramolecular composition and secondary mixing;

[0027] For the preparation of the supramolecular composition, β - cyclodextrin and ultrapure water are mixed and then stirred. The temperature during stirring is controlled at 25 - 40 °C, the stirring speed is 100 - 300 rpm. After stirring for 20 - 30 min, while keeping the temperature and stirring speed unchanged, an aqueous solution of betaine or its salt is added, and stirring is continued for 20 - 30 min. Then, spray drying is carried out. The inlet air temperature during spray drying is controlled at 130 - 150 °C, and the outlet air temperature is 70 - 80 °C to obtain the supramolecular composition;

[0028] In the preparation of the supramolecular composition, the dosage ratio of β - cyclodextrin, ultrapure water, and the aqueous solution of betaine or its salt is 9 - 9.2 g: 500 - 550 mL: 140 - 160 mL;

[0029] The mass concentration of the aqueous solution of betaine or its salt is 20%;

[0030] The betaine or its salt in the aqueous solution of betaine or its salt is one of betaine, betaine hydrochloride, betaine phosphate, and betaine citrate;

[0031] For the secondary mixing, ethyl cellulose, hydroxypropyl methylcellulose, triethyl citrate, colloidal silica, the supramolecular composition, and an ethanol solution are mixed and then stirred. The temperature during stirring is controlled at 30 - 50 °C, the stirring speed is 100 - 300 rpm. After stirring for 50 - 60 min, the secondary coating solution is obtained;

[0032] In the secondary mixing, the dosage ratio of ethyl cellulose, hydroxypropyl methylcellulose, triethyl citrate, colloidal silica, the supramolecular composition, and the ethanol solution is 40 - 43 g: 10 - 12 g: 10 - 12 g: 1.8 - 2 g: 7 - 8 g: 950 - 1000 mL;

[0033] The ethyl cellulose is ethyl cellulose N10;

[0034] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0035] The volume concentration of the ethanol solution is 85%;

[0036] For the first coating, the tablet cores are placed in a fluidized bed coater for heat preservation, keeping the temperature constant, and the first coating solution is used for the first coating to obtain the first coated products;

[0037] In the first coating, the temperature during heat preservation is 50 - 55 °C, and the heat preservation time is 9 - 10 min;

[0038] The weight gain of the first coating is 5 - 5.3%;

[0039] For the second coating, the first coated products are placed in a fluidized bed coater for heat preservation, keeping the temperature constant, and the second coating solution is used for the second coating to obtain the betaine composition with blood pressure lowering effect;

[0040] In the second coating, the temperature during heat preservation is 50 - 55 °C, and the heat preservation time is 9 - 10 min;

[0041] The weight gain of the second coating is 2.8 - 3%;

[0042] A betaine composition with blood pressure lowering effect prepared by the foregoing preparation method.

[0043] Compared with the prior art, the beneficial effects of the present invention are:

[0044] (1)Preparation method of betaine composition with blood pressure lowering effect. When preparing, the tablet core containing angiotensin converting enzyme inhibitor is coated successively with a primary coating solution and a secondary coating solution containing betaine or its salt. Among them, the primary coating solution contains a filler. When preparing the filler, first, microcrystalline silica is used to adsorb hydroxypropyl-β-cyclodextrin, so that a layer of hydroxypropyl-β-cyclodextrin is adsorbed on the surface of the microcrystalline silica. Then it is mixed with a citric acid aqueous solution, and citric acid crosslinks with the hydroxypropyl-β-cyclodextrin on the surface, so that a crosslinking product of hydroxypropyl-β-cyclodextrin and citric acid is coated on the surface of the microcrystalline silica to obtain the filler. After the filler is mixed with betaine or its salt, betaine or its salt is adsorbed on the surface of the crosslinking product of hydroxypropyl-β-cyclodextrin and citric acid. First, the crosslinking product of hydroxypropyl-β-cyclodextrin and citric acid can improve the dispersibility of microcrystalline silica. Second, the crosslinking product of hydroxypropyl-β-cyclodextrin and citric acid can play a role in fixing and protecting betaine or its salt through the interaction with betaine or its salt, thereby reducing the hygroscopicity of betaine or its salt. Third, the crosslinking product of hydroxypropyl-β-cyclodextrin and citric acid can be adsorbed on the intestinal surface to play a sustained release role for betaine or its salt. Fourth, the crosslinking product of hydroxypropyl-β-cyclodextrin and citric acid contains a large number of ester groups and hydroxyl groups, which can improve the interaction with ethyl cellulose in the secondary coating solution and improve the qualified rate of the prepared betaine composition. The secondary coating solution contains a supramolecular composition, and the supramolecular composition is a composition of β-cyclodextrin and betaine or its salt. There is an interaction between the hydroxyl groups on the outer layer of β-cyclodextrin and the nitrogen atoms in betaine or its salt, thereby reducing the hygroscopicity of the hydrophilic groups in β-cyclodextrin and betaine or its salt. The secondary coating solution also contains ethyl cellulose, and ethyl cellulose is insoluble in water, thereby further improving the storage stability of the prepared betaine composition. After using the betaine composition prepared by the present invention, first, the outermost coating layer ruptures and the supramolecular composition is dissolved. The β-cyclodextrin in the supramolecular composition can promote the absorption of betaine or its salt. Then the sub-outer coating layer ruptures and betaine or its salt is uniformly released, thus avoiding the problem of too low blood pressure caused by too fast release. Finally, the angiotensin converting enzyme inhibitor in the tablet core is uniformly released, so that the generation of angiotensin II can be reduced. After the release of betaine or its salt is completed, it can still continuously play a certain role in reducing peripheral vascular contraction and dilating peripheral blood vessels, thus not only controlling the release rate of the angiotensin converting enzyme inhibitor, but also avoiding the problem of too low blood pressure after using the prepared betaine composition;

