阅读说明：本技术 替米沙坦氢氯噻嗪双层片及其制备方法 (Telmisartan and hydrochlorothiazide double-layer tablet and preparation method thereof ) 是由 赵寅 王亚军 李自毅 冯小路 杨波 郭婷婷 殷晶莉 于 2019-09-27 设计创作，主要内容包括：本发明涉及替米沙坦氢氯噻嗪双层片及其制备方法,该替米沙坦氢氯噻嗪双层片包括：替米沙坦层,所述替米沙坦层包含替米沙坦、氢氧化钠、增溶剂、乳糖、交联聚维酮和二氧化硅；氢氯噻嗪层,所述氢氯噻嗪层包含氢氯噻嗪；所述增溶剂选自葡甲胺、十二烷基硫酸钠、十二烷基磺酸钠和羟丙基-β环糊精的至少之一；其中：所述乳糖、所述交联聚维酮和所述二氧化硅的重量比为(9.4～65):(3.8～5):1。该替米沙坦氢氯噻嗪双层片,不仅替米沙坦层的物料混合均匀且流动性好,而且溶出效果好,稳定性优异,有利于工业化生产。(The invention relates to a telmisartan hydrochlorothiazide double-layer tablet and a preparation method thereof, wherein the telmisartan hydrochlorothiazide double-layer tablet comprises the following components: a telmisartan layer comprising telmisartan, sodium hydroxide, a solubilizer, lactose, crospovidone, and silicon dioxide; a hydrochlorothiazide layer comprising hydrochlorothiazide; the solubilizer is selected from at least one of meglumine, sodium dodecyl sulfate and hydroxypropyl-beta cyclodextrin; wherein: the weight ratio of the lactose to the crospovidone to the silicon dioxide is (9.4-65): 3.8-5): 1. The telmisartan and hydrochlorothiazide double-layer tablet has the advantages that the materials of the telmisartan layer are uniformly mixed, the mobility is good, the dissolution effect is good, the stability is excellent, and the industrial production is facilitated.)

1. A telmisartan hydrochlorothiazide double-layer tablet is characterized by comprising:

a telmisartan layer comprising telmisartan, sodium hydroxide, a solubilizer, lactose, crospovidone, and silicon dioxide;

a hydrochlorothiazide layer comprising hydrochlorothiazide;

wherein:

the weight ratio of the lactose to the crospovidone to the silicon dioxide is (9.4-65): 3.8-5): 1,

the solubilizer is selected from at least one of meglumine, sodium dodecyl sulfate and hydroxypropyl-beta cyclodextrin.

2. The bi-layer tablet of claim 1, wherein the weight ratio of telmisartan, the sodium hydroxide, the lactose, the crospovidone, and the silicon dioxide is (1-20): 0.1-1.5): 9.4-65): 3.8-5): 1, preferably (3-17): 0.1-1.5): 9.4-65): 3.8-5): 1.

3. The bilayer tablet according to claim 1 or 2, wherein the telmisartan layer further comprises, based on 1 part by weight of the silica:

0.2-1 part by weight of magnesium stearate or sodium stearyl fumarate.

4. The bilayer tablet of claim 3, wherein the telmisartan layer further comprises a binder,

the binder is selected from at least one of povidone, hydroxypropyl cellulose, and sodium carboxymethyl cellulose.

5. The bilayer tablet of claim 4, wherein the telmisartan layer comprises, based on 1 part by weight of the silica:

1 to 20 parts by weight of telmisartan,

0.1 to 1.5 parts by weight of the sodium hydroxide,

0.8 to 5 parts by weight of the meglumine,

1-6 parts by weight of the povidone or sodium carboxymethylcellulose,

9.4 to 65 parts by weight of the lactose,

3.8 to 5 parts by weight of the crospovidone,

1 part by weight of the silica, and

0.2-1 part by weight of the magnesium stearate or the sodium stearyl fumarate.

