阅读说明：本技术 一种替米沙坦制剂中间体的制备方法 (Preparation method of telmisartan preparation intermediate ) 是由 李维思 许林菊 徐强 柳贞 孔鹏 许鹏飞 魏志平 于 2020-12-31 设计创作，主要内容包括：本发明公开了一种替米沙坦制剂的制备方法,将3-4质量份的氢氧化钠、40质量份的替米沙坦溶解于40-60质量份的溶剂中,搅拌或静置析晶得到替米沙坦钠固液混合物；将120-180质量份的稀释剂、5-15质量份的葡甲胺、0-10质量份的粘合剂、0-15质量份的崩解剂等辅料后加入替米沙坦钠固液混合物湿法制粒；干燥整粒后外加0-5质量份的润滑剂总混；总混颗粒压片或填充胶囊。本发明操作处理简单,通过溶液反应形成替米沙坦钠能达到改善药物溶出的目的,通过特定量的溶剂析晶后制粒能解决湿法制粒过程中物料粘结的问题。(The invention discloses a preparation method of a telmisartan preparation, which comprises the steps of dissolving 3-4 parts by mass of sodium hydroxide and 40 parts by mass of telmisartan in 40-60 parts by mass of solvent, and stirring or standing for crystallization to obtain a telmisartan sodium solid-liquid mixture; adding auxiliary materials such as 120-180 parts by mass of diluent, 5-15 parts by mass of meglumine, 0-10 parts by mass of adhesive, 0-15 parts by mass of disintegrant and the like into the telmisartan sodium solid-liquid mixture for wet granulation; drying, finishing granules, adding 0-5 parts by mass of lubricant, and mixing; the total mixed granules are tableted or filled into capsules. The method is simple in operation and treatment, the purpose of improving the dissolution of the medicament can be achieved by forming telmisartan sodium through solution reaction, and the problem of material adhesion in the wet granulation process can be solved by granulating after crystallization of a specific amount of solvent.)

1. A preparation method of a telmisartan preparation intermediate is characterized by comprising the following steps: dissolving 3-4 parts by mass of sodium hydroxide and 40 parts by mass of telmisartan in 40-60 parts by mass of solvent, and crystallizing to obtain a telmisartan sodium solid-liquid mixture; mixing 120-180 parts by mass of diluent, 5-15 parts by mass of meglumine, 0-10 parts by mass of adhesive and 0-15 parts by mass of disintegrant, and adding the mixture into a telmisartan sodium solid-liquid mixture for wet granulation; drying, finishing granules, adding 0-5 parts by mass of lubricant, and mixing to obtain a telmisartan preparation intermediate; the solvent is ethanol solution.

2. The method of claim 1, wherein the solvent is 95% ethanol.

3. The process according to claim 1, wherein the amount of the solvent is 1.2 times the amount of telmisartan.

4. The process of claim 1, wherein the binder is povidone K30 or povidone K25.

5. The preparation method according to claim 1, wherein the diluent is one or more of microcrystalline cellulose, starch and lactose.

6. The preparation method according to claim 1, wherein the disintegrant is one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch.

7. The method of claim 1, wherein the lubricant is one or both of magnesium stearate and talc.

8. The preparation method according to claim 1, wherein the components are added in the following amounts:

9. the preparation method according to claim 1, wherein the components are added in the following amounts:

10. the method according to any one of claims 1 to 9, wherein the method comprises the steps of:

(1) dissolving sodium hydroxide in ethanol, adding telmisartan for dissolving, stirring or standing for more than 0.5h until crystallization is carried out to obtain a telmisartan sodium solid-liquid mixture;

(2) and (3) wet granulation: weighing the diluent, the disintegrant, the meglumine and the adhesive according to the prescription amount, uniformly mixing to obtain a mixed auxiliary material, adding the telmisartan sodium solid-liquid mixture into the mixed auxiliary material to prepare a soft material, and sieving to obtain wet granules; drying until the water content is less than 3.0%, and sieving to obtain dry granules;

(3) total mixing: and adding a lubricant into the dry auxiliary material particles, and uniformly mixing to obtain the telmisartan preparation intermediate.

