Pharmaceutical composition containing dabigatran etexilate and preparation method thereof

Abstract

Disclosed is a pharmaceutical composition containing dabigatran etexilate and a preparation method thereof. The pharmaceutical composition comprises a pharmaceutically active ingredient, dabigatran etexilate and/or dabigatran etexilate mesylate, and a amphiphilic polymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The mass ratio of the two is 1:0.23 to 1:3. The pharmaceutical composition not only increases the bioavailability of the pharmaceutically active ingredient, but also reduces absorption variability, and provides a more stable concentration of dabigatran in plasma, thereby reducing adverse side effects.

Claims

1. A pharmaceutical composition containing dabigatran etexilate, comprising an active pharmaceutical ingredient and an amphiphilic 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 a mass ratio of the active pharmaceutical ingredient to the amphiphilic polymer is 1:0.23 to 1:3; the pharmaceutical composition further comprises a hydrophilic polymer, 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 90 wt %; and the active pharmaceutical ingredient, the amphiphilic polymer and the hydrophilic polymer in the pharmaceutical composition form a solid dispersion.

2. The pharmaceutical composition containing dabigatran etexilate as defined in claim 1, wherein a mass of the active pharmaceutical ingredient in the pharmaceutical composition is 30 to 180 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, the mass ratio of the active pharmaceutical ingredient to the amphiphilic polymer is 1:0.24 to 1:3.

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

4. The pharmaceutical composition containing dabigatran etexilate as defined in claim 1, wherein the pharmaceutical composition comprises the components of following mass fraction: 13% to 44% of the active pharmaceutical ingredient, 6% to 39% of the amphiphilic polymer, 16% to 36% of a hydrophilic polymer, 9% to 39% of a diluent, 5% to 23% of a disintegrating agent and 0.4% to 0.5% of a lubricant; wherein, the diluent is mannitol or lactose monohydrate; the disintegrating agent is one or more selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate and crospovidone; the antistatic agent is one or more selected from the group consisting of long-chained alkylphenol, ethoxylated amine, glyceride and silica; 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.

5. 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.

6. The pharmaceutical composition containing dabigatran etexilate as defined in claim 1, wherein the pharmaceutical composition exists in the following forms: powder, pellets, granules, capsules or tablets; and the pellet is divided into a neutral-core pellet and an acid-core pellet according to the difference of core thereof.

7. The pharmaceutical composition containing dabigatran etexilate as defined in claim 6, wherein, when the pharmaceutical composition exists in the form of powder, a method for preparing the powder comprises following steps: dissolving all the components of the pharmaceutical composition in an ethanol aqueous solution, and carrying out spray-drying; when the pharmaceutical composition exists in the form of the neutral-core pellet, the neutral-core pellet is provided with a neutral core and drug layers wrapping the neutral core, a method for preparing the neutral-core pellet comprises following steps: dissolving all the components of the pharmaceutical composition in an ethanol aqueous solution, and spraying the obtained solution to the neutral core; when the pharmaceutical composition exists in the form of an acid-core pellet, the acid-core pellet comprises an acid core, isolation layer and drug layer, the isolation layer wraps the surface of the acid core, and the drug layer wraps the surface of the isolation layer; and the isolation layer comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyoxyethylene-polyoxypropylene glycol block copolymer P407; when the pharmaceutical composition exists in the form of granules, a method for preparing the granules is wet granulation, rolling granulation, fluidized bed granulation or hot melting granulation.

8. The pharmaceutical composition containing dabigatran etexilate as defined in claim 6, wherein the pharmaceutical composition exists in the forms of powder, pellets, granules, capsules or tablets; and the active pharmaceutical ingredient and other components in the pharmaceutical composition jointly form a solid dispersion.

9. The pharmaceutical composition containing dabigatran etexilate as defined in claim 6, wherein the pharmaceutical composition exists in the forms of powder, pellets, granules, capsules or tablets, the amphiphilic polymer in the pharmaceutical composition exists in two forms simultaneously, the first form is that the amphiphilic polymer and the active pharmaceutical ingredient form a solid dispersion, and the second form is that the amphiphilic polymer exists in a form of solid granules.

10. The pharmaceutical composition containing dabigatran etexilate as defined in claim 9, wherein the solid granule of the amphiphilic polymer comprises the components of following mass fraction: 40% to 58% of the amphiphilic polymer, 0% to 55% of a hydrophilic polymer, 0% to 55% of a diluent, 5% to 20% of a disintegrating agent, 0% to 5% of an antistatic agent and 0% to 2% of a lubricant; or, the solid granule of the amphiphilic polymer comprises the components of following mass fraction: 41.9% to 50% of the amphiphilic polymer, 19.8% to 51.9% of hydrophilic polymer, 24.7% to 51.9% of a diluent, 5.0% to 5.25% of a disintegrating agent, 0.1% to 1% of an antistatic agent and 0.1% to 1% of a lubricant; wherein or lactose monohydrate; the disintegrating agent is one or more selected from the group consisting of croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate and crospovidone; the antistatic agent is one or more selected from the group consisting of long-chained alkylphenol, ethoxylated amine, glyceride and silica; 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.

11. The pharmaceutical composition containing dabigatran etexilate as defined in claim 10, wherein a method for preparing the solid granule is wet granulation, rolling granulation, fluidized bed granulation or hot melting granulation; or a method for preparing the solid granule is hot melting granulation; or a solvent adopted in the wet granulation is isopropanol.

12. A method for preparing the pharmaceutical composition as defined in claim 1, wherein when the pharmaceutical composition does not contain a neutral core and exists in a form of powder, the method for preparing the powder comprises the following steps: dissolving all components of the pharmaceutical composition in an ethanol aqueous solution, and carrying out spray-drying; when the pharmaceutical composition does not contain a neutral core and exists in a form of a granule, the method for preparing the granule comprises the following steps: with isopropanol as a granulation solvent, carrying out wet granulation on a mixture of all components of the pharmaceutical composition to obtain wet granule; and then carrying out drying after the wet granule is sieved by a 20-mesh sieve; when the pharmaceutical composition contains a neutral core and exists in a form of a neutral-core pellet, the method for preparing the neutral-core pellet comprises the following steps: spraying a coating solution to the neutral core, wherein the coating solution is formed by dissolving other components in the pharmaceutical composition except the neutral core into an organic solvent, the neutral core is pre-dried neutral core; when the pharmaceutical composition contains an acid core and exists in a form of an acid-core pellet, the method for preparing the acid-core pellet comprises the following steps: (1) spraying a coating solution to the acid core to obtain an acid granule, wherein the coating solution is formed by dissolving all components of an isolation layer in an organic solvent; and (2) spraying a coating solution to the acid granule, wherein the coating solution is formed by dissolving all components of a drug layer in an organic solvent; in step (1), the acid core is pre-dried acid core.

13. The pharmaceutical composition containing dabigatran etexilate as defined in claim 2, wherein, the mass of the active pharmaceutical ingredient in the pharmaceutical composition is 39.1 to 173 mg; or, the mass ratio of the active pharmaceutical ingredient to the amphiphilic polymer is 1:0.24, 1:0.25, 1:0.33, 1:0.77, 1:1, 1:1.2, 1:1.5, 1:1.6, 1:2, or 1:2.3.

14. 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; the mass percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 10 wt % to 55 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 %.

15. The pharmaceutical composition containing dabigatran etexilate as defined in claim 3, wherein, when the pharmaceutical composition comprises a disintegrating agent, then 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 5 wt % excluding 0 wt %; or, when the pharmaceutical composition comprises an antistatic agent, then 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 % excluding 0 wt %; or, when the pharmaceutical composition comprises a lubricant, then 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 % excluding 0 wt %; or, when the pharmaceutical composition further comprises a diluent, then the diluent is mannitol or lactose monohydrate; or a mass percentage of the diluent in the pharmaceutical composition is 0 wt % to 40 wt % excluding 0 wt %.