[0045] (2) The preparation method of the betaine composition with blood pressure lowering effect of the present invention can avoid the problem of too low blood pressure after the prepared betaine composition is used by controlling the release rate of the angiotensin converting enzyme inhibitor. The dissolution rate of the betaine composition with blood pressure lowering effect prepared by the present invention is detected according to the second paddle method in the second step dissolution determination method of the Chinese Pharmacopoeia 2010 edition. Using distilled water as the dissolution medium, controlling the temperature at 37 °C and the rotation speed at 50 rpm, the dissolution rate of the angiotensin converting enzyme inhibitor is 10.10 - 10.51% at 2 h, 20.58 - 21.22% at 4 h, 48.22 - 49.10% at 8 h, 68.76 - 69.83% at 12 h, and 98.01 - 99.13% at 24 h;

[0046] (3) The preparation method of the betaine composition with blood pressure lowering effect of the present invention has good storage resistance for the prepared betaine mixture. The betaine composition with blood pressure lowering effect prepared by the present invention is left standing in an environment with a temperature of 25 °C and a relative humidity of 92.5% for 7 days, and the weight gain rate is 0.085 - 0.092%;

[0047] (4) The preparation method of the betaine composition with blood pressure lowering effect of the present invention has a high qualified rate for the prepared betaine mixture, and the qualified rate can reach 98.9 - 99.4%;

[0048] (5) The preparation method of the betaine composition with blood pressure lowering effect of the present invention has a small difference in the content of the angiotensin converting enzyme inhibitor among the prepared betaine mixtures. Randomly select 20 grains from the betaine composition with blood pressure lowering effect prepared by the present invention, test the content of the angiotensin converting enzyme inhibitor therein, and use the largest content of the angiotensin converting enzyme inhibitor as the dividend and the smallest content of the angiotensin converting enzyme inhibitor as the divisor respectively. The division result obtained is 1.016 - 1.025. Detailed implementation manners

[0049] For a clearer understanding of the technical features, purposes and effects of the present invention, the detailed implementation manners of the present invention are now described.

[0050] Example 1

[0051] A preparation method of a betaine composition with blood pressure lowering effect is specifically as follows:

[0052] 1. Preparation of the tablet core: After separately pulverizing the angiotensin-converting enzyme inhibitor, microcrystalline cellulose, hydroxypropyl methylcellulose mixture, crospovidone, and magnesium stearate, sieve them through a 100-mesh sieve to obtain the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, and pulverized magnesium stearate. Mix the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, and ultrapure water, then sieve through a 24-mesh sieve to make wet granules. Dry them at 50 °C for 55 min, sieve through a 24-mesh sieve for sizing, and then mix with the pulverized magnesium stearate. Perform tabletting, controlling the pressure during tabletting at 30 N to obtain the tablet core;

[0053] The angiotensin-converting enzyme inhibitor is enalapril;

[0054] The hydroxypropyl methylcellulose composition is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M, wherein the mass ratio of the mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M is 1:1;

