TWI525086B - Pharmaceutical composition containing dronedarone - Google Patents

Description

Dronedarone Pharmaceutical Composition

The present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, an amphiphilic lipid surfactant and a phospholipid.

The chemical name of Dronedarone is 2-n-butyl-3[4-(3-di-n-butyl-aminopropoxy)benzylidene]-5-methylsulfonamide benzofuran. Molecular formula C ₃₁ H ₄₄ N ₂ O ₅ S, molecular weight 556.765.

Dronedarone hydrochloride is a newly developed treatment for arrhythmia drugs by Sanofi-Synthelabo. This product is an iodine-free benzofuran derivative with similar structure and characteristics to amiodarone, but dronedarone contains no iodine and has low lipophilicity, thus maintaining the efficacy of amiodarone and no amine. The side effects of iodophenone outside the heart, and half-life of 1 to 2 days, it is easier to adjust the drug dose.

The solubility of dronedarone hydrochloride in an aqueous medium is very low, in particular, its solubility is pH dependent at room temperature, and has a large solubility in the range of pH 3 to 5, about 1-2 mg/ml. In the range of pH about 6 to 7, the solubility becomes very low because his solubility at pH 7 is only 10 μg/ml.

Due to the low solubility of dronedarone hydrochloride, the bioavailability of administration through the gastrointestinal tract is low, because the process from the stomach to the intestine is a process of gradually increasing pH, which means that the solution is drone. The solubility of dalong gradually decreases, which causes dronedarone hydrochloride to be insoluble or poorly eluted from the solid preparation in the higher pH environment of the intestinal tract. In order to improve the bioavailability of dronedarone hydrochloride, it is necessary to find a way to increase the dissolution rate of dronedarone hydrochloride.

US20040044070 discloses an injection of dronedarone hydrochloride. This invention incorporates a beta-cyclodextrin derivative in a buffer system (pH range 3 to 5) to increase the solubility of the active ingredient. However, this method of increasing the solubility of dronedarone hydrochloride is complicated in manufacturing process and may be inferior in stability.

Patent ZL98808158.X discloses a solid pharmaceutical composition containing a benzofuran derivative. The invention finds that a nonionic surfactant, especially a poloxamer-based nonionic surfactant, can be dissolved at pH 4.5. The active ingredient in the left and right solution can be kept in the pH6-7 solution after being diluted by the high pH solution, and the precipitate is precipitated without being affected by the pH increase, thereby improving the activity of dronedarone hydrochloride under the fasting Utilization. The screening process described in this patent specification shows that although the use of a series of nonionic surfactants can improve the retention of dronedarone hydrochloride in solution, only poloxamer 407 is When the dosage is not large, it can show a more obvious effect. Other types of surfactants require larger amounts.

In addition, according to incomplete statistics, about 40% of new drugs have low solubility problems. Oral administration of such drugs often has problems such as low bioavailability and large individual differences. In order to solve this problem, in recent years, the use of lipid matrices, particularly amphiphilic lipid surfactants having self-emulsification ability, to improve the bioavailability of poorly soluble drugs has become a hot spot in the field of pharmacy. However, in practical applications, such amphiphilic lipid surfactants tend to be used in large amounts, which limits their application to some extent.

Based on the previous experience, the present invention has surprisingly found that the addition of phospholipids in the presence of an amphiphilic lipid surfactant can greatly increase the solubility of dronedarone hydrochloride.

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof as an active ingredient, one or more pharmaceutically acceptable two A hydrophilic lipid surfactant, one or more phospholipids, combined with one or more pharmaceutical additives. It has anti-arrhythmia activity and is clinically applied to anti-arrhythmia.

The pharmaceutically acceptable salts of dronedarone include, but are not limited to, hydrochloride, sulfate, nitrate, citrate, maleate, tartrate, methanesulfonate and fumarate, preferably For the hydrochloride.

