Pharmaceutical composition containing dabigatran etexilate and preparation method thereof

1 . A pharmaceutical composition containing dabigatran etexilate, comprising an active pharmaceutical ingredient, an amphiphilic polymer and a hydrophilic polymer, wherein

the active pharmaceutical ingredient is dabigatran etexilate and/or dabigatran etexilate mesylate, the amphiphilic polymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the hydrophilic polymer is polyoxyethylene-polyoxypropylene glycol block copolymer;

a mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 5 wt % to 60 wt %; a mass percentage of the amphiphilic polymer in the pharmaceutical composition is 3 wt % to 40 wt %; and a mass percentage of the hydrophilic polymer in the pharmaceutical composition is 10 wt % to 80 wt %.

2 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , wherein

the pharmaceutical composition exists in the forms of granules, powder, pellets, noodle-like body or ribbon-like body,

or, the dosage forms of the pharmaceutical composition are granules, capsules, tablets or dry suspension,

or, the pharmaceutical composition is prepared by hot-melt process,

or, the pharmaceutical composition further comprises a disintegrating agent,

or, the pharmaceutical composition further comprises an antistatic agent,

or, the pharmaceutical composition further comprises a lubricant,

or, the pharmaceutical composition further comprises a glidant,

or, the pharmaceutical composition further comprises a diluent.

3 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 2 , wherein the hot-melt process comprises hot-melt granulation, hot-melt extrusion and hot-melt extrusion-spheronization;

wherein the hot-melt granulation comprises stirring hot-melt granulation in granulators with heating jacket, screw hot-melt granulation, roller-compaction hot-melt granulation, and hot-melt spray granulation;

the hot-melt extrusion comprises twin-screw extrusion, single-screw extrusion;

the hot-melt extrusion-spheronization refers to the process of cutting the noodles-like products prepared by a hot-melt extruder into small cylinders and then further preparing pellets through a spheronizer;

wherein the stirring hot-melt granulation in granulators with heating jacket comprises high-shear or low-shear granulator stirring granulation;

the screw hot-melt granulation comprises twin-screw granulation or single-screw granulation;

the roller-compaction hot-melt granulation refers to a roller-compaction granulation with heating jacket;

the hot-melt spray granulation comprises the process by hot-melt spraying onto a carrier or the process by hot-melt spraying and cooling without a carrier.

4 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , wherein

a mass of the active pharmaceutical ingredient in the pharmaceutical composition is 20 to 180 mg or 23 to 173 mg;

or, the number of repeat units of vinyl caprolactam in the amphiphilic polymer is 57 or below;

or, the number of repeat units of vinyl acetate in the amphiphilic polymer is 30 or below;

or, the number of repeat units of polyethylene glycol in the amphiphilic polymer is 13 or above;

or, monomers in the amphiphilic polymer are polyethylene glycol 6000, vinyl caprolactam and vinyl acetate, and a mole ratio of the three monomers, namely the polyethylene glycol 6000, the vinyl caprolactam and the vinyl acetate, in the amphiphilic polymer is 13:57:30;

or, a molecular weight of the amphiphilic polymer is 90,000 to 140,000 g/mol;

or, a glass transition temperature of the amphiphilic polymer is 69 to 71° C.;

or, a mass ratio of the active pharmaceutical ingredient to the amphiphilic polymer is 1:0.2-1:3, 1:0.23-1:3, 1:0.3-1:3, 1:0.5-1:3, 1:1.5-1:3, 1:1.5-1:2.3, 1:0.23, 1:0.33, 1:0.77, 1:1, 1:1.2, 1:1.5, 1:1.6, 1:2 or 1:2.3.

5 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , wherein

the polyoxyethylene-polyoxypropylene glycol block copolymer is polyoxyethylene-polyoxypropylene glycol block copolymer P188 or polyoxyethylene-polyoxypropylene glycol block copolymer P407;

or, a mass ratio of the active pharmaceutical ingredient to the hydrophilic polymer is 1:0.25-1:4, 1:0.5-1:3, 1:1.2, 1:1.25, 1:1.9, 1:2, 1:2.5 or 1:2.85;

or, the mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 10 wt % to 55 wt %, 20 wt % to 45 wt %, 13.3 wt %, 14.4 wt %, 16.9 wt %, 17.0 wt %, 18.0 wt %, 24.0 wt %, 39.1 wt % or 43.4 wt %;