[0055] The mass ratio of the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, ultrapure water, and pulverized magnesium stearate is 40:100:45:3:50:24;

[0056] 2. Preparation of the first coating solution:

[0057] (1) Preparation of the filler: Mix 50 g of hydroxypropyl-β-cyclodextrin and 1000 mL of ultrapure water and stir, controlling the temperature during stirring at 25 °C and the stirring speed at 100 rpm. After stirring for 20 min, keep the temperature and stirring speed unchanged, add 100 g of silica micropowder, stir for 2 h, perform centrifugation, controlling the rotation speed during centrifugation at 2500 rpm for 10 min. Mix the precipitate with 1000 mL of ultrapure water and stir, controlling the temperature during stirring at 25 °C and the stirring speed at 100 rpm for 5 min. Raise the temperature to 85 °C, keep the stirring speed unchanged, perform stirring reflux, add 550 mL of citric acid aqueous solution, stir and reflux for 3.5 h, perform centrifugation, controlling the rotation speed during centrifugation at 2500 rpm for 10 min. Wash the precipitate 4 times with ultrapure water, using 700 mL of ultrapure water each time, and then dry at 110 °C to obtain the filler;

[0058] The particle size of the silica micropowder is 5 μm;

[0059] The mass concentration of the citric acid aqueous solution is 20%;

[0060] (2)Primary mixing: Mix 120 g of filler and 1000 mL of ultrapure water, then stir. Control the temperature during stirring at 30 °C and the stirring speed at 100 rpm. After stirring for 20 min, keep the temperature and stirring speed unchanged, add 45 g of betaine, stir for 2 h, continue to keep the temperature and stirring speed unchanged, add 50 g of hydroxypropyl methylcellulose, and stir for 1 h to obtain the primary coating solution;

[0061] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0062] 3. Preparation of the secondary coating solution:

[0063] (1)Preparation of the supramolecular composition: Mix 9 g of β-cyclodextrin and 500 mL of ultrapure water, then stir. Control the temperature during stirring at 25 °C and the stirring speed at 100 rpm. After stirring for 20 min, keep the temperature and stirring speed unchanged, add 140 mL of an aqueous solution of betaine, stir for 20 min, and perform spray drying. Control the inlet air temperature during spray drying at 130 °C and the outlet air temperature at 70 °C to obtain the supramolecular composition;

[0064] The mass concentration of the aqueous solution of betaine is 20%;

[0065] (2)Secondary mixing: Mix 40 g of ethyl cellulose, 10 g of hydroxypropyl methylcellulose, 10 g of triethyl citrate, 1.8 g of colloidal silica, 7 g of the supramolecular composition, and 950 mL of an ethanol solution, then stir. Control the temperature during stirring at 30 °C and the stirring speed at 100 rpm. After stirring for 50 min, obtain the secondary coating solution;

[0066] The ethyl cellulose is ethyl cellulose N10;

[0067] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0068] The volume concentration of the ethanol solution is 85%;

[0069] 4. Primary coating: Place the tablet cores into a fluidized bed coater for heat preservation. Control the temperature during heat preservation at 50 °C for 9 min. Keep the temperature unchanged, and perform primary coating with the primary coating solution. Control the coating weight gain at 5% to obtain the primary coated products;

[0070] 5. Secondary coating: Place the primary coated products into a fluidized bed coater for heat preservation. Control the temperature during heat preservation at 50 °C for 9 min. Keep the temperature unchanged, and perform secondary coating with the secondary coating solution. Control the coating weight gain at 2.8% to obtain the betaine composition with blood pressure lowering effect.

[0071] This embodiment also provides a betaine composition with blood pressure lowering effect prepared by the aforementioned preparation method.

