Synergistic pharmaceutical composition containing rebamipide and probucol as well as preparation method and application thereof

Abstract

The invention relates to a synergistic pharmaceutical composition containing rebamipide and probucol as well as a preparation method and application of the synergistic pharmaceutical composition, and belongs to the field of pharmaceutical preparations. The pharmaceutical composition comprises a therapeutically effective amount of rebamipide, probucol and a pharmaceutically acceptable carrier, wherein the mass ratio of rebamipide to probucol is (1: 1)-(1: 5). The dosage form of the pharmaceutical composition can be tablets or capsules. The pharmaceutical composition disclosed by the invention takes rebamipide and probucol as active ingredients, and can be used for preventing and treating gastrointestinal diseases. Through the synergistic effect of the composition, the protection and repair effects on gastrointestinal mucosa are remarkably improved, and meanwhile, the composition has the anti-inflammatory and anti-oxidation effects. The invention also relates to a preparation method of the composition and application of the composition in the field of medicines.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a synergistic pharmaceutical composition comprising rebamipide and probucol, and a preparation method and application thereof. Background Art

[0002] The pathogenesis of gastrointestinal diseases (such as gastritis, gastric ulcer, and NSAIDs-induced intestinal damage) is complex, involving mucosal repair disorders, oxidative stress, and inflammatory responses.

[0003] Rebamipide is a white powder with the chemical name (±)-2-(4-chlorobenzamide)-3-[2(1H)-quinolone-4-yl]propionic acid. As a mucosal protectant, it enhances mucosal repair by promoting prostaglandin synthesis and epidermal growth factor (EGF) expression, but the single drug has limited regulation on oxidative stress and deep inflammation.

[0004] Probucol, also known as probucol, is a white or off-white crystalline powder with a special odor. Its chemical name is 4,4'-[(1-methylethylidene) dithio]bis[2,6-di(1,1-dimethylethyl)phenol]. As a potent antioxidant, it can reduce lipid peroxides (such as MDA) and pro-inflammatory factors (such as IL-6, TNF-α), but lacks direct mucosal repair effects.

[0005] Existing treatment options for gastrointestinal diseases are mostly single-drug, with limited efficacy and unable to synergistically intervene in the pathological process through multiple targets. Summary of the invention

[0006] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a synergistic pharmaceutical composition comprising rebamipide and probucol and a preparation method and application thereof. The present invention is achieved by the following technical solutions:

[0007] The present invention first provides a synergistic pharmaceutical composition comprising rebamipide and probucol, which comprises a therapeutically effective amount of rebamipide, probucol, and a pharmaceutically acceptable carrier, wherein the mass ratio of rebamipide to probucol is 1:1 to 1:5.

[0008] According to an embodiment of the present invention, the dosage form of the pharmaceutical composition is a tablet or a capsule. When the dosage form is a tablet, the acceptable carrier comprises a filler, a binder, a disintegrant, a lubricant, a surfactant and a film coating premix; when the dosage form is a capsule, the acceptable carrier comprises a filler, a binder, a lubricant and a capsule shell.

[0009] Preferably, the content of rebamipide is 100 mg, and the content of probucol is 100-500 mg.

[0010] In a specific embodiment of the present invention, the dosage form of the pharmaceutical composition is a tablet, the filler is microcrystalline cellulose and lactose, the binder is hydroxypropyl cellulose, the disintegrant is cross-linked sodium carboxymethyl cellulose, the lubricant is magnesium stearate, the surfactant is polysorbate 80, and the film coating premix is ​​a gastric soluble film coating premix.

[0011] Preferably, the method for preparing a pharmaceutical composition in the form of a tablet comprises the following steps:

[0012] (1) Weigh the raw and auxiliary materials according to the required amount;

[0013] (2) adding hydroxypropyl cellulose and polysorbate 80 into purified water to prepare an aqueous solution;

[0014] (3) adding rebamipide, probucol, filler, and disintegrant into a wet granulator and mixing them evenly, then adding the aqueous solution prepared in step (2) to granulate, and sieving the granulated intermediate for later use;

[0015] (4) adding a lubricant to the particles obtained in step (3) and mixing them uniformly;

[0016] (5) The granules obtained in step (4) are compressed into tablets and coated with a film coating premix, with the coating increasing the weight by 2 to 3%, to obtain a finished product.

[0017] In another specific embodiment of the present invention, the dosage form of the pharmaceutical composition is a capsule, the filler is microcrystalline cellulose and pregelatinized starch, the binder is hydroxypropyl cellulose, the lubricant is magnesium stearate, and the capsule shell is a gelatin capsule shell.

[0018] A method for preparing a pharmaceutical composition in the form of a capsule comprises the following steps:

[0019] (1) Weigh the raw and auxiliary materials according to the required amount;

[0020] (2) adding hydroxypropyl cellulose to purified water to prepare an aqueous solution;

[0021] (3) adding rebamipide, probucol and filler into a wet granulator and mixing them evenly, then adding the aqueous solution prepared in step (2) to granulate, and sieving the granulated intermediate for later use;

[0022] (4) adding a lubricant to the particles obtained in step (3) and mixing them uniformly;

[0023] (5) Filling the granules obtained in step (4) into capsule shells to obtain a finished product.

