# US 10,864,204 B2 · Pharmaceutical composition and preparation method therefor

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- Number: US 10,864,204 B2
- Document ID: US10864204B2
- Status: Granted
- Kind: B2
- Application number: 16/156,983
- Filed: 2018-10-10
- Published: 2019-02-07
- Granted: 2020-12-15
- Earliest claimed: 2014-12-31
- Assignees: Shenzhen Pharmacin Co., Ltd.
- Applicants: Shenzhen Pharmacin Co., Ltd.
- Inventors: Zeren Wang; Yulan Zhao; Lijiang Wang; Xiao Zhang; Jun Xu; Shunqin Chen; Meili Sun; Guisheng Jiang
- Web page: https://patentgrep.com/patent/US10864204B2

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 9/4858: {Organic compounds}
- A61K 9/5015: {Organic compounds, e.g. fats, sugars}
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides an oral pharmaceutical composition and a usage thereof, comprising a pharmaceutically acceptable acidic medicinal auxiliary material whose surface is modified and dabigatran etexilate or pharmaceutically acceptable salts or aquo-complexes thereof. The present invention further provides a surface modification method for a medicinal auxiliary material.

## Claims

### Claim 1

An oral pharmaceutical composition, comprising:
(i) a first component, wherein the first component comprises dabigatran etexilate or a pharmaceutically acceptable salt or hydrate thereof; and
(ii) a second component, wherein the second component comprises:
(a) a pharmaceutically acceptable surface-modified acidic auxiliary material, wherein the surface of the pharmaceutically acceptable surface-modified acidic auxiliary material comprises a neutral salt layer that comprises: 1) an anion of an acidic medicinal auxiliary material in a powdered form; and 2) a cation of a pharmaceutically acceptable alkaline substance for surface modification; or
(b) a pharmaceutically acceptable surface-modified alkaline auxiliary material, wherein the surface of the pharmaceutically acceptable surface-modified alkaline auxiliary material comprises a neutral salt layer that comprises: 1) a cation of an alkaline medicinal auxiliary material in a powdered form; and 2) an anion of a pharmaceutically acceptable acidic substance for modification.

### Claim 2 (depends on 1)

The oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable alkaline substance for modification or pharmaceutically acceptable acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of up to 10%.

### Claim 3 (depends on 2)

The oral pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable alkaline substance for modification or pharmaceutically acceptable acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of 0.1% to 10%.

### Claim 4 (depends on 3)

The oral pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable alkaline substance for modification or pharmaceutically acceptable acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of 0.67% to 4%.

### Claim 5 (depends on 1)

The oral pharmaceutical composition of claim 1, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid having a water solubility of greater than 1 g/250 mL at 20° C., or wherein the alkaline medicinal auxiliary material is a pharmaceutically acceptable alkaline substance having a water solubility of greater than 1 g/250 mL at 20° C.

### Claim 6 (depends on 1)

The oral pharmaceutical composition of claim 1, wherein the acidic medicinal auxiliary material is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, and an acidic salt; and wherein the pharmaceutically acceptable alkaline substance for surface modification is selected from the group consisting of aqueous ammonia, meglumine, trihydroxymethylaminomethane, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium stearate, potassium stearate, lysine, arginine and histidine, and a hydrate thereof.

### Claim 7 (depends on 1)

The oral pharmaceutical composition of claim 1, wherein the alkaline medicinal auxiliary material is selected from the group consisting of lysine, arginine and histidine, and a hydrate thereof and wherein the pharmaceutically acceptable acidic substance for modification is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, and an acidic salt.

### Claim 8 (depends on 1)

The oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of dabigatran etexilate is dabigatran etexilate mesylate.

### Claim 9 (depends on 1)

The oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable alkaline substance for modification is selected from the group consisting of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, lysine, arginine and a hydrate thereof.

### Claim 10 (depends on 1)

The oral pharmaceutical composition of claim 1, wherein the acidic medicinal auxiliary material or the alkaline medicinal auxiliary material has a particle size of 0.4 to 1.5 mm.

### Claim 11 (depends on 1)

The oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of dabigatran etexilate is dabigatran etexilate mesylate, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid, and wherein the pharmaceutically acceptable alkaline substance for surface modification is a carbonate base.

### Claim 12 (depends on 11)

The oral pharmaceutical composition of claim 11, wherein the pharmaceutically acceptable organic acid is tartaric acid, and wherein the carbonate base is sodium carbonate.

### Claim 13

An oral pharmaceutical composition, comprising:
(i) a first component, wherein the first component comprises dabigatran etexilate or a pharmaceutically acceptable salt or hydrate thereof; and
(ii) a second component, wherein the second component comprises:
(a) a pharmaceutically acceptable surface-modified acidic auxiliary material, wherein the surface of the pharmaceutically acceptable surface-modified acidic auxiliary material comprises a neutral salt layer formed by reacting: 1) a powdered form of an acidic medicinal auxiliary material; and 2) an aqueous solution comprising a pharmaceutically acceptable alkaline substance for surface modification,
wherein the acidic medicinal auxiliary material is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, and an acidic salt thereof, and
wherein the pharmaceutically acceptable alkaline substance for modification is selected from the group consisting of aqueous ammonia, meglumine, trihydroxymethylaminomethane, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium stearate, potassium stearate, lysine, arginine and histidine, and a hydrate thereof; or
(b) a pharmaceutically acceptable surface-modified alkaline auxiliary material, wherein the surface of the pharmaceutically acceptable surface-modified alkaline auxiliary material comprises a neutral salt layer formed by reacting: 1) a powdered form of an alkaline medicinal auxiliary material; and 2) an aqueous solution comprising a pharmaceutically acceptable acidic substance for modification,
wherein the alkaline medicinal auxiliary material is selected from the group consisting of lysine, arginine, histidine, and a hydrate thereof, and
wherein the pharmaceutically acceptable acidic substance for modification is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, and an acidic salt.

### Claim 14 (depends on 13)

The oral pharmaceutical composition of claim 13, wherein the alkaline substance for modification or acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of up to 10%.

### Claim 15 (depends on 14)

The oral pharmaceutical composition of claim 14, wherein the alkaline substance for modification or acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of 0.1% to 10%.

### Claim 16 (depends on 15)

The oral pharmaceutical composition of claim 15, wherein the alkaline substance for modification or acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of 0.67% to 4%.

### Claim 17 (depends on 13)

The oral pharmaceutical composition of claim 13, wherein the acidic medicinal auxiliary material or the alkaline medicinal auxiliary material has a particle size of 0.4 to 1.5 mm.

### Claim 18 (depends on 13)

The oral pharmaceutical composition of claim 13, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid having a water solubility of greater than 1 g/250 mL at 20° C., or wherein the alkaline medicinal auxiliary material is a pharmaceutically acceptable alkaline substance having a water solubility of greater than 1 g/250 mL at 20° C.

### Claim 19 (depends on 13)

The oral pharmaceutical composition of claim 13, wherein the pharmaceutically acceptable salt of dabigatran etexilate is dabigatran etexilate mesylate.

### Claim 20 (depends on 19)

The oral pharmaceutical composition of claim 19, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid, and wherein the pharmaceutically acceptable alkaline substance for surface modification a carbonate base.

### Claim 21 (depends on 20)

The oral pharmaceutical composition of claim 20, wherein the pharmaceutically acceptable organic acid is tartaric acid, and the carbonate base is sodium carbonate.