CN115252574B

CN115252574B - Telmisartan pellets, preparation method thereof and pharmaceutical preparation

Info

Publication number: CN115252574B
Application number: CN202210664920.8A
Authority: CN
Inventors: 李莎莎
Original assignee: Suzhou Chunghwa Chemical & Pharmaceutical Industrial Co ltd
Current assignee: Suzhou Chunghwa Chemical & Pharmaceutical Industrial Co ltd
Priority date: 2022-06-13
Filing date: 2022-06-13
Publication date: 2023-06-20
Anticipated expiration: 2042-06-13
Also published as: CN115252574A

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a telmisartan pellet, a preparation method thereof and a pharmaceutical preparation, wherein the telmisartan pellet comprises a pill-containing core and a bioadhesive film coating layer coated outside the pill-containing core, the bioadhesive film coating layer comprises an adhesive and pore-forming particles containing enteric materials and water-soluble materials, and the pill-containing core comprises the following components in percentage by mass: 4-7 of telmisartan and a first metal hydroxide and phosphoric acid alkali metal salt and a second alkali metal hydroxide with the mass ratio of 51-71:4.5-11, wherein the pellets avoid repeated dissolution and precipitation processes of the medicament due to the pH change of gastrointestinal tracts, ensure the dissolution and absorption of the telmisartan, further improve the dissolution and bioavailability of the telmisartan, reduce the dosage of the medicament, reduce adverse reactions and achieve the result of attenuation and synergy.

Description

Telmisartan pellets, preparation method thereof and pharmaceutical preparation

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to a telmisartan pellet and a preparation method and a pharmaceutical preparation thereof.

Background

Hypertension is currently the most common cardiovascular disease worldwide and is mainly characterized by chronic diseases in which arterial blood pressure rises beyond normal range and gradually accompanies functional changes or organic lesions of organs such as heart, brain, kidney, blood vessels and the like. There are hundreds of millions of patients suffering from cardiovascular and cerebrovascular diseases in China, most of which are from patients suffering from hypertension. Therefore, research on novel antihypertensive drugs or improvement on existing antihypertensive drugs is of great importance to patients and even public health industry.

Currently common antihypertensive agents mainly include diuretics, beta blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin ii receptor blockers. Telmisartan is a classical angiotensin ii receptor blocker drug which is absorbed after oral administration, specifically binds to the AT1 receptor and thereby replaces the binding of protoangiotensin ii, and this binding effect is long-acting. The oral telmisartan preparation generally reaches the highest blood concentration after 0.5-1.5 h, the absolute bioavailability of 40mg and 160mg of telmisartan is not high, 42% and 58% respectively, which is related to the poor solubility of telmisartan raw materials, modern researches show that the solubility of telmisartan is highly dependent on the environmental pH value, the pka is 3.5, 4.1 and 6.0, the telmisartan and the sodium salt thereof have obvious solubility drop intervals (see table 1 and figure 1) between pH3.0 and 6.0, and the pH intervals are just the main biological pH ranges of human gastrointestinal tracts.

Table 1 pH-solubility table of telmisartan

At present, the main telmisartan preparation on the market is telmisartan tablets developed by the original research of Boringer John company in Germany

Telmisartan hydrochlorothiazide tablets and compound preparation thereof>

Patent numbers CN200580005270 and CN100571695C are also filed in China, however, because the pH ranges of the fasting intestinal tract and the postprandial gastrointestinal tract of a human body are the regions of abrupt change of telmisartan solubility, the prior telmisartan preparation has the problems of complex repeated dissolution and precipitation in the pH environment of the gastrointestinal tract, telmisartan is extremely easy to precipitate in the intestinal tract, especially small intestinal blocks (such as the duodenum section, the environmental pH value is 4-5), and the dissolution rate of telmisartan is low, so that the drug absorption stability and the bioavailability are greatly influenced.

Disclosure of Invention

Therefore, the technical problem to be solved by the invention is to overcome the defect of low dissolution rate of the telmisartan preparation in the prior art, thereby providing a telmisartan pellet, a preparation method thereof and a pharmaceutical preparation.

The invention provides a telmisartan pellet, which comprises a pellet-containing core and a bioadhesive film coating layer coated outside the pellet-containing core, wherein the bioadhesive film coating layer comprises an adhesive and pore-forming particles containing an enteric material and a water-soluble material, and the pellet-containing core comprises the following components in percentage by mass: 4-7 of telmisartan and a first metal hydroxide and a mass ratio of 51-71:4.5-11 of alkali metal phosphate and a second alkali metal hydroxide.