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of a telmisartan preparation.

Background

Telmisartan is a novel antihypertensive drug, is a specific angiotensin II receptor (ATI type) antagonist, and is used for treating essential hypertension. The telmisartan tablet preparation is used for treating essential hypertension of adults and reducing cardiovascular risks, and is suitable for patients aged 55 years and older who are at high risk of suffering from serious cardiovascular events and cannot be treated by Angiotensin Converting Enzyme (ACE) inhibitors, so that the risk of death caused by myocardial infarction, stroke or cardiovascular diseases is reduced.

Domestic telmisartan preparations are produced by a plurality of manufacturers, and most telmisartan preparations are ordinary tablets and capsules. Because telmisartan is insoluble in water, the problems of low dissolution rate, poor curative effect and the like are easy to occur after the telmisartan is prepared into a preparation. At present, domestic enterprises mainly react telmisartan and alkaline substances to form salt, so that the telmisartan which is difficult to dissolve is changed into telmisartan potassium salt or telmisartan sodium salt which is easy to dissolve, and the dissolution problem of telmisartan tablets is solved.

However, because the potassium salt or sodium salt of telmisartan is easily dissolved in water and has strong hygroscopicity, most manufacturers adopt a direct powder compression method during tablet production, which puts higher requirements on auxiliary materials, and carefully screen main fillers, glidants and lubricants in the research process; some manufacturers adopt a wet granulation process by mixing raw materials and auxiliary materials, but the telmisartan after being salified can generate a sticky phenomenon after meeting with a binder solution, so that the problems of uneven granulation and difficulty in sieving a bonded screen can be caused, and finally the content uniformity problem can be caused.

Disclosure of Invention

The invention aims to overcome the defects of the prior art, provides an improved preparation method of a telmisartan preparation, and solves the problem of material adhesion in a wet granulation process after the telmisartan is salified in the prior art.

The purpose of the invention is realized by the following technical scheme:

a preparation method of a telmisartan preparation intermediate comprises the following steps: dissolving 3-4 parts by mass of sodium hydroxide and 40 parts by mass of telmisartan in 40-60 parts by mass of solvent, and stirring or standing for crystallization to obtain a telmisartan sodium solid-liquid mixture; adding auxiliary materials such as 120-180 parts by mass of diluent, 5-15 parts by mass of meglumine, 0-10 parts by mass of adhesive, 0-15 parts by mass of disintegrant and the like into the telmisartan sodium solid-liquid mixture for wet granulation; drying, granulating, adding 0-5 parts by mass of lubricant, and mixing.

If no adhesive, disintegrant or lubricant is added in the preparation method of the telmisartan preparation intermediate, the preparation method comprises the steps of dissolving 3-4 parts by mass of sodium hydroxide and 40 parts by mass of telmisartan in 40-60 parts by mass of solvent, and stirring or standing for crystallization to obtain a telmisartan sodium solid-liquid mixture; mixing 120-180 parts by mass of diluent and 5-15 parts by mass of meglumine, and adding a telmisartan sodium solid-liquid mixture for wet granulation; drying, granulating and mixing to obtain a telmisartan preparation intermediate; the solvent is ethanol solution.

The total mixed granules are tableted or filled into capsules.

The solvent is ethanol solution, preferably 95% ethanol.

The using amount of the solvent is 1-1.5 times, preferably 1.2 times of that of telmisartan.

In the step, after the sodium hydroxide and the telmisartan are dissolved in a proper amount of solvent, a crystallization process is needed.

The preparation method comprises the following steps:

the diluent is one or more of microcrystalline cellulose, starch and lactose.

The disintegrant is one or more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch.

The addition amounts of the components are preferably as follows:

the lubricant is one or two of magnesium stearate and talcum powder.

