CN112691082A

CN112691082A - Solid preparation containing telmisartan in compound form and preparation method thereof

Info

Publication number: CN112691082A
Application number: CN202110200050.4A
Authority: CN
Inventors: 汪淮胜; 陈太博; 王辉
Original assignee: Hainan Taosheng Pharmaceutical Technology Research Institute Co Ltd
Current assignee: Hainan Taosheng Pharmaceutical Technology Research Institute Co Ltd
Priority date: 2021-02-23
Filing date: 2021-02-23
Publication date: 2021-04-23

Abstract

The invention provides a telmisartan solid preparation containing low-content alkaline substances and improving dissolution and a preparation method thereof, wherein the telmisartan solid preparation comprises telmisartan sodium composite particles, micronized solid dispersion prepared from telmisartan small particles with high uniformity and proper auxiliary agents; the solid preparation is a tablet or a coated tablet. Wherein the mass dosage of the micronized solid dispersion of telmisartan in the telmisartan solid preparation is not more than 40wt% of the compound particles of telmisartan sodium. The telmisartan solid preparation has low content of alkaline substances, and has the characteristics of rapid dissolution of active components, rapid release of medicaments and good stability.

Description

Solid preparation containing telmisartan in compound form and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a composite telmisartan solid preparation with low content of alkaline substances and a preparation method thereof.

Background

Telmisartan is an oral non-peptide angiotensin II receptor antagonist, can effectively control blood pressure, and has strong lipid solubility and is insoluble in water. Telmisartan is usually prepared in the acid form, and crystalline telmisartan exists in a polymorphic form. Currently, telmisartan is mostly in the form of solid tablets and capsules. However, telmisartan is difficult to dissolve in water, and the tablet form of telmisartan generally has the problems of low dissolution rate, poor solubility of an aqueous solution and the like.

In order to improve the problem of solubility of telmisartan in the stomach and intestine and overcome the defect that telmisartan is difficult to dissolve in water, a certain amount of alkaline substances such as sodium hydroxide and/or meglumine can be added during production to form salt, so that the solubility is improved. Specifically, in the prior art, telmisartan and alkaline substances (such as sodium hydroxide, meglumine and the like) are usually mixed and granulated to prepare a preparation, the preparation contains a high-content alkaline substance, has high alkalinity, is easy to absorb in intestinal tracts, but has high irritation to the stomach, and the telmisartan sodium salt is acidified in gastric juice to generate telmisartan, so that the solubility cannot be remarkably improved.

In addition, other methods are also used in the prior art, such as: dissolving telmisartan in 95% ethanol, reacting with alkaline substance (such as sodium hydroxide) in water or ethanol water solution, adding meglumine to convert telmisartan into water-soluble telmisartan salt, spray drying to obtain telmisartan sodium salt, and adding other adjuvants to obtain the preparation. The telmisartan sodium prepared by the preparation is not further processed, and is directly mixed with auxiliary materials to prepare the preparation which is also rapidly released in gastric juice and is acidified to generate telmisartan precipitate and also contains higher-content alkaline substances. That is, the existing telmisartan tablet preparations contain high-content alkaline substances, so that the telmisartan tablet preparations not only can generate strong irritation to the stomach when being taken orally, but also have low solubility and dissolution rate in gastric juice, and are not beneficial to stomach absorption.

In the prior art, CN101219120A discloses a telmisartan dispersible tablet and a preparation method thereof, which comprises mixing telmisartan, sodium hydroxide and meglumine, adding into a solvent for dissolution, spray-drying to obtain main drug granules, mixing other auxiliary materials to prepare soft materials, granulating, and tabletting the auxiliary material granules. CN1684665A discloses a telmisartan solid pharmaceutical preparation, which is a solid pharmaceutical composition consisting of telmisartan, alkaline substances, surfactants and water-soluble diluents. CN1799543A discloses a telmisartan dispersible tablet and a preparation method thereof, wherein: 2 to 99 percent of telmisartan and 1 to 98 percent of auxiliary material. The auxiliary materials comprise a disintegrating agent, a filling agent or a diluting agent, a bonding agent, a glidant or a lubricant.

EP1545467 discloses a pharmaceutical composition of telmisartan, which improves the solubility of telmisartan. The main dissolution bases in the composition are alkaline agents, surfactants and most of the water soluble diluents and are described for fluid bed granulation and spray dried granulation. The special pharmaceutical composition adopts a large amount of indispensable surfactants.

WO2007061415 discloses a telmisartan pharmaceutical composition, which mainly comprises telmisartan, an alkaline agent, a surfactant and a water-soluble diluent. Wherein a surfactant is essential.

CN 105726500A discloses an improved telmisartan tablet and a preparation method thereof, wherein the telmisartan tablet is prepared from the following components in parts by weight: 90-110 parts of telmisartan, 8-9 parts of sodium hydroxide, 25-35 parts of meglumine, 320-360 parts of sorbitol, 80-90 parts of a mixture of calcium hydrogen phosphate and calcium dihydrogen phosphate, 20-30 parts of povidone and 10-14 parts of magnesium stearate; wherein the weight ratio of the calcium hydrogen phosphate to the calcium dihydrogen phosphate is 7-8: 1. The telmisartan tablet provided has strong moisture resistance.

CN 107174570A discloses telmisartan tablets with stable dissolution performance and a preparation method thereof, wherein the telmisartan tablets are prepared from the following components in parts by weight: 90-110 parts of telmisartan sodium; sorbitol, 320 portions; 80-90 parts of calcium hydrogen phosphate and calcium dihydrogen phosphate, wherein the weight ratio of the calcium hydrogen phosphate to the calcium dihydrogen phosphate is 7-8: 1; 20-30 parts of povidone; 10-14 parts of magnesium stearate; 3-5 parts of magnesium lauryl sulfate; and 2-4 parts of lactose. The telmisartan tablets provided have similar dissolution curves to those of the original research.

CN 105726502A discloses a preparation method of telmisartan tablets, which is characterized by comprising the following steps: step S1: firstly, taking potassium hydroxide and meglumine, and adding water to dissolve; then adding telmisartan, adding ethanol, shaking to dissolve telmisartan, drying at 40 ℃ under reduced pressure to obtain white fluffy solid, and crushing and sieving by a 200-mesh sieve to obtain telmisartan salt powder; step S2: pulverizing sorbitol, calcium hydrogen phosphate, calcium dihydrogen phosphate and polyvidone, sieving with 100 mesh sieve, sieving magnesium stearate with 40 mesh sieve, and mixing with telmisartan salt powder; step S3: and tabletting the mixed powder to obtain the telmisartan tablets.

