CN102552257A - Compound preparation containing ranitidine hydrochloride and troxipide and application thereof - Google Patents

Abstract

The invention provides a compound preparation containing ranitidine hydrochloride and troxipide and its application. The ratio of the ranitidine hydrochloride to the troxipide in the compound preparation is 6:1 to 1:6 by weight. Compared with the prior art, the compound preparation has the following advantages and positive effects: the ranitidine hydrochloride and troxipide in the compound preparation have a synergistic pharmacological effect, and can treat acute gastritis and gastric mucosal lesions in the acute attack stage of chronic gastritis It can also enhance the defense factors, promote the repair of ulcer lesions, improve the blood circulation and metabolism of the gastric mucosa at the ulcer site, and normalize the composition of gastric membrane tissue; The effective doses of ranitidine hydrochloride and troxipide in the compound preparation can be guaranteed; the compound preparation also has the advantages of effective oral administration, close peak time and rapid absorption.

Description

A compound preparation containing ranitidine hydrochloride and troxipide and its application

technical field

The invention belongs to the field of pharmacy, and in particular relates to a drug compound preparation containing ranitidine hydrochloride and troxipide.

Background technique

Ranitidine hydrochloride is an antagonist of histamine H2 receptors. Ranitidine hydrochloride has been widely used clinically since the 1980s. It has been included in the list of essential drugs in my country, and is included in the current Chinese Pharmacopoeia, as well as in the latest editions of the Pharmacopoeia published by the United States and the United Kingdom. At present, this drug is still one of the safest, most effective and most commonly used drugs for the treatment of peptic ulcer disease. In addition, its price is lower than that of similar drugs, making it the best choice for clinical treatment of peptic ulcer disease since its inception. One of the drugs.

Traxipide is a new gastric mucosal protective agent. It has no effect on gastric acid secretion, can independently enhance defense factors, promote the repair of ulcer lesions, improve the blood circulation and metabolism of gastric mucosa at the ulcer site, and normalize the composition of gastric membrane tissue. In addition, it can also increase the content of prostaglandins with cytoprotective effect in the gastric mucosa.

Although the drugs ranitidine hydrochloride and troxipide have been clinically used for many years and have very definite clinical therapeutic effects, there are no reports at home and abroad that the two drugs ranitidine hydrochloride and troxipide are made into compound preparations. .

Contents of the invention

In order to solve the above-mentioned problems in the prior art, the present invention provides a compound preparation of ranitidine hydrochloride and troxipide.

Specifically, the present invention provides:

(1) A compound preparation, which contains ranitidine hydrochloride and troxipide; wherein the proportioning ratio of said ranitidine hydrochloride and said troxipide is 6:1 to 1:6 by weight .

(2) The compound preparation according to (1), wherein the ratio of the ranitidine hydrochloride to the troxipide is 3:1 to 1:4 by weight.

(3) The compound preparation according to (2), wherein the content of the ranitidine hydrochloride in each single dose is 50-150 mg, and the content of the troxipide is 50-200 mg.

(4) The compound preparation according to (3), wherein the ratio of the ranitidine hydrochloride to the troxipide is 2:1 to 1:3 by weight.

(5) The compound preparation according to any one of (1)-(4), which is one of tablet, capsule or granule.

(6) The compound preparation according to (5), wherein the tablet contains the ranitidine hydrochloride and the troxipide, as well as diluents, binders, lubricants and disintegrants.

(7) The compound preparation according to (5), wherein, the capsule comprises the ranitidine hydrochloride and the troxipide, as well as diluents, adhesives, lubricants, glidants and Disintegrant.

(8) The compound preparation according to (5), wherein, the granules comprise the ranitidine hydrochloride and the troxipide, as well as diluents, binders, glidants, lubricants, Flavoring and effervescent excipients.

(9) The compound preparation according to any one of (6)-(8), wherein the diluent is one or more of starch, lactose, and microcrystalline cellulose.

(10) The compound preparation according to any one of (6)-(8), wherein the binder is starch slurry and/or ethanol.

(11) The compound preparation according to any one of (6)-(8), wherein the lubricant is magnesium stearate and/or silicon dioxide.

(12) The compound preparation according to (6) or (7), wherein the disintegrant is sodium carboxymethyl starch and/or polyvinylpolypyrrolidone.

(13) The compound preparation according to (7) or (8), wherein the glidant is talc and/or micronized silica gel.