[0072] Example 2

[0073] A preparation method of a betaine composition with blood pressure lowering effect is as follows:

[0074] 1. Prepare the tablet core: After separately pulverizing the angiotensin-converting enzyme inhibitor, microcrystalline cellulose, hydroxypropyl methylcellulose mixture, crospovidone, and magnesium stearate, sieve them through a 100-mesh sieve to obtain the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, and pulverized magnesium stearate. Mix the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, and ultrapure water, then sieve through a 24-mesh sieve to make wet granules, dry at 55 °C for 57 min, sieve through a 24-mesh sieve for granulation, and then mix with the pulverized magnesium stearate and press tablets, controlling the pressure during tablet pressing to be 32 N to obtain the tablet core;

[0075] The angiotensin-converting enzyme inhibitor is captopril;

[0076] The hydroxypropyl methylcellulose composition is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M, wherein the mass ratio of hydroxypropyl methylcellulose E5 to hydroxypropyl methylcellulose K100M is 1:1.1;

[0077] The mass ratio of the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, ultrapure water, and pulverized magnesium stearate is 42:103:48:3.2:53:25;

[0078] 2. Prepare the primary coating solution:

[0079] (1) Preparation of the filler: Mix 52 g of hydroxypropyl-β-cyclodextrin and 1020 mL of ultrapure water and stir. Control the temperature during stirring at 28 °C and the stirring speed at 200 rpm. After stirring for 22 min, keep the temperature and stirring speed unchanged, add 102 g of silica micropowder, stir for 2.5 h, centrifuge, control the rotation speed during centrifugation at 2600 rpm, centrifuge for 11 min. Mix the precipitate with 1040 mL of ultrapure water and stir. Control the temperature during stirring at 30 °C and the stirring speed at 150 rpm. Stir for 8 min, raise the temperature to 90 °C, keep the stirring speed unchanged, carry out stirring reflux, add 580 mL of citric acid aqueous solution, stir and reflux for 3.5 h, centrifuge, control the rotation speed during centrifugation at 2700 rpm, centrifuge for 11 min, wash the precipitate 5 times with ultrapure water, using 750 mL of ultrapure water each time, and then dry at 120 °C to obtain the filler;

[0080] The particle size of the silica micropowder is 5 μm;

[0081] The mass concentration of the citric acid aqueous solution is 20%;

[0082] (2) Primary mixing: Mix 122 g of the filler and 1030 mL of ultrapure water and stir. Control the temperature during stirring at 35 °C and the stirring speed at 150 rpm. After stirring for 23 min, keep the temperature and stirring speed unchanged, add 46 g of betaine hydrochloride, stir for 2 h, continue to keep the temperature and stirring speed unchanged, add 52 g of hydroxypropyl methylcellulose, stir for 1 h to obtain the primary coating solution;

[0083] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0084] 3. Preparation of the secondary coating solution:

[0085] (1) Preparation of the supramolecular composition: Mix 9.1 g of β-cyclodextrin and 510 mL of ultrapure water and stir. Control the temperature during stirring at 30 °C and the stirring speed at 100 rpm. After stirring for 23 min, keep the temperature and stirring speed unchanged, add 145 mL of an aqueous solution of betaine hydrochloride, stir for 23 min, carry out spray drying, control the inlet air temperature during spray drying at 135 °C and the outlet air temperature at 72 °C to obtain the supramolecular composition;

[0086] The mass concentration of the aqueous solution of betaine hydrochloride is 20%;

[0087] (2) Secondary mixing: Mix 41 g of ethylcellulose, 10.5 g of hydroxypropyl methylcellulose, 10.5 g of triethyl citrate, 1.8 g of colloidal silicon dioxide, 7.2 g of supramolecular composition, and 960 mL of ethanol solution, and then stir. Control the temperature during stirring at 35 °C, the stirring speed at 150 rpm. After stirring for 52 min, a secondary coating solution is obtained;

[0088] The ethylcellulose is ethylcellulose N10;

[0089] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0090] The volume concentration of the ethanol solution is 85%;

[0091] 4. Primary coating: Place the tablet core in a fluidized bed coater for heat preservation. Control the temperature during heat preservation at 52 °C for 9.5 min. Keep the temperature unchanged, and use the primary coating solution for primary coating. Control the coating weight gain at 5.1% to obtain a primary coated product;

[0092] 5. Secondary coating: Place the primary coated product in a fluidized bed coater for heat preservation. Control the temperature during heat preservation at 52 °C for 9 min. Keep the temperature unchanged, and use the secondary coating solution for secondary coating. Control the coating weight gain at 2.8% to obtain a betaine composition with blood pressure lowering effect.

[0093] This example also provides a betaine composition with blood pressure lowering effect prepared by the foregoing preparation method.