6. The bilayer tablet of claim 5, wherein the telmisartan layer comprises, based on 1 part by weight of the silica:

3 to 17 parts by weight of telmisartan,

0.2 to 1.5 parts by weight of the sodium hydroxide,

0.9 to 5 parts by weight of the meglumine,

1-6 parts by weight of the povidone or sodium carboxymethylcellulose,

9.4 to 65 parts by weight of the lactose,

3.8 to 5 parts by weight of the crospovidone,

1 part by weight of the silica, and

0.2-1 part by weight of the magnesium stearate or the sodium stearyl fumarate.

7. The bilayer tablet of claim 1, wherein the hydrochlorothiazide layer further comprises diluents, binders, disintegrants and lubricants;

the diluent is selected from at least one of lactose, microcrystalline cellulose, mannitol, and polyethylene glycol;

the adhesive is selected from at least one of starch, povidone and sodium carboxymethyl cellulose;

the disintegrant is selected from at least one of sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, and croscarmellose sodium;

the lubricant is selected from at least one of magnesium stearate, calcium carbonate and talc.

8. The bilayer tablet of claim 7, wherein said hydrochlorothiazide layer comprises, based on 1 part by weight of said hydrochlorothiazide:

1 part by weight of the hydrochlorothiazide,

1 to 20 parts by weight of the lactose,

1 to 10 parts by weight of the microcrystalline cellulose or the mannitol,

0.1 to 1 part by weight of the sodium carboxymethyl starch or the croscarmellose sodium,

0.1 to 1 part by weight of the starch, and

0.05-0.5 parts by weight of the magnesium stearate or the talcum powder;

preferably, the hydrochlorothiazide layer comprises, based on 1 part by weight of the hydrochlorothiazide:

1 part by weight of the hydrochlorothiazide,

5 to 10 parts by weight of the lactose,

3 to 7 parts by weight of the microcrystalline cellulose or the mannitol,

0.1 to 0.5 part by weight of the sodium carboxymethyl starch or the croscarmellose sodium,

0.2 to 0.6 parts by weight of the starch, and

0.05-0.15 parts by weight of the magnesium stearate or the talcum powder.

9. A method for preparing the telmisartan hydrochlorothiazide bilayer tablet according to any one of claims 1 to 8, comprising:

pressing a telmisartan layer serving as a first layer and a hydrochlorothiazide layer serving as a second layer to obtain the telmisartan and hydrochlorothiazide double-layer tablet;

the telmisartan layer comprises telmisartan, sodium hydroxide, lactose, crospovidone and silicon dioxide in a predetermined proportion, and the hydrochlorothiazide layer comprises hydrochlorothiazide.

10. The method according to claim 9, wherein the telmisartan layer is obtained by:

carrying out first mixing treatment on the telmisartan, the sodium hydroxide, the meglumine, the binder and water, wherein the binder is the povidone or the sodium carboxymethyl cellulose;

drying the first mixed treatment product to obtain telmisartan sodium salt particles;

carrying out second mixing treatment on the telmisartan sodium salt particles, the lactose and the crospovidone;

performing third mixing treatment on the second mixed treatment product, the silicon dioxide and a lubricant to obtain the telmisartan layer, wherein the lubricant is the magnesium stearate or the sodium stearyl fumarate;

wherein, in the second mixing treatment, the D90 of the telmisartan sodium salt particles is not more than 40 μm.

Technical Field

The invention relates to the field of medicinal preparations, in particular to telmisartan and hydrochlorothiazide double-layer tablets and a preparation method thereof.

Background

Telmisartan (Telmisartan, TELM) is a highly specific non-peptide angiotensin II receptor (AT1 subtype) antagonist, has high affinity with the ATl subtype, inhibits angiotensin II by selectively binding to ATl, lowers aldosterone levels to lower blood pressure, and selectively activates the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) to produce an anti-atherosclerotic effect. The product is developed by Boringer Vargahil company, has good antihypertensive effect, is taken once a day, has few adverse reactions, reliable curative effect and high safety, has direct protective effect on target organs, and has developed into one of the first-choice medicines for treating hypertension. Has the following structure:

hydrochlorothiazide is a thiazide diuretic for the treatment of hypertension. The antihypertensive effect is mild and lasting, is suitable for mild and moderate hypertension, and is particularly suitable for treating systolic hypertension and heart failure complicated hypertension of the old. The chemical name of the compound is 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfamide-1, 1-dioxide. Has the following structure:

after a hypertension patient uses the diuretic alone, the blood pressure can be reduced only to a certain extent, because the diuretic activates a neurohumoral mechanism and stimulates the release of renin, so that the antihypertensive effect of the diuretic is antagonized; and clinically, a plurality of mild and moderate hypertension patients cannot achieve the target blood pressure by using telmisartan alone. After the hydrochlorothiazide and the telmisartan are used together, the activity of neurohormone is antagonized by the telmisartan and certain adverse effects of the hydrochlorothiazide can be compensated, and the compound preparation of the hydrochlorothiazide and the telmisartan can further improve the antihypertensive curative effect, reduce the side effect of the medicament and improve the compliance of patients.

The conventional method of the compound preparation is to prepare a powder mixture or compound granules of the two active substances and proper pharmaceutical excipients, and then prepare the compound preparation. However, the method is not suitable for preparing the compound telmisartan and hydrochlorothiazide tablets. This is because telmisartan, which is usually present in the free acid form, has very poor water solubility in the physiological pH range of the gastrointestinal tract between pH1 and pH7, and needs to be improved by adding an alkaline agent such as sodium hydroxide, meglumine, etc. in the preparation of a formulation in order to increase its water solubility; however, after the alkaline reagent is added, the telmisartan particles are alkaline, and hydrochlorothiazide is easily hydrolyzed by alkali, so that the 4-amino-6-chlorobenzene-1, 3-disulfonamide (hydrochlorothiazide impurity B) exceeds the standard, and therefore, the telmisartan particles and the hydrochlorothiazide particles containing alkaline solubilizing components cannot be simply mixed and tableted.

Telmisartan hydrochlorothiazide tablets were first marketed in 2001 in the United states by Burlingger Invarhan, Germany under the trade name TelmisartanHCT, original research company applied for patent protection to the product, is a double-layer tablet preparation, however, the stability and dissolution of the existing published formula still need to be improved, and if common auxiliary materials are used, the mixing uniformity of telmisartan layers has a problem.

Therefore, the research and development of the telmisartan hydrochlorothiazide double-layer tablet which has good stability, good dissolution effect and uniformly mixed telmisartan layers is significant.

Disclosure of Invention

The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention provides the telmisartan hydrochlorothiazide double-layer tablet which has good stability, high dissolution rate, even mixing of telmisartan layers and good fluidity and the preparation method thereof.

