阅读说明：本技术 甲磺酸达比加群酯包合物、制备方法及应用 (Dabigatran etexilate mesylate inclusion compound, preparation method and application ) 是由 郭桢 应述欢 覃伟 何新怡 王婷婷 于 2021-10-28 设计创作，主要内容包括：本发明提供了甲磺酸达比加群酯包合物、制备方法及应用。本发明提供了一种甲磺酸达比加群酯包合物其包括甲磺酸达比加群酯和环糊精。本发明的甲磺酸达比加群酯包合物能够有效提高药物的溶解度,比甲磺酸达比加群酯的溶解度提高2-5倍,生物利用度提高,避免使用有机酸肠胃刺激小。该方法可连续化加工,生产效率高,工艺重现性好,市场化前景好。(The invention provides a dabigatran etexilate mesylate inclusion compound, a preparation method and application thereof. The invention provides a dabigatran etexilate mesylate inclusion compound which comprises dabigatran etexilate mesylate and cyclodextrin. The dabigatran etexilate mesylate inclusion compound can effectively improve the solubility of a medicament, is improved by 2-5 times compared with the solubility of dabigatran etexilate mesylate, improves the bioavailability, and avoids small intestine and stomach irritation caused by using an organic acid. The method has the advantages of continuous processing, high production efficiency, good process reproducibility and good marketization prospect.)

1. A dabigatran etexilate mesylate clathrate compound is characterized in that: which comprises dabigatran etexilate mesylate and cyclodextrin.

2. The dabigatran etexilate mesylate clathrate of claim 1, wherein:

the cyclodextrin is one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin.

3. The dabigatran etexilate mesylate clathrate of claim 1, wherein:

the molar ratio of the cyclodextrin to the dabigatran etexilate mesylate is 0.1-100.

4. The dabigatran etexilate mesylate clathrate of claim 3, wherein:

the molar ratio of the cyclodextrin to the dabigatran etexilate mesylate is 0.2-10.

5. The dabigatran etexilate mesylate clathrate of claim 4, wherein:

the molar ratio of the cyclodextrin to the dabigatran etexilate mesylate is 0.3-5.

6. The dabigatran etexilate mesylate clathrate of claim 1, wherein: the dabigatran etexilate mesylate inclusion compound consists of dabigatran etexilate mesylate and cyclodextrin.

7. The dabigatran etexilate mesylate clathrate compound according to any one of claims 1 to 6, wherein: the dabigatran etexilate mesylate clathrate compound further comprises a pH value regulator, a solubilizer and a cosolvent.

8. The preparation method of the dabigatran etexilate mesylate clathrate compound according to any one of claims 1 to 6, characterized by comprising the following steps: and (3) clathrating dabigatran etexilate mesylate with cyclodextrin to obtain the dabigatran etexilate mesylate clathrate compound.

9. The method for preparing the dabigatran etexilate mesylate clathrate compound according to claim 8, wherein the method comprises the following steps:

the preparation method of the dabigatran etexilate mesylate inclusion compound is carried out in a solvent or under the condition of no solvent;

in the preparation method of the dabigatran etexilate mesylate inclusion compound, when the inclusion is carried out in a solvent, the solvent is water or a mixed solvent of water and an organic solvent;

and/or the presence of a gas in the gas,

in the preparation method of the dabigatran etexilate mesylate clathrate compound, the mass volume ratio of the dabigatran etexilate mesylate to the organic solvent is 0.001 g/mL-1 g/mL;

and/or the presence of a gas in the gas,

in the preparation method of the dabigatran etexilate mesylate inclusion compound, the inclusion temperature is 20-80 ℃;

and/or the presence of a gas in the gas,

in the preparation method of the dronedarone hydrochloride clathrate compound, the inclusion time is 0.5 to 20 hours;

and/or the presence of a gas in the gas,

the preparation method of the dabigatran etexilate mesylate clathrate compound comprises the following post-treatment steps: and after the inclusion is finished, cooling, removing the solvent, filtering and drying to obtain the dabigatran etexilate mesylate inclusion compound.