[0094] Example 3

[0095] A preparation method of a betaine composition with blood pressure lowering effect, specifically:

[0096] 1. Preparation of tablet core: Crush the angiotensin converting enzyme inhibitor, microcrystalline cellulose, hydroxypropyl methylcellulose mixture, crospovidone, and magnesium stearate respectively, and pass through a 100-mesh sieve to obtain the crushed angiotensin converting enzyme inhibitor, crushed microcrystalline cellulose, crushed hydroxypropyl methylcellulose mixture, crushed crospovidone, and crushed magnesium stearate. Mix the crushed angiotensin converting enzyme inhibitor, crushed microcrystalline cellulose, crushed hydroxypropyl methylcellulose mixture, crushed crospovidone, and ultrapure water, and then pass through a 24-mesh sieve to make wet granules. Dry at 60 °C for 58 min, pass through a 24-mesh sieve for sizing, and then mix with the crushed magnesium stearate and press tablets. Control the pressure during tablet pressing at 34 N to obtain the tablet core;

[0097] The angiotensin converting enzyme inhibitor is benazepril hydrochloride;

[0098] The hydroxypropyl methylcellulose composition is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M, wherein the mass ratio of hydroxypropyl methylcellulose E5 to hydroxypropyl methylcellulose K100M is 1:1.1;

[0099] The mass ratio of the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, ultrapure water, and pulverized magnesium stearate is 44:108:52:3.8:57:26;

[0100] 2. Prepare the primary coating solution:

[0101] (1) Prepare the filler: Mix 60 g of hydroxypropyl-β-cyclodextrin and 1050 mL of ultrapure water and stir. Control the temperature during stirring at 35 °C and the stirring speed at 250 rpm. After stirring for 28 min, keep the temperature and stirring speed unchanged, add 107 g of colloidal silica, stir for 2.5 h, centrifuge, control the rotation speed during centrifugation at 3000 rpm, and centrifuge for 14 min. Mix the precipitate with 1080 mL of ultrapure water and stir. Control the temperature during stirring at 35 °C and the stirring speed at 250 rpm. Stir for 8 min, raise the temperature to 95 °C, keep the stirring speed unchanged, and carry out stirring reflux. Add 620 mL of citric acid aqueous solution, stir and reflux for 4 h, centrifuge, control the rotation speed during centrifugation at 3000 rpm, and centrifuge for 14 min. Wash the precipitate 5 times with ultrapure water, using 850 mL of ultrapure water each time, and then dry at 125 °C to obtain the filler;

[0102] The particle size of the colloidal silica is 5 μm;

[0103] The mass concentration of the citric acid aqueous solution is 20%;

[0104] (2) Primary mixing: Mix 128 g of the filler and 1070 mL of ultrapure water and stir. Control the temperature during stirring at 45 °C and the stirring speed at 250 rpm. After stirring for 27 min, keep the temperature and stirring speed unchanged, add 48 g of betaine phosphate, stir for 2.5 h, continue to keep the temperature and stirring speed unchanged, add 54 g of hydroxypropyl methylcellulose, and stir for 1.5 h to obtain the primary coating solution;

[0105] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0106] 3. Prepare the secondary coating solution:

[0107] (1) Preparation of supramolecular composition: Mix 9.1 g of β-cyclodextrin and 540 mL of ultrapure water, and stir. Control the temperature during stirring at 35 °C and the stirring speed at 250 rpm. After stirring for 28 min, keep the temperature and stirring speed unchanged, add 155 mL of an aqueous solution of betaine phosphate, stir for 28 min, and then perform spray drying. Control the inlet air temperature during spray drying at 145 °C and the outlet air temperature at 78 °C to obtain the supramolecular composition;

[0108] The mass concentration of the aqueous solution of betaine phosphate is 20%;

[0109] (2) Secondary mixing: Mix 42 g of ethyl cellulose, 11.5 g of hydroxypropyl methylcellulose, 11.7 g of triethyl citrate, 2 g of microcrystalline silica gel, 7.7 g of supramolecular composition, and 980 mL of an ethanol solution, and stir. Control the temperature during stirring at 45 °C and the stirring speed at 250 rpm. After stirring for 57 min, obtain the secondary coating solution;

[0110] The ethyl cellulose is ethyl cellulose N10;

[0111] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0112] The volume concentration of the ethanol solution is 85%;

[0113] 4. Primary coating: Place the tablet core in a fluidized bed coater for heat preservation. Control the temperature during heat preservation at 54 °C for 10 min. Keep the temperature unchanged, and perform primary coating with the primary coating solution. Control the coating weight gain at 5.2% to obtain the primary coated product;

[0114] 5. Secondary coating: Place the primary coated product in a fluidized bed coater for heat preservation. Control the temperature during heat preservation at 54 °C for 10 min. Keep the temperature unchanged, and perform secondary coating with the secondary coating solution. Control the coating weight gain at 2.9% to obtain the betaine composition with antihypertensive effect.