16. The pharmaceutical composition containing dabigatran etexilate as defined in claim 7, wherein, when the pharmaceutical composition exists in the form of powder, then a mass fraction of ethanol in the ethanol aqueous solution is 90% to 95%; or, in the powder, the active pharmaceutical ingredient existing in a molecular dispersion form or an amorphous form accounts for 15 wt % to 100 wt % of total mass of the active pharmaceutical ingredient; or, when the pharmaceutical composition exists in the form of the neutral-core pellet, then in the neutral-core pellet, the active pharmaceutical ingredient existing in a molecular dispersion form or an amorphous form accounts for 15 wt % to 100 wt % of total mass of the active pharmaceutical ingredient; or, the neutral core is microcrystalline cellulose core or sugar spheres; or, when the pharmaceutical composition exists in the form of the neutral-core pellet, then the neutral-core pellet comprises the components of following mass fraction: 12% to 30% of the active pharmaceutical ingredient, 6% to 24% of the amphiphilic polymer, 15% to 42% of the hydrophilic polymer and 33% to 50% of the neutral cores; or, the neutral-core pellet comprises the components of following mass fraction: 12% to 30% of dabigatran etexilate mesylate, 6% to 24% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 15% to 42% of polyoxyethylene-polyoxypropylene glycol block copolymer P407 and 33% to 50% of sugar spheres; or, the neutral-core pellet comprises the components of following mass fraction: 13.3% to 24% of the active pharmaceutical ingredient, 3.33% to 28.27% of the amphiphilic polymer, 16.7% to 36% of the hydrophilic polymer and 40% to 66.7% of the neutral core; or, the neutral-core pellet comprises the components of following mass fraction: 13.3% to 24% of dabigatran etexilate mesylate, 3.33% to 28.27% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 16.7% to 36% of polyoxyethylene-polyoxypropylene glycol block copolymer P407 and 40% to 66.7% of sugar spheres; or, when the pharmaceutical composition exists in the form of the neutral-core pellet, then the pharmaceutical composition is composed of the components of following mass fraction: 18% of dabigatran etexilate mesylate, 6% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 36% of polyoxyethylene-polyoxypropylene glycol block copolymer P407 and 40% of sugar spheres; or the pharmaceutical composition is composed of the components of following mass fraction: 24% of dabigatran etexilate mesylate, 6% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 30% of polyoxyethylene-polyoxypropylene glycol block copolymer P407 and 40% of sugar spheres; or, the pharmaceutical composition is composed of the components of following mass fraction: 13.3% of dabigatran etexilate mesylate, 3.33% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 16.7% of polyoxyethylene-polyoxypropylene glycol block copolymer P407 and 66.7% of sugar spheres; or, when the pharmaceutical composition exists in the form of the neutral-core pellet, then in a method for preparing the neutral-core pellet comprises following steps, a mass fraction of ethanol in the ethanol aqueous solution is 90% to 95%; or, when the pharmaceutical composition exists in the form of an acid-core pellet, then the acid core is tartaric acid core; or, a mass percentage of the acid core in the acid-core pellet is 17% to 36%; or, when the pharmaceutical composition exists in the form of an acid-core pellet, then a mass percentage of the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer of the isolation layer in the acid-core pellet is 9% to 13%; a mass percentage of polyoxyethylene-polyoxypropylene glycol block copolymer P407 in the isolation layers in the acid-core pellet is 4% to 6%; or, when the pharmaceutical composition exists in the form of an acid-core pellet, then the drug layer comprises the active pharmaceutical ingredient, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyoxyethylene-polyoxypropylene glycol block copolymer P407, a mass percentage of the active pharmaceutical ingredient in the drug layer in the acid-core pellet is 14% to 19%, a mass percentage of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in the drug layer in the acid-core pellet is 12% to 17%, and a mass percentage of polyoxyethylene-polyoxypropylene glycol block copolymer P407 in the drug layer in the acid-core pellet is 22% to 29%; or, when the pharmaceutical composition exists in the form of an acid-core pellet, then the mass percentage of the acid core in the acid-core pellet is 17% to 36%; the mass percentage of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in the isolation layer in the acid-core pellet is 9% to 13%, and the mass percentage of polyoxyethylene-polyoxypropylene glycol block copolymer P407 in the isolation layer in the acid-core pellet is 4% to 6%; the drug layer comprises the active pharmaceutical ingredient, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyoxyethylene-polyoxypropylene glycol block copolymer P407, the mass percentage of the active pharmaceutical ingredient in the drug layer in the acid-core pellet is 14% to 19%, the mass percentage of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in the drug layer in the acid-core pellet is 12% to 17%, and the mass percentage of polyoxyethylene-polyoxypropylene glycol block copolymer P407 in the drug layer in the acid-core pellet is 22% to 29%; or, when the pharmaceutical composition exists in the form of an acid-core pellet, then the mass percentage of the acid core in the acid-core pellet is 35.7%; the mass percentage of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in the isolation layer in the acid-core pellet is 9.6%, and the mass percentage of polyoxyethylene-polyoxypropylene glycol block copolymer P407 in the isolation layer in the acid-core pellet is 4.7%; the drug layer comprises the active pharmaceutical ingredient, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyoxyethylene-polyoxypropylene glycol block copolymer P407, the mass percentage of the active pharmaceutical ingredient in the drug layer in the acid-core pellet is 14.4%, the mass percentage of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in the drug layer in the acid-core pellet is 12.9%, and the mass percentage of polyoxyethylene-polyoxypropylene glycol block copolymer P407 in the drug layer in the acid-core pellet is 22.6%; or, when the pharmaceutical composition exists in the form of granules, and the method for preparing the granules is wet granulation, then the a solvent adopted in the wet granulation is isopropanol; or when the pharmaceutical composition exists in the form of granules, a method for preparing the granules is hot melting granulation.

17. The pharmaceutical composition containing dabigatran etexilate as defined in claim 10, wherein, the solid granule comprises the components of following mass fraction: 40% to 50% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 0% to 55% of lactose, 5% to 20% of croscarmellose sodium, 0% to 5% of silica and 0% to 2% of magnesium stearate; or, the solid granule comprises the components of following mass fraction: 40% to 50% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 0% to 55% of polyoxyethylene-polyoxypropylene glycol block copolymer P407, 5% to 20% of croscarmellose sodium, 0% to 5% of silica and 0% to 2% of magnesium stearate; or, the solid granule comprises the components of following mass fraction: 41% to 58% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 3% to 33% of mannitol, 13% to 26% of polyoxyethylene-polyoxypropylene glycol block copolymer P407, 5% to 20% of croscarmellose sodium, 0% to 5% of silica and 0% to 2% of magnesium stearate; or, the solid granule is composed of the components of following mass fraction: 41.88% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 51.87% of lactose monohydrate, 5.25% of croscarmellose sodium, 0.5% of magnesium stearate and 0.5% of silica; or, the solid granule is composed of the components of following mass fraction: 41.88% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 51.87% of polyoxyethylene-polyoxypropylene glycol block copolymer P407, 5.25% of croscarmellose sodium, 0.5% of magnesium stearate and 0.5% of silica; or, the solid granule is composed of the components of following mass fraction: 49.5% of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 24.7% of mannitol, 19.8% of polyoxyethylene-polyoxypropylene glycol block copolymer P407, 5.0% of croscarmellose sodium, 0.5% of magnesium stearate and 0.5% of silica; or, a mass percentage of mass of the solid granule in total mass of the pharmaceutical composition is 9% to 35%.

18. The method for preparing the pharmaceutical composition as defined in claim 12, wherein, when the pharmaceutical composition does not contain a neutral core and exists in a form of powder, a mass fraction of ethanol in the ethanol aqueous solution is 90% to 95%; when the pharmaceutical composition contains a neutral core and exists in a form of a neutral-core pellet, moisture content of the pre-dried neutral cores is lower than 1.0 wt %; or, the organic solvent is an ethanol solution; or, a mass fraction of ethanol in the ethanol aqueous solution is 90% to 95%; or, a mass percentage of the pharmaceutical composition in the coating solution is 20% to 24%; or, in the spraying process, an inlet temperature of air is 45 to 60° C.; or, in the spraying process, a temperature of the granule is 30 to 50° C.; and after spraying is finished, the granule is dried till moisture content is lower than 1.0 wt %; when the pharmaceutical composition contains an acid core and exists in a form of an acid-core pellet, in step (1), moisture content of the pre-dried acid core is lower than 1.0 wt %; or, in step (1), the organic solvent is an ethanol aqueous solution; or, a mass fraction of ethanol in the ethanol aqueous solution is 90% to 95%; or, in step (1), a mass percentage of the pharmaceutical composition in the coating solution is 20% to 26%; or, in step (1), in the spraying process, an inlet temperature of air is 45 to 60° C.; or, in step (1), in the spraying process, a temperature of the acid granules is 30 to 32° C.; or, in step (1), after spraying is finished, the acid granule is dried till moisture content is lower than 1.0 wt %; or, in step (2), the organic solvent is an ethanol solution; or, a mass fraction of ethanol in the ethanol aqueous solution is 90% to 95%; or, in step (2), a mass percentage of the pharmaceutical composition in the coating solution is 20% to 24%; or, in step (2), in the spraying process, an inlet temperature of air is 45 to 60° C.; or, in step (2), in the spraying process, a temperature of the acid-core pellets is 30 to 32° C.; or, in step (2), after spraying is finished, the acid-core pellet is dried till moisture content is lower than 1.0 wt %.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows a curve graph of solubility of APIs in a pharmaceutical composition with a polymer being Soluplus® and a pharmaceutical composition of a control group in Example 1 changing over time in a pH 6.8 and 25° C. phosphate buffer solution.