10. The method for preparing the dabigatran etexilate mesylate clathrate compound according to claim 9, wherein: the method comprises the following specific steps:

a) preparing a cyclodextrin aqueous solution;

b) adding a solution formed by dabigatran etexilate mesylate and water or an organic solvent into the cyclodextrin water solution prepared in the step a) to obtain a dabigatran etexilate mesylate-cyclodextrin solution;

c) performing inclusion on the dabigatran etexilate mesylate-cyclodextrin solution obtained in the step b) to obtain an inclusion solution of the dabigatran etexilate mesylate-cyclodextrin;

d) cooling, removing the solvent, filtering and drying the inclusion solution of dabigatran etexilate mesylate-cyclodextrin prepared in the step c) to obtain the dabigatran etexilate mesylate inclusion compound.

11. A dabigatran etexilate mesylate pharmaceutical preparation is characterized in that: the pharmaceutical preparation comprises the dabigatran etexilate mesylate inclusion compound as claimed in any one of claims 1 to 7 and pharmaceutic adjuvants.

12. The pharmaceutical formulation of claim 11, wherein: the dabigatran etexilate mesylate pharmaceutical preparation comprises but is not limited to tablets, granules, capsules, pellets, sustained release tablets, osmotic pump tablets, orally disintegrating tablets, oral liquid, injection and freeze-dried powder injection.

13. The pharmaceutical formulation of claim 11, wherein: the "pharmaceutical excipients" include, but are not limited to, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, sequestering agents, permeation enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, and release retardants.

14. The use of the dabigatran etexilate mesylate inclusion compound according to any one of claims 1 to 7 in the preparation of a dabigatran etexilate mesylate pharmaceutical preparation.

15. The use of claim 14, wherein: the medicament or the pharmaceutical preparation is an oral anticoagulant medicament.

Technical Field

The invention relates to a dabigatran etexilate mesylate clathrate compound, a preparation method and application thereof.

Background

The dabigatran etexilate is a novel oral anticoagulant drug and has a structural formula shown in a formula I. After oral absorption, the dabigatran etexilate is converted into dabigatran with direct anticoagulant activity in vivo. Dabigatran binds with fibrin specific binding sites of thrombin, preventing fibrinogen from being cracked into fibrin, thereby blocking the final step of a blood coagulation waterfall network and thrombus formation. Dabigatran can be dissociated from a fibrin-thrombin conjugate to exert reversible anticoagulation.

Compared with the traditional oral anticoagulant warfarin, the dabigatran etexilate has the advantages of low adverse reaction incidence rate, no need of conventional monitoring, wide treatment window, no influence of diet and the like.

The dabigatran etexilate is absorbed quickly after being taken orally, the peak reaching time is about 1-2 h, but the oral bioavailability is only 3% -7%. The solubility of the compound in aqueous solution is pH dependent, the solubility in acidic solution is high, and the compound is almost insoluble at pH > 4.0. Dabigatran etexilate has low bioavailability in humans.

Patent US9925174 discloses a process for formulating dabigatran etexilate capsules, which are pellet capsules containing tartaric acid pellet cores, and provide an acidic microenvironment to increase drug solubility through organic acids, but the preparation process is complex, and researches show that the bioavailability of the commercially available preparation is only 3% -7%. In the prior art, most of the preparations related to the dabigatran etexilate capsules provide an acidic microenvironment by organic acid, but have high irritation to gastrointestinal tracts and low bioavailability in intestinal tracts. Therefore, the finding of the dabigatran formulation with low gastrointestinal irritation, high stability, high solubility, in vitro dissolution and in vivo bioavailability is a technical problem to be solved urgently at present.