[0115] This example also provides a betaine composition with antihypertensive effect prepared by the aforementioned preparation method.

[0116] Example 4

[0117] A preparation method of a betaine composition with antihypertensive effect, specifically:

[0118] 1. Preparation of the tablet core: After separately pulverizing the angiotensin-converting enzyme inhibitor, microcrystalline cellulose, hydroxypropyl methylcellulose mixture, crospovidone, and magnesium stearate, sieve them through a 100-mesh sieve to obtain the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, and pulverized magnesium stearate. Mix the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, and ultrapure water, then sieve through a 24-mesh sieve to make wet granules. Dry at 60 °C for 60 min, sieve through a 24-mesh sieve for granule sizing, and then mix with the pulverized magnesium stearate and press tablets, controlling the pressure during tableting to be 35 N to obtain the tablet core;

[0119] The angiotensin-converting enzyme inhibitor is enalapril;

[0120] The hydroxypropyl methylcellulose composition is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M, wherein the mass ratio of the mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M is 1:1.2;

[0121] The mass ratio of the pulverized angiotensin-converting enzyme inhibitor, pulverized microcrystalline cellulose, pulverized hydroxypropyl methylcellulose mixture, pulverized crospovidone, ultrapure water, and pulverized magnesium stearate is 45:110:55:4:60:27;

[0122] 2. Preparation of the first coating solution:

[0123] (1) Preparation of the filler: Mix 60 g of hydroxypropyl-β-cyclodextrin and 1100 mL of ultrapure water and stir, controlling the temperature during stirring to be 40 °C and the stirring speed to be 300 rpm. After stirring for 30 min, keep the temperature and stirring speed unchanged, add 110 g of colloidal silica, stir for 3 h, then centrifuge, controlling the rotation speed during centrifugation to be 3000 rpm and the centrifugation time to be 15 min. Mix the precipitate with 1100 mL of ultrapure water and stir, controlling the temperature during stirring to be 40 °C and the stirring speed to be 300 rpm. Stir for 10 min, then raise the temperature to 95 °C, keep the stirring speed unchanged, and carry out stirring reflux. Add 650 mL of citric acid aqueous solution and stir reflux for 4 h, then centrifuge, controlling the rotation speed during centrifugation to be 3000 rpm and the centrifugation time to be 15 min. Wash the precipitate 6 times with ultrapure water, using 900 mL of ultrapure water each time, and then dry at 130 °C to obtain the filler;

[0124] The particle size of the colloidal silica is 5 μm;

[0125] The mass concentration of the citric acid aqueous solution is 20%;

[0126] (2)Primary mixing: Mix 130 g of filler and 1100 mL of ultrapure water and stir. Control the temperature during stirring at 50 °C and the stirring speed at 300 rpm. After stirring for 30 min, keep the temperature and stirring speed unchanged, add 50 g of betaine citrate, stir for 2.5 h, continue to keep the temperature and stirring speed unchanged, add 55 g of hydroxypropyl methylcellulose, and stir for 1.5 h to obtain the primary coating solution;

[0127] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0128] 3. Preparation of the secondary coating solution:

[0129] (1)Preparation of the supramolecular composition: Mix 9.2 g of β-cyclodextrin and 550 mL of ultrapure water and stir. Control the temperature during stirring at 40 °C and the stirring speed at 300 rpm. After stirring for 30 min, keep the temperature and stirring speed unchanged, add 160 mL of an aqueous solution of betaine citrate, stir for 30 min, and perform spray drying. Control the inlet air temperature during spray drying at 150 °C and the outlet air temperature at 80 °C to obtain the supramolecular composition;

[0130] The mass concentration of the aqueous solution of betaine citrate is 20%;

[0131] (2)Secondary mixing: Mix 43 g of ethyl cellulose, 12 g of hydroxypropyl methylcellulose, 12 g of triethyl citrate, 2 g of colloidal silica, 8 g of the supramolecular composition, and 1000 mL of an ethanol solution and stir. Control the temperature during stirring at 50 °C and the stirring speed at 300 rpm. After stirring for 60 min, obtain the secondary coating solution;