(2) FIG. 2 shows a curve graph of solubility of APIs in pharmaceutical compositions with polymers being Eudragit® L100 and Kolliphor® P407 and the pharmaceutical composition of the control group in Example 1 changing over time in the pH 6.8 and 25° C. phosphate buffer solution.

(3) FIG. 3 shows a curve graph of solubility of APIs in pharmaceutical compositions with other polymers and the pharmaceutical composition of the control group in Example 1 changing over time in the pH 6.8 and 25° C. phosphate buffer solution.

(4) FIG. 4 shows solubility of APIs in all SDFs and a control group in Example 2 at the 60.sup.th minute in a pH 6.8 and 37° C. phosphate buffer solution.

(5) FIG. 5 shows a dissolution profile graph of APIs in all SDFs and control groups in Example 3 changing over time in a pH 4.5 and 37° C. acetate buffer solution.

(6) FIG. 6 shows a dissolution profile graph of the APIs in all the SDFs and the control groups in Example 3 changing over time in a pH 6.8 and 37° C. phosphate buffer solution.

(7) FIG. 7 shows a dissolution profile graph of APIs in all pharmaceutical compositions in Example 4 changing over time in a 37° C. pH 4.5 acetate buffer solution.fwdarw.pH 6.8 phosphate buffer solution two-stage dissolution experiment.

(8) FIG. 8 shows a dissolution profile graph of the APIs in all the pharmaceutical compositions in Example 4 changing over time in the 37° C. pH 4.5 acetate buffer solution.fwdarw.pH 6.8 phosphate buffer solution two-stage dissolution experiment.

(9) FIG. 9 shows a dissolution profiles graph of the APIs in all the pharmaceutical compositions in Example 4 changing over time in the 37° C. pH 4.5 acetate buffer solution.fwdarw.pH 6.8 phosphate buffer solution two-stage dissolution experiment.

(10) FIG. 10 denotes dissolution profile of pellets (F1) in Example 5 in solutions containing amphiphilic polymer of different concentrations, wherein an error bar represents a standard deviation of n=3.

(11) FIG. 11 denotes dissolution profiles of the pellets (F1) in Example 5, pellet+Soluplus® powder in Example 5 (namely pellets in Example 6) and Pradaxa Pellets, wherein the Pradaxa Pellets are capsule contents of Pradaxa Capsules, the Chinese trade name of the Pradaxa Capsules is Pradaxa, the strength is 150 mg, a manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(12) FIG. 12 denotes dissolution profiles of capsules (F2-A, F2-B and F2+Soluplus® powder) in Example 7 and the pellets in Example 6, wherein an error bar represents a standard deviation of n=3.

(13) FIG. 13 denotes dissolution profiles of capsules (F3) in Example 8, capsules (F2-A) in Example 7 and the Pradaxa Capsules in a pH 1.2.fwdarw.pH 6.8 two-stage dissolution experiment, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the strength is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(14) FIG. 14 denotes dissolution profiles of the capsules (F3) in Example 8, the capsules (F2-A) in Example 7 and the Pradaxa Capsules in a pH 2.0.fwdarw.pH 6.8 two-stage dissolution experiment, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the strength is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(15) FIG. 15 denotes dissolution profiles of the capsules (F3) in Example 8, the capsules (F2-A) in Example 7 and the Pradaxa Capsules in a pH 3.0.fwdarw.pH 6.8 two-stage dissolution experiment, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the specification is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(16) FIG. 16 denotes dissolution profiles of capsules (F4 and F5) in Example 8 and the Pradaxa Capsules in a pH 2.0.fwdarw.pH 6.8 two-stage dissolution experiment, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the specification is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(17) FIG. 17 denotes dissolution profiles of capsules (F10 and F11) respectively containing two disintegrating agents in a pH 2.0 hydrochloric acid solution in Example 10, wherein an error bar represents a standard deviation of n=3.

(18) FIG. 18 denotes dissolution profiles of pellets (F6) in Example 11, a solution or suspension (F6 solution) obtained after dispersion of the pellets (F6) and the Pradaxa Capsules in a pH 2.0.fwdarw.pH 6.8 two-stage dissolution experiment, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the strength is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(19) FIG. 19 denotes dissolution profiles of the pellets (F6) in Example 11, the solution or suspension (F6 solution) obtained after dispersion of the pellets (F6) and the Pradaxa Capsules in a pH 6.0.fwdarw.pH 6.8 two-stage dissolution experiment, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the strength is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(20) FIG. 20 denotes dissolution profiles of acid-core pellets (F7) in Example 12 and the Pradaxa Capsules in a pH 2.0.fwdarw.pH 6.8 two-stage dissolution experiment, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the strength is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(21) FIG. 21 denotes dissolution profiles of the acid-core pellets (F7) in Example 12 and the Pradaxa Capsules in a pH 6.0.fwdarw.pH 6.8 two-stage dissolution experiment, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the strength is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

(22) FIG. 22 denotes dissolution profiles of capsules (F8 and F9) and the Pradaxa Capsules in a pH 2.0.fwdarw.pH 6.8 two-stage dissolution experiment in Example 13 and Comparative Example 1, wherein the Chinese trade name of the Pradaxa Capsules is Pradaxa, the strength is 150 mg, the manufacturer is Boehringer Ingelheim GmbH, and an error bar represents a standard deviation of n=3.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(23) The present disclosure is further illustrated below through examples, but the present disclosure is not thus limited within the scope of the examples. Experiment methods in which specific conditions are not indicated in the following examples are in accordance with conventional methods and conditions, or selected according to product instructions.

(24) In the following examples, a manufacturer of Eudragit® L100 is Evonik Special Chemistry (Shanghai) Co., Ltd; a manufacturer of Klucel™ EF is Ashland; a manufacturer of Kollicoat® IR is BASF; a manufacturer of Kollidon® VA64 is BASF; a manufacturer of Kolliphor® P188 is BASF; a manufacturer of Kolliphor® P407 is BASF; a manufacturer of HPMC E5 is DOW; a manufacturer of HPMC VLV is DOW; a manufacturer of HPMCP® HP55 is Samsung Precision Chemistry Company of the South Korea; a manufacturer of HPMCAS MG is Shin/Etsu; a manufacturer of PVP K12 is Ashland; a manufacturer of PVP K30 is Ashland; a manufacturer of Soluplus® is BASF; a manufacturer of croscarmellose sodium is FMC; and a manufacturer of low-substituted hydroxypropyl cellulose is Shin/Etsu.

(25) In the following examples, in dissolution measuring experiments, an adopted pH 1.2 solution is a 0.085 N hydrochloric acid solution; an adopted pH 2.0 solution is a 0.01 N hydrochloric acid solution; an adopted pH 3.0 solution is a 0.001 N hydrochloric acid solution; an adopted pH 6.0 solution is a 0.000001 N hydrochloric acid solution; an adopted pH 4.5 solution is a 50 mM sodium acetate buffer solution; an adopted pH 6.8 solution is a 50 mM sodium phosphate buffer solution; and an adopted alkaline solution is a sodium hydroxide and sodium phosphate mixed solution.

Example 1

(26) A screening experiment is performed in Example 1, the screening experiment aims to find polymers which may inhibit DEM precipitation under neutral pH, and the followings are polymers to be used for the screening experiment:

(27) Eudragit® L100, Klucel™ EF, Kollicoat® IR, Kollidon® VA64, Kolliphor® P188, Kolliphor® P407, HPMC E5, HPMC VLV, HPMCP® HP55, HPMCAS MG, PVP K12, PVP K30 and Soluplus®.

(28) The screening experiment includes the following steps.

(29) 1. A DEM stock solution is prepared with the drug concentration of 50 mg/mL in 0.1 N HCL.

(30) 2. 40 mg of the above polymer is placed in a 5 mL vial, and 3.6 mL of the pH 6.8 sodium phosphate buffer solution is added to dissolve the polymer to obtain a polymer solution.

(31) 3. 0.4 mL of the stock solution of step 1 is added into the polymer solution of step 2, and simultaneously 0.4 mL of the stock solution is added into a pH 6.8 phosphate buffer solution without polymers to serve as a control group.

(32) 4. The vial is shaken at 250 rpm under a room-temperature environment condition.

(33) 5. 0.4 mL of equivalent sample is taken at each time point of the 10.sup.th minute, the 20.sup.th minute, the 30.sup.th minute, the 45.sup.th minute, the 60.sup.th minute and the 120.sup.th minute.

(34) 6. The aliquots are centrifuged at 12,000 rpm for 5 minutes to obtain a supernatent.

(35) 7. The supernatent is diluted by 20 folds with a methanol and water mixed solution (the volume ratio of methanol to water is 1:1).

(36) 8. The DEM solution of step 7 is analyzed through HPLC.

(37) Screening results are listed in Table 1, and the results are drawn in FIG. 1, FIG. 2 and FIG. 3. As can be seen from Table 1, FIG. 1, FIG. 2 and FIG. 3, as for the effect of inhibiting DEM precipitation under neutral pH 6.8, the Soluplus® is the optimal of all the screened polymers.

