CN102276445B - Colloidal bismuth tartrate compound, medicaments thereof, preparation method thereof and application thereof - Google Patents

Abstract

The invention relates to a colloidal bismuth tartrate compound (i.e. bismuth potassium polytartrate), specifically bismuth potassium polytartrate tetrahydrate (molecular formula is C ₂₀ H ₁₉ O ₂₉ Bi ₂ K ₃ 4H ₂ O) and its medicine and Preparation methods and applications. The compound forms a stable colloidal solution in water with a sedimentation volume ratio ≥ 99%, and is insoluble in organic solvents such as ethanol and acetone. Said compound is added with pharmaceutically acceptable excipients as pharmaceutical active ingredients to make pharmaceutical compositions such as capsules, tablets, granules, solutions, etc., which can be used to treat chronic nonspecific Heterosexual ulcerative colitis, chronic colitis, irritable bowel syndrome, chronic diarrhea, Helicobacter pylori-associated peptic ulcer, chronic erosive gastritis, and chronic atrophic gastritis.

Description

A kind of colloidal bismuth tartrate compound and its medicine, preparation method and application

technical field

The present invention relates to a colloidal bismuth tartrate compound (i.e. bismuth potassium polytartrate), especially bismuth potassium polytartrate tetrahydrate (its molecular formula is C ₂₀ H ₁₉ O ₂₉ Bi ₂ K ₃ 4H ₂ O) and its preparation method and application. The compound is used as a pharmaceutical active ingredient and a pharmaceutical composition prepared from a pharmaceutically acceptable auxiliary material, which can be used to treat chronic colon diseases with high clinical incidence, long course of disease, easy recurrence, and cancer tendency, and can also treat peptic ulcer and gastritis. It belongs to the field of medicine.

Background technique

In 1928, the U.S. patent (U.S.pad.1663,201) disclosed and in 1949, the British Pharmacopoeia included bismuth sodium tartrate as a drug for treating hyperacidity and indigestion. In 1993, the British company Glencoxol applied for a patent in China on the preparation method of furan derivatives involving bismuth tartrate. In 1992, Yu Xuemin, a researcher at the Datong Institute of Materia Medica, obtained a Chinese invention patent for the preparation method of colloidal bismuth tartrate (patent number: ZL92114664.7). The structural formula of sodium bismuth tartrate disclosed in the above-mentioned patent or colloidal bismuth tartrate compound is:

Molecular formula C ₈ H ₉ 0 ₁₂ Bi or C ₈ H ₈ O ₁₂ BiNa, molecular weight 506 or 529, bismuth content 35%-75%, generally 70%-74%. Elemental analysis found values: C, 18.44%; H, 1.81%; O, 39.04%; Bi, 40%. Calculated values: C, 18.70%; H, 1.93%; O, 38.70%; Bi, 40.7%; measured moisture 1.54%, equivalent to 0.43 moles.

Invention patent (application number 200810004304.X inventor: Yu Xuemin) "a colloidal bismuth tartrate drug and its preparation method and application", the disclosed colloidal bismuth tartrate drug is: an oxide of tartaric acid and trivalent metal bismuth or its Pharmaceutical composition and capsule formed of salt and low methoxy-D-polygalacturonic acid.

Contents of the invention

One of the objects of the present invention is to provide a colloidal bismuth tartrate compound (bismuth potassium polytartrate). Specifically, the invention provides a bismuth potassium polytartrate compound, especially bismuth potassium polytartrate hydrate,

Significantly different from the aforementioned patents.

In order to realize the foregoing invention object, the technical scheme of the present invention is as follows:

The present invention provides a compound of the following formula (I), its pharmaceutically acceptable salt or hydrate:

The compound of the present invention as described above is preferably a hydrate.

As a preferred compound as described above, it is colloidal bismuth tartrate (bismuth potassium polytartrate hydrate) such as formula (I), the molecular formula is C ₂₀ H ₁₉ O ₂₉ Bi ₂ K ₃ ·nH ₂ O, wherein n is not 0 integer.

As one of the most preferred compounds of the present invention, the above-mentioned compound is polybismuth potassium polytartrate tetrahydrate of the above-mentioned formula (I), the molecular formula is C ₂₀ H ₁₉ O ₂₉ Bi ₂ K ₃ ·4H ₂ O, its The molecular weight is 1330. It has colloidal properties, so it is also called colloidal bismuth tartrate. It forms a translucent colloidal solution in water with a sedimentation volume ratio of ≥99.99%. It is insoluble in organic solvents such as ethanol, acetone, and ether, and easily soluble in alkaline solutions such as ammonia, Na ₂ CO ₃ , NaOH, and KOH. The aqueous solution is acidic, the pH value is 3.5-5.5, and the bismuth content is 30-34%.