To this end, in a first aspect of the invention, the invention provides a telmisartan hydrochlorothiazide bilayer tablet. According to an embodiment of the present invention, the telmisartan hydrochlorothiazide bilayer tablet includes: a telmisartan layer comprising telmisartan, sodium hydroxide, a solubilizer, lactose, crospovidone, and silicon dioxide; a hydrochlorothiazide layer comprising hydrochlorothiazide; the solubilizer is selected from at least one of meglumine, sodium dodecyl sulfate and hydroxypropyl-beta cyclodextrin; wherein: the weight ratio of the lactose to the crospovidone to the silicon dioxide is (9.4-65): 3.8-5): 1; in other words, the telmisartan layer comprises, based on 1 part by weight of the silica: 9.4 to 65 parts by weight of said lactose, such as 9.4, 9.5, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60 or 65 parts by weight of said lactose; 3.8 to 5 parts by weight of said crospovidone, such as 3.8, 4, 4.5 or 5 parts by weight of said crospovidone; and 1 part by weight of the silica. Note that povidone is PVP, CAS number: 9003-39-8, dissolving in water; and crospovidone is abbreviated as PVPP, CAS number: 25249-54-1, insoluble in water. In order to increase the water solubility of telmisartan, alkaline reagents such as sodium hydroxide, meglumine and the like need to be added for improvement when a preparation is prepared; however, after the alkaline reagent is added, telmisartan particles are alkaline, hydrochlorothiazide is easily hydrolyzed by alkali, so that the content of 4-amino-6-chlorobenzene-1, 3-disulfonamide (hydrochlorothiazide impurity B) exceeds the standard, and in the placing process, the content of 4-amino-6-chlorobenzene-1, 3-disulfonamide (hydrochlorothiazide impurity B) is easily increased, so that the stability of telmisartan and hydrochlorothiazide double-layer tablets is directly poor. Therefore, in the preparation process of the telmisartan hydrochlorothiazide double-layer tablet, how to control the content of the 4-amino-6-chlorobenzene-1, 3-disulfonamide (hydrochlorothiazide impurity B) is a technical problem. In the placing process of the prepared telmisartan and hydrochlorothiazide double-layer tablet, if the content of the specific impurity is obviously increased, the prepared telmisartan and hydrochlorothiazide double-layer tablet is poor in stability, and if the content change of the specific impurity is small, the prepared telmisartan and hydrochlorothiazide double-layer tablet is good in stability, and further, the content of the impurity can be used for reflecting the stability of the telmisartan and hydrochlorothiazide double-layer tablet to a certain extent. The inventor finds that, in the telmisartan layer, if the weight of the lactose and the crospovidone is too large or too small compared with that of the silicon dioxide, not only is the material mixing uniformity and the fluidity of the telmisartan layer poor, but also the dissolution rate of the telmisartan and hydrochlorothiazide double-layer tablet is remarkably reduced, and more importantly, the stability of the telmisartan and hydrochlorothiazide double-layer tablet is remarkably reduced. Therefore, the telmisartan layer containing the lactose, the crospovidone and the silicon dioxide in the proportion is beneficial to improving the dissolution rate of the telmisartan and hydrochlorothiazide double-layer tablet and the material mixing uniformity and the fluidity of the telmisartan layer, and more importantly, the stability of the telmisartan and hydrochlorothiazide double-layer tablet is beneficial to improving. Furthermore, according to the telmisartan-hydrochlorothiazide double-layer tablet disclosed by the embodiment of the invention, the materials of the telmisartan layer are easy to mix uniformly, the flowability is good, the dissolution effect is good, and the stability is excellent.

According to an embodiment of the present invention, the above-mentioned double-layer sheet may further comprise at least one of the following additional technical features:

according to the embodiment of the invention, the weight ratio of the telmisartan, the sodium hydroxide, the lactose, the crospovidone and the silicon dioxide is (1-20): 0.1-1.5): 9.4-65): 3.8-5): 1. In other words, the telmisartan layer comprises, based on 1 part by weight of the silica: 1 to 20 parts by weight, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 parts by weight of the telmisartan; 0.1 to 1.5 parts by weight, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5 parts by weight of the sodium hydroxide; 9.4-65 parts by weight of the lactose, 3.8-5 parts by weight of the crospovidone, and 1 part by weight of the silicon dioxide. In some embodiments, the weight ratio of the telmisartan, the sodium hydroxide, the lactose, the crospovidone, and the silicon dioxide is (3-17): (0.1-1.5): (9.4-65): (3.8-5): 1. Therefore, the material mixing uniformity and the flowability of the telmisartan layer are better, and the telmisartan and hydrochlorothiazide double-layer tablet has better dissolution effect and better stability.

According to an embodiment of the present invention, the telmisartan layer further comprises, based on 1 part by weight of the silica: 0.2-1 part by weight of magnesium stearate or sodium stearyl fumarate, such as 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1 part by weight of magnesium stearate or sodium stearyl fumarate. Therefore, the material mixing uniformity and the flowability of the telmisartan layer are better, and the telmisartan and hydrochlorothiazide double-layer tablet has better dissolution effect and better stability.

According to an embodiment of the present invention, the telmisartan layer further comprises a binder selected from at least one of povidone, hydroxypropyl cellulose, and sodium carboxymethyl cellulose.

According to an embodiment of the present invention, the telmisartan layer comprises, based on 1 part by weight of the silica: 1-20 parts by weight of the telmisartan; 0.1 to 1.5 parts by weight of the sodium hydroxide; 0.8 to 5 parts by weight, such as 0.8, 0.9, 1.0, 1.3, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 parts by weight of said meglumine; 1-6 parts by weight, such as 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 parts by weight of said povidone or said sodium carboxymethylcellulose; 9.4-65 parts by weight of the lactose, 3.8-5 parts by weight of the crospovidone, 1 part by weight of the silicon dioxide, and 0.2-1 part by weight of the magnesium stearate or the sodium stearyl fumarate. Therefore, the material mixing uniformity and the flowability of the telmisartan layer are better, and the telmisartan and hydrochlorothiazide double-layer tablet has better dissolution effect and better stability.