Disclosure of Invention

The invention aims to solve the technical problems that in the prior art, the dabigatran etexilate mesylate inclusion compound is low in drug solubility, low in bioavailability, large in gastrointestinal irritation due to the need of organic acid and the like, and provides a preparation method and application of the dabigatran etexilate mesylate inclusion compound. The dabigatran etexilate mesylate inclusion compound can effectively improve the solubility of the drug, thereby improving the bioavailability, and can reduce the irritation of the drug to the gastrointestinal tract by avoiding using organic acid. The method has the advantages of continuous processing, high production efficiency, good process reproducibility and good marketization prospect.

The invention provides a dabigatran etexilate mesylate inclusion compound which comprises dabigatran etexilate mesylate and cyclodextrin.

In the invention, the cyclodextrin is preferably one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin, and is further preferably hydroxypropyl-beta-cyclodextrin and/or sulfobutyl-beta-cyclodextrin.

In the present invention, the molar ratio of the cyclodextrin to the dabigatran etexilate mesylate is preferably 0.1 to 100, more preferably 0.2 to 10, still more preferably 0.3 to 5, for example 1 or 2.

In the invention, the dabigatran etexilate mesylate inclusion compound is preferably composed of dabigatran etexilate mesylate and cyclodextrin.

In the invention, the dabigatran etexilate mesylate clathrate compound can further comprise a pH value regulator, a solubilizer and a cosolvent.

The invention also provides a preparation method of the dabigatran etexilate mesylate clathrate compound, which comprises the following steps: and (3) in a solvent, performing inclusion on the dabigatran etexilate mesylate and cyclodextrin to obtain the dabigatran etexilate mesylate inclusion compound.

The dabigatran etexilate mesylate inclusion compound can be prepared by adopting the conventional inclusion conditions in the field, and the following inclusion conditions are preferred in the invention:

the preparation method of the dabigatran etexilate mesylate clathrate compound can be carried out in a solvent or under the condition of no solvent. When carried out in a solvent, the solvent is preferably water or a mixed solvent of water and an organic solvent; the organic solvent is preferably an alcohol solvent and/or a halogenated hydrocarbon solvent; the alcohol solvent is preferably methanol and/or ethanol; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The "mixed solvent of water and an organic solvent" is more preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water.

In the method for preparing the dabigatran etexilate mesylate inclusion compound, the cyclodextrin is preferably used in the form of an aqueous solution thereof, the mass concentration of the aqueous cyclodextrin solution is preferably 1% to 50%, more preferably 5% to 20%, for example 9%, and the mass concentration refers to the percentage of the mass of the cyclodextrin to the total mass of the aqueous cyclodextrin solution.

In the method for preparing the dabigatran etexilate mesylate clathrate compound, the mass-volume ratio of the dabigatran etexilate mesylate to the organic solvent is preferably 0.001 g/mL-1 g/mL, more preferably 0.005 g/mL-0.1 g/mL, for example 0.05 g/mL. The mass-to-volume ratio is the ratio of the mass of the dabigatran etexilate mesylate to the volume of the organic solvent.

In the method for preparing the dabigatran etexilate mesylate inclusion compound, the inclusion temperature is preferably 20-80 ℃, more preferably 40-70 ℃, for example 60 ℃.

In the method for preparing dronedarone hydrochloride clathrate, the time for inclusion is preferably 0.5 to 20 hours, more preferably 2 to 10 hours, for example 7 hours.

The preparation method of the dabigatran etexilate mesylate clathrate compound preferably adopts the following post-treatment steps: and after the inclusion is finished, cooling, removing the solvent, filtering and drying to obtain the dabigatran etexilate mesylate inclusion compound.

In the post-treatment step of the preparation method of the dabigatran etexilate mesylate inclusion compound, the cooling temperature is preferably 10-30 ℃, and more preferably 20-25 ℃.