As another object of the present invention, there is also provided a pharmaceutical composition prepared with the compound of the present invention as an active ingredient. The pharmaceutical composition provided by the present invention contains a therapeutically effective amount of the above-mentioned compound and pharmaceutically acceptable auxiliary materials. Wherein, the pharmaceutical composition, for example, can be capsules, tablets, granules, controlled-release preparations, sustained-release preparations, enteric-coated preparations, effervescent preparations, suppositories, pills, powders, solutions, syrups, mixed Dosage forms such as suspensions.

As the third object of the present invention, there is also provided a method for preparing the compound of the present invention, which includes the step of generating the colloidal bismuth tartrate (ie bismuth potassium polytartrate) compound by reacting tartaric acid with potassium metabismuthate.

Wherein, the above-mentioned method preferably further includes the step of reacting bismuth nitrate and potassium hydroxide in water to generate potassium metabismuthate.

As a preferred version, the method includes bismuth nitrate or bismuth oxynitrate and various tartrate optical isomers [comprising left-handed (-), dextro-rotary (+), meso (±), racemate (dt)] as a raw material, in the presence or absence of KOH, NaOH, ammonia water, under heating or non-heating conditions, adding or not adding a water-miscible organic solvent to prepare the above compound. The specific steps are: (1) adding tartaric acid (which can be various optical isomers of tartaric acid) into hot purified water under stirring, stirring to dissolve completely, and letting it cool. (2) Add bismuth nitrate into pure water under stirring, stir to suspend, add potassium hydroxide solution and stir to complete hydrolysis (the filtrate is added to potassium hydroxide solution and no precipitation occurs). (3) Centrifugal filtration, repeated washing with pure water until there is almost no NO ₃ ^- (tested with p-aminobenzenesulfonic acid-α-naphthylamine test solution and zinc powder), centrifugal drying, to obtain bismuth potassium oxynitrate (metabismuth acid Potassium) filter cake. (4) Suspending the potassium metabismuth filter cake in pure water under stirring, adding polyhydric alcohol co-solvents such as sorbitol under stirring, adding potassium hydroxide solution, and stirring until the white precipitate becomes a translucent colloidal solution to obtain partial Potassium bismuthate solution. (5) Add the tartaric acid solution into the potassium metabismuthate solution under stirring, react for 0.5-1h, and cool to obtain a bismuth potassium polytartrate solution. (6) Add ethanol sinking gel into the bismuth potassium polytartrate solution under stirring, centrifugally filter, top wash with ethanol, and obtain the wet crude product of polycolloidal bismuth tartrate. (7) Add the wet crude product of colloidal bismuth tartrate into pure water under stirring, heat and stir to form a colloidal dispersion, cool, add ethanol to sink the gel, centrifugally filter, and dry to obtain the product, which can also be obtained by spray drying the colloidal dispersion product.

As the fourth object of the present invention, it also provides a method for preparing a pharmaceutical composition comprising a therapeutically effective dose of the compound of the present invention as an active ingredient and pharmaceutically acceptable auxiliary materials. Including active ingredient and auxiliary material ratio, mixing, adding appropriate amount of binder to granulate, or dry powder mixed without granulation to form a solid oral preparation made by direct tableting, capsules, bags, etc. Including solutions, syrups and other liquid oral preparations made by dissolving or suspending, adding cosolvents or suspending agents, etc. Wherein the excipients can be selected from one or more of pectin, sodium alginate, microcrystalline cellulose, kaolin, starch, dextrin, powdered sugar, talcum powder, stearic acid, propylene glycol, glycerin, etc. .

As the fifth object of the present invention, the application of the compound of the present invention and its pharmaceutical composition is also provided. Specifically, the compounds or pharmaceutical compositions of the present invention described above can be used for the treatment of gastrointestinal diseases, especially chronic non-specific ulcerative colitis, chronic colitis, irritable bowel syndrome, chronic diarrhea, and Helicobacter pylori Bacillus-associated gastric ulcer, duodenal ulcer, chronic erosive gastritis, chronic atrophic gastritis.

The advantages of the present invention are highlighted in: compared with the existing bismuth tartrate medicine, the compound of the present invention is roughly the same in treating diseases, but because the compound of the present invention is a polymer with large molecular weight and high bismuth content, it can be used as a prodrug in the stomach Slow depolymerization in the intestinal juice releases bismuth tartrate monomer, which has the function of sustained release preparation, prolongs the residence time of the drug in the gastrointestinal tract, increases the effective drug concentration of the drug in the target cells, reduces the dosage of the drug, and reduces the side effects. For example, the dosage in comparative literature (such as patent No. ZL92114664.7) is 165 mg (calculated as bismuth) each time, three times a day, half an hour before meals, and once before going to bed. And medicine of the present invention is 110mg (calculated in bismuth) every time taking dosage, twice a day, all can take before and after meals.