Amphiphilic lipid surfactants for use in the pharmaceutical compositions of the present invention include, but are not limited to, lauric acid polyethylene glycol glyceride, stearic acid polyethylene glycol glyceride, oleic acid polyethylene glycol glyceride, Caprylic acid phthalic acid polyethylene glycol glyceride, caprylic acid triglyceride, polyglycerin fatty acid ester, vitamin E succinate and the like.

Phospholipids, which are a core part of the present invention, include, but are not limited to, soybean phospholipids, egg yolk phospholipids, polyene phospholipids, choline, hydrogenated soybean phospholipids and the like.

The pharmaceutical composition of the present invention is any solid pharmaceutical composition suitable for oral administration, and is basically considered to be a pharmaceutical composition formed of a powdery or granular solid component, which can be prepared into granules and tablets at normal temperature. , capsules.

A further subject of the invention is therefore a pharmaceutical composition as described above in the form of a tablet, capsule, granule or powder.

The pharmaceutical composition of the present invention contains an active ingredient, an amphiphilic lipid surfactant, a phospholipid and an excipient.

In general, dronedarone or a pharmaceutically acceptable salt thereof, such as a hydrochloride salt, in the pharmaceutical composition of the present invention, each of the basic administration units, such as each tablet or capsule, or granules per package, The amount may be from 50 mg to 500 mg, preferably from 200 mg to 400 mg.

In general, the amphoteric lipid surfactant in the pharmaceutical composition of the present invention is 1.25 to 50% by weight based on the weight of the active ingredient in the dosage form. The ratio of the amphiphilic lipid surfactant is from 1.5 to 20%, preferably from 2 to 10% by weight of the active ingredient in the dosage form in the form of a tablet, capsule, granule or the like.

Generally, in the pharmaceutical composition, the proportion of phospholipid is from 0.5 to 15% by weight of the active ingredient in the dosage form. In the form of an oral administration form such as a tablet, a capsule or a granule, the proportion of the phospholipid is from 1 to 10%, preferably from 2 to 7.5% by weight of the active ingredient in the dosage form.

In addition to the amphiphilic surfactant and phospholipid, the pharmaceutical composition of the present invention may also contain other pharmaceutical excipients, such as microcrystalline cellulose, micronized silicone, which are commonly used in the research, development, and production of drugs in oral form. , croscarmellose sodium, methylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, polyethylene glycol (eg polyethylene glycol 6000), vinylpyrrolidone polymer or copolymer ( For example, polyvinylpyrrolidone) and magnesium stearate.

The pharmaceutical composition of the present invention can be prepared by an appropriate method:

a) dissolving the active ingredient, the amphiphilic lipid surfactant and the phospholipid in an organic solvent selected from the group consisting of ethanol, methanol, dichloromethane, and acetone;

b) adding an excipient, absorbing the solvent, and stirring the granulation, the excipient being selected from one or more of cerium oxide, aluminum oxide or a cellulose derivative for preparing a pharmaceutical tablet or capsule; Further, a disintegrating agent, a lubricant or the like may be further used, and it may be further compressed into a tablet, a coating or a filled capsule.

Through extensive research and experimentation, the researchers of the present invention have surprisingly found that in the presence of an amphiphilic lipid surfactant, the addition of an appropriate amount of phospholipid to the formulation of dronedarone hydrochloride can greatly increase the original basis. The solubility of the drug increases the dissolution of the solid preparation, thereby increasing the bioavailability of the drug. The beneficial effects of the present invention are that the addition of phospholipids to the pharmaceutical composition solves the solubility problem of dronedarone hydrochloride while reducing the amount of the amphiphilic lipid surfactant.

In order to better explain the present invention, the present invention will be described below by way of specific embodiments. The following examples and examples are given for the purpose of illustrating the invention, and are not intended to be construed as limiting the scope of the invention.