According to an embodiment of the present invention, the telmisartan layer comprises, based on 1 part by weight of the silica: 3-17 parts by weight of telmisartan, 0.2-1.5 parts by weight of sodium hydroxide, 0.9-5 parts by weight of meglumine, 1-6 parts by weight of povidone or sodium carboxymethylcellulose, 9.4-65 parts by weight of lactose, 3.8-5 parts by weight of crospovidone, 1 part by weight of silicon dioxide, and 0.2-1 part by weight of magnesium stearate or sodium stearate fumarate. Therefore, the material mixing uniformity and the flowability of the telmisartan layer are better, and the telmisartan and hydrochlorothiazide double-layer tablet has better dissolution effect and better stability.

According to an embodiment of the present invention, the hydrochlorothiazide layer further comprises a diluent, a binder, a disintegrant, and a lubricant; the diluent is selected from at least one of lactose, microcrystalline cellulose, mannitol, and polyethylene glycol; the adhesive is selected from at least one of starch, povidone and sodium carboxymethyl cellulose; the disintegrant is selected from at least one of sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, and croscarmellose sodium; the lubricant is selected from at least one of magnesium stearate, calcium carbonate and talc.

According to an embodiment of the present invention, the hydrochlorothiazide layer comprises, based on 1 part by weight of the hydrochlorothiazide: 1 part by weight of said hydrochlorothiazide; 1 to 20 parts by weight, such as 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17 or 19 parts by weight of said lactose; 1 to 10 parts by weight, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 parts by weight of said microcrystalline cellulose or said mannitol; 0.1 to 1 part by weight, such as 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8 or 0.9 part by weight of the sodium carboxymethyl starch or the croscarmellose sodium; 0.1 to 1 part by weight, such as 0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.7, 0.8 or 0.9 part by weight of said starch, and 0.05 to 0.50 part by weight, such as 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.17, 0.2, 0.25, 0.3, 0.35, 0.4 or 0.45 part by weight of said magnesium stearate or said talc. Therefore, the telmisartan and hydrochlorothiazide double-layer tablet has better dissolution effect and better stability.

According to an embodiment of the present invention, the hydrochlorothiazide layer comprises, based on 1 part by weight of the hydrochlorothiazide: 1 part by weight of hydrochlorothiazide, 5-10 parts by weight of lactose, 3-7 parts by weight of microcrystalline cellulose or mannitol, 0.1-0.5 part by weight of sodium carboxymethyl starch or croscarmellose sodium, 0.2-0.6 part by weight of starch, and 0.05-0.15 part by weight of magnesium stearate or talcum powder. Therefore, the telmisartan and hydrochlorothiazide double-layer tablet has better dissolution effect and better stability.

In a second aspect of the invention, the invention proposes a process for the preparation of the previously described telmisartan hydrochlorothiazide bilayer tablet. According to an embodiment of the invention, the method comprises:

pressing a telmisartan layer serving as a first layer and a hydrochlorothiazide layer serving as a second layer to obtain the telmisartan and hydrochlorothiazide double-layer tablet; the telmisartan layer comprises telmisartan, sodium hydroxide, lactose, crospovidone and silicon dioxide in a predetermined proportion, and the hydrochlorothiazide layer comprises hydrochlorothiazide. It should be noted that the "predetermined ratio" refers to the weight ratio of the components in the above-described telmisartan and hydrochlorothiazide double-layer tablet, and those skilled in the art can prepare the above-described telmisartan and hydrochlorothiazide double-layer tablet according to the weight ratio of the components in the above-described telmisartan and hydrochlorothiazide double-layer tablet. In addition, the preparation of the hydrochlorothiazide layer can be carried out according to conventional methods by those skilled in the art. The telmisartan hydrochlorothiazide double-layer tablet prepared by the method provided by the embodiment of the invention has the advantages that the materials of the telmisartan layer are easy to mix uniformly and have good fluidity, the dissolution effect is good, and the stability is excellent.