The compound of the present invention and preparation are to the therapeutic effect of rabbit experimental ulcerative colitis, the total number of ulcers (one) after treatment is 5.5 ± 1.6, and lesion length (cm) is 13.33 ± 4.89, and ulcer diffusion length (cm) is 4.42 ± 1.78, The number of ulcers with a diameter greater than 5cm (pieces) was 0.33±0.5, and the ulcer inhibition rate (%) was 47.6±5.77. The total number of ulcers, lesion length, ulcer diffusion length, number of large ulcers, and ulcer inhibition rate in the model control group were: 10.5±4.2, 23.97±3.8, 7.92±2.5, 1.5±1.05, 0; ± 2.9, 16.63 ± 4.27, 5.45 ± 1.11, 1.33 ± 0.5, 36.5 ± 4.87; the difference between the drug of the present invention and the model control group and the drug group in the comparative literature is significant (P<0.01), and the curative effect of the former is significantly better than that of the latter . The above-mentioned indexes of matched group sulfasalazine (SASP) are respectively 4.6 ± 1.4, 10.60 ± 3.77, 2.4 ± 1.14, 0.31 ± 0.4, 49.2 ± 7.16, and there is no significant difference between the medicine of the present invention and SASP (P > 0.05). The same efficacy in the treatment of experimental ulcerative colitis in rabbits. However, the medicine of the present invention has no toxic and side effects of SASP, and has the same curative effect as the medicine in comparative literature in the aspect of treating rabbit experimental ulcerative colitis.

Compound of the present invention and preparation thereof clinically treat chronic ulcerative colitis, chronic colitis, irritable bowel syndrome total effective rate is respectively: 89.5%, 84.6%, 88.8%; knot), 58.9% (slow knot); the total effective rate of the contrast drug norfloxacin in the treatment of chronic colitis was 50.0%; the total effective rate of the contrast drug phenethylpiperidine in the treatment of irritable bowel syndrome was 59.6%. The curative effect of the medicine of the present invention is equivalent to that of SASP in clinical treatment of chronic ulcerative colitis, but it has no toxic and side effects such as nausea, vomiting, fever, rash, granulocytopenia, aplastic anemia, and sperm count reduction that SASP has. The curative effect in treating chronic colitis is obviously better than SASP and norfloxacin, and the curative effect in treating irritable bowel syndrome is obviously better than diphenethylpiperidine. In clinical treatment of peptic ulcer, chronic erosive gastritis (superficial gastritis) and chronic atrophic gastritis, it is equivalent to bismuth preparations and colloidal pectin bismuth in comparative literature.

Detailed ways

The following examples are for understanding and illustrating the technical solution of the present invention, but are not intended to limit the scope of the invention.

Example 1

Add 22.75g of bismuth nitrate into 75ml of water under stirring, add 12.5ml of potassium hydroxide solution (equivalent to 4.75g of solid alkali), and filter with suction to obtain a filter cake, which is washed until there is almost no NO ₃ ^- . Add 37.5ml of water to the filter cake, add 16.2ml of sorbitol and other polyhydric alcohol co-solvents (content 20%), fully stir, add 10ml of potassium hydroxide solution and stir to dissolve. Dissolve 16.4g of tartaric acid in 28.75ml of hot water, let cool, add to bismuth oxynitrate solution with stirring, cool, add ethanol (or acetone) with stirring, filter with suction, and dry to obtain the compound of the present invention.

Product properties: form a colloidal solution in water, the sedimentation volume ratio is ≥99.99%. Insoluble in ethanol, acetone, ether and other organic solvents, the pH value is 3.5-5.5, and the appearance is white amorphous powder.

Take about 0.1g of this product, acidify with 3ml of dilute sulfuric acid, add potassium iodide test solution dropwise to form a dark brown solution, and dissolve in excess potassium iodide test solution to form an orange solution.

Take about 0.1g of this product, add 10ml of water, shake well, acidify with dilute sulfuric acid, add 10% thiourea solution to produce yellow color.

Take about 0.2g of this product, add 2ml of water, shake well, add sodium bicarbonate solution to adjust to neutral, add ammonia to prepare a few drops of silver nitrate test solution, heat it on a water bath, and a silver mirror appears on the test tube wall.