(38) It should be further stated here that assuming that DEM is completely dissolved in the pH 6.8 phosphate buffer solution containing the polymers, the theoretical concentration of the DEM in the obtained DEM solution is about 5 mg/mL. It can thus be seen that after the DEM and the Soluplus® are matched, the DEM may be proximate to a complete dissolving state.

(39) TABLE-US-00001 TABLE 1 Solubility of APIs in Example 1 Changing over Time Time (min) / 10 15 30 45 60 120 Solubility 1 Eudragit L100 353.56 338.07 330.5 327.35 337.25 400.65 (μg/mL) 2 Klucel EF 51.07 65.74 78.24 55.59 54.55 46.73 3 Kollicoat IR 60.45 53.3 77.02 67.12 92.58 53.63 4 Kollidon VA64 72.59 69.64 67.76 66.81 67.53 65.94 5 Kolliphor P188 58.97 57.81 57.56 51.56 48.4 12.4 6 Kolliphor P407 374.01 323.44 9.52 6.75 7.44 6.81 7 HPMC E5 52.04 47.85 54.66 49.88 48.32 47.73 8 HPMC VLV 50.65 51.66 63.09 58.15 49.5 47.76 9 HPMCP HP55 28.86 28.25 30.87 33.74 34.21 39.15 10 HPMCAS MG 34.61 53.4 46.54 49.35 39.3 31.88 11 PVP K12 49.53 48.49 47.91 44.99 44.86 44.6 12 PVP K30 51.47 50.31 49.88 49.86 50.37 49.77 13 Soluplus ® 4448.9 3980.25 3992.25 4099.17 4186.57 4005.52 Control Control 40.9 42.52 40.9 41.46 39.56 4.15 Group Group

Example 2

(40) A mini-dissolution experiment is performed in Example 2, the mini-dissolution experiment aims to evaluate dissolution behaviors of DEM solid dispersion films (SDF), the table below shows the composition of the SDFs to be evaluated in the mini-dissolution experiment, and all percentages are mass percentages.

(41) TABLE-US-00002 Number BN- BN- BN- BN- BN- BN- BN- BN- BN- BN- 009057-E 009057-K 009058-A 009057-I 009057-G 009058-C 009079-K 009079-J 009058-E 009079-I DEM 20% 20% 20% 20% 20% 20% 20% 20% 100% 100% (film) (powder) Soluplus ® 40% 40% 40% 40% 40% 80% / / / / PVP K12 40% / / / / / 80% / / / Kolliphor / 40% / / / / / / / / P188 HPMC / / 40% / / / / / / / VLV Klucel EF / / / 40% / / / / / / HPMC E5 / / / / 40% / / / / / Eudragit / / / / / / / 80% / / L100

(42) In the example, a DEM SDF containing 3 mg of DEM is prepared in a 20 mL glass vials through a solvent evaporation method, then a dissolution medium is added, a dissolution experiment is performed at 37° C., and specific experiment steps are as follows:

(43) 1. ADEM stock solution with the drug concentration of 100 mg/mL is prepared in an ethanol solution with the volume fraction being 95%.

(44) 2. A polymer stock solution with the polymer concentration of 100 mg/mL is prepared in an ethanol solution with the volume fraction being 95%.

(45) 3. The stock solutions of step 1 and step 2 are added into 20 mL vials according to volumes shown in the following table, and full mixing is performed to obtain mixed solutions.

(46) Wherein, BN-009058-E is a mixed solution obtained by adding the solution of step 1 into an ethanol solution with the volume fraction being 95% and fully mixing them, and BN-009079-J is not treated in this-step.

(47) TABLE-US-00003 Number BN- BN- BN- BN- BN- BN- BN- BN- BN- BN- BN- 009057-E 009057-K 009058-A 009057-I 009057-G 009058-C 009079-K 009079-J 009055-A 009058-E 009079-I DEM 200 μL 200 μL 200 μL 200 μL 200 μL 200 μL 200 μL 200 μL 200 μL 200 μL 3 mg Soluplus ® 400 μL 400 μL 400 μL 400 μL 400 μL 800 μL / / 400 μL / / PVP K12 400 μL / / / / / 800 μL / / / / Kolliphor / 400 μL / / / / / / / / / P188 HPMC / / 400 μL / / / / / / / / VLV Klucel EF / / / 400 μL / / / / / / / HPMC E5 / / / / 400 μL / / / / / / Kollidon / / / / / / / / 400 μL / / VA64 Eudragit / / / / / / / 800 μL / / / L100 95%EtOH / / / / / / / / / 800 μL /

(48) 4. 150 μL of each mixed solution or 3 mg of DEM powder is added into a 20 mL vial.

(49) 5. The mixed solutions and the 3 mg of DEM powder are dried for 30 minutes under environment conditions (flue), and then drying is performed in a vacuum drying box (drying conditions: 50° C., 10 mbar, 30 minutes) to ensure that films are rapidly and completely dried, so that the SDFs with the numbers in the above table are obtained.

(50) 6. 18 mL of the pH 6.8 sodium phosphate buffer solution is added into the vials of step 5, including the vial which only contains the DEM powder.

(51) 7. The vials are shaken at 200 rpm at 37° C.

(52) 8. Samples are taken at the 60.sup.th minute.

(53) 9. The samples of step 8 are centrifuged at 12,000 rpm for 5 minutes to obtain a supernatent.

(54) 10. The supernatent is diluted by 20 times with a methanol and water mixed solution (the volume ratio of methanol to water is 1:1).

(55) 11. The DEM solution of step 10 is analyzed through HPLC.

(56) Screening results are listed in Table 2, and the results are drawn in FIG. 4. As can be seen from Table 2 and FIG. 4, combinations of Soluplus®/PVP K12 and Soluplus®/Kolliphor® P188 show the best results at the aspect of promoting dissolution under a neutral pH condition.

(57) It should be further stated here that assuming that the DEM is completely dissolved in the pH 6.8 phosphate buffer solution containing the polymers, the theoretical concentration of the DEM in the obtained DEM solution is about 150 μg/mL.

(58) TABLE-US-00004 TABLE 2 Solubility of APIs in All SDFs and Control Group at 60.sup.th Minute in Example 2 Number Solubility (g/mL) BN-009057-E (Soluplus ®:PVP K12 = 1:1) 19.954 BN-009057-K (Soluplus ®:Kolliphor P188 = 1:1) 18.344 BN-009058-A (Soluplus ®:HPMC VLV = 1:1) 9.128 BN-009060-A (Soluplus ®:Kollidon VA64 = 1:1) 8.93 BN-009057-I (Soluplus ®:Klucel EF = 1:1) 6.912 BN-009057-G (Soluplus ®:HPMC E5 = 1:1) 6.882 BN-009079-K (PVP K12) 6.605 BN-009058-C (Soluplus ®) 3.318 BN-009058-E (DEM Film control) 2.473 BN-009079-I (DEM Powder control) 2.442 BN-009079-J (Eudragit L100) 1.243

Example 3

(59) A mini-dissolution experiment is performed in Example 3, the mini-dissolution experiment aims to evaluate dissolution behaviors of DEM SDFs in the pH 4.5 sodium acetate buffer solution and the pH 6.8 sodium phosphate buffer solution, and specific experiment steps are the same as Example 2 and are as follows:

(60) 1. ADEM stock solution with the drug concentration of 100 mg/mL is prepared in a 95% ethanol solution.

(61) 2. A polymer stock solution with the polymer concentration of 100 mg/mL is prepared in a 95% ethanol solution.

(62) 3. The stock solutions of step 1 and step 2 are added into 20 mL vials according to volumes shown in the following table, and full mixing is performed to obtain mixed solutions.

(63) Wherein, DEM F is a mixed solution obtained by adding the solution of step 1 into an ethanol solution with the volume fraction being 95% and fully mixing them, DEM P is not treated in this step, and DEM F and DEM P are control groups.

(64) TABLE-US-00005 Number D/S D/K12 D/P407 D/S/K12 D/S/P407 DEM DEM (2:8) (2:8) (2:8) (2:4:4) (2:4:4) F P DEM 200 μL 200 μL 200 μL 200 μL 200 μL 200 μL 3 mg Soluplus ® 800 μL / / 400 μL 400 μL / / PVP K12 / 800 μL / 400 μL / / / Kolliphor / / 800 μL / 400 μL / / P407 95%EtOH / / / / / 800 μL /

(65) 4. 150 μL of each mixed solution or 3 mg of DEM powder is added into a 20 mL vial.

(66) 5. The mixed solutions and the 3 mg of DEM powder are dried for 30 minutes under environment conditions (flue), and then drying is performed in a vacuum drying cabinet (drying conditions: 50° C., 10 mbar, 30 minutes) to ensure that films are rapidly and completely dried, so that the SDFs with the numbers in the above table are obtained, wherein two films are prepared from each composition.

