阅读说明：本技术 一种缬沙坦氨氯地平复方制剂的制备方法 (Preparation method of valsartan amlodipine compound preparation ) 是由 周世旺 杨加庚 于 2021-11-22 设计创作，主要内容包括：本发明提供了一种缬沙坦氨氯地平复方制剂的制备方法。本发明所述的制备方法是将粉碎过200目筛的缬沙坦、苯磺酸氨氯地平和适宜的药用辅料在湿法制粒混合机中预混,再转移至流化床中,喷入粘合剂溶液制粒,然后加入润滑剂混合,压片和包衣。本发明制备的缬沙坦氨氯地平复方制剂含量均匀度好,稳定性好,与市售制剂体外溶出行为一致；另外,本发明工艺简单易操作,适于工业化生产。(The invention provides a preparation method of a valsartan amlodipine compound preparation. The preparation method comprises the steps of premixing the valsartan, the amlodipine besylate and proper pharmaceutical excipients which are crushed and sieved by a 200-mesh sieve in a wet granulation mixer, transferring the mixture into a fluidized bed, spraying a binder solution for granulation, adding a lubricant for mixing, tabletting and coating. The valsartan amlodipine compound preparation prepared by the invention has good content uniformity and good stability, and is consistent with the in-vitro dissolution behavior of a commercially available preparation; in addition, the method has simple and easy operation, and is suitable for industrial production.)

1. The preparation method of the valsartan amlodipine compound preparation is characterized in that each 1000 tablets are composed of the following components in parts by weight: 80-160g of valsartan, 2-10g of amlodipine besylate, 10240-100 g of microcrystalline cellulose PH, 304-10 g of povidone K, 10-40g of crospovidone XL, 1-10g of magnesium stearate, 1-10g of silicon dioxide and 3-10g of gastric-soluble film coating premix; and the method comprises the following steps:

the method comprises the following steps: pulverizing valsartan, and sieving with a 200-mesh sieve;

step two: dissolving povidone K30 in 60% ethanol solution to obtain povidone K30 alcoholic solution;

step three: premixing the valsartan, microcrystalline cellulose PH102, amlodipine besylate and crospovidone XL which are sieved by a 200-mesh sieve in a wet granulation mixer, transferring the mixture into a fluidized bed, and spraying povidone K30 alcohol solution for granulation;

step four: granulating the prepared granules by using a 20-mesh screen;

step five: transferring the granules into a mixer, adding magnesium stearate and silicon dioxide, and mixing for 5 minutes;

step six: tabletting by using a rotary tablet press, and controlling the hardness to be 4-15 kg;

step seven: coating with high-efficiency coating machine with the coating weight increased by 2-5%.

2. The use of a valsartan amlodipine compound preparation prepared by the method of claim 1 to improve the dissolution rate of the preparation and reduce the amount of impurities.

Technical Field

The invention relates to the technical field of antihypertensive drugs, in particular to a preparation method and application of a valsartan amlodipine compound preparation.

Background

Valsartan is a fine powder of white to almost white color, soluble in ethanol and methanol, and slightly soluble in water. Valsartan blocks the type I (AT1) receptor of angiotensin II, increases the blood plasma level of angiotensin II, stimulates the unblocked AT2 receptor and simultaneously resists the action of AT1 receptor, thereby achieving the effects of dilating blood vessels and lowering blood pressure.

Valsartan has the following structural formula:

amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and slightly soluble in ethanol. Amlodipine acts directly on vascular smooth muscle, resulting in a decrease in peripheral vascular resistance and a decrease in blood pressure.

Amlodipine has the following structural formula:

at present, the effect of the clinically used antihypertensive drug after single treatment is poor, and about 70 percent of patients cannot control the blood pressure after single treatment by using one drug; the combined antihypertensive drug treatment can obtain the similar or larger antihypertensive amplitude with the doubled dosage of the single drug with respectively smaller dosage, and greatly improves the antihypertensive standard reaching rate of the antihypertensive drug treatment. The valsartan and the amlodipine are respectively used as an angiotensin receptor blocker and a dihydropyridine calcium channel blocker, and the combined treatment has excellent antihypertensive curative effect and complementary action; the two antihypertensive drugs are combined into one, so that the curative effect can be improved in principle, and the tolerance of the drugs is better. The valsartan and amlodipine are clinically prepared into a compound preparation for treating hypertension, and the compound preparation can reduce the dosage and improve the medication compliance of patients on one hand and can reduce the side effect caused by the increase of the dosage of a single-dose medicament on the other hand.