(14) The compound preparation according to (8), wherein the flavoring agent is stevioside and/or sucrose.

(15) The compound preparation according to (8), wherein the effervescent adjuvant is citric acid and sodium bicarbonate.

(16) Use of the compound preparation according to any one of (1)-(15) in the preparation of medicines for treating gastrointestinal diseases, wherein the gastrointestinal diseases include: acute gastritis and chronic gastritis acute Gastric mucosal lesions in the attack period, heartburn caused by hyperacidity, and acid regurgitation in stomach diseases.

Compared with the prior art, the compound preparation of the present invention has the following advantages and positive effects:

1. The ranitidine hydrochloride and troxipide in the compound preparation have synergistic pharmacological effects.

Ranitidine hydrochloride is an antagonist of histamine H2 receptors, and it is one of the safest, most effective and most commonly used drugs for the treatment of peptic ulcer disease. One of the best medicines; and troxipide is a new type of gastric mucosal protective agent, which has no effect on gastric acid secretion, can independently enhance defense factors, promote the repair of ulcer lesions, improve the metabolism of blood circulation in the gastric mucosa at the ulcer site, and make The normalization of gastric membrane tissue components plays a role in synergistic treatment of ulcer disease, and then improves the therapeutic effect. The present invention also finds through research that the compound preparation has a better therapeutic effect than the single prescription of the two medicines.

2. The compound preparation of ranitidine hydrochloride and troxipide has the advantages of effective oral administration, similar peak time and rapid absorption.

Both have the same and similar indications, and their pharmacokinetic characteristics are similar, that is, both are effective for oral administration, have similar peak time and rapid absorption.

3. After ranitidine hydrochloride and troxipex are made into compound preparations, the effective dosage of individual components can be guaranteed.

The two drugs are both compound preparations with definite chemical structures, and the effective dosage of individual components can be guaranteed after being made into compound preparations.

Detailed ways

The present invention will be further described below through the description of specific embodiment, but this is not limitation to the present invention, those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as not departing from the basic principle of the present invention Thoughts are all within the scope of the present invention.

The molecular formula of ranitidine hydrochloride is: C ₁₃ H ₂₂ N ₄ O ₃ S·HCl, the molecular weight is 350.87, and its structural formula is shown in formula I below:

The molecular formula of troxipide is: C ₁₅ H ₂₂ N ₂ O ₄ , the molecular weight is 294.35, and its structural formula is shown in Formula II below:

In this article, "compound preparation" refers to the mixed preparation of two or more drugs. In addition to the active pharmaceutical ingredients ranitidine hydrochloride and troxipide, the compound preparation may also contain diluted Agents, lubricants, disintegrants and other ingredients.

In this article, "tablet" refers to a sheet-like preparation made of a drug and suitable auxiliary materials through preparation technology.

In this article, "capsule" refers to a preparation made by filling a hollow hard capsule with medicine or medicine with auxiliary materials through preparation technology.

Herein, "granule" refers to a granular preparation prepared by compounding a drug with suitable auxiliary materials.

A "single dose" as used herein refers to a prescribed dose of a dosage form.

The definitions of diluents, binders, lubricants, disintegrants, glidants, flavoring agents, and effervescent excipients described herein can be defined in accordance with the 6th edition of "Pharmacy" published by People's Health Publishing House in April 2008. (Ed. Triford) Definition.

The invention provides a compound preparation, which contains ranitidine hydrochloride and troxipide; wherein the ratio of ranitidine hydrochloride and troxipide is 6:1-1:6 by weight. Preferably, the ratio of ranitidine hydrochloride to troxipide is 3:1 to 1:4 by weight. Preferably, each single dose of the compound preparation contains 50-150 mg of ranitidine hydrochloride and 50-200 mg of troxipide. Wherein, more preferably, the ratio of the ranitidine hydrochloride and the troxipide in each single dose of the compound preparation is 2:1 to 1:3 by weight.