According to an embodiment of the present invention, the method may further include at least one of the following additional technical features:

according to an embodiment of the invention, the telmisartan layer is obtained by the following steps: carrying out first mixing treatment on the telmisartan, the sodium hydroxide, the meglumine, the binder and water, wherein the binder is the povidone or the sodium carboxymethyl cellulose; drying the first mixed treatment product to obtain telmisartan sodium salt particles; carrying out second mixing treatment on the telmisartan sodium salt particles, the lactose and the crospovidone; subjecting the second mixed processed product to a third mixing process with the silica and the lubricant, so as to obtain the telmisartan layer, wherein the lubricant is the magnesium stearate or the sodium stearyl fumarate; wherein, in the second mixing treatment, the D90 of the telmisartan sodium salt particles is not more than 40 μm (i.e. 40 μm or less), such as 30 μm. The inventor finds that if the D90 of the telmisartan sodium salt particles is too large in the second mixing treatment, the material mixing uniformity and the flowability of the telmisartan sodium salt particles are poor, the dissolution rate of the prepared telmisartan hydrochlorothiazide double-layer tablet is remarkably reduced, and more importantly, the stability of the prepared telmisartan hydrochlorothiazide double-layer tablet is remarkably influenced. Therefore, in the second mixing treatment, when the D90 of the telmisartan sodium salt particles is not more than 40 micrometers, the material mixing uniformity and the flowability of the telmisartan layer in the prepared telmisartan hydrochlorothiazide double-layer tablet are better, and the dissolution effect and the stability of the telmisartan hydrochlorothiazide double-layer tablet are better. In some embodiments, the first mixing treatment is performed at a rotation speed of 200 to 300rpm for 1 to 3 hours; the second mixing treatment is carried out for 270-330 s under the condition that the rotating speed is 130-170 rpm; the third mixing treatment is carried out for 70-100s under the condition that the rotating speed is 130-170 rpm.

The technical effects are as follows:

the telmisartan and hydrochlorothiazide double-layer tablet or the telmisartan and hydrochlorothiazide double-layer tablet prepared by the method disclosed by the invention has the advantages that the materials of the telmisartan layer are uniformly mixed, the flowability is good, the dissolution effect is good, the stability is excellent, and the industrial production is facilitated.

Detailed Description

The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. While the advantages of the invention will be apparent and readily appreciated by the description.

Example 1

The composition ratios of the double-layer sheet are shown in tables 1-2 below.

Table 1: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Lactose	133
Cross-linked polyvidone	29.9
		Silicon dioxide	7.5
Magnesium stearate	2.4

Table 2: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt; telmisartan sodium salt, D90: and (3) mixing telmisartan sodium salt, lactose and crospovidone at the speed of 30 mu m, stirring at 150rpm for 300s, and adding silicon dioxide and magnesium stearate for total mixing for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Example 2

The composition ratios of the two-layer sheet are shown in tables 3 to 4 below.

Table 3: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Lactose	156
Cross-linked polyvidone	12
		Silicon dioxide	2.4
Magnesium stearate	2.4

Table 4: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and 20um, mixing telmisartan sodium salt, lactose and crospovidone, stirring at 150rpm for 300s, and adding silicon dioxide and magnesium stearate for 70 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Example 3

The composition ratios of the double-layer sheet are shown in the following tables 5-6.

Table 5: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Lactose	112.8
Cross-linked polyvidone	45.6
		Silicon dioxide	12
Magnesium stearate	2.4

Table 6: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) 40um, mixing telmisartan sodium salt, lactose and crospovidone, stirring at 150rpm, mixing for 300s, and then adding silicon dioxide and magnesium stearate and mixing for 100 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Example 4

The composition ratios of the double-layer sheet are shown in the following tables 7 to 8.