As can be seen from the prior art, there are two main approaches to the preparation of telmisartan tablets in the prior art: one is wet granulation, which comprises direct granulation in the form of telmisartan, or the main ingredient is present in the form of telmisartan sodium in the prescription and subsequent granulation is carried out. Generally, the tablet prepared by the former has the problem of slow dissolution due to the insoluble characteristic of telmisartan; the latter is easy to be sticky in the granulating process, easy to be hardened in the drying process and easy to be sticky in the tabletting process. The other is that the main drug strengthens the basic substance to prepare solution, then spray-dries to the material existing in the form of telmisartan sodium, and then adds other accessories to mix and tablet; firstly, the method has strict requirements on the particle size control, and if the particle size of the subsequent total mixed material is larger, the mixing uniformity is difficult due to large particle size difference; if the particle size of the total mixed material is small, the particle size of the whole material is small, the tabletting process is difficult, and sticking is easy to occur.

In view of the above prior art, in addition to the disadvantages of the above preparation process, the telmisartan tablets prepared by the existing preparation process mainly have one or more of the following technical problems:

1) the dissolution rate of the telmisartan free acid tablet in the matrix is low.

2) The matrix of the telmisartan sodium tablet contains high-content alkaline substances, and the alkalinity is strong; it is easy to stimulate the stomach, has low solubility in stomach and affects drug absorption.

3) The telmisartan active substance in the form of sodium salt in the telmisartan sodium tablet cannot effectively meet gastrointestinal absorption in the range of slightly acidic pH and neutral pH. In addition, the auxiliary materials contain undesirable components such as surfactants.

4) The drying condition and the dosage of alkali such as sodium hydroxide and the like in the preparation process of the tablet are the key factors related to the quality of the preparation. Improper drying conditions and the presence of high-content alkaline substances such as sodium hydroxide can cause the problems of hardening, tabletting sticking, moisture absorption and the like of the telmisartan sodium salt, so that the drying conditions and proper auxiliaries need to be selected and controlled according to a specific process.

Therefore, there is still a need in the art for further improvements in solid formulations of telmisartan.

Disclosure of Invention

In view of the above-mentioned deficiencies of the prior art, the present invention provides a telmisartan formulation having an excellent dissolution effect and a low content of basic substances, and a method for preparing the same.

Specifically, the invention aims to provide a telmisartan solid preparation containing low-content alkaline substances and having improved dissolution rate, so as to solve the technical problems of high content of alkaline substances, poor dissolution rate, slow dissolution rate and the like of telmisartan preparations in the prior art.

The telmisartan solid preparation comprises telmisartan and telmisartan sodium salt with specific proportional content; the telmisartan solid preparation has low content of alkaline substances, and has the characteristics of rapid dissolution of active components, rapid release of medicaments and good stability.

Wherein the telmisartan solid preparation comprises telmisartan sodium composite particles, micronized solid dispersion prepared from telmisartan with small particles with high uniformity, and proper auxiliaries; the solid formulation is preferably a tablet or a coated tablet. In order to reduce the influence of particle size difference on subsequent forming, the mass consumption of the micronized telmisartan solid dispersion in the telmisartan solid preparation is not more than 40wt% of the telmisartan sodium composite particles, and preferably not more than 30 wt%; more preferably not more than 20% by weight, and may for example be from 5 to 20% by weight.

Secondly, another object of the present invention is to provide a method for preparing the above solid formulation composition comprising telmisartan and telmisartan sodium salt in a specific proportional amount.

In general, solid dosage compositions of the prior art are often prepared from a single active ingredient or two active ingredients and the necessary adjuvants (e.g., excipients). For example, telmisartan tablets mainly consist of both telmisartan free acid tablets and telmisartan sodium salt tablets, and also include complex formulations in combination with other active drugs. Although telmisartan free acid tablets and telmisartan sodium salt tablets each have advantages and disadvantages, for example, telmisartan free acid tablets can reduce gastric irritation; the telmisartan sodium tablet has good solubility and dissolution rate, and is easy to wet in the preparation process.

However, in the prior art, no report is provided on the preparation form of combining telmisartan and telmisartan sodium salt. This is because a method of directly combining two different in acid base is not feasible, and a high content of basic substances such as meglumine (N-methyl-D-glucosamine) and sodium hydroxide which is not reacted completely are generally present in telmisartan sodium salt preparations, which are difficult to be compatibly combined with telmisartan free acid, and there are differences in particle morphology and dissolution rate under different pH conditions between the two.

Thus, the prior art has generally employed the form of bilayer tablet tablets, e.g. comprising a first layer comprising a first active ingredient and a second layer comprising a second active ingredient, to achieve compounding of the different components. However, the composite tablet has the problems of high requirements on the compression process and unstable interlayer combination.

Through a large number of research studies, the invention discovers that the problem of compounding of components with different acid and alkali can be solved without adopting a conventional double-layer tablet form when the solid preparation composition containing telmisartan and telmisartan sodium is prepared.

The solid preparation composition can not only enable the telmisartan with poor water solubility to be easily dissolved out and quickly released, but also can be simultaneously blended and tabletted with the basic telmisartan sodium composite particles without influencing the physical and chemical properties of each other; the stability problem caused by incompatibility of two forms of the free acid and the sodium salt of the telmisartan is solved, and the advantages of the free acid and the sodium salt are considered at the same time. One of the main reasons is by using low levels of alkaline materials. Specifically, in order to overcome the problem of the form incompatibility, the invention prepares the micronized telmisartan solid dispersion by coating or coating telmisartan free acid-cyclodextrin premix particles with a water-soluble high molecular polymer such as polyvinylpyrrolidone solution in a fluidized bed granulator or a coating machine; on the other hand, the content of alkaline substances in the telmisartan sodium composite particles is reduced, the existence of strong alkaline substances (such as sodium hydroxide) is avoided, the telmisartan and the alkaline substances in the telmisartan sodium composite particles are prevented from contacting through a telmisartan free acid secondary coating process and the use of low-content alkaline substances, the surface contact between two telmisartan particles in different forms in the mixing and compressing processes is avoided, and the purposes of prolonging the storage life and improving the stability are achieved.