(67) 6. 18 mL of the pH 4.5 acetate buffer solution is added into one film of step 5, including the vial which only contains the DEM powder, and

(68) 18 mL of the pH 6.8 phosphate buffer solution is added into the other film of step 5, including the vial which only contains the DEM powder.

(69) 7. The vials are shaken at 200 rpm at 37° C.

(70) 8. Samples are taken at the 10.sup.th minute, the 20.sup.th minute, the 30.sup.th minute, the 45.sup.th minute, the 60.sup.th minute and the 120.sup.th minute.

(71) 9. The samples of step 8 are centrifuged at 12,000 rpm for 5 minutes to obtain a supernatent.

(72) 10. The supernatent is diluted by 20 times with a methanol and water mixed solution (the volume ratio of methanol to water is 1:1).

(73) 11. The DEM solution of step 10 is analyzed through HPLC.

(74) Screening results are listed in Table 3 and Table 4, and the results are drawn in FIG. 5 and FIG. 6. As can be seen from Table 3, Table 4, FIG. 5 and FIG. 6, the SDFs of D/K12 (2:8) and D/S/P407 (2:4:4) show rapid dissolution under pH 4.5, and the SDFs of D/S/K12 (2:4:4), D/P407 (2:8) and D/S/P407 (2:4:4) show relatively good dissolution under pH 6.8.

(75) It should be further stated here that assuming that the DEM is completely dissolved in the pH 6.8 phosphate buffer solution containing the polymers, the theoretical concentration of the DEM in the obtained DEM solution is about 150 μg/mL.

(76) TABLE-US-00006 TABLE 3 Solubility of APIs in All SDFs and Control Groups in Example 3 Changing over Time (μg/mL) D/S/ D/S/ Time DEM DEM D/S D/K12 D/P407 K12 P407 (min) P F (2:8) (2:8) (2:8) (2:4:4) (2:4:4) 0 0 0 0 0.00 0.00 0.00 0.00 10 31.46 70.16 43.86 139.40 66.02 58.73 121.19 20 37.81 100.66 47.90 135.81 85.07 79.30 138.69 30 42.20 115.10 60.67 136.42 93.00 91.54 141.55 45 49.05 126.52 69.41 136.49 103.44 104.69 145.90 60 53.10 133.33 77.50 136.15 110.42 115.80 148.44 120 53.44 144.65 100.29 135.25 117.14 128.32 148.20

(77) TABLE-US-00007 TABLE 4 Solubility of APIs in All SDFs and Control Groups in Example 3 Changing over Time (μg/mL) D/S/ D/S/ Time DEM DEM D/S D/K12 D/P407 K12 P407 (min) P F (2:8) (2:8) (2:8) (2:4:4) (2:4:4) 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 10 1.23 4.21 0.37 5.13 16.38 16.47 13.00 20 2.13 5.01 0.69 5.37 17.43 17.49 13.04 30 1.92 4.11 1.08 4.93 17.25 16.17 12.88 45 0.93 2.73 1.38 4.90 8.23 16.12 5.24 60 0.40 0.75 1.46 4.53 3.39 15.25 2.15 120 0.38 0.00 1.78 2.28 1.01 11.47 1.08

Example 4

(78) Example 4 aims to evaluate the influence of the amount of Soluplus® in and out of SDFs on solubility, especially the influence on drug precipitation in pH 6.8 neutral media.

(79) The SDFs are prepared by repeating the steps in Example 2 in Example 4, and the difference is that SDF dissolution tests are performed through a two-stage dissolution method, wherein the first stage is performed in the pH 4.5 solution, and the second stage is performed in the pH 6.8 solution.

(80) The following table shows compositions of the SDFs to be evaluated through the two-stage dissolution method.

(81) TABLE-US-00008 Mass of Components/mg Number D/S/K12 D/K12 + S D/S/K12 D/K12 + S D/K12 + S D/S/P407 D/S/P407 + S (2/4/4) (2/4 + 4) (2/2/6) (2/6 + 2) (2/6 + 4) (2/3/5) (2/1/5 + 2) Compositions DEM 3.0 3.0 3.0 3.0 3.0 3.0 3.0 of SDFs Soluplus ® 6.0 / 3.0 / / 4.5 1.5 PVP K12 6.0 6.0 9.0 9.0 9.0 / / Kolliphor P407 / / / / / 7.5 7.5 Soluplus ® out of SDFs / 6 / 3 6 / 3 Total 15 15 15 15 18 15 15

(82) Firstly, the SDFs with or without the Soluplus® out of the films are placed in 18 mL of the acetate buffer solution (pH 4.5 solution); at the 10.sup.th minute, 0.4 mL of aliquots are taken, and then 2 mL of the alkaline solution is added to regulate pH to the target pH 6.8 (6.5 to 7.0); 10 minutes after pH regulation, aliquots (0.4 mL) are taken again; and the DEM concentration in each aliquot is analyzed.

(83) Results are listed in Table 5, FIG. 7, FIG. 8 and FIG. 9, as can be seen from the results, dissolution is slowed down by the Soluplus® in the films, and therefore by replacing the Soluplus® in the films with the Soluplus® out of the films, not only is dissolution under acid pH (pH 4.5) accelerated, but also DEM separation under neutral pH (pH 6.8) is prevented.

(84) TABLE-US-00009 TABLE 5 Solubility of APIs in All Pharmaceutical Compositions in Example 4 Changing over Time (μg/mL) D/S/K12 D/K12 + S D/S/K12 D/K12 + S D/K12 + S D/S/P407 D/S/P407 + S Time (min) (2:4:4) (2:4 + 4) (2:2:6) (2:6 + 2) (2:6 + 4) (2:3:5) (2:1:5 + 2) 10 (pH 4.5) 66.23 134.59 101.19 143.42 134.11 130.02 141.52 20 (pH 6.8) 20.87 43.18 19.87 34.02 45.41 22.68 40.16

Example 5

(85) According to Table 6, pellets are prepared by spraying a solid dispersion composition to neutral cores, and the solid dispersion composition includes 30 wt % of DEM, 10 wt % of Soluplus®, and 60 wt % of Kolliphor® P407.

(86) A specific preparation method is as follows:

(87) Firstly, the solid dispersion composition is dissolved in 95 wt % ethanol to prepare a coating solution, wherein the coating solution contains 20 wt % of the solid dispersion composition; then, the neutral cores (300 to 500 μm) are pre-dried in an 80° C. convection oven until the moisture content of the neutral cores is lower than 1.0%; and afterwards, 300 g of the coating solution containing 60 g of the solid dispersion composition is sprayed to 40 g of the pre-dried neutral cores on a fluidized bed granulator with a Wurster insert under proper inlet air pressure and the 45 to 60° C. air inlet temperature, and in a spraying process, the spraying speed and atomization pressure are adjusted to enable the product temperature to be kept at 30 to 50° C. After the coating solution is used up, a product is dried in a fluidized bed until the moisture content is lower than 1.0%, and a target mass ratio of solid dispersion layers wrapping the neutral cores to the neutral cores is 1.5/1.0, so that the pellets in Example 5 are obtained.

(88) TABLE-US-00010 TABLE 6 Compositions of Pellets F1 / Action Components Wt/% Wt/mg Solid API DEM 18.0 173.0 dispersion Amphiphilic Polymer Soluplus ® 6.0 57.7 composition Hydrophilic Polymer Kolliphor P407 36.0 346.0 Neutral Cores Sugar Spheres 40.0 388.4

(89) By using a USP basket type two-step method, at 100 rpm and 37° C., dissolution profiles of the pellets containing 173.0 mg of the DEM (equivalent to 150 mg of DEM freebase) are measured. In the first stage, the pellets are placed in 500 mL of acid media (the pH 2.0 solution), wherein the acid media contain Soluplus® with different mass (0 mg, 75 mg, 150 mg and 300 mg); and in the second stage (45.sup.th minute), 500 mL of the alkaline solution is added into the acid media to regulate pH to 6.8. 3 mL of aliquots are taken at the time points of the 10.sup.th minute, the 45.sup.th minute, the 55.sup.th minute and the 90.sup.th minute. The aliquots are centrifuged at 12,000 rpm for 5 minutes, and a supernate is diluted by 10 folds with a 1/1-volume-ratio methanol/water mixed solution so as to be used for HPLC analysis.

(90) Results are shown in Table 7 and FIG. 10, and as can be seen from FIG. 10, by adding 75 mg or more Soluplus® powder outside the pellets, the situation that more DEM is precipitated under neutral pH (pH 6.8) may be prevented.