Table 7: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Sodium carboxymethylcellulose	13.0
		Lactose	133
Cross-linked polyvidone	29.9
		Silicon dioxide	7.5
Stearic acid sodium fumarate	2.4

Table 8: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Mannitol	65
Croscarmellose sodium	4.0
		Starch	7.0
Talcum powder	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and sodium carboxymethylcellulose in water, preparing telmisartan sodium salt granules by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, lactose and crospovidone at the speed of 30 mu m, stirring at 150rpm, mixing for 300s, adding silicon dioxide and sodium stearyl fumarate, and mixing for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, mannitol and croscarmellose sodium, adding starch slurry, granulating, drying, and adding pulvis Talci.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 1

The composition ratios of the double-layer sheet are shown in the following tables 9-10.

Table 9: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Sorbitol	170.4
Magnesium stearate	2.4

Table 10: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt; the resulting telmisartan sodium salt, D90: and (3) mixing telmisartan sodium salt and sorbitol by 30um, stirring at 150rpm for 300s, and adding magnesium stearate and mixing for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 2

The composition ratios of the two-layer sheet are shown in tables 11 to 12 below.

Table 11: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Lactose	154
Cross-linked polyvidone	14.2
		Silicon dioxide	2.2
Magnesium stearate	2.4

Table 12: composition ratio of hydrochlorothiazide layer

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt, D90: and (3) mixing telmisartan sodium salt, lactose and crospovidone at the speed of 30 mu m, stirring at 150rpm for 300s, adding silicon dioxide and magnesium stearate, and mixing for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 3

The composition ratios of the two-layer sheet are shown in tables 13 to 14 below.

Table 13: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Lactose	108.4
Cross-linked polyvidone	48
		Silicon dioxide	14
Magnesium stearate	2.4

Table 14: composition ratio of hydrochlorothiazide layer

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, lactose and crospovidone at the speed of 30 mu m, stirring at 150rpm for 300s, and adding silicon dioxide and magnesium stearate for total mixing for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 4

The composition ratios of the two-layer sheet are shown in tables 15-16 below.

Table 15: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Lactose	133
Cross-linked polyvidone	29.9
		Silicon dioxide	7.5
Magnesium stearate	2.4

Table 16: composition ratio of hydrochlorothiazide layer

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, lactose and crospovidone at 60 mu m, stirring at 150rpm for 300s, and adding silicon dioxide and magnesium stearate for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 5

The composition ratios of the two-layer tablets are shown in the following tables 17 to 18.

Table 17: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Sorbitol	133
Microcrystalline cellulose	29.9
		Silicon dioxide	7.5
Magnesium stearate	2.4

Table 18: composition ratio of hydrochlorothiazide layer

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt with a 80-mesh sieve to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, microcrystalline cellulose and sorbitol for 30um, stirring at 150rpm for 300s, and adding silicon dioxide and magnesium stearate for total mixing for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 6

The composition ratios of the double-layer tablets are shown in the following tables 19 to 20.

Table 19: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Mannitol	133
Croscarmellose sodium	29.9
		Silicon dioxide	7.5
Magnesium stearate	2.4

Table 20: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, mannitol and croscarmellose sodium at 30um, stirring at 150rpm for 300s, and adding magnesium stearate and mixing for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 7

The composition ratios of the two-layer sheet are shown in tables 21 to 22 below.

Table 21: composition ratio of telmisartan layer

Prescription	1000 tablets prescription (g)
		Telmisartan	40
Sodium hydroxide	3.2
		Meglumine	11.0
Povidone	13.0
		Lactose	133
Cross-linked polyvidone	29.9
		Magnesium stearate	9.9

Table 22: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, lactose and crospovidone by 30um, stirring at 150rpm for 300s, and adding magnesium stearate for total 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 8

The composition ratios of the two-layer tablets are shown in the following tables 23 to 24.

Table 23: composition ratio of telmisartan layer

Table 24: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, sucrose and crospovidone at 30um for 150rpm, mixing for 300s, and adding silicon dioxide and magnesium stearate and mixing for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 9

The composition ratios of the two-layer sheet are shown in the following tables 25 to 26.

Table 25: composition ratio of telmisartan layer

Table 26: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, lactose and croscarmellose sodium at 30um, stirring at 150rpm for 300s, and adding talcum powder and magnesium stearate for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Comparative example 10

The composition ratios of the two-layer sheet are shown in tables 27 to 28 below.