Preferably, the solid formulation of the present invention is a tablet, typically containing 10-100mg (preferably 20-60 mg) of the complex telmisartan component; wherein the mass content of the telmisartan sodium salt is more than 3 times, preferably more than 5 times or more than 10 times of that of telmisartan. Illustratively, a tablet containing 5mg of the telmisartan compound contains 50mg of telmisartan sodium.

In summary, the present invention includes the following aspects.

In a first aspect, the present invention provides a high uniformity small particle telmisartan and micronized solid dispersion thereof and a method for preparing the same. Wherein the small telmisartan particles have a particle size of 5 to 20 μm, preferably 5 to 15 μm.

In a second aspect, the present invention provides a telmisartan sodium composite granule formulation having a low content of basic substances, wherein the granules do not contain a strong basic substance of hydroxide type, such as sodium hydroxide or potassium hydroxide, and a method for preparing the same.

Preferably, the telmisartan sodium composite particle preparation is prepared from a crude telmisartan sodium product, sodium carbonate, meglumine, povidone and sorbitol. Preferably, the particles do not contain strongly basic species of hydroxide type, such as sodium hydroxide or potassium hydroxide.

Wherein the low-content alkaline substance at least comprises meglumine, and preferably also comprises carbonate. Wherein the carbonate is selected from sodium carbonate or sodium bicarbonate, preferably sodium carbonate.

Preferably, the low content of alkalis means that the content of meglumine is less than 10wt%, preferably less than 5wt% of the mass of telmisartan sodium; when carbonate is contained, the molar amount of the carbonate is not more than 20 percent of the molar amount of telmisartan sodium. Further preferably, when the carbonate is sodium carbonate, the mass ratio is not more than 3wt% of the mass of telmisartan sodium, and for example, the mass ratio can be 0.5 to 3 wt%.

According to the invention, through a specific process, a large amount of alkaline substances are not required to be added in the preparation process of the telmisartan sodium composite particle to obtain the telmisartan sodium composite particle, and the telmisartan sodium composite particle has better bioavailability and stability and is simple in preparation process.

In a third aspect, the invention provides a telmisartan solid preparation, which contains the above-mentioned micronized telmisartan solid dispersion, telmisartan sodium composite particles, and appropriate auxiliaries; in addition, the solid preparation is preferably a tablet or a coated tablet. Wherein the mass consumption of the telmisartan micronized solid dispersion is not more than 40wt% of the telmisartan sodium composite particles, and preferably not more than 30 wt%.

The present invention has found that a telmisartan solid preparation body prepared by a combination of a micronized solid dispersion of telmisartan in a specific content ratio and telmisartan sodium composite particles containing a low content of a basic substance does not affect not only the preparation of solid preparations such as tablets and the stability of products but also the overall effect of excellent solubility and dissolution rate can be obtained. Without being limited by theory, the effects of the present invention may be a result of synergy.

In a fourth aspect, the present invention provides a method for preparing the telmisartan formulation as described above. The preparation method of the telmisartan solid preparation comprises the steps of preparing high-uniformity small-particle telmisartan micronized solid dispersion and telmisartan sodium composite particles in advance by adopting specific process conditions, and mixing the telmisartan micronized solid dispersion and the telmisartan sodium composite particles with other preparation aids (such as a lubricant, an excipient and the like) to prepare the telmisartan solid preparation.

Further, the above-mentioned specific technical solution of the present invention is realized by the following method steps.

The preparation method of the micronized solid dispersion of telmisartan comprises the following steps of S1-S3:

s1: preparing telmisartan crystal with high uniformity and small particles

1) Dissolving a pure telmisartan product (the purity is more than 99%) in a formic acid-alcohol (volume ratio is 1: 2-5) mixed organic solvent in a reaction kettle with reflux condensation, preparing a telmisartan solution A with the concentration of 5-10g/100mL, heating and refluxing until the telmisartan solution A is completely dissolved, and cooling to 75-80 ℃ for later use; simultaneously, cooling the deionized water to 0-5 ℃ to be used as a solvent B;

wherein the alcohol is preferably isopropanol;

2) in a turbulent flow reactor or a tubular reactor connected with a crystal kettle, the telmisartan solution A and the solvent B are fed into the reactor through different inlets by a flow pump to form a turbulent flow state and generate crystal nuclei; wherein the flow rate of the telmisartan solution A is 10-20mL/s, and the flow rate of the solvent B is 50-100mL/s (preferably 4-5 times of the flow rate of the solution A); the formed mixed liquid with the crystal nucleus particles enters a crystal kettle to grow;

3) controlling the temperature in a crystal kettle at 2-5 ℃, and stirring the mixed solution for 0.5-1h at a medium and low speed under the ultrasonic condition of 50-100KHz (preferably with the power of 80-150W), wherein the stirring speed is 200-300 rpm; and standing for 15-30min, performing suction filtration, and performing vacuum drying at 60 ℃ to obtain a small telmisartan crystal product with high uniformity and a particle size of about 5-15 micrometers (the average particle size d50=10 micrometers).

Wherein, the HPLC purity of the obtained crystal is more than 99.5 percent, and the yield is more than 65 percent.

Preferably, the crystallization conditions are controlled such that d₅₀Is 5-20 μm, preferably 5-15 μm.

The invention forms turbulent flow in the reactor through two flows of solution and anti-solvent, leads the solution flow and the anti-solvent flow to collide and generate crystal nucleus quickly under the control of specific temperature difference and feeding flow ratio parameters, and further controls the growth condition in the crystal kettle to adjust the grain size distribution of the crystal product. Crystal products with required uniformity and grain size are obtained by controlling crystal growth conditions such as crystal growth temperature, stirring speed, ultrasonic frequency and the like, and the crystal products have narrow grain size distribution and high controllability.

The preparation method provided by the invention can obtain the small-particle telmisartan product without complicated crushing and sieving, and has the advantages of simple process, convenience in operation and good purity.

S2: preparation of a Telmisartan-Cyclodextrin derivative premix

1) According to the mass ratio of 1: 5-10, weighing the small-particle telmisartan and the modified cyclodextrin derivative; adding a certain volume of mixed solvent of ethanol and water (the volume of the ethanol accounts for 50-70%) into a water bath reaction kettle in advance, adding a cyclodextrin derivative (the proportion is 1g:20-30 ml) into the reaction kettle, heating to 70-80 ℃, stirring until the cyclodextrin derivative is clear, adding the telmisartan, and continuing to stir for 10-30 min; stopping heating and stirring, and cooling to room temperature;

2) spray-drying the solution in a spray dryer to obtain fine particles which are off-white; the spray pressure was about 3bar and the outlet air temperature was about 80 ℃. The resulting dry granular powder is sieved through a 120-160 mesh sieve (preferably 140-160 mesh) to obtain a telmisartan-cyclodextrin premix.