[0132] The ethyl cellulose is ethyl cellulose N10;

[0133] The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5;

[0134] The volume concentration of the ethanol solution is 85%;

[0135] 4. Primary coating: Place the tablet cores in a fluidized bed coater for heat preservation. Control the temperature during heat preservation at 55 °C for 10 min. Keep the temperature unchanged and perform primary coating with the primary coating solution. Control the coating weight gain at 5.3% to obtain the primary coated products;

[0136] 5. Secondary coating: Place the primary coated products in a fluidized bed coater for heat preservation. Control the temperature during heat preservation at 55 °C for 10 min. Keep the temperature unchanged and perform secondary coating with the secondary coating solution. Control the coating weight gain at 3% to obtain the betaine composition with blood pressure lowering effect.

[0137] This embodiment also provides a betaine composition with blood pressure lowering effect prepared by the foregoing preparation method.

[0138] Comparative Example 1

[0139] This comparative example provides a preparation method of a betaine composition with blood pressure lowering effect. The preparation method is adjusted on the basis of the preparation method of Example 1. The specific adjustment is as follows:

[0140] In the step of preparing the primary coating solution in the second step, the step of preparing the filler in the first step is omitted, and in the secondary mixing step in the second step, microcrystalline silica with a particle size of 5 μm is used to replace the filler in equal mass.

[0141] This comparative example also provides a betaine composition with blood pressure lowering effect prepared by the foregoing preparation method.

[0142] Comparative Example 2

[0143] This comparative example provides a preparation method of a betaine composition with blood pressure lowering effect. The preparation method is adjusted on the basis of the preparation method of Example 1. The specific adjustment is as follows:

[0144] In the step of preparing the secondary coating solution in the third step, the step of preparing the supramolecular composition in the first step is omitted, and in the secondary mixing step in the second step, 5.3 g of betaine is used to replace 7 g of the supramolecular composition.

[0145] This comparative example also provides a betaine composition with blood pressure lowering effect prepared by the foregoing preparation method.

[0146] Test Example 1

[0147] The release rates of angiotensin-converting enzyme inhibitors in the betaine compositions with blood pressure lowering effect prepared in Examples 1-4 and Comparative Examples 1-2 were respectively detected. The detection methods and results are as follows:

[0148] According to the second paddle method in the dissolution test method in the 2010 edition of the Chinese Pharmacopoeia, using distilled water as the dissolution medium, controlling the temperature at 37 °C and the rotation speed at 50 rpm, samples were taken at 2 h, 4 h, 8 h, 12 h, and 24 h respectively to detect the dissolution degrees of angiotensin-converting enzyme inhibitors in the betaine compositions with blood pressure lowering effect in Examples 1-4 and Comparative Examples 1-2. The detection results are as follows:

[0149]

[0150] It can be seen from the results of this test example that the sustained release effect of the betaine composition with blood pressure lowering effect prepared in Example 1 is better than that of the betaine compositions with blood pressure lowering effect prepared in Comparative Examples 1-2.

[0151] Test Example 2

[0152] Prepare 1000 capsules according to the preparation methods of the betaine compositions with blood pressure lowering effects in Examples 1-4 and Comparative Examples 1-2, and respectively count the qualified rates. The statistical results are as follows:

[0153]

[0154] Then randomly select 20 capsules respectively, test the content of angiotensin converting enzyme inhibitor in them, and respectively use the maximum content of angiotensin converting enzyme inhibitor as the dividend and the minimum content of angiotensin converting enzyme inhibitor as the divisor to obtain the division result. The statistical results are as follows:

[0155]

[0156] It can be seen from the results of this test example that the qualified rate of the betaine composition with blood pressure lowering effect prepared in Example 1 is better than that of the betaine compositions with blood pressure lowering effect prepared in Comparative Examples 1-2, and compared with the betaine compositions with blood pressure lowering effect prepared in Comparative Examples 1-2, the difference in the content of angiotensin converting enzyme inhibitor between the betaine mixtures prepared in Example 1 is small.

[0157] Test Example 3

[0158] Respectively leave the betaine compositions with blood pressure lowering effects prepared in Examples 1-4 and Comparative Examples 1-2 standing for 7 days in an environment with a temperature of 25°C and a relative humidity of 92.5%, and then respectively count the weight gain rates. The statistical results are as follows:

[0159]

[0160] It can be seen from the results of this test example that the storage stability of the betaine composition with blood pressure lowering effect prepared in Example 1 is better than that of the betaine compositions with blood pressure lowering effect prepared in Comparative Examples 1-2.