The preparation method comprises the following specific steps:

(1) dissolving sodium hydroxide in ethanol, adding the raw material medicines for dissolving, stirring or standing for more than 0.5h to obtain a telmisartan sodium solid-liquid mixture;

(2) and (3) wet granulation: weighing the diluent, the disintegrant, the meglumine, the adhesive and the like according to the prescription amount, uniformly mixing, adding the telmisartan sodium solid-liquid mixture into the mixed auxiliary materials to prepare a soft material, and sieving by a 40-mesh sieve to obtain wet granules; drying by blowing at 60 deg.C until the water content is less than 3.0%, and sieving with 40-60 mesh sieve to obtain dry granule;

(3) total mixing: adding a lubricant into the auxiliary material dry particles and uniformly mixing;

(4) the total mixed granules are tableted or filled into capsules.

Advantageous effects

The preparation method of the telmisartan preparation is simple, the purpose of improving the dissolution of the medicament can be achieved by forming telmisartan sodium through solution reaction, and the step of spray drying or decompression drying the solution of telmisartan sodium to obtain solid telmisartan sodium in the prior art can be omitted; according to the invention, a specific amount of solvent such as ethanol is adopted to dissolve sodium hydroxide and telmisartan firstly and then the telmisartan is crystallized to obtain a solid-liquid mixture of telmisartan sodium, and then wet granulation is carried out, so that the problem of material adhesion in the wet granulation process after the telmisartan is salified in the prior art can be solved.

Drawings

FIG. 1 is a photograph of pelletization in comparative example 1

FIG. 2 is a photograph of pelletization in example 1

Detailed Description

The invention is further illustrated by the following examples, which are intended to be illustrative and not limiting. It will be understood by those of ordinary skill in the art that these examples are not intended to limit the present invention in any way and that suitable modifications and data transformations may be made without departing from the spirit and scope of the present invention.

Example 1:

preparing telmisartan capsules, and weighing the components according to the following formula:

the preparation method comprises the following steps: dissolving sodium hydroxide in ethanol, adding telmisartan for dissolving, standing for 0.5h for crystallization to obtain a telmisartan sodium solid-liquid mixture; weighing microcrystalline cellulose, lactose, meglumine and povidone according to the formula amount, uniformly mixing, adding the telmisartan sodium solid-liquid mixture into the mixed auxiliary materials to prepare a soft material, and sieving by a 40-mesh sieve to obtain wet granules; blast drying at 60 deg.C until the water content is less than 3.0%, and sieving with 60 mesh sieve to obtain dried granule; and (4) filling the capsules.

Example 2:

preparing telmisartan capsules, and weighing the components according to the following formula:

the preparation method comprises the following steps: dissolving sodium hydroxide in ethanol, adding telmisartan for dissolving, standing for 3h for crystallization to obtain a telmisartan sodium solid-liquid mixture; weighing starch, lactose, meglumine and croscarmellose sodium according to the formula amount, uniformly mixing, adding the telmisartan sodium solid-liquid mixture into the mixed auxiliary materials to prepare a soft material, and sieving by a 40-mesh sieve to obtain wet granules; blast drying at 60 deg.C until the water content is less than 3.0%, and sieving with 40 mesh sieve to obtain dry granule; adding talcum powder and mixing; and (4) filling the capsules.

Example 3:

preparing telmisartan capsules, and weighing the components according to the following formula:

the preparation method comprises the following steps: dissolving sodium hydroxide in ethanol, adding telmisartan for dissolving, stirring for 2h, and crystallizing to obtain a telmisartan sodium solid-liquid mixture; weighing starch, lactose, meglumine and crospovidone according to the formula amount, uniformly mixing, adding the telmisartan sodium solid-liquid mixture into the mixed auxiliary materials to prepare a soft material, and sieving by a 40-mesh sieve to obtain wet granules; blast drying at 60 deg.C until the water content is less than 3.0%, and sieving with 60 mesh sieve to obtain dried granule; and (4) filling the capsules.