Wherein the modified cyclodextrin derivative consists of 80-90wt% of beta-cyclodextrin derivative and 10-20wt% of gamma-cyclodextrin derivative; wherein the beta-cyclodextrin is sulfobutyl ether modified beta-cyclodextrin (sulfobutyl ether-beta-cyclodextrin) or (2, 6-di-O-methyl) -beta-cyclodextrin, and the gamma-cyclodextrin is sulfobutyl ether modified gamma-cyclodextrin (sulfobutyl ether-gamma-cyclodextrin) or (2-hydroxypropyl) -gamma-cyclodextrin.

In this stage, due to the poor solubility of telmisartan, despite the use of a large amount of modified cyclodextrins, the premix is still incompletely coated, requiring a subsequent secondary coating.

S3: preparation of micronized solid Dispersion

Preparing 10-20g/L solution of octenyl succinate starch and deionized water, adding povidone to 5-10g/L under stirring, and uniformly stirring to obtain dispersion solution; uniformly spraying and coating telmisartan-cyclodextrin premix particle powder by using the dispersion solution at room temperature to form micro powder particles, drying in vacuum, and sieving by using a 60-100-mesh sieve (preferably 80-100 meshes) to obtain the telmisartan micronized solid dispersion.

In the method, the telmisartan-cyclodextrin premix is subjected to micronization coating or coating, so that the particle size of finished medicine particles can be reduced, the dissolution rate of the medicine is remarkably improved, and the secondary coating micronization process of the composite high molecular substance is adopted, so that the exposure of active components caused by insufficient cyclodextrin coating is avoided, and the stability of the dispersion is improved.

The solid dispersion system prepared by the invention has the advantages that the telmisartan is uniformly dispersed in the solid carrier substance in a particle/microcrystal state, and the telmisartan can be highly dispersed by adopting water-soluble polymer carriers with different properties, so that the solubility and the release speed of the telmisartan are increased.

Alternatively, the step S3 can also be performed by spray drying: for example, to the above dispersion solution at room temperature, a 1g: adding telmisartan-cyclodextrin premix powder into 5-20ml of solid-liquid ratio, and mixing and stirring to obtain a suspension; the resulting suspension was spray dried.

The preparation method of the telmisartan sodium composite particle comprises the following steps of S1-S3:

s1: preparation of crude Telmisartan sodium product

Dissolving sodium hydroxide or sodium carbonate in deionized water at room temperature to obtain an alkaline solution, and stirring to fully dissolve the alkaline solution; adding telmisartan (pharmaceutical grade purity), and stirring at 30-35 deg.C for 15-60 min; slowly adding the obtained product mixed solution into ethanol at room temperature under the stirring condition, stirring for 1-2h at 4 ℃, standing for 15-30min, and filtering or centrifuging to obtain a crude product of telmisartan sodium; the crude product obtained does not need to be recrystallized.

Wherein the telmisartan can be medicinal telmisartan sold in the market and also can be small-particle telmisartan crystals prepared by the invention. The crystal particle size has little influence on the prepared telmisartan sodium after being dissolved.

S2: preparation of telmisartan sodium composite particle

1) Sequentially adding the crude telmisartan sodium product, sodium carbonate, meglumine and povidone into deionized water at room temperature under the condition of rapid stirring, and stirring until the mixture is completely clear to obtain a telmisartan sodium premixed solution;

wherein, the mass usage of the sodium carbonate is preferably not more than 3 percent of the crude product of the telmisartan sodium; the mass consumption of the meglumine is not more than 10 percent of the crude product of the telmisartan sodium, and preferably not more than 5 percent; the mass consumption of the povidone is 20-40% of the crude product of the telmisartan sodium;

2) sieving sorbitol with a sieve of 80-100 meshes (preferably 80 meshes), adding half of sorbitol into a fluidized bed, performing liquid spraying granulation in stages, spraying 50% by volume of the prepared telmisartan sodium premixed solution in the first stage, and performing granulation in the second stage after the spray granulation is completed: adding the rest sorbitol into the fluidized bed, spraying the rest telmisartan sodium premixed solution, and drying the obtained particles;

preferably, the fluidized bed parameters are as follows: the frequency of a fan is 35 plus or minus 5Hz, the internal atomization is 2.8 plus or minus 0.2 bar, the external atomization is 3.0 plus or minus 0.2 bar, the material temperature is 55 plus or minus 5 ℃, and the rotating speed of a peristaltic pump is 20 plus or minus 10 rpm;

3) drying and granulating: drying for 25-30min after the liquid spraying is finished to obtain a granulation intermediate, namely telmisartan sodium composite particles; the dried particles are granulated by a 40-60 mesh sieve crushing granulator;

s3: mixing the granules with magnesium stearate and micropowder silicon dioxide for 10-20 min; a mixture containing telmisartan sodium composite particles is obtained.

In the mixture, for example, the preparation components of the telmisartan sodium composite particles and the dosage ratio of magnesium stearate to aerosil are shown in the following table 1:

TABLE 1 raw material dosage ratio of telmisartan sodium composite particles

The preparation method of the telmisartan solid preparation comprises the following steps:

s1: preparing micronized telmisartan solid dispersion particles; in a high shear mixer, sorbitol and telmisartan micronized solid dispersion particles in a mass ratio of 1-3:1 are mixed at high speed for 3-5 min; and adding microcrystalline cellulose into the premix, and mixing at high speed for 1-2min again to obtain the telmisartan micronized solid dispersion mixture.

Wherein the mass consumption of the microcrystalline cellulose is 3-5% of the telmisartan micronized solid dispersion particles.

S2: preparing telmisartan sodium composite particles; mixing the telmisartan micronized solid dispersion mixture and a mixture containing telmisartan sodium composite particles in a mixer or a blender, adding sodium stearyl fumarate, mixing until the mixture is uniform, and performing vacuum drying at 55 ℃ to obtain a tabletting mixture.

Wherein the dosage ratio of the two mixtures is adjusted so that the mass ratio of the telmisartan micronized solid dispersion particles to the telmisartan sodium composite particles is 0.5-3:10, preferably 1-2: 10.

Wherein the mass amount of the sodium stearyl fumarate is 0.1-5wt% of the telmisartan sodium composite particles.