Further, the pore-forming particles have a particle size D90 of 25 to 200. Mu.m, preferably 75 to 125. Mu.m, more preferably 85 to 101. Mu.m.

Further, the pill-containing core satisfies at least one of the following a-E:

A. the phosphoric acid alkali metal salt is at least one selected from disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate; and/or the first alkali metal hydroxide is selected from sodium hydroxide and/or potassium hydroxide; and/or the second alkali metal hydroxide is selected from sodium hydroxide and/or potassium hydroxide;

B. the sum of the masses of telmisartan and the first alkali metal hydroxide accounts for 10-20wt% of the total mass of the pill-containing core;

C. the sum of the mass of the phosphoric acid alkali metal salt and the second alkali metal hydroxide accounts for 20-30wt% of the total mass of the pill-containing core;

D. the medicated core further comprises at least one of a filler, a binder and a lubricant, preferably, based on the total mass of the medicated core, the medicated core further comprises 40-60wt% of a filler, 5-7wt% of a binder and 2-4wt% of a lubricant; preferably, the filler is selected from at least one of microcrystalline cellulose, lactose, starch, dextrin and chitosan; preferably, the adhesive is at least one selected from povidone, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose and methyl cellulose; preferably, the lubricant is at least one of polyethylene glycol, polyoxyethylene, glyceryl behenate, stearic acid, glyceryl monostearate and glyceryl palmitat;

E. the pill-containing core further comprises 0.5-1.2wt% of a thickener, preferably at least one of carob, acacia, shellac, carrageenan, xanthan, tragacanth, guar and sodium alginate, based on the total mass of the pill-containing core.

Further, the bioadhesive film coating layer satisfies at least one of the following (1) - (3):

(1) The adhesive is at least one selected from hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate, chitosan, polycarbophil and carbomer; and/or the water-soluble material is selected from at least one of lactose, sucrose, sorbitol, xylitol, ali sugar, trehalose and sodium chloride; and/or the enteric material is selected from at least one of cellulose acetate phthalate, polypropylene alcohol phthalate, methacrylic acid copolymer, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate and acrylic resin;

(2) The mass ratio of the pill-containing core to the bioadhesive film coating layer is 263:35-40;

(3) Based on the total mass of the bioadhesive film coating layer, the content of the adhesive is 60-80wt%, the content of the pore-forming particles is 20-40wt%, and the mass ratio of the enteric material to the water-soluble material in the pore-forming particles is 1:7-12.

The invention also provides a method for preparing telmisartan pellets according to any of the above, comprising,

the preparation method of the pill-containing core comprises the following steps: mixing the components of the pill-containing core with a solvent to prepare a soft material, and preparing the soft material into the pill-containing core by adopting an extrusion spheronization method;

the preparation method of the pore-forming particles comprises the following steps: mixing an enteric material with a solvent to prepare a granulating liquid, and carrying out fluidization granulation on the water-soluble material by adopting the granulating liquid to prepare a pore-forming granule;

coating liquid preparation and coating steps: dispersing the adhesive and the quality control particles in a solvent to prepare a coating liquid, coating the pill-containing cores by adopting the coating liquid in a fluidization coating method, and drying to prepare the telmisartan micropills.

Further, in the preparation process of the telmisartan pellets, the adopted solvent is water; and/or the solid content of the granulating liquid is 15-30wt%; and/or the solid content of the coating liquid is 30-40wt%.

Further, the preparation method of the soft material comprises the following steps:

(1) Mixing telmisartan, a binder, a first alkaline metal hydroxide and a solvent to obtain a medicated binder solution;

(2) Mixing the other components of the drug-containing pellets, and adding the drug-containing adhesive solution to prepare a drug-containing soft material.

Wherein, other components of the drug-containing pellets comprise a pH buffer pair and can also comprise a filling agent, a lubricant and a thickening agent. The solvent used may be a conventional solvent for preparing soft materials, such as water.

Further, the solid content of the medicated binder solution is 25-40wt%.

The invention also provides a pharmaceutical preparation, which comprises any one of the telmisartan micropills or the telmisartan micropills prepared by any one of the preparation methods and pharmaceutically acceptable auxiliary materials (such as hollow capsules).