The preferred dosage form of compound preparation is one of tablet, capsule or granule. The medicine in the tablet of the present invention comprises ranitidine hydrochloride and troxipide, and adjuvant comprises but not limited to filler, binding agent, lubricant, disintegrant; The medicine in the capsule of the present invention comprises ranitidine hydrochloride Dinghe and troxipide, auxiliary materials include but not limited to diluents, binders, lubricants, glidants, disintegrants, hollow hard capsule shells or elastic soft capsule shells can be gelatin, glycerin, water and other medicinal materials; the medicine in the granules of the present invention includes ranitidine hydrochloride and troxipide, and the auxiliary materials include but are not limited to diluents, binders, glidants, lubricants, flavoring agents, Effervescent excipients. Preferably, wherein the diluent is one or more of starch, lactose, and microcrystalline cellulose; the binder is starch slurry and/or ethanol; the lubricant is magnesium stearate and/or silicon dioxide; Sodium carboxymethyl starch and/or polyvinylpolypyrrolidone are the decontaminants; talcum powder and/or micronized silica gel are the glidants; stevioside and/or sucrose are the flavoring agents; citric acid and sodium bicarbonate are effervescent excipients .

The present invention also includes the use of the compound preparation in the preparation of medicines for treating gastrointestinal diseases, wherein the gastrointestinal diseases preferably include: acute gastritis and gastric mucosal lesions in the acute attack stage of chronic gastritis, hyperacidity caused heartburn and acid reflux.

The content of the present invention is further explained or illustrated by examples below, but these examples should not be construed as limiting the protection scope of the present invention.

Wherein, in the following example, both ranitidine hydrochloride and troxipide can be purchased from Southwest Synthetic Pharmaceutical Co., Ltd.

The principle requirements for drug compounding are: the curative effect of the same dose of the compound is better than that of the single drug; the compound drug has a synergistic effect; the bioavailability of the compound drug is higher than that of the single drug; pharmacodynamics; compounding can prevent drug abuse.

During the research process of the present invention, it is found that when Traxipide and ranitidine hydrochloride are used in combination, a strong synergistic effect can be produced. Improve gastric mucosal lesions (erosion, bleeding, redness, edema) in acute gastritis and acute attack of chronic gastritis. The experimental models used to test the therapeutic effect of drugs on gastric ulcer can generally be divided into acetic acid burning type and pyloric ligation type. The following two experimental models will be used in the present invention to test the therapeutic effect of compound preparations on gastric ulcer.

Test Example 1 The experimental model of compound preparation on the therapeutic effect of acetic acid burning type gastric ulcer The control test of the acetic acid burning type ulcer model

Grouping of animals: Healthy SD rats, half of ♀♂ and half of each, randomly divided into groups according to body weight. Administration was divided into blank control group (vehicle is 1% sodium methylcellulose solution), troxipide (S) group, ranitidine hydrochloride group (R) and compound 1, 2, 3, 4 groups (two drug compatibility group). Each experimental group was given medicine once at 8:00 am on the first day, starved for 24 hours, and had free access to water. In the morning of the next day, the drug was administered again, and 6 hours later, the abdominal cavity was opened under anesthesia with pentobarbital sodium (5 mg/kg) and ether anesthesia to expose the gastric body. A glass tube with an inner diameter of 5 mm and a length of 30 mm was placed vertically on the serosa surface of the gastric body, and 0.2 ml of glacial acetic acid was injected into the lumen. After 15 minutes, the glacial acetic acid was moistened with a cotton swab, and the surgical incision was sutured. After the operation, a normal diet and free drinking water were given. Irrigation once a day, a total of 10 days. After 10 days, they were sacrificed, their stomachs were dissected, fixed with 1% formaldehyde, and the number and area of ulcers were measured. Data statistical processing: SPSS11.0 statistical software was used for analysis. Y test was used: P<0.05 was considered statistically significant.

The dosage and experimental results are shown in Table 1.

Table 1 Therapeutic effect of troxipide and ranitidine hydrochloride on acetic acid burning type gastric ulcer model

Note: Compared with the blank control group, P<0.01; compared with the troxipide group (S), P<0.05 (F2, 3); P<0.01 (F4); compared with the ranitidine hydrochloride group (R) , P<0.05 (F1, 3); P<0.01 (F2, 4).

Experimental conclusion: the therapeutic effect on the model of acetic acid burning gastric ulcer

As can be seen from Table 1, the administration groups have significant anti-gastric ulcer effects; the curative effect of the combination of the two drugs is better than that of troxipide and ranitidine hydrochloride alone. The therapeutic effect is better when combined with ranitidine hydrochloride. The experimental results show that the compound preparation made of the two drugs can play a synergistic therapeutic effect, thereby improving the therapeutic effect.