[0024] The present invention also provides the use of the pharmaceutical composition in preparing a drug for treating gastrointestinal mucosal damage, wherein the gastrointestinal mucosal damage includes one or more of gastric ulcer, NSAIDs-related enteropathy or radiation enteritis.

[0025] Compared with the prior art, the present invention first discovered that the combination of rebamipide and probucol has a synergistic effect, wherein rebamipide enhances mucosal repair, and probucol inhibits oxidative stress and inflammation, and the two complement each other to cover the key pathological links of the disease. The pharmaceutical composition of the present invention can be used to prevent and treat gastrointestinal diseases. The composition significantly improves the protection and repair effects on the gastrointestinal mucosa through synergistic effects, and has anti-inflammatory and antioxidant effects. Experiments have shown that the pharmaceutical composition of the present invention significantly reduces the ulcer index and improves the mucosal healing rate compared to a single drug, and has good safety. DETAILED DESCRIPTION

[0026] The following examples provide those of ordinary skill in the art with an understanding of how to make and evaluate the present invention, which are exemplary of the present disclosure and are not intended to limit the scope of the invention. Although every effort has been made to ensure accuracy with respect to numerical values ​​(e.g., amounts, temperatures, etc.), some errors and deviations should be considered. Unless otherwise stated, temperatures are in ° C or at ambient temperature, and pressures are at or near atmospheric pressure.

[0027] The preparation method for the disclosed compound described in the present embodiment is one of many methods, and there are many other methods for the preparation method of the disclosed compound in the present application, and the present application does not limit the scope. Therefore, those skilled in the art of the present disclosure can easily modify the described method or use different methods to prepare one or more of the disclosed compounds. The following method is only exemplary, and temperature, catalyst, concentration, reactant composition, and other process conditions can be changed, and for the desired compound, those skilled in the art of the present disclosure can easily select suitable reactants and conditions for preparation.

[0028] Example 1: Pharmaceutical composition composition

[0029] Active ingredients:

[0030] Rebamipide: 100 mg / unit dose

[0031] Probucol: 100-500 mg / unit dose

[0032] Pharmaceutically acceptable carriers (pharmaceutical excipients):

[0033] Tablet excipients:

[0034] Excipient name model Dosage mg / tablet Microcrystalline Cellulose 101 80mg lactose 200 mesh 10mg Croscarmellose Sodium / 20mg Hydroxypropylcellulose EF 6–18 mg Polysorbate 80 / 3–9 mg Magnesium Stearate / 12mg Gastric film coating premix / 20mg

[0035] Capsule excipients:

[0036] Excipient name model Dosage mg / tablet Microcrystalline Cellulose 101 100mg Pregelatinized starch / 30mg Hydroxypropylcellulose EF 6–18 mg Magnesium Stearate / 12mg Gelatin capsule shell 0# 1

[0037] Tablet preparation process:

[0038] (1) Weigh the raw and auxiliary materials according to the required amount;

[0039] (2) adding hydroxypropyl cellulose and polysorbate 80 to an appropriate amount of purified water to prepare a 5 wt % aqueous solution;

[0040] (3) adding rebamipide, probucol, microcrystalline cellulose and lactose into a wet granulator and mixing for 10 minutes, then adding the aqueous solution prepared in step (2) and granulating for 5 minutes, and sieving the intermediate after granulation for later use;

[0041] (4) adding magnesium stearate to the granules obtained in step (3) and mixing evenly;

[0042] (5) The granules obtained in step (4) are compressed into tablets and coated with a film coating premix, with the coating increasing the weight by 2 to 3%, to obtain a finished product.

[0043] Capsule preparation process:

[0044] (1) Weigh the raw and auxiliary materials according to the required amount;

[0045] (2) Preparation of adhesive: Hydroxypropyl cellulose was added to an appropriate amount of purified water to prepare a 5 wt % aqueous solution;

[0046] (3) adding rebamipide, probucol, microcrystalline cellulose, and pregelatinized starch into a wet granulator and mixing for 10 min, then adding a binder and granulating for 5 min, and sieving the granulated intermediate for later use;

[0047] (4) adding magnesium stearate to the granules obtained in step (3) and mixing for 5 minutes;

[0048] (5) Filling the granules obtained in step (4) into capsule shells to obtain a finished product.

[0049] Example 2: Synergistic Mechanism

[0050] The synergistic effect was verified by experiments. A rat ethanol-induced gastric ulcer model was selected and divided into four groups for drug administration. The control group was not administered, the rebamipide monotherapy group was only given commercially available rebamipide tablets (specification: 100 mg) alone, the probucol monotherapy group was given commercially available probucol tablets (specification: 250 mg) alone, and the third group was given rebamipide-probucol combination tablets (prepared according to the tablet preparation method of Example 1, dosage form: tablets, specifications: rebamipide 100 mg, probucol 150 mg), and the following experimental data were obtained.

