阅读说明：本技术 一种治疗动脉硬化合并心绞痛的药物组合物及制备方法 (Pharmaceutical composition for treating arteriosclerosis complicated with angina pectoris and preparation method thereof ) 是由 张峰 郁晨燕 李晓明 于 2019-12-17 设计创作，主要内容包括：本发明公开了一种治疗动脉硬化合并心绞痛的药物组合物,其包括缓释部和速释部,所述缓释部包括雷诺嗪、盐酸雷诺嗪或雷诺嗪的可药用盐,所述速释部包括槲皮素。本公开的药物组合物可以大大降低主药雷诺嗪的用量,同时降低给药剂量的复方组可有效发挥治疗效果,由此可以降低由于药物剂量效应带来的副作用。(The invention discloses a pharmaceutical composition for treating arteriosclerosis complicated with angina, which comprises a slow release part and a quick release part, wherein the slow release part comprises ranolazine, ranolazine hydrochloride or pharmaceutical salt of ranolazine, and the quick release part comprises quercetin. The pharmaceutical composition disclosed by the invention can greatly reduce the dosage of ranolazine serving as a main drug, and the compound group with the reduced administration dosage can effectively exert the treatment effect, so that the side effect caused by the drug dosage effect can be reduced.)

1. A pharmaceutical composition for treating arteriosclerosis complicated with angina comprises a slow-release part and a quick-release part, wherein the slow-release part comprises ranolazine, ranolazine hydrochloride or a pharmaceutically acceptable salt of ranolazine, and the quick-release part comprises quercetin.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the sustained release portion to the immediate release portion is 10:1 to 20:1, preferably 12:1 to 15:1, preferably the pharmaceutically acceptable salt of ranolazine is selected from the group consisting of hydrochloride, sulfate, hydrobromide, citrate, succinate, phosphate, lactate, pyruvate, acetate, benzenesulfonate, p-benzenesulfonate, glutamate or mixtures thereof of ranolazine.

3. The pharmaceutical composition according to claim 1 or 2, wherein the sustained release portion further comprises microcrystalline cellulose and ethyl methacrylate copolymer, preferably the immediate release portion further comprises microcrystalline fiber, corn starch, colloidal silicon dioxide, and magnesium stearate.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is a tablet, capsule or granule, preferably the tablet is a bilayer tablet, preferably the capsule is a dual release capsule, preferably the granule is a dual release granule.

5. The preparation method of the pharmaceutical composition comprises the following steps

Dissolving the sustained-release part in an alkali solution, and granulating to obtain sustained-release granules;

mixing the immediate release portion with the sustained release granules.

6. A method of preparing a pharmaceutical composition according to claim 5, wherein the extended release portion comprises ranolazine, ranolazine hydrochloride or a pharmaceutically acceptable salt of ranolazine, the immediate release portion comprises quercetin, preferably the weight ratio of the extended release portion to the immediate release portion is 10:1 to 20:1, preferably 12:1 to 15:1, preferably the pharmaceutically acceptable salt of ranolazine is selected from the group consisting of hydrochloride, sulfate, hydrobromide, citrate, succinate, phosphate, lactate, pyruvate, acetate, benzenesulfonate, p-benzenesulfonate, glutamate and mixtures thereof, preferably the extended release portion further comprises microcrystalline cellulose and ethyl methacrylate copolymer, preferably the immediate release portion further comprises microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate, preferably the alkaline solution is selected from the group consisting of sodium hydroxide solution, potassium hydroxide solution, sodium hydroxide, potassium carbonate solution, sodium carbonate solution, potassium hydrogen carbonate solution, sodium methoxide solution, sodium ethoxide solution or a mixture thereof.

7. The method for preparing the pharmaceutical composition according to claim 5 or 6, wherein the slow release part is mixed by a high speed granulator before granulation, preferably the mixing time is 5 to 8min, preferably the slow release part is dissolved in the alkali solution and then the stirring step is included, preferably the stirring time is 3 to 5min, preferably the drying step is included after granulation, preferably the drying temperature is 30 ℃ to 100 ℃, more preferably 40 ℃ to 80 ℃, even more preferably 60 ℃, preferably the drying time is 30 to 50min, or the moisture of the granules is controlled to be less than or equal to 3.0%.

8. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 5 to 7 wherein more than 70% of the extended release particles have a particle size of 20 to 80 mesh.