The valsartan and the amlodipine have large specification difference when combined clinically, the minimum specification of the valsartan is 80mg, the minimum specification of the amlodipine is only 2.5mg, and the valsartan has low mass and density, so that the problem of uneven mixing is easily caused by a powder direct pressing process during production, and the content uniformity of a preparation is unqualified. The amlodipine is unstable when meeting moisture and meeting light, and experiments show that the amlodipine can be degraded and related substances can be increased by adopting a wet granulation process. In addition, dry granulation has problems of long time consumption, flying dust and the like during production, and is not an optimal choice.

Disclosure of Invention

The preparation method of the valsartan amlodipine compound preparation has a plurality of patents, and not only adopts a dry granulation process, but also adopts a hot-melt granulation process, and even adopts a wet granulation process; the invention aims to provide a preparation method of a novel valsartan amlodipine compound preparation. The invention adopts a fluidized bed granulation process, firstly putting valsartan, amlodipine besylate and pharmaceutically acceptable auxiliary materials into a wet granulation mixer, and starting stirring and a cutting knife to mix, thereby well solving the problem of uneven mixing caused by large specification difference of the two medicines and different material specific gravity; and transferring the material into a fluidized bed, spraying povidone K30 alcohol solution for granulation, controlling the air inlet temperature and air quantity, and quickly drying the granules to overcome the problem that the amlodipine besylate is unstable when wetted.

In order to achieve the purpose, the invention provides the following technical scheme:

a preparation method of a valsartan amlodipine compound preparation is disclosed, the compound preparation is prepared by taking valsartan and amlodipine besylate as active ingredients and various pharmaceutically acceptable auxiliary materials; every 1000 tablets of the valsartan amlodipine compound preparation consist of the following components in parts by weight: 80-160g of valsartan, 2-10g of amlodipine besylate, 10240-100 g of microcrystalline cellulose PH, 304-10 g of povidone K, 10-40g of crospovidone XL, 1-10g of magnesium stearate, 1-10g of silicon dioxide and 3-10g of gastric-soluble film coating premix.

The preparation method comprises the following steps:

the method comprises the following steps: pulverizing valsartan, and sieving with a 200-mesh sieve;

step two: dissolving povidone K30 in 60% ethanol solution to obtain povidone K30 alcoholic solution;

step three: mixing the crushed valsartan, microcrystalline cellulose PH102, amlodipine besylate and crospovidone XL in a wet granulation mixer, transferring the mixture into a fluidized bed, and spraying povidone K30 alcohol solution for granulation and drying;

step four: granulating the prepared granules by using a 20-mesh screen;

step five: transferring the granules into a mixer, adding magnesium stearate and silicon dioxide, and mixing for 5 minutes;

step six: tabletting by using a rotary tablet press, and controlling the hardness to be 4-15 kg;

step seven: coating with high-efficiency coating machine with the coating weight increased by 2-5%.

The invention further discloses application of the valsartan amlodipine compound preparation prepared by the method in improving the dissolution rate and stability of the preparation. The experimental results show that: the valsartan amlodipine compound preparation prepared by the invention can meet the condition that related substances do not have obvious change in the 6-month placing process under the accelerated condition; the valsartan and amlodipine besylate have excellent dissolution effect, and the dissolution rates of the valsartan and the amlodipine besylate in a phosphate buffer solution with the pH value of 6.8 within 30 minutes can reach more than 90 percent; in addition, the compound preparation prepared by the invention has consistent in-vitro dissolution behavior with the preparation sold in the market.

It should be noted that, in order to make the contents and technical connotations of the present invention more clearly understood by those skilled in the art, the inventor of the present invention makes the following descriptions of the related terms and symbols, applied to the reagent consumables and the apparatus and equipment:

"day 0": refers to the time when sample preparation is complete;

"acceleration condition": the temperature is 40 ℃ plus or minus 2 ℃, and the relative humidity is 75% + orminus 5%.