(91) TABLE-US-00011 TABLE 7 Dissolution of F1 in Media Containing Soluplus ® of Different Concentrations in Example 5 Changing over Time F1 + 300 mg F1 + 150 mg F1 + 75 mg Soluplus ® Soluplus ® Soluplus ® F1 Disso- Disso- Disso- Disso- lution SD lution SD lution SD lution SD Time % % % % % % % % (min) pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 10 97.90 1.95 94.74 4.65 98.23 0.76 98.59 3.42 45 98.05 2.15 98.22 0.58 97.68 1.22 97.76 1.05 55 48.88 3.89 45.15 0.06 40.22 3.87 21.51 16.67 90 40.28 7.11 42.05 1.94 36.90 9.20 15.90 6.37

Example 6

(92) Pellets F1 are prepared by repeating the steps in Example 5, and the difference from Example 5 is that externally-added Soluplus® in Example 6 is added in a form of powder.

(93) Firstly, Soluplus® granules are milled and screened by an 80-mesh sieve to obtain 150 mg of Soluplus® powder (less than 80 meshes); then, the Soluplus® powder and 0.5 wt % (based on the mass of the Soluplus® powder, 150 mg) of silica are mixed to obtain solid granules; and finally, the pellets F1 are mixed with the solid granules to obtain pellets in Example 6.

(94) The test method which is the same as that in Example 5 is adopted to measure dissolution profile of the pellets F1, the pellets in Example 6 and Pradaxa Pellets (contents of Pradaxa Capsules), and results are shown in Table 8 and FIG. 11.

(95) As can be seen from Table 8 and FIG. 11, compared with the Pradaxa Pellets, the pellets F1 may prevent DEM dissolved out from acid media from being precipitated under pH 6.8. However, the pellets containing the externally-added Soluplus® powder in Example 6 relieve dissolution of the DEM from the acid media.

(96) TABLE-US-00012 TABLE 8 Dissolution of preparations in Example 6 Changing over Time Pradaxa Pelltes F1 F1 + Soluplus ® (150 mg) (150 mg) (150 mg) Disso- Disso- Disso- lution/ SD lution/ SD lution/ SD Time % % % % % % (min) pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 98.66 0.84 98.59 3.42 79.39 2.44 45 98.85 1.13 97.76 1.05 95.45 3.61 55 6.26 0.55 21.51 16.67 34.34 5.00 90 4.39 0.08 15.90 6.37 33.78 5.35

Example 7

(97) Pellets F2 are prepared by adopting the preparation method in Example 5.

(98) Isopropyl alcohol (IPA) is used as a granulation solvent, and a mixture of all components of solid granules is subjected to wet granulation to obtain wet granules; and the wet granules are screened by a 20-mesh sieve and dried in a laminar flow hood under the ambient temperature to obtain solid granules.

(99) TABLE-US-00013 TABLE 9 Compositions of Capsules F2-A and F2-B in Example 7 Pellets F2 Action Components Wt % Wt/capsule, mg API DEM 24.0 57.7 Amphiphilic Polymer Soluplus ® 6.0 14.4 Hydrophilic Polymer Kolliphor P407 30.0 72.1 Neutral Cores Sugar Spheres 40.0 96.1 / Total 100.0 240.3 Solid Granules A B Wt/ Wt/ capsule, capsule, Action Components Wt % mg Wt % mg Amphiphilic Soluplus ® 41.88 75.0 41.88 75.0 Polymer Diluting Agent Lactose 51.87 92.9 / / Monohydrate Hydrophilic Kolliphor P407 / / 51.87 92.9 Polymer Disintegrating croscarmellose 5.25 9.4 5.25 9.4 Agent sodium Lubricant Magnesium 0.50 0.9 0.50 0.9 Stearate Antistatic Agent Silica 0.50 0.9 0.50 0.9 / Total 100.00 179.1 100.00 179.1

(100) According to Table 9, gelatin capsules (#0) are filled with the pellets (240.3 mg) and the solid granules (179.1 mg) to obtain capsules F2-A and F2-B.

(101) The test method which is the same as that in Example 5 is adopted to measure dissolution profile of the capsules F2-A and F72-B3, and results are shown in Table 10 and FIG. 12.

(102) As can be seen from Table 10 and FIG. 12, compared with F2+Soluplus® powder (containing 75.0 mg of Soluplus® powder), the pellet preparations (F2-A and F2-B3) containing the solid granules in Example 7 show faster dissolution in the acid media.

(103) TABLE-US-00014 TABLE 10 Dissolution of Preparations in Example 7 Changing over Time in Media containing Soluplus ® of Different Concentrations F2-A F2-B F2 + Soluplus ® (50 mg) (50 mg) Powder (50 mg) Disso- Disso- Disso- lution/ SD lution/ SD lution/ SD Time % % % % % % (min) pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 85.65 2.21 92.99 4.73 37.93 2.68 20 98.91 3.74 100.92 0.97 55.98 1.95 30 100.38 2.73 100.03 1.43 67.31 4.12 45 102.40 2.85 101.15 1.40 76.81 7.02 55 45.57 7.07 41.13 12.00 40.74 3.30 90 44.79 5.93 39.45 10.44 40.92 3.06

Example 8

(104) Granules F3 containing DEM are prepared by repeating the wet granulation steps in Example 7.

(105) TABLE-US-00015 Action Components Wt/% Wt/capsule, mg API DEM 17.0 57.7 Amphiphilic Polymer Soluplus ® 39.2 132.9 Diluting Agent Lactose Monohydrate 38.3 130.0 Disintegrating Agent croscarmellose sodium 5.0 17.0 Lubricant Magnesium Stearate 0.5 1.7 / Total 100.0 339.3

(106) According to the above table, gelatin capsules (#0) are filled with the granules (339.3 mg) containing the DEM.

(107) Test Method:

(108) Different from the test method in Example 5, considering change of pH values of stomachs, pH of the first stage is set as 1.2 or 2.0 or 3.0 (namely acid media adopted in the first stage are respectively: the pH 1.2 solution, the pH 2.0 solution and the pH 3.0 solution), and other aspects are the same as the test method in Example 5. By adopting the test method, dissolution profile of Pradaxa Capsules (150 mg), F2-A and F3 are measured, and results are shown in Table 11, FIG. 13, FIG. 14 and FIG. 15. As can be seen from the results, compared with the Pradaxa Capsules, the preparations (F2-A and F3) of the present disclosure show faster dissolution obviously under acid pH, and precipitations are fewer under neutral pH.

(109) TABLE-US-00016 TABLE 11 Dissolution of F3, F2-A and Pradaxa Capsules Changing over Time Pradaxa Capsules F3 F2-A (150 mg) (50 mg) (50 mg) Disso- Disso- Disso- Time lution/ lution/ lution/ (min) % SD % SD % SD pH 1.2 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 31.03 25.20 77.34 9.37 87.93 11.25 20 78.59 7.23 86.76 6.70 99.11 2.53 30 89.33 5.03 90.90 2.14 103.88 3.00 45 93.83 2.70 90.04 1.72 100.50 2.51 55 3.71 0.14 65.24 0.92 59.87 3.30 90 3.77 0.08 66.46 0.94 58.54 3.93 pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 16.43 25.26 88.78 4.86 85.65 2.21 45 94.90 5.03 92.32 1.69 102.40 2.85 55 5.37 1.20 55.58 2.30 45.57 7.07 90 4.38 0.79 54.76 2.02 44.79 5.93 pH 3.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 3.84 3.32 63.89 5.76 74.40 5.75 20 31.63 17.89 80.95 9.67 94.05 2.88 30 51.02 34.80 85.57 4.59 95.94 3.12 45 58.19 32.30 89.30 1.15 98.36 2.32 55 3.65 0.15 59.75 1.61 49.74 3.67 90 3.57 0.04 61.48 0.77 50.51 1.58

Example 9

(110) In the example, solid granules in capsules F4 and granules in capsules F5 are prepared through a hot melting granulation process.

(111) Table 12 Compositions of Solid Granules Obtained through Hot Melting Granulation Process in Capsules F4

(112) TABLE-US-00017 TABLE 12 Compositions of Solid Granules Obtained through Hot Melting Granulation Process in Capsules F4 Action Components Wt % Wt/capsule, mg Amphiphilic Polymer Soluplus ® Powder 49.5 75.00 Diluting Agent Mannitol 24.7 37.50 Hydrophilic Polymer Kolliphor P407 19.8 30.00 Disintegrating Agent Croscarmellose sodium 5.0 7.50 Lubricant Magnesium Stearate 0.5 0.75 Antistatic Agent Silica 0.5 0.75 / Total 100.0 151.50

(113) TABLE-US-00018 TABLE 13 Compositions of Granules Obtained through Hot Melting Granulation Process in Capsules F5 Action Compositions Wt % Wt/capsule, mg API DEM 16.9 57.7 Amphiphilic Polymer Soluplus ® Powder 38.8 132.5 Diluting Agent Mannitol 18.9 64.5 Hydrophilic Polymer Kolliphor P188 19.9 67.9 Disintegrating Agent croscarmellose sodium 5.0 17.1 Lubricant Magnesium Stearate 0.5 1.7 / Total 100.0 341.4

(114) The hot melting granulation process includes the following steps:

(115) Firstly, Soluplus® is milled and screened by a 120-mesh sieve to obtain the Soluplus® powder, and then the Soluplus® powder and the other components except the magnesium stearate are mixed in a glass beaker by a stainless steel spatula at 70 to 75′C according to mass percentages in Table 12 until uniform granules are formed; and afterwards, the granules and the magnesium stearate are mixed to obtain the solid granules in F4.