Further, the dosage form of the pharmaceutical preparation is a capsule.

The technical scheme of the invention has the following advantages:

1. the telmisartan micropill provided by the invention comprises a pill-containing core and a bioadhesive film coating layer coated outside the pill-containing core; the bioadhesive film coating layer comprises an adhesive and porogenic particles containing an enteric material and a water-soluble material, wherein the pill-containing core comprises a pH buffer pair and a mass ratio of 30:4-7 with a first alkali metal hydroxide, wherein the pH buffer pair comprises the following components in mass ratio of 51-71:4.5-11 and a second alkali metal hydroxide.

In the invention, besides the first alkali metal hydroxide which forms salt with telmisartan, the second alkali metal hydroxide which forms a pH buffer pair with phosphoric acid alkali metal salt is also added, and the micro-environment pH value of the dissolution part of the pill core is maintained to be above 6.0 (for example, 6.5-7.5) by controlling the ratio of telmisartan to the first alkali metal hydroxide and the ratio of phosphoric acid alkali metal salt to the second alkali metal hydroxide. The porous particles composed of enteric materials and water-soluble materials are continuously dissolved in the intestinal tract, a large number of drug release holes are formed on the surface of the bioadhesive film coating layer, and water permeates into the pill core, so that the drug-containing pellets continuously release active drugs in the intestinal tract at a sufficient and uniform speed. Meanwhile, due to the existence of the adhesive, the telmisartan pellets are stably fixed on the surface of intestinal mucosa and stably maintained at the adhesion position, so that the pH value of the microenvironment of a drug release system is stably maintained above 6.0, the repeated dissolution and precipitation processes of the drug are avoided, the dissolution and absorption of telmisartan are ensured, the dissolution and bioavailability of telmisartan are further improved, the dosage of the drug is reduced, adverse reactions are reduced, and the 'attenuation and synergy' result is achieved.

2. According to the telmisartan pellet provided by the invention, the granularity D90 of the pore-forming particles is controlled to be 25-200 mu m, the release of a pH buffer pair and telmisartan medicaments can be ensured under the condition that the adhesion capability is not influenced, and particularly, when the granularity D90 is controlled to be 85-101 mu m, the medicaments in the telmisartan pellet have more proper dissolution rate.

3. The telmisartan micropill provided by the invention also comprises 0.5-1.2wt% of thickening agent in the pill-containing core; the addition of the thickener can maintain the pH value of the micro environment of the dissolution part of the pill core at 6.5-7.5 more stably, and further improve the dissolution rate of the medicine.

4. The telmisartan pellet provided by the invention has the mass ratio of the pellet-containing core to the bioadhesive film coating layer of 263:35-40, so that the medicine has better and proper dissolution speed and good adhesion effect.

5. The telmisartan pellet provided by the invention takes the total mass of a pellet-containing core as a reference, the content of the adhesive is controlled to be 60-80wt%, the content of pore-forming particles is controlled to be 20-40wt%, and the mass ratio of enteric materials to water-soluble materials in the pore-forming particles is 1:7-12, so that the medicine has better and proper dissolution speed and good adhesion effect.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.

Fig. 1 is a graph of the amount of telmisartan sodium dissolved (wt%) versus ambient pH in the background.

Detailed Description

The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.

The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge. Povidone, model K30, from boy new open source pharmaceutical company, microcrystalline cellulose, model 101, from Anhui mountain river pharmaceutical company, carob gum from merck, hydroxyethylcellulose from leishmania, acrylic resin with acrylic resin (II), from yun hong yang pharmaceutical company, stearic acid from lakeside exhibition pharmaceutical company, telmisartan from Jiangsu middle-bang pharmaceutical company.

Example 1 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

The embodiment provides a telmisartan pellet, which has the following prescription:

the preparation method comprises the following steps:

(1) According to the formula of the table, telmisartan, a binder and a first alkali metal hydroxide are weighed and mixed, purified water is added for dissolution, and a drug-containing binder solution (the solid content is 32 wt%);

adding the pH buffer pair, the filler, the thickener and the lubricant into a wet granulator, stirring at 150rpm, shearing at 1200rpm and for 5min, adding the drug-containing adhesive solution, and stirring at 150rpm, shearing at 1000rpm and for 2min to prepare a drug-containing soft material. The soft material containing the medicine is put into an extruder, extruded by a sieve plate with 2.0mm, and the extrusion speed is controlled to 25r/min. Putting the extrudate into a spheronizer, setting parameters of the spheronizer, and carrying out spheronization at a spheronization speed of 750r/min for 3min to obtain a pill-containing core, putting the pill-containing core into a fluidized bed for boiling and drying, and controlling the drying weight loss of the pellets to be within 3%.