S3: tabletting: the tableting mixture is compressed into tablets using a rotary tablet press, and optionally a coating step.

Illustratively, the hardness of the tablets is controlled to 10 to 15kgf during tabletting.

Illustratively, the tablet weight is 50-500mg, such as 100-300 mg.

The technical effects of the invention include but are not limited to the following aspects:

1) through a large number of screening experiments, the inventor discovers that in the prior art, telmisartan active components and alkali (sodium hydroxide, meglumine and the like) are dissolved to prepare a solution, and then the solution is spray-dried to obtain a telmisartan sodium material which often has higher content of alkaline substances; and the telmisartan is prepared into a crude telmisartan sodium product (without purification, wherein a small amount of free telmisartan can be contained), a small amount of alkaline substances are added, and the telmisartan sodium composite particles with excellent dissolution performance can be obtained through a specific particle forming process.

The telmisartan micronized solid dispersion prepared by the invention has excellent quality stability and dissolution rate by matching a small-particle-size crystallization technology with high uniformity with a micronized solid dispersion process, can greatly improve the solubility of telmisartan, also obviously improves the bioavailability and stability, and has the advantages of high dissolution rate, simple preparation process and high yield.

In addition, the dissolution rate of the micronized solid dispersion in the environment of pH6.8 can reach about 90% in 25 minutes, so that higher blood concentration can be quickly reached, the bioavailability is effectively improved, and the drug effect is favorably exerted.

2) The high-uniformity small-particle telmisartan micronized solid dispersion contained in the invention can dissolve telmisartan with poor water solubility without being influenced by pH to a great extent, so that active components in a non-sodium salt form are easy to dissolve at a weak acid or neutral physiological pH level, and the high-uniformity telmisartan can be rapidly disintegrated and released from a matrix by the micronized solid dispersion. Has the properties of immediate release and rapid dissolution.

3) Meanwhile, the double-component composition of the telmisartan and the telmisartan sodium salt overcomes the stability problem caused by overhigh alkaline components or incompatible physical and chemical properties of different active components in a single-component telmisartan preparation. The telmisartan in the free acid form of the present invention has high seeding uniformity and a small particle size, can avoid the generation of agglomerates by forming a micronized solid dispersion, and is easy to wet and dissolve in vivo.

4) The prior art has generally employed the combination of different components in the form of bilayer tablet tablets, for example comprising a first layer containing a first active component and a second layer containing a second active component. However, the composite tablet has the problems of high requirements on the compression process and unstable interlayer combination. Through exploration and research, the invention discovers that the problem of compounding of components with different acid and alkali can be solved without adopting a conventional double-layer tablet form in the preparation of the solid preparation composition containing telmisartan and telmisartan sodium.

According to the solid preparation composition of the present invention, an improved dissolution effect can be obtained in a wider pH range, i.e., it can be applied to the gastrointestinal overall environment. Through specific preparation process control, the telmisartan with poor water solubility can be dissolved out easily and released quickly, and can be blended and tabletted with alkaline telmisartan sodium composite particles simultaneously without influencing the proportion physicochemical property; the stability problem caused by incompatibility of two forms of the free acid and the sodium salt of the telmisartan is solved.

In order to overcome the incompatibility problem, the invention, on one hand, prepares the micronized solid dispersion of telmisartan by coating the particles of the telmisartan free acid-cyclodextrin premix with water-soluble high molecular polymer such as polyvinylpyrrolidone solution in a fluidized bed granulator or a coating machine; on the other hand, the content of alkaline substances in the telmisartan sodium composite particles is reduced, the existence of strong alkaline substances (such as sodium hydroxide) is avoided, the telmisartan is prevented from contacting with the alkaline substances in the telmisartan sodium preparation through a secondary coating process and the use of low-content alkaline substances, the surface contact of telmisartan particles in different forms in the mixing and compressing processes is avoided, and the storage life is prolonged and the stability is improved.

5) The preparation method of the intermediate of the telmisartan sodium composite particle, which is a main component, has simple process, combines granulation and drying together through fluidized bed granulation, namely, obtains the dried granulation intermediate in one step, and then can prepare a finished product through one-step mixing and one-step tabletting. Wherein, sorbitol is added into the fluidized bed as a substrate for granulation, so that the adding steps in the total mixing process can be reduced, and the prepared granules can be directly mixed and then tabletted.

6) The agglomeration phenomenon caused by drying after common wet granulation can be avoided by a fluidized bed granulation mode, and the particle size of the intermediate can be controlled by parameter control of a fluidized bed, so that the dissolution is improved, and the same dissolution effect as the original preparation is achieved; and the particle size can be controlled to be close to that of the solid dispersion, so that the forming difficulty caused by overlarge difference of the particle size of the solid dispersion and the particle size of the solid dispersion is avoided. The process can control the moisture of the intermediate, and can avoid the sticking phenomenon in the tabletting process.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The present invention is described in detail below with reference to specific preparation examples and examples, but the use and purpose of these exemplary embodiments are merely to illustrate the present invention, and do not constitute any limitation to the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.

Preparation example 1: preparing telmisartan crystal with high uniformity and small particles

S1: preparing telmisartan crystal with high uniformity and small particles

1) Dissolving telmisartan (the purity is more than 99%) in a formic acid-isopropanol (volume ratio is 1: 5) mixed organic solvent in a reaction kettle with reflux condensation to prepare telmisartan solution A with the concentration of 8g/100mL, heating and refluxing until the telmisartan solution A is completely dissolved, and cooling to about 75 ℃ for later use; simultaneously, cooling the deionized water to 1-2 ℃ to be used as a solvent B;

2) in a tubular reactor connected with a crystal growth kettle, the telmisartan solution A and a solvent B are metered into the reactor through two different inlets at the top and the side to form a turbulent flow state and generate crystal nuclei; wherein the flow rate of the solution A is 10 mL/s, and the flow rate of the solvent B is 60 mL/s; the formed mixed liquid with the crystal nucleus particles enters a crystal kettle to grow;

3) carrying out ultrasonic treatment and stirring on the mixed solution for 0.5h in a crystal kettle at the temperature of 2-3 ℃ under the ultrasonic condition of 50KHz (with the power of 100W), wherein the stirring speed is 200 rpm; then standing for 25min, carrying out vacuum filtration and separation, recycling the mother liquor, and carrying out vacuum drying on the obtained solid at 60 ℃ to obtain a small telmisartan crystal product with high uniformity and a particle size distribution range of mainly 5-15 micrometers (the average particle size d50 is about 10 micrometers); the HPLC purity of the crystals was 99.5% with a one-shot yield of about 70%.