Example 4:

preparing telmisartan tablets, weighing the component substances according to the following formula:

the preparation method comprises the following steps: dissolving sodium hydroxide in ethanol, adding telmisartan for dissolving, standing for 3h for crystallization to obtain a telmisartan sodium solid-liquid mixture; weighing microcrystalline cellulose, lactose, meglumine and croscarmellose sodium according to the formula, uniformly mixing, adding the telmisartan sodium solid-liquid mixture into the mixed auxiliary materials to prepare a soft material, and sieving by a 40-mesh sieve to obtain wet granules; blast drying at 60 deg.C until the water content is less than 3.0%, and sieving with 60 mesh sieve to obtain dried granule; adding magnesium stearate and mixing; and (6) tabletting.

Example 5:

preparing telmisartan capsules, and weighing the components according to the following formula:

the preparation method comprises the following steps: dissolving sodium hydroxide in ethanol, adding telmisartan for dissolving, standing for 1h for crystallization to obtain a telmisartan sodium solid-liquid mixture; weighing microcrystalline cellulose, lactose and meglumine according to the formula amount, uniformly mixing, adding the telmisartan sodium solid-liquid mixture into the mixed auxiliary materials to prepare a soft material, and sieving by a 40-mesh sieve to obtain wet granules; blast drying at 60 deg.C until the water content is less than 3.0%, and sieving with 60 mesh sieve to obtain dried granule; and (4) filling the capsules.

Comparative example 1:

preparing telmisartan capsules, and weighing the components according to the following formula:

the preparation method comprises the following steps: dissolving sodium hydroxide in ethanol, adding telmisartan for dissolving, drying under reduced pressure and crushing to obtain telmisartan sodium; weighing telmisartan sodium, microcrystalline cellulose, lactose and meglumine according to the formula, uniformly mixing, granulating by using povidone solution, and sieving by using a 40-mesh sieve to obtain wet granules; blast drying at 60 deg.C until the water content is less than 3.0%, and sieving with 40 mesh sieve to obtain dry granule; and (4) filling the capsules.

Comparative example 2:

preparing telmisartan tablets, weighing the component substances according to the following formula:

the preparation method comprises the following steps: dissolving sodium hydroxide in purified water, adding telmisartan for dissolution, and spray-drying to obtain telmisartan sodium; weighing telmisartan sodium, microcrystalline cellulose, lactose, meglumine and croscarmellose sodium according to the formula, uniformly mixing, granulating by using a povidone solution, and sieving by using a 40-mesh sieve to obtain wet granules; blast drying at 60 deg.C until the water content is less than 3.0%, and sieving with 40 mesh sieve to obtain dry granule; adding magnesium stearate and mixing; and (6) tabletting. (the materials are bonded after granulation, the sieving is difficult, the yield is lower)

Example 6

Dissolution curve study method:

taking a sample, taking 900mL of pH7.5 phosphate buffer as a dissolution medium according to a dissolution and release determination method (second method of 0931 in general), rotating at 50 revolutions per minute, taking about 10mL of solution for filtration when 5min, 10min, 15min, 20min, 30min, 45min and 60min respectively according to the method operation, simultaneously supplementing the medium with the same volume, taking 5mL of subsequent filtrate in precise amount, placing in a 10mL measuring flask, adding the dissolution medium for dilution to scale, shaking up, and taking the solution as a sample solution; the dissolution amount of each granule is calculated according to the method under the content measurement item.

Examples the results of the measurements were:

as can be seen from the above table, the telmisartan formulation prepared in example 1 of the present invention has a drug dissolution effect comparable to that of comparative example 1, but the operation treatment of example 1 is simple and the two steps of drying and pulverizing can be reduced.

From the above table, it can be seen that the yield of the product prepared by the processes of examples 1 to 5 of the present invention can reach more than 95%, the yield of comparative example 1 is slightly low due to the loss caused by the two steps of drying and pulverizing, and the yield of comparative example 2 is low due to the large loss caused by the binding and sieving of the materials.