Detailed Description

In order to facilitate understanding of the present invention by those skilled in the art, the present invention provides the following embodiments to further explain the valsartan amlodipine compound preparation and the preparation method thereof:

example 1

Prescription (1000 tablets)

The preparation method comprises the following steps:

1. pulverizing valsartan, and sieving with a 200-mesh sieve;

2. dissolving povidone K30 in 60% ethanol solution to obtain povidone K30 alcoholic solution;

3. mixing the crushed valsartan, microcrystalline cellulose PH102, amlodipine besylate and crospovidone XL in a wet granulation mixer, transferring the mixture into a fluidized bed, and spraying povidone K30 alcohol solution for granulation and drying;

4. granulating the prepared granules by using a 20-mesh screen;

5. transferring the granules into a mixer, adding magnesium stearate and silicon dioxide, and mixing for 5 minutes;

6. using a rotary tablet press with a shallow concave punch with the diameter of 8.0 mm to perform tabletting, and controlling the hardness to be 7 kg;

7. the coating is coated by using an efficient coating machine, and the weight of the coating is increased by 3 percent.

Example 2

Prescription (1000 tablets)

The preparation method comprises the following steps:

1. pulverizing valsartan, and sieving with a 200-mesh sieve;

2. dissolving povidone K30 in 60% ethanol solution to obtain povidone K30 alcoholic solution;

3. mixing the crushed valsartan, microcrystalline cellulose PH102, amlodipine besylate and crospovidone XL in a wet granulation mixer, transferring the mixture into a fluidized bed, and spraying povidone K30 alcohol solution for granulation and drying;

4. granulating the prepared granules by using a 20-mesh screen;

5. transferring the granules into a mixer, adding magnesium stearate and silicon dioxide, and mixing for 5 minutes;

6. using an oval punch with the diameter of 6 mm by 12mm to perform tabletting by using a rotary tablet machine, and controlling the hardness to be 10 kg;

7. the coating is coated by using an efficient coating machine, and the weight of the coating is increased by 3 percent.

Example 3

Prescription (1000 tablets)

The preparation method comprises the following steps:

1. pulverizing valsartan, and sieving with a 200-mesh sieve;

2. dissolving povidone K30 in 60% ethanol solution to obtain povidone K30 alcoholic solution;

3. mixing the crushed valsartan, microcrystalline cellulose PH102, amlodipine besylate and crospovidone XL in a wet granulation mixer, transferring the mixture into a fluidized bed, and spraying povidone K30 alcohol solution for granulation and drying;

4. granulating the prepared granules by using a 20-mesh screen;

5. transferring the granules into a mixer, adding magnesium stearate and silicon dioxide, and mixing for 5 minutes;

6. using a rotary tablet press with a shallow concave punch with the diameter of 8.0 mm to perform tabletting, and controlling the hardness to be 6 kg;

7. the coating is coated by using an efficient coating machine, and the weight of the coating is increased by 3 percent.

Comparative example 1

Prescription (1000 tablets)

The preparation method comprises the following steps:

1. pulverizing valsartan, and sieving with a 200-mesh sieve;

2. placing the crushed valsartan, microcrystalline cellulose PH102, amlodipine besylate and crospovidone XL into a mixer, mixing for 20 minutes, adding magnesium stearate and silicon dioxide, and continuously mixing for 5 minutes;

3. using a rotary tablet press with a shallow concave punch with the diameter of 8.0 mm to perform tabletting, and controlling the hardness to be 7 kg;

4. the coating is coated by using an efficient coating machine, and the weight of the coating is increased by 3 percent.