Experimental Model of Experimental Example 2 Therapeutic Effect of Compound Preparation on Pyloric Ligation Type Gastric Ulcer

Establishment of Pylorus Ligated Gastric Ulcer Model

Grouping of animals: Healthy SD rats, half of ♀♂ and half of each, randomly divided into groups according to body weight. Administration was divided into blank control group (vehicle is 1% sodium methylcellulose solution), troxipide (S) group, ranitidine hydrochloride group (R) and compound 1, 2, 3, 4 groups (two drug compatibility group). The drug was administered one day before the 72-hour fast, once a day, 4 times in total. Six hours after the last administration, the pylorus was sutured after laparotomy and ligation under pentobarbital sodium plus ether anesthesia. Eighteen hours after the operation, the stomach was dissected and stored in a cryopreservation, and 8ml of 1% formaldehyde solution was injected into the gastric cavity. Immerse the stomach in 1% formalin solution, cut it open along the greater curvature of the stomach after 10 minutes, observe the occurrence of gastric ulcers, count the area of gastric ulcers, and convert them into ulcer index according to their sum and size. 5 levels. Ulcer area (mm): 1-12; 13-24; 25-37; 38-49; ≥50; the corresponding ulcer index: 1; 2; 3; 4; 5. Data statistical processing: SPSS11.0 statistical software was used for analysis. Y test was used: P<0.05 was considered statistically significant.

The dosage and experimental results are shown in Table 2.

Table 2 Therapeutic effect of troxipide (S) and ranitidine hydrochloride (R) on the pylorus-ligated gastric ulcer model

Note: Compared with the blank control group, the P<0.01 of F1, 2, 3, 4.

Experimental conclusion: the therapeutic effect on the pylorus-ligated gastric ulcer model

The independent administration of ranitidine hydrochloride and troxipide can reduce the ulcer index but not statistically significant; the combined use of the two drugs can further reduce the ulcer index, which has a significant preventive effect (P<0.01). The results showed that the compound prescription had a better therapeutic effect than the single prescription of the two medicines, and the difference was statistically significant.

In summary, the compound preparation of ranitidine hydrochloride and troxipide can treat gastric mucosal lesions in the acute attack stage of acute gastritis and chronic gastritis, as well as heartburn and acid regurgitation caused by hyperacidity, and other gastrointestinal diseases. It can also enhance defense factors, promote the repair of ulcer lesions, improve the blood circulation and metabolism of gastric mucosa at the ulcer site, and normalize the composition of gastric membrane tissue.

The following examples are respectively the examples of tablets, capsules and granules in compound preparations, wherein the preparation methods of these tablets, capsules and granules can be prepared according to conventional methods in this field, and the following formula contents all refer to amount used during preparation.

Embodiment 1 common tablet formula (in every tablet)

Ranitidine Hydrochloride 50mg

Troxipide 50 mg

Microcrystalline Cellulose 200mg

Starch 100 mg

Lactose 75 mg

8% starch slurry 200 mg

Sodium carboxymethyl starch 20mg

Magnesium stearate 2 mg

Embodiment 2 common tablet formula (in every tablet)

Ranitidine Hydrochloride 50mg

Troxipide 100 mg

Microcrystalline Cellulose 200 mg

Starch 75 mg

Lactose 45 mg

70% ethanol 200mg

Sodium carboxymethyl starch 20mg

Magnesium stearate 2 mg

Embodiment 3 common tablet formula (in every tablet)

Ranitidine Hydrochloride 50mg

Troxipide 200 mg

Microcrystalline Cellulose 150 mg

Starch 75 mg

8% starch slurry 200 mg

Polyvinylpolypyrrolidone 20mg

Magnesium stearate 2 mg

Embodiment 4 common tablet formula (in every tablet)

Ranitidine Hydrochloride 100mg

Troxipide 50 mg

Microcrystalline Cellulose 150 mg

Starch 100 mg

Lactose 75 mg

70% ethanol 200 mg

Sodium carboxymethyl starch 20 mg

Magnesium stearate 2 mg

Embodiment 5 common tablet formula (in every tablet)

Ranitidine Hydrochloride 100mg

Troxipide 100mg

Microcrystalline Cellulose 200 mg

Starch 45 mg

Lactose 35 mg

8% starch slurry 200 mg

Sodium carboxymethyl starch 20 mg

Magnesium stearate 2 mg

Embodiment 6 common tablet formula (in every tablet)