or, the mass percentage of the amphiphilic polymer in the pharmaceutical composition is 3.3 wt %, 6.0 wt %, 9.2 wt %, 10.0 wt %, 12.8 wt %, 12.9 wt %, 18.6 wt %, 21.3 wt %, 22.5 wt %, 22.8 wt %, 24.3 wt %, 28.3 wt %, 38.8 wt % or 39.2 wt %;

or, the mass percentage of the hydrophilic polymer in the pharmaceutical composition is 20 wt % to 80 wt %, 40 wt % to 60 wt %, 16.7 wt %, 19.2 wt %, 19.9 wt %, 22.2 wt %, 26.1 wt %, 27.4 wt %, 29.6 wt %, 31.0 wt %, 33.3 wt %, 35.9 wt %, 30.0 wt % or 36.0 wt %.

6 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 2 , wherein

the disintegrating agent is one or more selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate and crospovidone;

or, a mass percentage of the disintegrating agent in the pharmaceutical composition is 0 wt % to 20 wt %;

or, the antistatic agent is one or more selected from the group consisting of long-chained alkylphenol, ethoxylated amine, glyceride and silica;

or, a mass percentage of the antistatic agent in the pharmaceutical composition is 0 wt % to 5 wt %;

or, the lubricant is one or more selected from the group consisting of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, talcum powder, colloidal silica, magnesium silicate and calcium silicate;

or, a mass percentage of the lubricant in the pharmaceutical composition is 0 wt % to 5 wt %;

or, the glidant is one or more selected from the group consisting of talcum powder, colloidal silica, magnesium silicate and calcium silicate;

or, a mass percentage of the glidant in the pharmaceutical composition is 0 wt %-5 wt %;

or, the diluent is one or more selected from the group consisting of starch, mannitol, microcrystalline cellulose or lactose monohydrate;

or, a mass percentage of the diluent in the pharmaceutical composition is 0 wt %-50 wt %.

7 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 6 , wherein

the disintegrating agent is croscarmellose sodium or low-substituted hydroxypropyl cellulose;

or, the antistatic agent is silica;

or, the mass percentage of the antistatic agent in the pharmaceutical composition is 0.01 wt %-3 wt %, or 0.5 wt %-2 wt %;

or, the lubricant is magnesium stearate;

or, the mass percentage of the lubricant in the pharmaceutical composition is 0.01 wt %-3 wt %, or 0.5 wt %-2 wt %;

or, the glidant is colloidal silica;

or, the mass percentage of the glidant in the pharmaceutical composition is 0.01 wt %-3wt %, or 0.5 wt %-2 wt %;

or, the mass percentage of the diluent in the pharmaceutical composition is 9 wt %-38.3 wt %.

8 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , wherein the pharmaceutical composition comprises the components of following mass fraction: 9%-48% of dabigatran etexilate mesylate, 6%-40% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 10%-30% of polyoxyethylene-polyoxypropylene glycol block copolymer P407, 10%-23% of polyoxyethylene-polyoxypropylene glycol block copolymer P188, 0%-58% of lactose monohydrate, 0%-35% of mannitol, 0%-20% of croscarmellose sodium, 0%-5% of silica and 0-3% of magnesium stearate.

9 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , wherein

the pharmaceutical composition comprises the components of following mass fraction: 13%-44% of the active pharmaceutical ingredient, 6%-39% of the amphiphilic polymer, 16%-36% of the hydrophilic polymer, 9%-39% of a diluent, 5%-23% of a disintegrating agent and 0.4%-0.5% of a lubricant;

or, the pharmaceutical composition comprises the components of following mass fraction: 16%-18% of the active pharmaceutical ingredient, 26%-40% of the amphiphilic polymer, 17%-23% of the hydrophilic polymer, 0%-32% of a diluent, 5%-20% of a disintegrating agent and 0%-2% of a lubricant.

10 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 9 , wherein

the pharmaceutical composition comprises the components of following mass fraction: 16%-18% of dabigatran etexilate mesylate, 26%-40% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 0%-32% of mannitol, 17%-23% of polyoxyethylene-polyoxypropylene glycol block copolymer P188, 5%-20% of croscarmellose sodium and 0%-2% of magnesium stearate.

