阅读说明：本技术 盐酸伊托必利药物组合物及其制备方法 (Itopride hydrochloride pharmaceutical composition and preparation method thereof ) 是由 朱德其 于 2019-12-06 设计创作，主要内容包括：本发明属于药物制剂制备的技术领域,具体涉及一种盐酸伊托必利药物组合物及其制备方法。盐酸伊托必利药物组合物,是由以下重量份成分制备而成：盐酸伊托必利50～150份,交联羧甲纤维素钠20～80份,二甲硅油20～80份,气相二氧化硅5～20份,淀粉10～40份,乳糖20～80份,羟丙纤维素4～10份,硬脂酸镁1～5份。本发明制备的盐酸伊托必利药物组合物是由盐酸伊托必利与二甲硅油制成的组合物,二者药理作用不同,发挥各自的作用,但产生了协调增效作用,在增强胃肠蠕动的同时消除胃肠道胀气,明显缩短糖尿病胃轻瘫大鼠胃排空时间,保护胃肠道粘膜。(The invention belongs to the technical field of preparation of pharmaceutical preparations, and particularly relates to an itopride hydrochloride pharmaceutical composition and a preparation method thereof. The itopride hydrochloride pharmaceutical composition is prepared from the following components in parts by weight: 50-150 parts of itopride hydrochloride, 20-80 parts of croscarmellose sodium, 20-80 parts of simethicone, 5-20 parts of fumed silica, 10-40 parts of starch, 20-80 parts of lactose, 4-10 parts of hydroxypropyl cellulose and 1-5 parts of magnesium stearate. The itopride hydrochloride pharmaceutical composition prepared by the invention is a composition prepared from itopride hydrochloride and simethicone, has different pharmacological effects, plays respective roles, generates a coordination and synergism effect, eliminates flatulence of gastrointestinal tract while enhancing gastrointestinal peristalsis, obviously shortens the gastric emptying time of diabetic gastroparesis rats, and protects gastrointestinal mucosa.)

1. The itopride hydrochloride pharmaceutical composition is characterized by being prepared from the following components in parts by weight:

2. the itopride hydrochloride pharmaceutical composition according to claim 1, which is prepared from the following components in parts by weight:

3. the itopride hydrochloride pharmaceutical composition according to claim 1 or 2, which is prepared from the following components in parts by weight:

4. itopride hydrochloride pharmaceutical composition according to any one of claims 1 to 3, wherein the settled volume of croscarmellose sodium is 20 to 30 mL.

5. Itopride hydrochloride pharmaceutical composition according to any one of claims 1 to 3, wherein the dimethicone has a viscosity of 500mm²/s～1000mm²/s。

6. The itopride hydrochloride pharmaceutical composition according to any one of claims 1 to 3, wherein the fumed silica is hydrophobic, has a carbon content of 0.3 wt% or more, an average particle size of 10 to 20nm, and a specific surface area of 20 to 400m²/g。

7. The itopride hydrochloride pharmaceutical composition according to any one of claims 1 to 3, wherein the hydroxypropyl cellulose is of type EF or ELF.

8. The process for the preparation of itopride hydrochloride pharmaceutical composition according to any one of claims 1 to 7, characterized in that it comprises the following steps:

a: preparation of mixture of itopride hydrochloride and croscarmellose sodium

Mixing itopride hydrochloride and croscarmellose sodium according to a mass ratio of 1-5: 1, ball-milling, and collecting for later use;

b: preparation of mixture of dimeticone and fumed silica

Fully stirring and uniformly mixing dimeticone and fumed silica at a mass ratio of 2-5: 1 at 80-150 ℃, cooling to normal temperature, and sieving with a 200-mesh sieve for later use;

c: preparing an adhesive:

adding hydroxypropyl cellulose into boiling water, fully dispersing, continuously stirring, and cooling for later use, wherein the mass ratio of the hydroxypropyl cellulose to the water is 1: 5-20;

d: preparation of granules of the composition

Mixing the mixture of itopride hydrochloride and croscarmellose sodium prepared in the step A, starch, lactose and the adhesive prepared in the step C until the mixture is dry and wet uniformly, extruding and granulating through a 20-30-mesh sieve, drying at 40-70 ℃ until the moisture content of the granules is 1-6%, granulating through a 30-mesh sieve, adding a lubricant magnesium stearate and the mixture of the dimethicone and the fumed silica prepared in the step B, and mixing uniformly to obtain composition granules which are used for subpackaging into capsules or pressing into tablets;

E. subpackaging into capsule and pressing into tablet

① Capsule, which is prepared by filling the obtained medicinal granules into capsules according to the labeled amount of 50mg and 100mg of itopride hydrochloride;

② tabletting, namely, tabletting the obtained medicinal granules according to the marked amount of 50mg and 100mg of itopride hydrochloride, controlling the hardness of the tablets to be 30N-80N, and disintegrating for 1 min-5 min.