Preparation example 2: preparation of micronized solid Dispersion of Telmisartan

S1: preparation of a Telmisartan-Cyclodextrin derivative premix

1) Weighing 0.1kg of the prepared small-particle telmisartan and 0.5kg of composite cyclodextrin derivatives (consisting of 80wt% of sulfobutyl ether-beta-cyclodextrin and 20wt% of sulfobutyl ether-gamma-cyclodextrin), wherein the total weight is about 0.6 kg; adding 4.5L of mixed solvent of ethanol and water (ethanol volume ratio is 70%) into a water bath reaction kettle in advance, adding the weighed composite cyclodextrin derivative into the reaction kettle, heating to 70-72 ℃, stirring until the mixture is clear, adding the telmisartan, and continuously stirring for 15min for full stirring; stopping heating and stirring, and cooling to room temperature;

2) spray drying the cooled solution to obtain fine grey particles; the spray pressure was controlled at about 3bar and the outlet air temperature was about 80 ℃. And (3) sieving the obtained dry particle powder by a 140-mesh sieve to obtain the telmisartan-cyclodextrin premix.

S2: micronization

Preparing 18g/L solution of octenyl succinate starch and deionized water, adding polyvidone K30 to a concentration of 10g/L under stirring, and stirring uniformly to obtain a dispersion solution; and (3) atomizing the dispersion solution at room temperature under high pressure, uniformly spraying and coating the surfaces of telmisartan-cyclodextrin premix (preferably, introducing airflow to ensure that the telmisartan-cyclodextrin premix is in a boiling rolling state) particle powder until the surfaces of the particles are basically coated, and vacuum drying and sieving by using a 100-mesh sieve to obtain about 0.66kg of telmisartan micronized solid dispersion.

Preparation example 3A: preparation of Telmisartan sodium composite particle 1

1) Preparation of crude Telmisartan sodium salt

Dissolving 86g of sodium hydroxide in 1.2kg of deionized water at room temperature to obtain an alkaline solution, and stirring to fully dissolve the alkaline solution; adding 1kg of telmisartan, heating to 35 ℃, and stirring for 20 min; then cooling to room temperature; and slowly adding the obtained product mixed solution into about 10L of ethanol under the stirring condition, slowly stirring for 1h at the temperature of 4 ℃, standing for 30min, filtering, and drying the obtained filter cake to obtain a crude product of telmisartan sodium.

S2: preparation of telmisartan sodium composite particle

1) Under the conditions of room temperature and rapid stirring, sequentially adding 1kg of a telmisartan sodium crude product, 10.5g of sodium carbonate, 40g of meglumine and 320g of povidone into 5L of deionized water, and stirring until the materials are completely clarified after the materials are added to obtain a telmisartan sodium premixed solution;

2) sieving the weighed sorbitol with a 80-mesh sieve, adding half of the sorbitol into a fluidized bed, and carrying out liquid spraying granulation by stages: spraying 50% by volume of the prepared telmisartan sodium premixed solution in the first stage; and (3) carrying out second-stage granulation after the spray granulation is finished: adding the rest sorbitol into the fluidized bed, spraying the rest telmisartan sodium premixed solution, and drying the obtained particles;

wherein the fluidized bed parameters are set as follows: the frequency of a fan is 35Hz, the internal atomization is 2.8 bar, the external atomization is 3.0 bar, the material temperature is 55 ℃, and the rotating speed of a peristaltic pump is 20 rpm;

3) drying and granulating: drying for 30min after spraying is finished, and controlling the water content to be less than or equal to 1.5% to obtain a granulation intermediate, namely telmisartan sodium composite particles 1; granulating the dried granules by a 60-mesh sieve crushing granulator;

s3: mixing the granules with magnesium stearate and micropowder silicon dioxide for 10 min; a mixture containing telmisartan sodium composite particles was obtained and designated as mixture a 1.

The preparation components of the telmisartan sodium composite particles and the dosage of magnesium stearate and micropowder silicon dioxide are shown in the following table 2:

name of material	Amount by weight
		Crude product of telmisartan sodium	1kg
Sodium carbonate	10.5g
		Meglumine	40g
Povidone (K25)	320g
		Sorbitol	4kg
Magnesium stearate	40g
		Silica micropowder	20g
Deionized water	5L

Preparation example 3B: preparation of Telmisartan sodium composite particle 2

1) Under room temperature and rapid stirring, 1kg of crude telmisartan sodium, 300g of povidone K25 and 20g of meglumine are sequentially added into 5L of deionized water, and stirring is carried out until the solution is completely clear, so as to obtain a telmisartan sodium premixed solution.

2) Weighing 4kg of sorbitol and sieving the sorbitol with a 80-mesh sieve, adding half of the sorbitol into a fluidized bed, wherein the parameters of the fluidized bed are as follows: the frequency of a fan is 35Hz, the internal atomization is 2.8 bar, the external atomization is 3.0 bar, the material temperature is 55 ℃, and the rotating speed of a peristaltic pump is 20 rpm; and when the temperature of the materials reaches about 50 ℃, carrying out liquid spraying granulation by stages, controlling the air inlet temperature to be 65 ℃ in the first stage, spraying 50% of the prepared telmisartan sodium premixed solution, maintaining the temperature of the materials to be not lower than 40 ℃ in the first stage, and carrying out granulation in the second stage after the spray granulation is finished: in the second stage, the air inlet temperature is adjusted to be 75 ℃, the rest sorbitol is added into the fluidized bed, the rest telmisartan sodium premixed solution is sprayed, and the obtained particles are dried;

3) drying and granulating: drying for 30min after spraying is finished, and controlling the water content to be less than or equal to 1.5% to obtain a granulation intermediate, namely telmisartan sodium composite particles 2; granulating the dried granules by a 60-mesh sieve crushing granulator;

4) mixing the granules with 40g magnesium stearate and 20g silica gel micropowder for 10-20 min; a mixture containing telmisartan sodium composite particles 2 was obtained and designated as mixture a 2.

Example 1

Preparation of Telmisartan solid preparation 1

1) In a high-speed shearing mixer, mixing 0.3kg of sorbitol and 0.2kg of telmisartan micronized solid dispersion particles in a mass ratio for 5min at a high speed; then 8g of microcrystalline cellulose was added to the premix and mixed again for 2min at high speed to give a mixture containing a micronized solid dispersion of telmisartan, denoted as mixture B.