[0051]

[0052] At the same time, MDA (oxidative stress marker) in the combination group decreased by 65%, while a single drug only decreased by 30%-40%; the expression of mucosal growth factor (EGF) increased by 2.1 times (1.5 times for rebamipide alone).

[0053] The above data fully demonstrate that the rebamipide-probucol combination of the present invention has a synergistic effect in preventing or treating gastrointestinal mucosal damage and related diseases, and its therapeutic effect is far superior to that of rebamipide alone.

[0054] Example 3

[0055] Rebamipide and probucol tablets and capsules were prepared according to the following proportions and using the preparation process in Example 1.

[0056] Tablet prescription

[0057]

[0058]

[0059] Capsule prescription

[0060]

[0061] A total of 6 tablets and 6 capsules were obtained.

[0062] Example 4

[0063] A rat ethanol-induced gastric ulcer model was selected and divided into fourteen groups. The control group was not given any drug, the rebamipide monotherapy group was given commercially available rebamipide tablets (specification: 100 mg), and the other twelve groups were given drugs (12 drugs prepared in Example 3) respectively, and the following experimental data were obtained.

[0064]

[0065]

[0066] Compared with the rebamipide monotherapy group, groups 2 to 4 of the above data show that when the ratio of rebamipide to probucol in the rebamipide-probucol composition of the present invention is 1:1-1:5, the therapeutic effect is significantly enhanced with the increase of the probucol dosage; compared with the rebamipide monotherapy group, group 1 has no significant enhancement in therapeutic effect, indicating that when the probucol dosage is low, the synergistic effect of rebamipide and probucol is not obvious; at the same time, compared with group 4, groups 5 and 6 have no significant enhancement in therapeutic effect, indicating that the enhancement effect at the ratio of 1:6 and 1:7 is slightly lower. When the rebamipide dosage remains unchanged, when the probucol dosage is increased to 6 times or more of the rebamipide dosage, the synergistic effect and therapeutic effect of the two are no longer significantly increased. Therefore, the present invention preferably has a ratio of rebamipide to probucol of 1:1-1:5, that is, 100 mg of rebamipide and 100-500 mg of probucol.

[0067] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A synergistic pharmaceutical composition comprising rebamipide and probucol, characterized in that: The invention comprises a therapeutically effective amount of rebamipide, probucol, and a pharmaceutically acceptable carrier, wherein the mass ratio of rebamipide to probucol is 1:1 to 1:

5.

2. The pharmaceutical composition according to claim 1, characterized in that Its dosage form is tablet or capsule.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The content of rebamipide is 100 mg, and the content of probucol is 100-500 mg.

4. The pharmaceutical composition according to claim 2, characterized in that When the dosage form is a tablet, the acceptable carrier comprises a filler, a binder, a disintegrant, a lubricant, a surfactant and a film coating premix; when the dosage form is a capsule, the acceptable carrier comprises a filler, a binder, a lubricant and a capsule shell.

5. The pharmaceutical composition according to claim 4, characterized in that The dosage form of the pharmaceutical composition is tablets, the fillers are microcrystalline cellulose and lactose, the binder is hydroxypropyl cellulose, the disintegrant is cross-linked sodium carboxymethyl cellulose, the lubricant is magnesium stearate, the surfactant is polysorbate 80, and the film coating premix is ​​a gastric soluble film coating premix.

6. The pharmaceutical composition according to claim 4, characterized in that The dosage form of the pharmaceutical composition is a capsule, the filler is microcrystalline cellulose and pregelatinized starch, the binder is hydroxypropyl cellulose, the lubricant is magnesium stearate, and the capsule shell is a gelatin capsule shell.

7. A method for preparing the pharmaceutical composition according to claim 5, characterized in that: The steps include: (1) Weigh the raw and auxiliary materials according to the required amount; (2) adding hydroxypropyl cellulose and polysorbate 80 into purified water to prepare an aqueous solution; (3) adding rebamipide, probucol, filler, and disintegrant into a wet granulator and mixing them evenly, then adding the aqueous solution prepared in step (2) to granulate, and sieving the granulated intermediate for later use; (4) adding a lubricant to the particles obtained in step (3) and mixing them uniformly; (5) The granules obtained in step (4) are compressed into tablets and coated with a film coating premix, with the coating increasing the weight by 2 to 3%, to obtain a finished product.

8. A method for preparing the pharmaceutical composition according to claim 6, characterized in that: The steps include: (1) Weigh the raw and auxiliary materials according to the required amount; (2) adding hydroxypropyl cellulose to purified water to prepare an aqueous solution; (3) adding rebamipide, probucol and filler into a wet granulator and mixing them evenly, then adding the aqueous solution prepared in step (2) to granulate, and sieving the granulated intermediate for later use; (4) adding a lubricant to the particles obtained in step (3) and mixing them uniformly; (5) Filling the granules obtained in step (4) into capsule shells to obtain a finished product.

9. Use of the pharmaceutical composition according to claim 1 or 2 in the preparation of a drug for treating gastrointestinal mucosal damage, wherein the gastrointestinal mucosal damage includes one or more of gastric ulcer, NSAIDs-related enteropathy or radiation enteritis.

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