In the post-treatment step of the preparation method of the dabigatran etexilate mesylate inclusion compound, the filtration is preferably performed by using a filter element. The pore size of the filter element is preferably 0.22-0.8 micron, and further preferably 0.45-0.8 micron.

In the post-treatment step of the preparation method of the dabigatran etexilate mesylate inclusion compound, the drying mode is preferably one or more of freeze drying, reduced pressure drying, normal pressure drying and spray drying, and further preferably freeze drying and/or spray drying.

The preparation method of the dabigatran etexilate mesylate clathrate compound further preferably comprises the following specific steps:

a) preparing a cyclodextrin aqueous solution;

b) adding a solution formed by dabigatran etexilate mesylate and an organic solvent or water into the cyclodextrin water solution prepared in the step a) to obtain a dabigatran etexilate mesylate-cyclodextrin solution;

c) performing inclusion on the dabigatran etexilate mesylate-cyclodextrin solution obtained in the step b) to obtain an inclusion solution of the dabigatran etexilate mesylate-cyclodextrin;

d) cooling, removing the solvent, filtering and drying the inclusion solution of dabigatran etexilate mesylate-cyclodextrin prepared in the step c) to obtain the dabigatran etexilate mesylate inclusion compound.

In step c), the temperature of the inclusion is preferably from 20 ℃ to 80 ℃, more preferably from 40 ℃ to 70 ℃, for example, 60 ℃.

In step c), the time for inclusion is preferably 0.5 to 20 hours, more preferably 3 to 10 hours, for example 7 hours.

In step d), the cooling temperature is preferably 10 to 30 ℃, and more preferably 20 to 25 ℃.

In step d), the filtration is preferably performed using a filter membrane. The pore size of the filter membrane is preferably 0.22-0.8 micron, and more preferably 0.45-0.8 micron.

In step d), the drying manner is preferably one or more of freeze drying, reduced pressure drying, normal pressure drying and spray drying, and further preferably freeze drying and/or spray drying.

The invention also provides the dabigatran etexilate mesylate inclusion compound prepared by the preparation method of the dabigatran etexilate mesylate inclusion compound.

The invention also provides application of the dabigatran etexilate mesylate inclusion compound in preparation of a dabigatran etexilate mesylate medicinal preparation. The pharmaceutical preparation can be an oral anticoagulant.

The invention also provides a dabigatran etexilate mesylate pharmaceutical preparation, which comprises the dabigatran etexilate mesylate inclusion compound and pharmaceutic adjuvant.

In the present invention, the pharmaceutical excipients may be conventional in the art, including but not limited to, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, penetration enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulation agents, humectants, absorbents, flocculants and deflocculants, filter aids, release retardants, and the like.

The dabigatran etexilate mesylate pharmaceutical preparation comprises but is not limited to tablets, granules, capsules, pellets, sustained release tablets, osmotic pump tablets, orally disintegrating tablets, oral liquid, injection, freeze-dried powder injection and the like.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

In the invention, the room temperature refers to the environment temperature of 10-35 ℃.

The positive progress effects of the invention are as follows: the dabigatran etexilate mesylate inclusion compound can effectively improve the solubility of the drug, improves the solubility by 2 to 5 times compared with the dabigatran etexilate mesylate, improves the bioavailability, can reduce the administration dosage, and can effectively reduce the irritation of the drug to the gastrointestinal tract. The method has the advantages of continuous processing, high production efficiency, good process reproducibility and good marketization prospect.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1

Dabigatran etexilate mesylate: hydroxypropyl-beta-cyclodextrin ═ 1:1 (molar ratio of materials)

0.050g of dabigatran etexilate mesylate and 0.104g of hydroxypropyl-beta-cyclodextrin are respectively weighed, and the inclusion compound is prepared according to the following method.