(2) The enteric-coated material and water are mixed to prepare granulating liquid (solid content 20.5 wt%) and the water-soluble material is passed through 200 mesh screen to make treatment, then fed into fluidized bed, and the material temperature is controlled at 30 deg.C, pump speed is maintained at 8rpm and atomization pressure is 0.2Mpa so as to obtain the invented pore-forming granules, and the pore-forming granule grain size D90 is 92 micrometers.

(3) Dissolving the adhesive in water to prepare a solution (the solid content is 26 wt%) and adding the pore-forming particles, uniformly mixing to obtain a coating solution, and coating the pill-containing cores by using the coating solution in a fluidized coating method, wherein the liquid inlet speed is controlled to be 5ml/min, the atomization pressure is controlled to be 0.3Mpa, and the air outlet temperature is controlled to be 45 ℃ in the coating process, so as to prepare the telmisartan micropills.

The telmisartan pellets prepared in this example were filled with No. 2 capsules, the filling rate was controlled at 1000 pellets/min, and the filling amount was 300mg (+ -5%).

Example 2 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

the preparation method comprises the following steps:

(1) Adding the adhesive and the first alkali metal hydroxide into purified water for dissolution, and then adding telmisartan for dissolution to obtain a drug-containing adhesive solution (the solid content is 32 wt%);

adding the pH buffer pair and the thickener into a wet granulator, stirring at 150rpm, 1200rpm and 5min, adding the filler and the lubricant with prescribed amounts, stirring at 150rpm, 1200rpm and 5min, adding the binder solution containing the medicine, and stirring at 150rpm, 1000rpm and 2min to prepare the soft material containing the medicine. The soft material containing the medicine is put into an extruder, extruded by a sieve plate with 2.0mm, and the extrusion speed is controlled to 25r/min. Putting the extrudate into a spheronizer, setting parameters of the spheronizer, and carrying out spheronization at a spheronization speed of 750r/min for 3min to obtain a pill-containing core, putting the pill-containing core into a fluidized bed for boiling and drying, and controlling the drying weight loss of the pellets to be within 3%.

(2) Mixing enteric material with water to obtain granulating liquid (solid content 20.5 wt%) and sieving the water-soluble material with 200 mesh sieve, adding into fluidized bed, regulating air quantity of 500-1200 m ³ And/h, ensuring that the water-soluble material boils into a fluidized body, controlling the temperature of the material to 25 ℃, maintaining the pump speed to 8rpm and the atomization pressure to 0.2Mpa, and preparing the pore-forming particles. The pore-forming particle size D90 was tested to be 85 μm.

(3) Dissolving the adhesive in water to obtain solution (solid content is 26 wt%), adding pore-forming particles, mixing to obtain coating solution, and coating the pill-containing core with the coating solution by fluidized coating method, wherein the stirring speed of the coating solution is maintained at 200rpm/min during the coating process to ensure suspension state of the pore-forming particles, the liquid inlet speed is controlled at 5ml/min, the atomization pressure is 0.3Mpa, and the air outlet temperature is 45 ℃.

The embodiment also provides a telmisartan capsule, wherein the telmisartan pellet prepared in the embodiment is filled by a No. 2 capsule, the filling speed is controlled to be 1000 grains/min, and the filling amount is 300mg (+ -5%).

Example 3 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

the preparation method comprises the following steps:

(1) Adding the adhesive and the first alkali metal hydroxide into purified water for dissolution, and then adding telmisartan for dissolution to obtain a drug-containing adhesive solution (the solid content is 40 wt%);

adding the pH buffer pair and the thickener into a wet granulator, and stirring at a speed of 150rpm, a shearing speed of 1200rpm and for 5min to prepare a pH adjusting composition; adding filler, pH adjusting composition and lubricant in prescribed amount into wet granulator, stirring at 150rpm, shearing at 1200rpm for 5min, adding binder solution containing medicine, stirring at 150rpm, shearing at 1000rpm for 2min, and making into soft material containing medicine. The soft material containing the medicine is put into an extruder, extruded by a sieve plate with 2.0mm, and the extrusion speed is controlled to 25r/min. Putting the extrudate into a spheronizer, setting parameters of the spheronizer, and carrying out spheronization at a spheronization speed of 750r/min for 3min to obtain a pill-containing core, putting the pill-containing core into a fluidized bed for boiling and drying, and controlling the drying weight loss of the pellets to be within 3%.