Ranitidine Hydrochloride 100 mg

Troxipide 200 mg

Microcrystalline Cellulose 100mg

Starch 75 mg

70% ethanol 200 mg

Polyvinylpolypyrrolidone 20 mg

Magnesium stearate 2 mg

Embodiment 7 common tablet formula (in every tablet)

Ranitidine Hydrochloride 150mg

Troxipide 50 mg

Microcrystalline Cellulose 200 mg

Starch 50 mg

8% starch slurry 200 mg

Sodium carboxymethyl starch 20 mg

Magnesium stearate 2 mg

Silica 1 mg

Embodiment 8 common tablet formula (in every tablet)

Ranitidine Hydrochloride 150mg

Troxipide 100 mg

Microcrystalline Cellulose 100 mg

Starch 50 mg

Lactose 55 mg

70% ethanol 200mg

Sodium carboxymethyl starch 20mg

Magnesium stearate 2 mg

Embodiment 9 common tablet formula (in every tablet)

Ranitidine Hydrochloride 150 mg

Troxipide 200mg

Microcrystalline Cellulose 100 mg

Starch 30 mg

8% starch slurry 200mg

Polyvinylpolypyrrolidone 20mg

Magnesium stearate 2 mg

Embodiment 10 common capsule formula (in every capsule)

Ranitidine Hydrochloride 150mg

Troxipide 100 mg

Starch 50 mg

Lactose 50 mg

70% ethanol 200 mg

Sodium carboxymethyl starch 20 mg

Micronized silica gel 40mg

Magnesium stearate 2 mg

Embodiment 11 granule formulation (in every bag of granules)

Ranitidine Hydrochloride 150mg

Troxipide 100mg

Stevioside 100 mg

Citric Acid 60 mg

Sodium bicarbonate 100mg

Lactose 50 mg

70% ethanol 200mg

Micronized silica gel 40 mg

Magnesium stearate 2 mg

Claims (16)

1. A compound preparation, which contains ranitidine hydrochloride and troxipide; wherein the ratio of said ranitidine hydrochloride to said troxipide is 6:1 to 1:6 by weight. 2. The compound preparation according to claim 1, wherein the ratio of the ranitidine hydrochloride to the troxipide is 3:1 to 1:4 by weight. 3. The compound preparation according to claim 2, wherein the content of the ranitidine hydrochloride in each single dose is 50-150 mg, and the content of the troxipide is 50-200 mg. 4. The compound preparation according to claim 3, wherein the ratio of the ranitidine hydrochloride to the troxipide is 2:1 to 1:3 by weight. 5. The compound preparation according to any one of claims 1-4, which is one of tablet, capsule or granule. 6. The compound preparation according to claim 5, wherein the tablet comprises the ranitidine hydrochloride and the troxipide, and a diluent, a binding agent, a lubricant and a disintegrant. 7. The compound preparation according to claim 5, wherein, said capsule comprises said ranitidine hydrochloride and said troxipide, and diluent, binding agent, lubricant, glidant and disintegrant. antidote. 8. compound preparation according to claim 5, wherein, described granule comprises described ranitidine hydrochloride and described troxipide, and diluent, binding agent, glidant, lubricant, correction agent Flavoring agents and effervescent excipients. 9. The compound preparation according to any one of claims 6-8, wherein the diluent is one or more of starch, lactose, and microcrystalline cellulose. 10. The compound preparation according to any one of claims 6-8, wherein the binder is starch slurry and/or ethanol. 11. The compound preparation according to any one of claims 6-8, wherein the lubricant is magnesium stearate and/or silicon dioxide. 12. The compound preparation according to claim 6 or 7, wherein the disintegrant is sodium carboxymethyl starch and/or polyvinylpolypyrrolidone. 13. The compound preparation according to claim 7 or 8, wherein the glidant is talcum powder and/or micronized silica gel. 14. The compound preparation according to claim 8, wherein the flavoring agent is stevioside and/or sucrose. 15. The compound preparation according to claim 8, wherein the effervescent adjuvant is citric acid and sodium bicarbonate. 16. Use of the compound preparation according to any one of claims 1-15 in the preparation of medicines for treating gastrointestinal diseases, wherein the gastrointestinal diseases include: acute gastritis and chronic gastritis in the acute exacerbation phase Gastric mucosal lesions, heartburn and acid reflux due to hyperacidity.