[0161] Unless otherwise specified, the percentages used in the present invention are all mass percentages.

[0162] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing a betaine composition having a blood pressure lowering effect, characterized in that: include: (1) Preparing tablet cores: crushing enalapril, microcrystalline cellulose, hydroxypropyl methylcellulose mixture, crospovidone, and magnesium stearate, and sieving; mixing 40 parts by weight of the crushed enalapril, 100 parts by weight of the crushed microcrystalline cellulose, 45 parts by weight of the crushed hydroxypropyl methylcellulose mixture, 3 parts by weight of the crushed crospovidone, and 50 parts by weight of ultrapure water, granulating the mixture, and then mixing the mixture with 24 parts by weight of the crushed magnesium stearate, and tableting the mixture to obtain tablet cores; The hydroxypropyl methylcellulose mixture is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K100M in a mass ratio of 1:1; (2) Preparing a primary coating solution, comprising: step A, preparing a filler: mixing 50 g of hydroxypropyl-β-cyclodextrin and 1000 mL of ultrapure water, stirring at 25° C., adding 100 g of micropowdered silica gel, stirring, centrifuging, mixing the precipitate with 1000 mL of ultrapure water, stirring at 25° C., heating to 85° C., stirring and refluxing, adding 550 mL of citric acid aqueous solution, stirring and refluxing, centrifuging, washing the precipitate, and then drying to obtain a filler; step B, primary mixing: mixing 120 g of the filler and 1000 mL of ultrapure water, stirring at 30° C., adding 45 g of betaine, stirring, adding 50 g of hydroxypropyl methylcellulose, stirring, and obtaining a primary coating solution; (3) Preparing a secondary coating solution, comprising: step C, preparing a supramolecular composition: mixing 9 g of β-cyclodextrin and 500 mL of ultrapure water, stirring at 25° C., adding 140 mL of an aqueous solution of betaine, stirring, and spray drying to obtain a supramolecular composition; step D, secondary mixing: mixing 40 g of ethyl cellulose, 10 g of hydroxypropyl methylcellulose, 10 g of triethyl citrate, 1.8 g of micropowder silica gel, 7 g of the supramolecular composition, and 950 mL of an ethanol solution, stirring at 30° C. to obtain a secondary coating solution.

2. The method for preparing the betaine composition having a blood pressure lowering effect according to claim 1, characterized in that: In the preparation of the tablet core, the pressure during tableting is 30N.

3. The method for preparing the betaine composition having a blood pressure lowering effect according to claim 1, characterized in that: In the preparation of the filler, the particle size of the micropowder silica gel is 5 μm; The mass concentration of the citric acid aqueous solution is 20%.

4. The method for preparing the betaine composition having a blood pressure lowering effect according to claim 1, characterized in that: In the primary mixing, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5.

5. The method for preparing the betaine composition having a blood pressure lowering effect according to claim 1, characterized in that: In the preparation of the supramolecular composition, the mass concentration of the aqueous solution of betaine is 20%.

6. The method for preparing the betaine composition having a blood pressure lowering effect according to claim 1, characterized in that: In the secondary mixing, the ethyl cellulose is ethyl cellulose N10; The hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5; The volume concentration of the ethanol solution is 85%.

7. The method for preparing the betaine composition having a blood pressure lowering effect according to claim 1, characterized in that: The method further comprises (4) a primary coating: placing the tablet core in a fluidized bed coating machine for heat preservation, maintaining the temperature constant, and coating the tablet core once with a primary coating solution to obtain a primary coating layer; In the first coating, the temperature during the heat preservation is 50°C and the heat preservation time is 9 minutes; The weight gain of the first coating is 5%.

8. The method for preparing the betaine composition having a blood pressure lowering effect according to claim 1, characterized in that: The method further comprises (5) secondary coating: placing the primary coating material in a fluidized bed coating machine for heat preservation, maintaining the temperature constant, and performing secondary coating with a secondary coating liquid to obtain a betaine composition having a blood pressure lowering effect; In the secondary coating, the temperature during the heat preservation is 50°C and the heat preservation time is 9 minutes; The secondary coating weight gain was 2.8%.

9. A betaine composition having a blood pressure lowering effect prepared by the preparation method according to any one of claims 1 to 8.

Images