(2) Mixing enteric material with water to obtain granulating liquid (solid content is 30wt%) and sieving the water-soluble material with 200 mesh sieve, adding into fluidized bed, regulating air quantity of air intake to 500-1200 m ³ And/h, ensuring that the water-soluble material boils into a fluidized body, controlling the temperature of the material to be 35 ℃, maintaining the pump speed to be 8rpm and the atomization pressure to be 0.2Mpa, and preparing the pore-forming particles. The pore-forming particle size D90 was tested to be 101. Mu.m.

(3) Dissolving the adhesive in water to prepare a solution, adding the pore-forming particles, mixing uniformly to obtain coating liquid (the solid content is 30 wt%) and coating the pill-containing cores by using the coating liquid in a fluidized coating method, wherein the stirring speed of the coating liquid is maintained at 200rpm/min in the coating process to ensure the suspension state of the pore-forming particles, the liquid inlet speed is controlled at 5ml/min in the coating process, the atomization pressure is 0.3Mpa, and the air outlet temperature is 45 ℃.

Example 4 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

The present example provides telmisartan pellets and capsules, which are formulated as follows, prepared by the same method as in example 2, and the resulting porogenic particles have a particle size D90 of 89 μm.

Example 5 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

The present example provides telmisartan pellets and capsules, which are formulated as follows, prepared by the same method as in example 2, and the resulting porogenic particles have a size D90 of 97. Mu.m.

Example 6 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

The present example provides telmisartan pellets and capsules, which are substantially identical to the formulation and process of example 1, except that the pump speed in the preparation of the porogenic particles of step (2) is 12rpm, the atomization pressure is 0.1MPa, and the resulting porogenic particle size D90 is 125 μm.

Example 7 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

The present example provides telmisartan pellets and capsules, which are substantially identical to the formulation and process of example 1, except that the pump speed in the preparation of the porogenic particles of step (2) is 6rpm, the atomization pressure is 0.3MPa, and the resulting porogenic particle size D90 is 75 μm.

Example 8 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

The embodiment provides a telmisartan pellet and capsule, which are prepared as follows:

the preparation was essentially the same as in example 1, except that no thickener was added in step (1), and the resulting porogenic particles had a particle size D90 of 93. Mu.m.

Comparative example 1 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

The comparative example provides a telmisartan pellet, which is formulated as follows:

prescription of prescription	Raw and auxiliary materials	Prescription/g
			Active substances	Telmisartan	30
First alkali metal hydroxide	Sodium hydroxide	5
			Adhesive agent	Povidone	16
Filler (B)	Microcrystalline cellulose	204
			Lubricant	Stearic acid	8
Adhesive agent	Hydroxyethyl cellulose	26
			Enteric material	Acrylic resin	1
Water-soluble material	Lactose and lactose	10

The preparation process was essentially the same as in example 1, except that no pH buffer pair was added in step (1).

Comparative example 2 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

the preparation was essentially the same as in example 1, except that the adhesive was replaced with Opadry OY-C-7000A in step (2).

Comparative example 3 telmisartan capsules (each capsule contains 300mg telmisartan pellets)

the preparation process is essentially the same as in example 1, except that step (2) is omitted and no porogenic particles are added in step (3). The capsule filling amount was 300 mg/granule (+ -5%).

Experimental example 1 local pH adjusting ability test

The capsules obtained in examples 1 to 8 and comparative example 1 were placed in respective dissolution cups, and the dissolution conditions of 50rpm by paddle method were adopted, and the phosphate buffer medium having pH of 5.0 was used for the test, with a medium volume of 200ml. The pH values of the dissolution media when the tablets are just thrown and when the tablets are thrown for 1h, 2h and 3h are respectively measured.