9. The preparation method of the pharmaceutical composition according to any one of claims 5 to 8, wherein the mixing of the immediate release part and the sustained release granules further comprises the step of preparing the mixture into tablets, capsules or granules, preferably the tablets are double-layer tablets, preferably the capsules are bidirectional release capsules, and preferably the granules are bidirectional release granules.

10. A process for the preparation of a pharmaceutical composition according to claim 9, which further comprises coating the tablet, preferably with opadry.

Detailed Description

In one aspect, the present disclosure relates to a pharmaceutical composition for arteriosclerosis complicated with angina pectoris, which comprises a sustained-release portion comprising ranolazine, ranolazine hydrochloride or a pharmaceutically acceptable salt of ranolazine, and an immediate-release portion comprising quercetin.

In certain embodiments, the weight ratio of the sustained release portion to the immediate release portion is about 10:1 to 20: 1.

In certain embodiments, the weight ratio of the sustained release portion to the immediate release portion is about 12:1 to 15: 1.

In certain embodiments, illustrative examples of pharmaceutically acceptable salts of ranolazine that can be used in the present disclosure include, but are not limited to, hydrochloride, sulfate, hydrobromide, citrate, succinate, phosphate, lactate, pyruvate, acetate, benzenesulfonate, p-benzenesulfonate and glutamate salts of ranolazine.

In certain embodiments, the sustained release portion further comprises microcrystalline cellulose and an ethyl methacrylate copolymer.

In certain embodiments, the immediate release portion further comprises quercetin, microcrystalline fiber, corn starch, colloidal silicon dioxide, and magnesium stearate.

In certain embodiments, the pharmaceutical composition is a tablet, capsule, or granule.

In certain embodiments, the tablet is a bilayer tablet.

In certain embodiments, the capsule is a bi-directional release capsule.

In certain embodiments, the granule is a bi-directional release granule.

In another aspect, the present disclosure relates to a method of preparing a pharmaceutical composition comprising the steps of

Dissolving the sustained-release part in an alkali solution, and granulating to obtain sustained-release granules;

mixing the immediate release portion with the sustained release granules.

In certain embodiments, the weight ratio of the sustained release portion to the immediate release portion is 10:1 to 20: 1.

In certain embodiments, the weight ratio of the sustained release portion to the immediate release portion is from 12:1 to 15: 1.

In certain embodiments, illustrative examples of pharmaceutically acceptable salts of ranolazine that can be used in the present disclosure include, but are not limited to, hydrochloride, sulfate, hydrobromide, citrate, succinate, phosphate, lactate, pyruvate, acetate, benzenesulfonate, p-benzenesulfonate and glutamate salts of ranolazine.

In certain embodiments, the sustained release portion further comprises microcrystalline cellulose and an ethyl methacrylate copolymer.

In certain embodiments, the immediate release portion further comprises microcrystalline fiber, corn starch, colloidal silicon dioxide, and magnesium stearate.

In certain embodiments, illustrative examples of alkali solutions that can be used in the present disclosure include, but are not limited to, sodium hydroxide solution, potassium carbonate solution, sodium carbonate solution, potassium hydrogen carbonate solution, sodium methoxide solution, and sodium ethoxide solution.

In some embodiments, the granulating further comprises mixing the sustained release portion with a high speed granulator.

In certain embodiments, the mixing time is about 5 to 8 min.

In some embodiments, the step of stirring is further included after the slow release portion is dissolved in the alkaline solution.

In certain embodiments, the stirring time is about 3 to 5 min.

In certain embodiments, a drying step is included after granulation.

In certain embodiments, the drying temperature is about 30 ℃ to 100 ℃.

In certain embodiments, the drying temperature is about 0 ℃ to 80 ℃.

In certain embodiments, the drying temperature is about 60 ℃.

In certain embodiments, the drying time is from about 30 to 50 minutes, or the pellet moisture is controlled to be 3.0% or less.

In certain embodiments, greater than 70% of the sustained release particles in the sustained release granules have a particle size of about 20 mesh to 80 mesh.

In some embodiments, mixing the immediate release portion with the sustained release granules further comprises making the immediate release portion into a tablet, capsule or granule.

In certain embodiments, the tablet is a bilayer tablet.

In certain embodiments, the capsule is a bi-directional release capsule.

In certain embodiments, the granule is a bi-directional release granule.

In certain embodiments, further comprising coating the tablet.

In certain embodiments, the coating is performed using opadry.