Dissolving dabigatran etexilate mesylate with 1ml of methanol, dripping the dissolved dabigatran etexilate mesylate into a hydroxypropyl-beta-cyclodextrin water solution with the mass percent of 9% (the mass percent refers to the mass percent of the hydroxypropyl-beta-cyclodextrin and the mass percent of the hydroxypropyl-beta-cyclodextrin water solution), carrying out inclusion for 7 hours in a magnetic stirrer at 60 ℃ (water bath), cooling to room temperature (20-25 ℃), carrying out rotary evaporation, filtering, and carrying out freeze drying to obtain the dabigatran etexilate mesylate hydroxypropyl-beta-cyclodextrin inclusion compound.

Example 2

Dabigatran etexilate mesylate: hydroxypropyl-beta-cyclodextrin ═ 1:2 (molar ratio of materials)

0.200g of dabigatran etexilate mesylate and 0.832g of hydroxypropyl-beta-cyclodextrin are respectively weighed, and the inclusion compound is prepared according to the following method.

Dissolving dabigatran etexilate mesylate by using 4ml of methanol, dripping the dissolved dabigatran etexilate mesylate into a hydroxypropyl-beta-cyclodextrin water solution with the mass percent of 9% (the mass percent refers to the mass percent of the hydroxypropyl-beta-cyclodextrin and the mass percent of the hydroxypropyl-beta-cyclodextrin water solution), carrying out inclusion for 7 hours in a magnetic stirrer at 60 ℃ (water bath), cooling to room temperature (20-25 ℃), carrying out rotary evaporation, filtering, freezing and drying, and obtaining the hydroxypropyl-beta-cyclodextrin inclusion compound of the dabigatran etexilate mesylate.

Example 3:

dabigatran etexilate mesylate: sulfobutyl-beta-cyclodextrin ═ 1:1 (molar ratio of materials)

0.200g of dabigatran etexilate mesylate and 0.328g of sulfobutyl-beta-cyclodextrin are weighed respectively to prepare the inclusion compound according to the following method.

Dissolving dabigatran etexilate mesylate with 4ml of methanol, dripping the dissolved dabigatran etexilate mesylate into 9 mass percent sulfobutyl-beta-cyclodextrin aqueous solution (the mass percent refers to the mass percent of the mass of the sulfobutyl-beta-cyclodextrin and the mass percent of the sulfobutyl-beta-cyclodextrin aqueous solution), carrying out inclusion in a magnetic stirrer at 60 ℃ (water bath for 7 hours, cooling to room temperature (20-25 ℃), carrying out rotary evaporation, filtering, and freeze-drying to obtain the dabigatran etexilate mesylate hydroxypropyl-beta-cyclodextrin inclusion compound.

Example 4:

dabigatran etexilate mesylate: sulfobutyl-beta-cyclodextrin ═ 1:2 (molar ratio of materials)

0.101g of dabigatran etexilate mesylate and 0.332g of sulfobutyl-beta-cyclodextrin are weighed respectively, and the inclusion compound is prepared according to the following method.

Dissolving dabigatran etexilate mesylate with 2ml of methanol, dripping the dissolved dabigatran etexilate mesylate into 9 mass percent sulfobutyl-beta-cyclodextrin aqueous solution (the mass percent refers to the mass percent of the sulfobutyl-beta-cyclodextrin and the mass percent of the sulfobutyl-beta-cyclodextrin aqueous solution), carrying out inclusion in a magnetic stirrer at 60 ℃ (water bath for 7 hours, cooling to room temperature (20-25 ℃), carrying out rotary evaporation, filtering, and freeze-drying to obtain the dabigatran etexilate sulfobutyl-beta-cyclodextrin inclusion compound.

The solubility of the dabigatran etexilate mesylate inclusion compound prepared in examples 1 to 4 in water (37 ℃ C., 24 hours with shaking) is shown in Table 1.

TABLE 1 solubility of dabigatran etexilate mesylate inclusion compound in water

As can be seen from Table 1, the solubility of the dabigatran etexilate mesylate-cyclodextrin inclusion compound in water is remarkably improved.