(116) Firstly, Soluplus® is milled and screened by a 120-mesh sieve to obtain the Soluplus® powder, and then the Soluplus® powder and the other components except the magnesium stearate are mixed in a glass beaker by a stainless steel spatula at 70 to 75′C according to mass percentages in Table 13 until uniform granules are formed; and afterwards, the granules and the magnesium stearate are mixed to obtain the granules in F5.

(117) The pellets F2 (240.3 mg) in Example 7 and the solid granules (151.5 mg) obtained according to a formula of Table 12 are placed into gelatin capsules (#0), and the obtained capsules are recorded as F4. The gelatin capsules (#0) are also filled with the granules (341.4 mg) obtained according to a formula of Table 13 to obtain the capsules F5.

(118) The test method which is the same as that in Example 5 is adopted to measure dissolution profile of the capsules F4 and F5, and results are shown in Table 14 and FIG. 16.

(119) As can be seen from Table 14 and FIG. 16, compared with Pradaxa Capsules, the preparations (F4 and F5) of the present disclosure show faster dissolution obviously under acid pH, and precipitations are fewer under neutral pH. The mass percentages of dissolved-out DEM of the Pradaxa Capsules, the F4 and the F5 in the pH 2.0 solution at the 10.sup.th minute are respectively 16.4%, 83.4% and 78.5%. The mass percentages of dissolved-out DEM of the Pradaxa Capsules, the F4 and the F5 in the pH 6.8 solution at the 10.sup.th minute are respectively 5.4%, 39.7% and 47.4%.

(120) TABLE-US-00019 TABLE 14 Dissolution of F4, F5 and Pradaxa Capsules in Example 9 Changing over Time Pradaxa Capsules F4 F5 (150 mg) (50 mg) (50 mg) Disso- Disso- Disso- lution/ SD lution/ SD lution/ SD Time % % % % % % (min) pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 16.43 25.26 83.36 15.22 78.50 12.36 45 94.90 5.03 97.21 1.18 97.42 0.64 55 5.37 1.20 39.73 0.65 47.35 0.96 90 4.38 0.79 37.49 0.28 45.99 0.66

Example 10

(121) A hot melting granulation process includes the following steps:

(122) Firstly, Soluplus® is milled and screened by a 120-mesh sieve to obtain the Soluplus® powder, and then the Soluplus® powder and other components except magnesium stearate and externally-added croscarmellose sodium are mixed in a glass beaker by a stainless steel spatula at 70 to 75° C. according to mass percentages in Table 15 until uniform granules are formed; afterwards, the granules, the magnesium stearate and the externally-added croscarmellose sodium are mixed to obtain granules in F10; and gelatin capsules (#0) are filled with the granules obtained according to a formula of Table 15 to obtain the capsules F10.

(123) Firstly, Soluplus® is milled and screened by a 120-mesh sieve to obtain the Soluplus® powder, and then the Soluplus® powder and other components except magnesium stearate and externally-added low-substituted hydroxypropyl cellulose are mixed in a glass beaker by a stainless steel spatula at 70 to 75° C. according to mass percentages in Table 16 until uniform granules are formed; afterwards, the granules, the magnesium stearate and the externally-added low-substituted hydroxypropyl cellulose are mixed to obtain granules in F11; and gelatin capsules (#0) are filled with the granules obtained according to a formula of Table 16 to obtain the capsules F11.

(124) TABLE-US-00020 TABLE 15 Compositions of Granules F10 Obtained through Hot Melting Granulation Process Mg/ Percentage Action Compositions granule % API DEM 173.4 43.35 Amphiphilic Polymer Soluplus ® Powder 40.0 10.00 Diluting Agent Mannitol 36.0 9.00 Hydrophilic Polymer Kolliphor P407 88.6 22.15 Disintegrating Agent Internally-added 20.0 5 croscarmellose sodium Disintegrating Agent Externally-added 40.0 10 croscarmellose sodium Lubricant Magnesium Stearate 2.0 0.5 / Total 400 100

(125) TABLE-US-00021 TABLE 16 Compositions of Granules F11 Obtained through Hot Melting Granulation Process Mg/ Percentage Action Compositions granule % API DEM 173.4 43.35 AmphiphilicPolymer Soluplus ® Powder 40.0 10.00 Diluting Agent Mannitol 36.0 9.00 Hydrophilic Polymer Kolliphor P407 88.6 22.15 Disintegrating Agent Internally-added 20.0 5 Low-substituted Hydroxypropyl Cellulose Disintegrating Agent Externally-added 40.0 10 Low-substituted Hydroxypropyl Cellulose Lubricant Magnesium Stearate 2.0 0.5 / Total 400 100

(126) F10 and F11 are placed into the pH 2.0 solution to measure dissolution profile, and results are shown in Table 17 and FIG. 17. As can be seen from Table 17 and FIG. 17, dissolution results of the two dosage forms F10 and F11 have no remarkable difference.

(127) TABLE-US-00022 TABLE 17 Dissolution of F10 and F11 in Example 10 Changing over Time F10 (150 mg) F11 (150 mg) Dissolution/% SD % Dissolution/% SD % Time (min) pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 10 87.07 5.48 81.48 5.53 45 98.05 6.12 94.65 4.47

Example 11

(128) According to Table 18, pellets are prepared by spraying a solid dispersion composition to neutral cores, and the solid dispersion composition is composed of following components in percentage by mass: 40 wt % of DEM, 10 wt % of Soluplus®, and 50 wt % of Kolliphor® P407.

(129) A specific preparation method is as follows:

(130) Preparation of the pellets: The solid dispersion composition is dissolved in a mixed solution of 90 wt % of ethanol and 10 wt % of deionized water to prepare a coating solution, wherein the coating solution contains 24 wt % of the solid dispersion composition. Then, the neutral cores (300 to 500 μm) are pre-dried in an 80° C. convection oven until the moisture content of the neutral cores is lower than 1.0%.

(131) Afterwards, 104.2 g of the coating solution containing 25 g of the solid dispersion composition is sprayed to 50 g of the pre-dried sugar spheres on a fluidized bed granulator with a Wurster insert under proper inlet air pressure and the 45 to 50° C. air inlet temperature, and in a spraying process, the spraying speed and atomization pressure are adjusted to enable the product temperature to be kept at 30 to 50° C. After the coating solution is used up, a product is dried in a fluidized bed until the moisture content is lower than 1.0%, and a target mass ratio of solid dispersion layers wrapping the neutral cores to the neutral cores is 0.5/1.0, so that drug granules are obtained.

(132) Preparation of Soluplus® powder: Firstly Soluplus® granules are milled and then screened by an 80-mesh sieve to obtain Soluplus® powder (less than 80 meshes). The drug granules (pellets) and the Soluplus® powder are mixed to obtain the pellets (formulations) in Example 11.

(133) TABLE-US-00023 TABLE 18 Compositions of Pellets F6 Wt/ Name Action Components Wt/% capsule, mg Drug Granule Composition Solid Dispersion API DEM 13.3 57.7 Composition Amphiphilic Soluplus ® 3.33 14.4 Polymer Hydrophilic Kolliphor P407 16.7 72.1 Polymer Neutral Cores / Sugar Spheres 66.7 288.5 / Total 100.0 432.7 Solid Granules Amphiphilic Soluplus ® 100.0 120.0 Polymer Powder

(134) Test Method:

(135) The difference from the test method in Example 5 is that pH of the first stage is set as 2.0 or 6.0 (namely acid media adopted in the first stage are respectively: the pH 2.0 solution and the pH 6.0 solution), and other aspects are the same as the test method in Example 5.

(136) By adopting the above test method, dissolution profile of the pellets F6 are measured. For comparison, the pellets F6 are pre-dissolved in 25 mL of deionized water to obtain an F6 solution, dissolution profile of the F6 solution are measured through the same method, and results are shown in Table 19, FIG. 18 and FIG. 19.

(137) As can be seen from the results, compared with Pradaxa Capsules, F6 shows faster dissolution under acid pH 2 and pH 6, and precipitations are fewer under neutral pH 6.8. F6 may prevent 60% or more of dissolved-out DEM in the acid media (pH 2.0 and pH 6.0) from being precipitated. At the room temperature, the F6 solution may promote dissolution of the DEM and the Soluplus®, and therefore, the better precipitation inhibition effect is generated under neutral pH (pH 6.8).