11 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , wherein

the pharmaceutical composition is composed of the components of following mass fraction: 16.9% of dabigatran etexilate mesylate, 38.8% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 18.9% of mannitol, 19.9% of polyoxyethylene-polyoxypropylene glycol block copolymer P188, 5.0% of croscarmellose sodium and 0.5% of magnesium stearate;

or, the pharmaceutical composition is composed of the components of following mass fraction: 43.35% of dabigatran etexilate mesylate, 10% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 9% of mannitol, 22.15% of polyoxyethylene-polyoxypropylene glycol block copolymer P407, 15.0% of croscarmellose sodium and 0.5% of magnesium stearate;

or, the pharmaceutical composition is composed of the components of following mass fraction: 43.35% of dabigatran etexilate mesylate, 10% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 9% of mannitol, 22.15% of polyoxyethylene-polyoxypropylene glycol block copolymer P407, 15.0% of low-substituted hydroxypropyl cellulose and 0.5% of magnesium stearate;

or, the pharmaceutical composition is composed of the components of following mass fraction: 39.1% of dabigatran etexilate mesylate, 9.2% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 9.2% of mannitol, 19.2% of polyoxyethylene-polyoxypropylene glycol block copolymer P188, 23.0% of croscarmellose sodium and 0.4% of magnesium stearate.

12 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , wherein the pharmaceutical composition comprises the components of following mass fraction: 16%-45% of the active pharmaceutical ingredient, 6%-40% of the amphiphilic polymer, 15%-23% of the hydrophilic polymer, 9%-35% of a diluent, 4%-23% of a disintegrating agent, 0%-0.5% of an antistatic agent, 0.2%-0.6% of a lubricant and 0.4%-0.6% of a glidant.

13 . A method for preparing the pharmaceutical composition as defined in claim 1 , wherein the pharmaceutical composition is prepared by hot-melt process, the hot-melt process comprises the steps of:

mixing the active pharmaceutical ingredient, the amphiphilic polymer, the hydrophilic polymer and optionally a diluent, a disintegrating agent, an antistatic agent, and a glidant to obtain a mixture, then the mixture hot melts at 50-140° C. to obtain the pharmaceutical composition.

14 . The method as defined in claim 12 , wherein the mixture hot melts at 50-75° C.

15 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , the pharmaceutical composition further comprises a disintegrating agent, the disintegrating agent is at least one selected from the group consisting of croscarmellose sodium and sodium starch glycolate, a mass percentage of the disintegrating agent in the pharmaceutical composition is 0 wt % to 5 wt %, but not 0 wt %.

16 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , the pharmaceutical composition further comprises a lubricant, the lubricant is at least one selected from the group consisting of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, talcum powder, magnesium silicate and calcium silicate, a mass percentage of the lubricant in the pharmaceutical composition is 0 wt % to 5 wt %, but not 0 wt %.

17 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , the pharmaceutical composition further comprises a diluent, the diluent is mannitol and/or lactose monohydrate, a mass percentage of the diluent in the pharmaceutical composition is 0 wt % to 40 wt %, but not 0 wt %.

18 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , the pharmaceutical composition further comprises an antistatic agent, the antistatic agent is at least one selected from the group consisting of long-chained alkylphenol, ethoxylated amine, and glyceride, a mass percentage of the antistatic agent in the pharmaceutical composition is 0 wt % to 5 wt %, but not 0 wt %.

19 . The pharmaceutical composition containing dabigatran etexilate as defined in claim 1 , wherein the mass percentage of the hydrophilic polymer in the pharmaceutical composition is 10 wt % to 60 wt %.

20 . A pharmaceutical composition containing dabigatran etexilate, which consists of an active pharmaceutical ingredient, an amphiphilic polymer, a hydrophilic polymer, and optionally at least one selected from a disintegrating agent, an antistatic agent, a lubricant, and a diluent, wherein

the active pharmaceutical ingredient is dabigatran etexilate and/or dabigatran etexilate mesylate, the amphiphilic polymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the hydrophilic polymer is polyoxyethylene-polyoxypropylene glycol block copolymer; the disintegrating agent is at least one selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate and crospovidone; the antistatic agent is at least one selected from the group consisting of long-chained alkylphenol, ethoxylated amine, glyceride and silica; the lubricant is at least one selected from the group consisting of calcium stearate, glyceryl behenate, magnesium stearate, sodium stearyl fumarate, talcum powder, colloidal silica, magnesium silicate and calcium silicate; the diluent is mannitol and/or lactose monohydrate;

a mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 5 wt % to 60 wt %; a mass percentage of the amphiphilic polymer in the pharmaceutical composition is 3 wt % to 40 wt %; and a mass percentage of the hydrophilic polymer in the pharmaceutical composition is 10 wt % to 80 wt %.