9. The method for preparing itopride hydrochloride pharmaceutical composition according to claim 8, wherein the ball milling in step A is performed by a planetary mill at a rotation speed of 200 rpm for 30 minutes per milling, and 4 times of milling are performed in a cycle.

Technical Field

The invention belongs to the technical field of preparation of pharmaceutical preparations, and particularly relates to an itopride hydrochloride pharmaceutical composition and a preparation method thereof.

Background

Itopride hydrochloride has dopamine D2 receptor antagonistic activity and acetylcholinesterase inhibition activity, and plays a role in gastrointestinal motility under the synergistic action of the dopamine D2 receptor antagonistic activity and the acetylcholinesterase inhibition activity; in addition, the product has certain anti-vomiting effect due to the effect of antagonizing the activity of dopamine D2 receptor, and is clinically used for treating dyspepsia symptoms caused by gastrointestinal motility slowing (such as functional dyspepsia, chronic gastritis and the like), including upper abdominal fullness, upper abdominal pain, inappetence, nausea, vomiting and the like. Itopride hydrochloride is converted in the liver mainly through a flavin monooxygenase pathway to form metabolites Ml, M2 and M3, and only one of the 3 metabolites has weak dopamine D2 receptor blocking effect and has no pharmacological relevance. Itopride hydrochloride and its metabolites are mainly excreted by the kidney (75%), with a clearance half-life of about 6 hours. The actuation force of itopride hydrochloride is linearly related to the dose over the therapeutic dose range. Itopride hydrochloride tablets originally developed into abeyangshan factory ltd (abbott japan co., ltd., katsuyama plant) were marketed in a size of 50mg, and currently marketed in China are tablets, capsules and granules.

The dimethicone is also called methyl silicone oil, polydimethylsiloxane liquid, colorless transparent viscous liquid, and has no odor and toxicity, and molecular formula is CH₃[Si(CH₃)₂]_nSi(CH₃)₃And the average molecular weight is 5000-100000. The dimeticone is a dimethyl siloxane bulk polymer, is obtained by hydrolyzing and polycondensing dichlorodimethylsilane and a small amount of monochlorotrimethylsilane, has different viscosities due to different degrees of polymerization, can be divided into ten types of 20, 50, 100, 200, 350, 500, 750, 1000, 12500 and 30000 according to different kinematic viscosities, has small surface tension and strong defoaming force, can break residual bubbles in gastrointestinal tracts and discharge gas, thereby eliminating flatulence and protecting gastrointestinal mucosa. The simethicone tablets and the simethicone powder are available in the market at home.

The publication number is CN105267171A, the invention name is an itopride hydrochloride sustained-release tablet composition, and each 1000 tablet cores of the itopride hydrochloride sustained-release tablet contain 75g of itopride hydrochloride, 45g of hydroxypropyl methylcellulose, 15g of sodium alginate, 40g of microcrystalline cellulose, 8g of superfine silica gel powder, povidone K307 g and 3g of magnesium stearate. The publication number is CN102600091A, the invention name is itopride hydrochloride dispersible tablet composition, and the dispersible tablet composition with unit dose contains 50mg of itopride hydrochloride, 50-80 mg of microcrystalline cellulose, 12mg of crospovidone, 16mg of hydroxypropyl cellulose, 80-110 mg of lactose, 0.25mg of sodium dodecyl sulfate, 5mg of silicon dioxide, 1.25mg of magnesium stearate, 60mg of methylcellulose and 15mg of polyacrylic resin IV.

At present, the existing research is the preparation of itopride hydrochloride, and no development and application of the composition of itopride hydrochloride and simethicone exist.

Disclosure of Invention

The invention adopts modern pharmaceutical preparation technology to prepare the itopride hydrochloride and the dimeticone into a composition, wherein the itopride hydrochloride in the composition enhances gastrointestinal motility, the dimeticone silicon dioxide mixture eliminates gastrointestinal bubbles, and the etopride hydrochloride enhances the gastrointestinal motility to increase the defoaming capability of the dimeticone silicon dioxide mixture; the dimeticone silicon dioxide mixture eliminates bubbles in the gastrointestinal tract and reduces the gastrointestinal peristalsis resistance; the two have respective characteristics to generate synergistic action, accelerate elimination of flatulence of gastrointestinal tract while enhancing gastrointestinal peristalsis, obviously shorten gastric emptying time of diabetic gastroparesis rats and protect gastrointestinal tract mucosa.