2) The above micronized solid dispersion mixture B of telmisartan was completely mixed with mixture a1 containing telmisartan sodium composite particles 1 prepared in preparation example 3A in a mixer, 30g of sodium stearyl fumarate was added and mixed until uniform, and vacuum-dried at 55 ℃ to obtain a tableting mixture.

3) The tableting mixture was compressed into tablets using a rotary tableting machine, with tablet hardness controlled at 12 kgf.

Example 2

Preparation of Telmisartan solid preparation 2

1) In a high shear mixer, 0.2kg of sorbitol was mixed with 0.1kg of micronized solid dispersion particles of telmisartan at high speed for 3 min. Then 5g of microcrystalline cellulose was added to the premix and mixed again for 2min at high speed to obtain a micronized solid dispersion mixture B of telmisartan.

2) The micronized solid dispersion mixture of telmisartan above was mixed with the mixture a2 containing telmisartan sodium composite particles above prepared in preparation example 3B in a mixer, 50g of sodium stearyl fumarate was added and mixed until uniform, and vacuum-dried at 55 c to obtain a tableting mixture.

3) Compression of solid formulation: the final blend was compressed into tablets using a rotary tablet press, with tablet hardness controlled to about 12kgf, and coated.

Comparative example 1

(1) Preparing liquid: adding sodium hydroxide and meglumine into purified water according to the prescription amount in sequence, stirring until the sodium hydroxide and the meglumine are completely dissolved, adding telmisartan, stirring until the telmisartan is completely dissolved, adding povidone K25, stirring until the telmisartan is completely dissolved, and standing for later use.

(2) And (3) granulating: sieving sorbitol with a 80-mesh sieve, weighing the prescription amount, adding sorbitol into a fluidized bed, and setting the parameters of the fluidized bed to be the same as those of preparation example 3A; starting liquid spraying granulation when the temperature of the materials reaches about 50 ℃, and maintaining the temperature of the materials at 45 ℃ in the process;

(3) and (3) drying: continuously drying for 30min after spraying, collecting materials, and controlling the water content to be less than or equal to 1.5% to obtain a granulation intermediate;

(4) straightening: sieving the granulation intermediate with a 60-mesh sieve for granulation for later use; magnesium stearate was added to the above granulation intermediate and mixed for 10 min. And tabletting by a rotary tablet press, and controlling the hardness of the tablet to be 12kgf to obtain the telmisartan sodium tablet.

Wherein, the amounts of the components are shown in the following table 3.

Material(s)Name (R)	Dosage of
		Telmisartan	1000g
Sodium hydroxide	82g
		Meglumine	300g
Povidone K25	300g
		Sorbitol	4.2kd
Magnesium stearate	100g
		Purified water	4Kg

Effect example 1

The dissolution rates of the above-mentioned control sample and sample in 0.1M HCl medium and pH6.8 phosphate buffer medium were examined using the tablets prepared in example 1 and example 2, respectively, as a sample and the original tablet as a control, and the cumulative dissolution percentage was measured and calculated at 295nm wavelength using an automatic dissolution apparatus (SOTAX, Switzerland) and UV spectrophotometry, and the similarities were compared.

The results are shown in tables 4-5 below.

TABLE 4 dissolution results in 0.1M HCl medium

TABLE 5 dissolution results in pH6.8 medium (phosphate buffer)

The above test results show that: the dissolution curves of the samples prepared in the embodiments 1-2 of the application under the two pH conditions are similar to those of the original researched reference preparation, the dissolution effect similar to that of the original research preparation can be achieved, and the dissolution rate is relatively high; whereas the dissolution curves of the samples prepared in comparative example 1 under both pH conditions are similar to the former reference formulation by a factor of similarity of less than 60 (f)₂) The dissolution effect similarity is poor and the dissolution rate is relatively poor (the final dissolution rates under the corresponding two conditions of 120min/0.1M-HCl and 90min/pH6.8 are 83.3 percent and 86.5 percent respectively).

Effect example 2

Stability test

The tablet powders of examples 1-2 and comparative example 1 were placed in a petri dish (thickness about 5 mm), placed in a drug stability tester at a temperature of 40 ℃. + -. 2 ℃ and RH 75%. + -. 5% for 90 days, observed for appearance, and checked by HPLC for the total impurity content (sum of isomer and other impurity contents) associated with the active ingredient.

The results show that the products of examples 1-2 did not exhibit powder blocking or caking, while the product of comparative example 1 exhibited slight blocking or caking; and the total impurity content of the product of the comparative example 1 is 2.87 percent, which is obviously higher than that of 0.93 percent and 0.86 percent in the examples 1-2.

The technical solutions in the embodiments of the present invention are clearly and completely described above, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Claims

1. A telmisartan solid preparation characterized in that it comprises telmisartan sodium composite particles having a low content of basic substances, a micronized solid dispersion prepared from telmisartan small particles having a high uniformity, and a suitable adjuvant; wherein the mass consumption of the telmisartan micronized solid dispersion is not more than 40wt% of the telmisartan sodium composite particles, and the particle size range of the telmisartan with small high uniformity particles is 5-20 μm; the alkaline substance at least comprises meglumine, and the content of the alkaline substance is less than 10wt% of the weight of telmisartan sodium; the solid formulation is preferably a tablet.

2. The telmisartan solid formulation according to claim 1, wherein the basic substance further comprises sodium carbonate in an amount of not more than 3wt% based on the mass of the telmisartan sodium.

3. A method for preparing a telmisartan solid preparation as described in claim 1 or 2, comprising the steps of:

s1: preparing micronized telmisartan solid dispersion particles, and mixing sorbitol and the micronized telmisartan solid dispersion particles in a mass ratio of 1-3:1 in a mixer at a high speed for 3-5 min; adding microcrystalline cellulose into the premix, and mixing at high speed for 1-2min to obtain a telmisartan micronized solid dispersion mixture;

optionally, the mass amount of the microcrystalline cellulose is 3-5% of the telmisartan micronized solid dispersion particles;

s2: preparing telmisartan sodium composite particles, mixing the telmisartan micronized solid dispersion mixture with a mixture containing telmisartan sodium composite particles, adding sodium stearyl fumarate, mixing until the mixture is uniform, and performing vacuum drying at 55 ℃ to obtain a tabletting mixture; wherein the mixture containing the telmisartan sodium composite particles consists of telmisartan sodium composite particles, magnesium stearate and micropowder silicon dioxide;

preferably, the mass ratio of the telmisartan micronized solid dispersion particles to the telmisartan sodium composite particles is 0.5-3: 10; the mass amount of the sodium stearyl fumarate is 0.1-5wt% of the telmisartan sodium composite particles;

s3: tabletting: the tabletting mixture is compressed into tablets, and the hardness of the plain tablets is controlled to be 10-15 kgf.