Table 27: composition ratio of telmisartan layer

Table 28: composition ratio of hydrochlorothiazide layer

Prescription	1000 tablet (g)
		Hydrochlorothiazide	12.5
Lactose monohydrate	110.5
		Microcrystalline cellulose	65
Sodium carboxymethyl starch	4.0
		Starch	7.0
Magnesium stearate	1.0

And (3) telmisartan layer process: dissolving telmisartan, sodium hydroxide, meglumine and povidone in water, preparing telmisartan sodium salt particles by using spray drying equipment, and sieving the prepared telmisartan sodium salt to obtain telmisartan sodium salt D90: and (3) mixing telmisartan sodium salt, lactose and low-substituted hydroxypropyl cellulose at the speed of 30um, stirring at 150rpm for 300s, and adding silicon dioxide and magnesium stearate to the mixture for 80 s.

And (3) a hydrochlorothiazide layer process: pulverizing hydrochlorothiazide, mixing with lactose monohydrate, microcrystalline cellulose and sodium carboxymethyl starch, adding starch slurry, granulating, drying, and adding magnesium stearate.

Tabletting: and pressing the telmisartan layer as a first layer and the hydrochlorothiazide layer as a second layer to obtain the double-layer tablet.

Property testing

The inventors carried out property tests on the telmisartan hydrochlorothiazide double-layer tablets prepared in examples 1-4 and comparative examples 1-10.

Firstly, testing the mixing uniformity and the fluidity of telmisartan layer materials

The test method comprises the following steps:

slowly adding the powder before tabletting from the upper part of the funnel, and forming the inclination angle of a conical accumulation body on the horizontal plane by the material leaked from the bottom of the funnel. The angle of repose is less than or equal to 30 degrees, and the fluidity is good; the angle of repose is less than or equal to 40 degrees, and the requirement of fluidity in the production process can be met; the angle of repose is not less than 40 degrees, the fluidity is poor.

And (3) testing results:

the test results are shown in table 29 below.

Table 29: comparison of material mixing uniformity and fluidity of telmisartan layer

As can be seen from the above table 29, in the telmisartan hydrochlorothiazide double-layer tablet of the present invention, the material mixing uniformity and the flowability of the telmisartan layer are good.

Second, dissolution test

The test method comprises the following steps:

the dissolution curve method of telmisartan is determined by a paddle method and 75rpm in 900mL of dissolution medium with pH1.0,

and (3) testing results:

the test results are shown in table 30 below. Wherein, the reference reagent is: marketed by Boringer Invehringer (Boehringer Ingelheim) USAThe HCT specification is telmisartan hydrochlorothiazide tablets with the concentration of 40mg/12.5 mg. "similar" or "dissimilar" are based on a reference formulation. FDA and EMEA regulations: if the f2 value between the dissolution curves of the test and reference preparations is not less than 50, the two preparations are considered to be similar to each other.

Table 30: effect on dissolution

As can be seen from the above table 30, the dissolution rate of the telmisartan hydrochlorothiazide double-layer tablet of the present invention is similar to that of the reference preparation, and the dissolution effect is good.

Third, impurity and stability test

The test method comprises the following steps:

the bare chip is placed under the condition of 75% humidity for 30 days to detect related substances by HPLC.

And (3) testing results:

the test results are shown in table 31 below.

Table 31: impurities and stability

Referring to the specification of USP40, the content of other related substances in the telmisartan hydrochlorothiazide double-layer tablet is less than or equal to 0.2 percent.

As can be seen from the above table 31, after the telmisartan hydrochlorothiazide double-layer tablet in the embodiment of the present invention is placed for 30 days, the growth amplitude of a hydrochlorothiazide impurity B (4-amino-6-chlorobenzene-1, 3-disulfonamide), which is a specific impurity of the telmisartan hydrochlorothiazide double-layer tablet, is significantly lower than that of comparative examples 1 to 10. Therefore, the telmisartan hydrochlorothiazide double-layer tablet disclosed by the embodiment of the invention has good stability.

Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, e.g., two, three, etc., unless specifically limited otherwise.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.