Example 1

Screening of amphiphilic lipid surfactants

Maintenance test in pH 6.7 phosphate buffer

A solution of dronedarone hydrochloride 2 mg/ml in dronedarone was prepared using a pH 4.5 hydrogen phosphate (NaH ₂ PO ₄ ) buffer at 37 ° C for 2 hours. The solution was then diluted to 1/10 in a neutral phosphate medium (Na ₂ HPO ₄ + NaH ₂ PO ₄ ) and the pH of the final solution was 6.7. After 2 hours at 37 ° C, the solution was filtered through a 5.0 um glass fiber filter and the active ingredient in the solution was measured with an ultraviolet spectrophotometer.

The results are as follows:

Conclusion: In the presence of amphiphilic lipid surfactants, the percentage of dronedarone in higher pH solutions can be increased. After adding phospholipids, the percentage of dronedarone hydrochloride in the solution is more significant. improve.

Example 2:

Dronedarone hydrochloride tablets

prescription:

step:

According to the prescription ratio, dronedarone hydrochloride (synthesis of Jiangsu Hengrui Pharmaceutical Co., Ltd.), glycerol laurate and phospholipids were weighed. Add 50% of the active ingredient in dronedarone to the solution and heat to dissolve in a 50 ° C water bath. According to the prescription ratio, microcrystalline cellulose, micro-powder gelatin, croscarmellose sodium, absorbing solvent and stirring and granulating, after drying at 50 ° C, the granules are sieved through 20 mesh, and stearic acid is added according to the prescription ratio. Magnesium, after mixing, tableting.

Special Note: This prescription step can also be taken, and finally the capsules are filled or directly packaged to make capsules or granules. The following examples can also be made into capsules or granules in a similar manner and are not repeated.

Example 3:

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 4:

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 5:

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 6

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 7

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 8

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 9

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 10:

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 11

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 12

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Example 13

Dronedarone hydrochloride tablets

prescription:

step:

Same as Embodiment 2.

Comparative example

Dronedarone hydrochloride tablets

The dronedarone hydrochloride tablets were prepared according to the prescription procedure of the patent example ZL98808158.X.

Experimental Example 1: Maintenance test in pH 6.7 phosphate buffer

1) Dronedarone hydrochloride tablets (corresponding to 426 mg of dronedarone hydrochloride) were dissolved in a 200 ml volumetric flask by adding a phosphate buffer of pH 4.5 to a volume, and kept at 37 ° C for 2 hours.

2) This solution was diluted to 1/10 with a neutral phosphate medium (Na ₂ HPO ₄ + NaH ₂ PO ₄ ), and the pH of the final solution was 6.7. After 2 hours at 37 ° C, the solution was filtered through a 5.0 um glass fiber filter and the active ingredient in the solution was measured at a wavelength of 291 nm using an ultraviolet spectrophotometer.

Conclusion: Compared to Example 2 and Example 8 (without phospholipids), the solubility of dronedarone hydrochloride in formulations containing phospholipids (Examples 3 to 7, 9 to 13) was significantly improved. Compared with the comparative example, the formulation containing the amphiphilic lipid surfactant and the phospholipid can more significantly improve the retention ability of dronedarone hydrochloride in a high pH solution.

Experimental Example 2: Dissolution measurement

Referring to the Chinese Pharmacopoeia 2005 edition appendix XC, using the paddle method, the temperature is 37 ° C ± 0.5 ° C, pH 6.7 phosphate buffer 900ml as the medium, sampling in 45 minutes, and determining the A value by ultraviolet spectrophotometry, calculate the cumulative dissolution percentage .

Conclusion: Compared to Example 2 and Example 8 (without phospholipids), the dissolution of dronedarone hydrochloride in higher pH media was significantly improved in formulations containing phospholipids (Examples 3 to 7, 9 to 13). And generally higher than the dissolution rate of the comparative example.

Experimental Example 3: Bioavailability determination

Plasma collection: 39 Beagle dogs were given each of the experimental examples, and the preparations of the experimental examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, were compared by gavage. Dosage: after 30 mg/kg dronedarone hydrochloride, before administration (0h) and after administration 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 16.0, 18.0, 20.0, 22.0, 24.0h 2.0 ml of blood was taken from the forelimb vein, placed in heparinized tubes, centrifuged at 3000 rpm for 10 min, plasma was separated, and stored at -20 ° C for testing.