(138) TABLE-US-00024 TABLE 19 Dissolution of F6 and Pradaxa Capsules in Example 11 Changing over Time Pradaxa Capsules F6 F6 Solution (150 mg) (50 mg) (50 mg) Disso- Disso- Disso- Time lution/ lution/ lution/ (min) % SD % SD % SD pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 16.43 25.26 88.24 7.32 96.01 8.05 30 92.17 7.23 98.03 1.25 98.27 1.28 45 94.90 5.03 98.37 0.71 97.78 0.75 55 5.37 1.20 59.03 1.26 67.49 0.65 pH 6.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 8.47 9.05 51.31 12.08 85.70 1.09 30 63.63 12.18 77.19 10.91 86.85 2.17 45 72.60 13.09 85.38 6.91 86.05 2.57 55 4.94 0.11 61.30 5.28 69.33 2.20

Example 12

(139) A preparation method of acid-core pellets is as follows:

(140) According to Table 20, an isolation layer composition (the composition includes in percentage by mass: 67% of Soluplus® and 33% of Kolliphor® P407) is dissolved in a mixed solution of 95 wt % of ethanol and 5 wt % of deionized water to prepare a coating solution, wherein the coating solution contains 26% of the isolation layer composition by mass.

(141) Afterwards, tartaric acid cores (300 to 500 μm) are pre-dried in an 80° C. convection oven until the moisture content of the tartaric acid cores is lower than 1.00%.

(142) Then, the coating solution containing 20 g of the isolation layer composition is sprayed to 50 g of the pre-dried tartaric acid cores on a fluidized bed granulator with a Wurster insert under proper inlet air pressure and the 35° C. air inlet temperature, and in a spraying process, the spraying speed and atomization pressure are adjusted to enable the product temperature to be kept at 30 to 32° C. After the coating solution is used up, a product is dried in a fluidized bed until the moisture content is lower than 1.0% (if the moisture content is not lower than 1.0% after drying in the fluidized bed, a secondary drying process in the oven is necessary), and a target mass ratio of isolation layers to the tartaric acid cores is 0.4/1.0.

(143) A coating process of a drug layer composition is the same as that in Example 11. The drug layer composition is composed of following components in percentage by mass: 28.9 wt % of DEM, 25.9 wt % of Soluplus® and 45.3 wt % of Kolliphor® P407. A target mass ratio of drug layers to the tartaric acid cores wrapped with the isolation layers is 1.0/1.0.

(144) TABLE-US-00025 TABLE 20 Compositions of Acid-core Pellets F7 Wt/ Action Components Wt % capsule, mg Tartaric Acid Cores Acid Core Tartaric Acid 35.7 142.8 Isolation Layer Composition Amphiphilic Polymer Soluplus ® 9.6 38.3 Hydrophilic Polymer Kolliphor P407 4.7 18.9 Drug Layer Composition API DEM 14.4 57.7 Amphiphilic Polymer Soluplus ® 12.9 51.7 Hydrophilic Polymer Kolliphor P407 22.6 90.6 / Total 100.0 399.9

(145) Test Method:

(146) The difference from the test method in Example 5 is that pH of the first stage is set as 2.0 or 6.0 (namely acid media adopted in the first stage are respectively: the pH 2.0 solution and the pH 6.0 solution), and other aspects are the same as the test method in Example 5.

(147) Through the test method, dissolution profile of F7 are measured, and results are shown in Table 21, FIG. 20 and FIG. 21.

(148) As can be seen from the results, the DEM may be quickly dissolved out of F7, F7 may enhance a dissolution rate under acid environment (pH 6.0), and 40% to 47% of the DEM which has been dissolved out in acid environment (pH 2.0 and pH 6.0) will not precipitate under neutral pH (pH 6.8).

(149) TABLE-US-00026 TABLE 21 Dissolution of F7 and Pradaxa Capsules in Example 12 Changing over Time Pradaxa Capsules (150 mg) F7 (50 mg) Time (min) Dissolution/% SD Dissolution/% SD pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 10 16.43 25.26 82.65 11.24 30 92.17 7.23 97.69 1.32 45 94.90 5.03 98.29 1.13 55 5.37 1.20 40.28 3.31 pH 6.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 10 8.47 9.05 88.13 5.88 30 63.63 12.18 99.01 2.08 45 72.60 13.09 96.96 2.03 55 4.94 0.11 47.47 2.28

Example 13

(150) A hot melting granulation process includes the following steps:

(151) Firstly, Soluplus® is milled and screened by a 120-mesh sieve to obtain the Soluplus® powder, and then the Soluplus® powder and other components except magnesium stearate and externally-added croscarmellose sodium are mixed in a glass beaker by a stainless steel spatula at 70 to 75° C. according to mass percentages in Table 22 until uniform granules are formed. Afterwards, the above granules, the magnesium stearate and the externally-added croscarmellose sodium are mixed to obtain granules in F8. Gelatin capsules (#0) are filled with the granules obtained according to a formula of Table 22 to obtain capsules F8.

(152) TABLE-US-00027 TABLE 22 Compositions of Granules F8 Obtained through Hot Melting Granulation Process Number WD-033177-B Mg/ Percentage Action Compositions granule % API DEM 173.4 39.1 Amphiphilic Polymer Soluplus ® Powder 40.8 9.2 Diluting Agent Mannitol 40.8 9.2 Hydrophilic Polymer Kolliphor P188 85.0 19.2 Disintegrating Agent Internally-added 17.0 3.8 croscarmellose sodium Total 357 80.4 Lubricant Magnesium Stearate 1.8 0.4 Disintegrating Agent Externally-added 85.0 19.2 croscarmellose sodium Total 443.8 100.0

(153) The test method which is the same as that in Example 5 is adopted to measure dissolution profile of F8, and results are shown in Table 23 and FIG. 22.

(154) TABLE-US-00028 TABLE 23 Dissolution of F8 in Example 13 and F9 and Pradaxa Capsules in Comparative Example 1 Changing over Time Pradaxa Capsules F8 F9 (150 mg) (150 mg) (150 mg) Disso- Disso- Disso- lution/ lution/ lution/ Time % SD % SD % SD (min) pH 2.0 500 mL .fwdarw. pH 6.8 1000 mL 0 0.00 0.00 0.00 0.00 0.00 0.00 10 16.43 25.26 82.30 1.18 80.10 6.03 30 92.17 7.23 91.35 1.33 95.83 1.01 45 94.90 5.03 92.78 1.46 98.17 0.25 55 5.37 1.20 15.12 0.19 4.54 0.14

Example 14

(155) In the example, stability research is performed on two representative formulas (F4 and F5), namely the pellet formula and the hot melting granulation formula.

(156) F4 and F5 are packaged in HDPE bottles and then stored under the conditions that the temperature is 40° C. and the relative humidity is 75% for 6 months.

(157) The before-mentioned pH 2.0.fwdarw.pH 6.8 two-stage dissolution method is adopted to detect dissolution behaviors of samples. HPLC is adopted to detect the impurity content of the samples. A Karl-Fischer method is adopted to detect the moisture content.

(158) Results show that after the samples are stored under the conditions that the temperature is 40° C. and the relative humidity is 75% for 6 months, the dissolution behaviors and DEM content of the samples have no remarkable change, the impurity content is within a mass index limit range, and the moisture content meets requirements of mass indexes.

Comparative Example 1

(159) A hot melting granulation process includes the following steps:

(160) Other components except magnesium stearate and externally-added croscarmellose sodium are mixed in a glass beaker by a stainless steel spatula under 70 to 75° C. until uniform granules are formed. Then the above granules, the magnesium stearate and the externally-added croscarmellose sodium are mixed to obtain granules in F9. Gelatin capsules (#0) are filled with the granules obtained according to a formula of Table 24 to obtain capsules F9.

(161) TABLE-US-00029 TABLE 24 Compositions of Granules F9 Obtained through Hot Melting Granulation Process Number WD-033188-A Mg/ Percentage Action Compositions granule % API DEM 173.4 39.1 Amphiphilic Polymer Soluplus ® 0 0 Diluting Agent Mannitol 81.6 18.4 Hydrophilic Polymer Kolliphor P188 85.0 19.2 Disintegrating Agent Internally-added 17.0 3.8 croscarmellose sodium Total 357 80.4 Lubricant Magnesium stearate 1.8 0.4 Disintegrating Agent Externally-added 85.0 19.2 croscarmellose sodium Total 443.8 100.0

(162) The test method which is the same as that in Example 5 is adopted to measure dissolution profile of F9, and results are shown in FIG. 22.

(163) It can be seen from FIG. 22 that the precipitation condition of a formula (F9) containing no Soluplus® under pH 6.8 is close to that of existing commercially-available originally-researched products, and a formula (F8) with the Soluplus® added may remarkably improve the concentration of DEM under pH 6.8.