TABLE 1 dissolution medium pH

The experiment is a simulation test of human gastrointestinal environment pH, and results show that compared with comparative example 1, the capsules of examples 1-8 have obviously improved pH adjustment capability, and the pH value of a medium can be adjusted from about 5.0 to 6.0 or more in the simulated gastrointestinal environment, so that a low solubility interval of telmisartan pH 3.0-6.0 is avoided, particularly in examples 1-7, the pH value of the medium can be stably maintained between 6.5-7.5 within 2-3 hours, and further the drug dissolution is better improved. Example 8 the pH adjusting effect can be achieved without the thickener in the pH adjusting composition, but the later pH adjustment is slightly inferior in the maintenance effect, and there is a case that the loss of the adjusting buffer salt is faster. Comparative example 1 did not contain a pH adjusting composition to raise the local medium pH to a target value (e.g., above 6.0).

Experimental example 2 adhesion test

Accurately weighing 8.07g of sodium taurocholate, 2.84g of lecithin, 8.65g of acetic acid and 15.2g of potassium chloride, adding into a container, adding water, fully stirring, adding water to a constant volume to 1000ml after dissolving, and finally regulating the pH value to 5.0 by using a sodium hydroxide solution to obtain the artificial simulated intestinal juice.

SD rat small intestine mucosa sections were used as adhesive base films. The capsule is opened, the pellets are taken to be wetted by artificial simulated intestinal juice for 10min and then are contacted with the mucous membrane of the small intestine, and are continuously soaked in the artificial intestinal juice, the artificial intestinal juice adopts a circulating flow mode, the flow speed is 5ml/min, the adhesion time of the pellets on the mucous membrane surface of the small intestine is observed, the longest time for 90% of the pellets to remain and the time for 90% of the pellets to fall off are recorded, and the results are shown in the following table:

TABLE 2 adhesion results

From the above table data, the maximum time for 90% of pellets to remain and the time for 90% of pellets to fall off, as measured in examples 1-8 of the present invention, are significantly prolonged, especially over 3 hours, compared to comparative example 2, and are sufficient to meet telmisartan absorption time. The particle size of the porogenic particles can further increase the adhesion effect compared to example 1 from example 6 within the preferred range of the present invention.

Experimental example 3 artificial simulation intestinal juice dissolution test

The testing method comprises the following steps: accurately weighing 8.07g of sodium taurocholate, 2.84g of lecithin, 8.65g of acetic acid and 15.2g of potassium chloride, adding into a container, adding water, fully stirring, adding water to a constant volume to 1000ml after dissolving, and finally regulating the pH value to 5.0 by using a sodium hydroxide solution to obtain the artificial simulated intestinal juice.

According to the dissolution and release measurement method (second method of four general rules 0931 of Chinese pharmacopoeia 2020 edition), the dissolution of the invention examples 1-8, comparative example 1, comparative example 3 and reference preparation mecamylin are measured, 1000mL of artificial simulated intestinal juice is used as dissolution medium, the pulp method is operated at 75 revolutions per minute, 10mL of solution is respectively taken in the 5 th, 10 th, 15 th, 30 th, 45 th, 60 th, 90 th and 120 th minutes, 10mL of dissolution medium is filtered and timely supplemented, the content of telmisartan medicine in the filtrate is measured by adopting an ultra-high performance liquid chromatography, and the cumulative dissolution is calculated.

TABLE 3 cumulative dissolution results

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The above table data shows that examples 1-8 release is substantially uniform and release rates are uniform, which benefits from enteric porogens of specific particle size, close to the reference formulation, especially examples 1-5, 8.

Comparative example 1 shows that there was almost no drug elution after 30min because of the absence of the pH adjusting composition, and that telmisartan has a cumulative dissolution of only about 32% and could not be completely eluted.

In comparative example 3, the release of the internal medicine is seriously hindered by adopting a common bioadhesive drug release system without pore-forming particles, and the final dissolution is still not achieved after 2 hours, so that the internal absorption is not facilitated.

Compared with other examples, the dissolution of example 6 and example 7 is very fast, and the dissolution is complete within 45-60min, especially the dissolution of example 6 is the fastest, and the combination production process is the case, because the porous particles have larger particle size, the porous particles are unevenly dispersed and even precipitate during coating, the bioadhesive film coating layer is influenced by large particles, once the enteric materials in the porous particles dissolve, the bioadhesive film coating layer is damaged due to larger drug release holes, and the dissolution is quickened. In example 7, the distribution density in the bioadhesive film coating layer is higher due to the smaller particle size of the porogenic particles, which results in the falling off of the whole bioadhesive film coating layer once the porogenic particles are dissolved, and the dissolution is too fast due to the burst release time. Therefore, controlling the particle size of the porogen particles is of particular interest.