The invention provides an itopride hydrochloride pharmaceutical composition, which is prepared from the following components in parts by weight:

further, the itopride hydrochloride pharmaceutical composition is prepared from the following components in parts by weight:

further, the itopride hydrochloride pharmaceutical composition is prepared from the following components in parts by weight:

further, the ritonavir hydrochloride pharmaceutical composition has a settlement volume of 20-30 mL of croscarmellose sodium. Croscarmellose sodium is a crosslinked carboxymethyl ether of cellulose (about 70% of carboxyl groups are in the sodium salt form), is insoluble in water due to the presence of crosslinking bonds, can absorb water with the weight several times of the weight of the croscarmellose sodium to swell without dissolving, and has good disintegrating effect.

Simethicone emulsion or tablet, the main indication is 1, is used for improving abdominal symptoms caused by gas in gastrointestinal tract; 2. removing the foam mucus in stomach during the gastric endoscopy; 3. when the abdomen is examined by X-ray, intestinal gas is removed. Further, the itopride hydrochloride pharmaceutical composition has the viscosity of the dimeticone of 500mm²/s～1000mm²/s。

Further, the itopride hydrochloride pharmaceutical composition is hydrophobic in fumed silica, has a carbon content of not less than 0.3%, an average particle size of 10-20 nm and a specific surface area of 20-400 m²(ii) in terms of/g. The fumed silica is mainly used for enhancing the defoaming activity of the dimeticone and improving the defoaming force.

Further, the itopride hydrochloride pharmaceutical composition is characterized in that the type of the hydroxypropyl cellulose is EF or ELF. Hydroxypropyl cellulose is used as a wet granulation adhesive, wherein the type is EF or ELF with the best performance, and the compressibility and dissolution performance can be improved during tabletting.

The invention also provides a preparation method of the itopride hydrochloride pharmaceutical composition, which comprises the following steps:

a: preparation of mixture of itopride hydrochloride and croscarmellose sodium

Mixing itopride hydrochloride and croscarmellose sodium according to a mass ratio of 1-5: 1, ball-milling, and collecting for later use;

b: preparation of mixture of dimeticone and fumed silica

Fully stirring and uniformly mixing dimeticone and fumed silica at a mass ratio of 2-5: 1 at 80-150 ℃, cooling to normal temperature, and sieving with a 200-mesh sieve for later use;

c: preparing an adhesive:

adding hydroxypropyl cellulose into boiling water, fully dispersing, continuously stirring, and cooling for later use, wherein the mass ratio of the hydroxypropyl cellulose to the water is 1: 5-20;

d: preparation of granules of the composition

Mixing the mixture of itopride hydrochloride and croscarmellose sodium prepared in the step A, starch, lactose and the adhesive prepared in the step C until the mixture is dry and wet uniformly, extruding and granulating through a 20-30-mesh sieve, drying at 40-70 ℃ until the moisture content of the granules is 1-6%, granulating through a 30-mesh sieve, adding a lubricant magnesium stearate and the mixture of the dimethicone and the fumed silica prepared in the step B, and mixing uniformly to obtain composition granules for subpackaging into capsules or pressing into tablets;

E. subpackaging into capsule and pressing into tablet

① Capsule, which is prepared by filling the obtained medicinal granules into capsules according to the labeled amount of 50mg and 100mg of itopride hydrochloride;

② tabletting, wherein the obtained medicinal granule is tabletted according to the labeled amount of itopride hydrochloride 50mg and 100mg, and the hardness of the tablet is controlled

The degree is 30N-80N, and the disintegration time is 1 min-5 min.

Further, in the preparation method of the itopride hydrochloride pharmaceutical composition, in the step a, the ball milling is performed for 30 minutes at each time by using a planetary mill at a rotation speed of 200 revolutions per minute, and the grinding is performed for 4 times in a total cycle.

Compared with the prior art, the invention has the following beneficial effects:

1. the itopride hydrochloride pharmaceutical composition prepared by the invention is a composition prepared from itopride hydrochloride and dimethicone, the two exert respective effects and generate a coordination synergistic effect, gastrointestinal peristalsis is enhanced, gastrointestinal flatulence is eliminated, gastric emptying time of diabetic gastroparesis rats is obviously shortened, and gastrointestinal mucosa is protected.

2. The invention can effectively eliminate bubbles in the gastrointestinal tract, thereby exhausting gas and eliminating flatulence.

Detailed Description

The present invention will be described in further detail with reference to specific embodiments, but it should not be construed that the scope of the present invention is limited to the following examples. Various substitutions and alterations can be made by those skilled in the art and by conventional means without departing from the spirit of the method of the invention described above.