4. A method for preparing the telmisartan sodium composite particle as described in claim 1 or 2, comprising the steps of:

s1: preparation of crude Telmisartan sodium product

Dissolving sodium hydroxide or sodium carbonate in deionized water at room temperature to obtain an alkaline solution, and stirring to fully dissolve the alkaline solution; adding telmisartan, and stirring at 30-35 ℃ for 15-60 min; slowly adding the obtained product mixed solution into ethanol at room temperature under the stirring condition, stirring for 1-2h at 4 ℃, standing for 15-30min, and filtering or centrifuging to obtain a crude product of telmisartan sodium;

s2: preparation of telmisartan sodium composite particle

wherein the mass usage of the sodium carbonate is not more than 3% of the crude product of the telmisartan sodium, and the mass usage of the meglumine is not more than 10% of the crude product of the telmisartan sodium, preferably not more than 5%; the mass consumption of the povidone is 20-40% of the crude product of the telmisartan sodium;

2) sieving sorbitol by a sieve of 80 meshes, adding half of sorbitol into a fluidized bed, carrying out liquid spraying granulation by stages, spraying 50% of the prepared telmisartan sodium premixed solution by volume in the first stage, and carrying out granulation in the second stage after the spray granulation is finished: adding the rest sorbitol into the fluidized bed, spraying the rest telmisartan sodium premixed solution, and drying the obtained particles;

3) drying and granulating: drying for 25-30min after the liquid spraying is finished to obtain a granulation intermediate, namely telmisartan sodium composite particles; and (4) granulating the dried granules by a 40-60-mesh sieve crushing and granulating machine.

5. The method of claim 4, wherein the fluidized bed parameters are set as follows: the frequency of the fan is 35 plus or minus 5Hz, the inner atomization is 2.8 plus or minus 0.2 bar, the outer atomization is 3.0 plus or minus 0.2 bar, the material temperature is 55 plus or minus 5 ℃, and the rotating speed of the peristaltic pump is 20 plus or minus 10 rpm.

6. The preparation method according to claim 4, further comprising mixing the whole granules with magnesium stearate and aerosil for 10-20min to obtain a mixture containing telmisartan sodium composite granules.

7. The preparation method according to claim 3, wherein the step of preparing the micronized solid dispersion particles of telmisartan is as follows:

s1: preparing telmisartan crystal with high uniformity and small particles

1) Dissolving a pure telmisartan product in a formic acid-alcohol mixed organic solvent in a reaction kettle with reflux condensation, preparing a telmisartan solution A with the concentration of 5-10g/100mL, heating and refluxing until the telmisartan solution A is completely dissolved, and cooling to 75-80 ℃ for later use; simultaneously, cooling the deionized water to 0-5 ℃ to be used as a solvent B;

wherein the alcohol is isopropanol, and the volume ratio of formic acid-alcohol is 1: 2-5;

2) in a turbulent flow reactor or a tubular reactor connected with a crystal kettle, the telmisartan solution A and the solvent B are fed into the reactor through different inlets by a flow pump to form a turbulent flow state and generate a mixed solution with crystal nucleus particles formed by crystal nuclei to enter the crystal kettle for growth;

preferably, the flow rate of the telmisartan solution A is 10-20ml/s, and the flow rate of the solvent B is 50-100 ml/s;

3) stirring the mixed solution for 0.5-1h at a medium-low speed in a crystal kettle at the temperature of 2-5 ℃ under the ultrasonic condition of 50-100KHz, wherein the stirring speed is 200-300 rpm; then standing for 15-30min, carrying out suction filtration, and carrying out vacuum drying at 60 ℃ to obtain telmisartan crystals with high uniformity and small particles, wherein the particle size of the telmisartan crystals is 5-20 microns;

s2: preparation of a Telmisartan-Cyclodextrin derivative premix

1) According to the mass ratio of 1: 5-10, weighing the small-particle telmisartan and the modified cyclodextrin derivative; adding a certain volume of mixed solvent of ethanol and water into a water bath reaction kettle in advance, adding cyclodextrin derivatives into the solvent of the reaction kettle in a ratio of 1g to 20-30ml, heating to 70-80 ℃, stirring until the mixture is clear, adding the telmisartan, and continuing to stir for 10-30 min; stopping heating and stirring, and cooling to room temperature;

wherein, the volume ratio of ethanol in the mixed solvent is 50-70%;

2) spray drying the solution to obtain fine grey particles; wherein the spraying pressure is controlled to be 3bar, the temperature of air at an outlet is 80 ℃, and the obtained dry particle powder is sieved by a 140-mesh and 160-mesh sieve to obtain a telmisartan-cyclodextrin premix; wherein the modified cyclodextrin derivative consists of 80-90wt% of beta-cyclodextrin derivative and 10-20wt% of gamma-cyclodextrin derivative;

s3: preparation of micronized solid Dispersion

Preparing 10-20g/L solution of octenyl succinate starch and deionized water, adding povidone to 5-10g/L under stirring, and uniformly stirring to obtain dispersion solution; and (3) uniformly spraying and coating the surfaces of the telmisartan-cyclodextrin premix particle powder by using the dispersion solution at room temperature to form micro powder particles, drying in vacuum, and sieving by using a 80-100-mesh sieve to obtain the telmisartan micronized solid dispersion.

8. The process of claim 7, wherein the β -cyclodextrin derivative is selected from sulfobutyl ether- β -cyclodextrin or (2, 6-di-O-methyl) - β -cyclodextrin, and γ -cyclodextrin is selected from sulfobutyl ether-modified γ -cyclodextrin or (2-hydroxypropyl) - γ -cyclodextrin.

9. The method of claim 7, wherein step S3 can be replaced by spray drying as follows: to the above dispersion solution at room temperature was added 1g: adding telmisartan-cyclodextrin premix powder into 5-20ml of solid-liquid ratio, and mixing and stirring to obtain a suspension; the resulting suspension was spray dried and granulated.