Experimental example 4BE experiment

The BE test scheme is designed as follows: subjects were randomized into 2 groups, 6 persons each, two formulations were tested in two-cycle crossover, 10 days for elution period, and each cycle was given orally, with 240ml of warm water, 30mg for example 1, and 40mg for reference formulation mecamylin.

The design of the blood sampling points in the test is as follows: 0h, 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h, 2h, 2.33h, 2.67h, 3h, 3.33h, 3.67h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h (22 blood collection spots total), 4ml venous blood collection (first 0.3ml discard), test telmisartan content. And calculating the pharmacokinetic parameters, comparing the differences of the pharmacokinetic parameters AUC and Cmax of the two preparations, and evaluating the biological equivalence. The Cmax and AUC90% confidence interval data for the test and reference formulations are shown in the following table:

table 4 bioavailability results

The results show that 30mg of the micropill of the invention can be equivalent to 40mg of the reference preparation telmisartan (mecamylaceum), and the dosage is reduced by 25%.

It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.

Claims

1. A telmisartan pellet, which is characterized by comprising a pellet-containing core and a bioadhesive film coating layer coated outside the pellet-containing core, wherein the bioadhesive film coating layer comprises an adhesive and a pore-forming particle containing an enteric material and a water-soluble material, and the pellet-containing core comprises a pH buffer pair and has a mass ratio of 30:4-7 with a first alkali metal hydroxide, wherein the pH buffer pair comprises the following components in mass ratio of 51-71:4.5-11 alkali metal phosphate and a second alkali metal hydroxide, wherein the particle size D90 of the pore-forming particles is 85-101 mu m; the pill-containing core also comprises 0.5-1.2wt% of thickening agent based on the total mass of the pill-containing core.

2. Telmisartan pellets according to claim 1, characterized in that said pellet-containing core fulfils at least one of the following a-E:

D. the pill-containing core further comprises at least one of a filler, a binder, and a lubricant;

E. the thickener is at least one selected from the group consisting of carob, acacia, shellac, carrageenan, xanthan, tragacanth, guar and sodium alginate.

3. Telmisartan pellets according to claim 2, characterized in that the pellet-containing core further comprises 40-60wt% of a filler, 5-7wt% of a binder and 2-4wt% of a lubricant, based on the total mass of the pellet-containing core.

4. Telmisartan pellets according to claim 2, characterized in that the filler is selected from at least one of microcrystalline cellulose, lactose, starch, dextrin and chitosan; the adhesive is at least one of povidone, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose and methyl cellulose; the lubricant is at least one of polyethylene glycol, polyvinyl alcohol, glyceryl behenate, stearic acid, glyceryl monostearate and glyceryl palmitat.

5. Telmisartan pellets according to any of claims 1-4, characterized in that said bioadhesive film coating layer satisfies at least one of the following (1) - (3):

6. A process for the preparation of telmisartan pellets according to any of claims 1 to 5 comprising,

coating liquid preparation and coating steps: dispersing the adhesive and the pore-forming particles in a solvent to prepare a coating liquid, coating the pill-containing cores by adopting the coating liquid in a fluidization coating method, and drying to prepare the telmisartan micropills.

7. The preparation method according to claim 6, wherein in the preparation process of the telmisartan pellets, the solvent used is water; and/or the solid content of the granulating liquid is 15-30wt%; and/or the solid content of the coating liquid is 30-40wt%.

8. The preparation method of telmisartan pellets according to claim 6 or 7, characterized in that the preparation method of the soft material comprises the following steps:

(2) Mixing the other components of the medicated pill core, and adding the medicated adhesive solution to prepare medicated soft material.

9. The process for the preparation of telmisartan pellets according to claim 8, characterized in that the solid content of the drug-containing binder solution is 25-40wt%.

10. A pharmaceutical formulation comprising telmisartan pellets according to any of claims 1-5 or telmisartan pellets obtainable by the process of any of claims 6-9, and pharmaceutically acceptable excipients.

11. The pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation is in the form of a capsule.