Determination of plasma samples: After the liquid-liquid extraction of the canine plasma samples, the LC/MS method was used.

Conclusion: Compared to Example 2 and Example 8 (without phospholipids), the bioavailability of dronedarone hydrochloride was significantly improved in the phospholipid-containing formulation (Examples 3 to 7, 9 to 13). Compared with the comparative example, the formulation containing the amphiphilic lipid surfactant and the phospholipid can significantly improve the bioavailability of dronedarone hydrochloride.

Claims (19)

A pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof as an active ingredient, one or more pharmaceutically acceptable amphiphilic lipid surfactants, one or more phospholipids, and a Or a combination of various pharmaceutically acceptable excipients. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of dronedarone is selected from the group consisting of a hydrochloride, a sulfate, a nitrate, a citrate, a maleate or a tartrate. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of dronedarone is a hydrochloride. The pharmaceutical composition according to claim 1, wherein the amphiphilic lipid surfactant is selected from the group consisting of polyglycol laurate, polyethylene glycol glyceryl stearate, and polyethylene glycol glyceride oleate. , octanoic acid polyethylene glycol glyceride, caprylic acid triglyceride, polyglycerin fatty acid ester or vitamin E succinate. The pharmaceutical composition according to claim 1, wherein the phospholipid is selected from the group consisting of soybean phospholipid, egg yolk phospholipid, polyene phospholipid choline or hydrogenated soybean phospholipid. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an oral dosage form. The pharmaceutical composition according to claim 6, wherein the oral dosage form is a tablet, a capsule or a granule. The pharmaceutical composition according to claim 6, wherein the ratio of the amphiphilic lipid surfactant is from 1.25% to 50% by weight of the active ingredient in the dosage form. The pharmaceutical composition according to claim 6, wherein the ratio of the amphiphilic lipid surfactant is from 1.5% to 20% by weight of the active ingredient in the dosage form. The pharmaceutical composition according to claim 6, wherein the ratio of the amphiphilic lipid surfactant is from 2% to 10% by weight of the active ingredient in the dosage form. The pharmaceutical composition according to claim 6, wherein the proportion of the phospholipid is from 0.5% to 15% by weight of the active ingredient in the dosage form. The pharmaceutical composition according to claim 6, wherein the proportion of the phospholipid is from 1% to 10% by weight of the active ingredient in the dosage form. The pharmaceutical composition according to claim 6, wherein the proportion of the phospholipid is from 2% to 7.5% by weight of the active ingredient in the dosage form. The pharmaceutical composition according to any one of claims 1 to 13, which contains 50 to 500 mg of the active ingredient per administration unit. The pharmaceutical composition according to any one of claims 1 to 13, which contains 200 to 400 mg of the active ingredient per administration unit. The pharmaceutical composition according to any one of claims 1 to 13, which contains 200 to 400 mg of the active ingredient in the dosage form per administration unit, and 2 to 10 of the active ingredient in the dosage form. % amphiphilic lipid surfactant and 2 to 7.5% phospholipid. A method for preparing a pharmaceutical composition according to claim 1, which comprises the steps of: a) dissolving an active ingredient, an amphiphilic lipid surfactant and a phospholipid in an organic solvent or a mixture of an organic solvent and water. The organic solvent in the solution Selected from the group consisting of ethanol, methanol, dichloromethane, acetone; b) adding an excipient, absorbing the solvent, and stirring and granulating, the excipient being selected from the group consisting of cerium oxide, aluminum oxide or cellulose for preparing a pharmaceutical tablet or capsule One or more of the derivatives. The preparation method according to claim 17, which further comprises the steps of coating, filling the capsule or compressing into a tablet. The preparation method according to claim 17 or 18, which further uses a disintegrating agent, a lubricant, and a binder.