Comparative example 2

Prescription (1000 tablets)

The preparation method comprises the following steps:

1. dissolving povidone K30 in 60% ethanol solution to obtain povidone K30 alcoholic solution;

2. mixing valsartan, microcrystalline cellulose PH102, amlodipine besylate and crospovidone XL in a wet granulation mixer, transferring the mixture into a fluidized bed, and spraying povidone K30 alcohol solution for granulation and drying;

3. granulating the prepared granules by using a 20-mesh screen;

4. transferring the granules into a mixer, adding magnesium stearate and silicon dioxide, and mixing for 5 minutes;

5. using a rotary tablet press with a shallow concave punch with the diameter of 8.0 mm to perform tabletting, and controlling the hardness to be 7 kg;

6. the coating is coated by using an efficient coating machine, and the weight of the coating is increased by 3 percent.

Comparative example 3

Prescription (1000 tablets)

The preparation method comprises the following steps:

1. pulverizing valsartan, and sieving with a 200-mesh sieve;

2. dissolving povidone K30 in 60% ethanol solution to obtain povidone K30 alcoholic solution;

3. mixing the crushed valsartan, microcrystalline cellulose PH102, amlodipine besylate and crospovidone XL in a wet granulation mixer, and spraying povidone K30 alcohol solution for granulation;

4. drying the prepared granules by a fluidized bed, and finishing the granules by a 20-mesh screen after drying;

5. transferring the granules into a mixer, adding magnesium stearate and silicon dioxide, and mixing for 5 minutes;

6. using a rotary tablet press with a shallow concave punch with the diameter of 8.0 mm to perform tabletting, and controlling the hardness to be 7 kg;

7. the coating is coated by using an efficient coating machine, and the weight of the coating is increased by 3 percent.

Test example 1

Checking content uniformity:

the checking method comprises the following steps: taking 1 tablet of the product, placing in a 50ml measuring flask, adding 5ml of water for disintegration, adding 30ml of solvent [ acetonitrile-water (1: 1) ], shaking, performing ultrasonic treatment for 15 minutes, diluting with solvent to scale, shaking uniformly, filtering, precisely measuring 5ml of subsequent filtrate, placing in a 25ml measuring flask, diluting with solvent to scale, shaking uniformly to obtain a sample solution; and taking appropriate amount of amlodipine besylate reference substance and valsartan reference substance respectively, precisely weighing, adding a solvent to dissolve and dilute to prepare a solution containing about 0.02 mg of amlodipine besylate and 0.32 mg of valsartan per 1ml, and taking the solution as a reference substance solution. Measuring by high performance liquid chromatography, and using octadecylsilane chemically bonded silica as filler; using phosphate buffer solution (2% triethylamine solution, adjusting pH value to 3.0 with phosphoric acid) -methanol-acetonitrile (50: 25: 25) as mobile phase; the column temperature was 40 ℃; the flow rate was 1.8ml per minute; the detection wavelength was 237 nm. The tailing factors of the amlodipine peak and the valsartan peak are not more than 1.5. Precisely measuring 10 μ l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram; the content of valsartan and amlodipine in each tablet is respectively calculated by peak areas according to an external standard method (the conversion factor of amlodipine and amlodipine besylate is 0.721).

Samples of examples 1-3, comparative example 1 and the commercial formulation were taken for content uniformity examination and the results were as follows:

the data in the table show that the content uniformity of valsartan and amlodipine in the valsartan amlodipine compound preparation prepared according to the embodiments 1 to 3 of the invention is good, and the result is far less than the requirement that A +2.2S is less than or equal to 15.0 specified in the current Chinese pharmacopoeia. While being superior to the commercial formulation and the sample prepared in comparative example 1.

Test example 2

And (3) dissolution rate inspection:

the checking method comprises the following steps: taking the product, according to a dissolution determination method (0931 second method of the general regulation of 2020 edition of Chinese pharmacopoeia), taking 1000ml of phosphate buffer solution (taking 6.805g of monopotassium phosphate and 0.896g of sodium hydroxide, adding water to dissolve and dilute to 1000ml, adjusting pH value to 6.8 with 0.2mol/L of sodium hydroxide or 1mol/L of phosphoric acid) as a dissolution medium, rotating at 75 revolutions per minute, operating according to the method, taking a dissolution liquid and filtering when 30 minutes pass, and taking a subsequent filtrate as a test solution; taking 28mg of an amlodipine besylate reference substance, precisely weighing, putting the reference substance into a 200ml measuring flask, adding methanol to dissolve the reference substance, diluting the reference substance to a scale by using a dissolution medium, and uniformly shaking the reference substance to obtain an amlodipine stock solution; taking 40mg of a valsartan reference substance, precisely weighing, placing in a 25ml measuring flask, adding methanol to dissolve and dilute to a scale, and shaking uniformly to obtain a valsartan stock solution; respectively and precisely measuring 5ml of each of the amlodipine stock solution and the valsartan stock solution, placing the amlodipine stock solution and the valsartan stock solution into a 100ml measuring flask, diluting the amlodipine stock solution and the valsartan stock solution to a scale by using a dissolution medium, and shaking the solution uniformly to serve as a reference solution. According to the determination of high performance liquid chromatography, octadecylsilane chemically bonded silica is used as a filling agent, acetonitrile-water-trifluoroacetic acid (500: 500: 2) is used as a mobile phase, the column temperature is 40 ℃, the flow rate is 1.2ml per minute, and the detection wavelength is 230 nm. The separation degree of the amlodipine peak and the valsartan peak is more than 2.0, and the tailing factors of the amlodipine peak and the valsartan peak are not more than 2.0. Precisely measuring the sample solution and the reference solution by 50 μ l each, injecting into a liquid chromatograph, and recording chromatogram. The dissolving amounts of valsartan and amlodipine in each tablet are respectively calculated by peak areas according to an external standard method (the conversion factor of amlodipine and amlodipine besylate is 0.721).

Dissolution tests were performed on samples of examples 1-3, comparative example 2, and a commercial formulation, and the results were as follows:

as can be seen from the above table, the dissolution performance of the valsartan amlodipine compound preparation obtained in embodiments 1 to 3 of the present invention is superior to that of the valsartan amlodipine compound preparation obtained in comparative example 2. Dissolution rates of valsartan and amlodipine in a valsartan and amlodipine compound preparation prepared according to embodiments 1-3 of the invention in a medium with pH6.8 for 30 minutes are both higher than 95%, which is far higher than the requirement of 80% of the limit specified by the quality standard, and the valsartan and amlodipine compound preparation has an excellent dissolution effect.

Test example 3

And (3) comparison of dissolution curves:

the samples of examples 1 to 3 of the present invention were compared with a commercially available preparation to calculate a similarity factor f2, as measured by the second method of 0931, the fourth guideline of the edition of "chinese pharmacopoeia" 2015, using four media, ph1.0 hydrochloric acid solution, ph4.5 phosphate buffer solution, ph6.8 phosphate buffer solution, and water, respectively, to determine the dissolution curves. The results are shown in the following table.

As can be seen from the above table, the dissolution curves of the valsartan amlodipine compound preparation obtained in the embodiments 1 to 3 of the present invention in four media, namely, a ph1.0 hydrochloric acid solution, a ph4.5 phosphate buffer solution, a ph6.8 phosphate buffer solution, and water, are far greater than 50 compared with the commercially available preparation f2, and the in vitro dissolution behavior of the sample prepared in the present invention is highly consistent with that of the commercially available preparation.

Test example 4

And (3) stability investigation:

the samples of examples 1-3 and comparative example 3 are packaged in a market, and are placed under an accelerated condition together with a commercial preparation, taken out at 0, 3 and 6 months, and the content, dissolution rate, related substances and the like are detected to examine the stability of the samples. The results are as follows:

the inspection results in the table above show that: the properties, contents and dissolution rates of the prepared sample in example 1 are basically consistent after the sample is placed for 6 months under the accelerated condition compared with 0 day; the substances involved increase slightly, but the maximum increase was only 0.1%, which is much smaller than the commercial formulation, whereas the sample of comparative example 3 accelerated for 6 months before the maximum single impurity, impurity D and total impurity were exceeded by the limit [ maximum single impurity (0.2%), impurity D (0.5%) and total impurity (1.2%) ]. The preparation method can meet the requirement that related substances of the sample have no obvious change in the process of being placed under the acceleration condition for 6 months.

The above description of the embodiments is only intended to facilitate the understanding of the method and the core idea of the present invention. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications are also within the scope of the present invention as defined in the appended claims.