Elemental Analysis Results:

Measured values: C, 17.72%; H, 2.27%; O, 39.02%; Bi, 32.09%; K, 8.40%;

Calculated values: C, 18.04%; H, 2.02%; O, 39.70%; Bi, 31.43%; K, 8.8%;

Infrared spectrum (KBr pellet) data and analysis. At 2600cm ^-1 to 3000cm ^-1 , the peaks of carboxyl and alcoholic hydroxyl groups in the carboxyl group are given, at 1730cm ^-1 is the peak of the carbonyl group of the associated hydroxyl group, at 1590cm ^-1 is the peak of the carbonyl group of the asymmetric carboxylate anion, Symmetric carboxylate anion carboxyl peaks are located at 1380cm ^-1 and 1310cm ^-1 .

Carboxylic acid has a characteristic absorption peak at 2600cm ^-1 to 3000cm ^-1 , the peak is 2974.0cm ^-1 and the intensity is 39.84, which clearly shows the carbonyl and hydroxyl in the carboxylic acid molecule. The free hydroxyl group has a characteristic absorption peak at 2400cm ^-1 to 2800cm ^-1 , the peak is 2504.0cm ^-1 and the intensity is 51.76. In addition, there are also characteristic absorption peaks at 1050cm ^-1 to 1280cm ^-1 , the peaks are 1066.0cm ^-1 , 1134.0cm ^-1 , 1213.0cm ^-1 , 1263.0cm ^-1 , and the intensities are 7.74, 10.40, 9.61, 7.69, respectively. There is a characteristic absorption peak at 1650cm ^-1 to 1750cm ^-1 , the peak is 1725cm ^-1 and the intensity is 20.91. Carboxylate ions have characteristic absorption peaks at 1500cm ^-1 to 1650cm ^-1 , the peak is at 1590cm ^-1 and the intensity is 5.70. In summary, the infrared spectrum clearly shows that the molecule contains carboxylic acid (carbonyl and hydroxyl), free hydroxyl, ester bond and carboxylate ion (salt), supporting the existence of

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and other functional groups.

Mass spectrometry data and analysis. In the high-quality area of the spectrum, the fragment corresponding to mass number 508 is [M+2H] ⁺ , the fragment corresponding to mass number 483 is [M-HCO ₂ H+Na] ⁺ , and the fragment corresponding to mass number 445 is [M-CO ₂ HH ₂ O+2H] ⁺ , the fragment corresponding to mass number 426 is [M-CO ₂ H-2H ₂ O+H] ⁺ , the fragment corresponding to mass number 416 is [M-2CO ₂ H] ⁺ , mass number 407 The corresponding fragment is [M-CO ₂ H-3H ₂ O] ⁺ , the fragment corresponding to mass number 550 is [M-2CO ₂ HH ₂ O+2H] ⁺ , the fragment corresponding to mass number 601 is [M-CO ₂ H -2H ₂ O+Na+3H] ⁺ . Hydrogenation and sodium addition of molecular ions and fragment ions are characteristic of fast atom bombardment mass spectrometry. Decarboxylation and dehydration are common cracking methods of carboxylic acids. Fragments corresponding to mass numbers of 508, 483, 445, 426, 416, and 407 are clearly given with a molecular weight of 506, and the molecules contain hydroxyl and carboxyl groups. Fragments corresponding to masses 550 and 601 clearly give a fragment molecular weight of 656 with the presence of hydroxyl and carboxyl groups. The molecular formula corresponding to the molecular weight of 506 is C ₈ H ₉ O ₁₂ ·Bi, the molecular formula corresponding to the molecular weight of 656 is C ₁₂ H ₁₅ O ₁₈ ·Bi, and the molecular formula of C ₈ H ₉ O ₁₂ ·Bi and C ₁₂ H ₁₅ O ₁₈ in the product molecule · Bi is linked by an ester bond.

UV spectrum data and analysis. This product has a maximum absorption at 200nm, corresponding to the carboxylate n-π transition.

Comprehensive element analysis, infrared spectrum analysis, mass spectrometry analysis, ultraviolet spectrum analysis, the compound molecule contains hydroxyl, carboxyl ion, ester bond, showing the structure of hydroxy acid, the results of element analysis also support the molecule contains five tartaric acid, two bismuth ions, three potassium ions and about 4 moles of water (5.40%). The chemical structural formula is as follows, the molecular formula is C ₂₀ H ₁₉ O ₂₉ Bi ₂ K ₃ ·4H ₂ O, the molecular weight is 1330, and the bismuth content is 32±2%. It forms a stable colloidal solution in water, and the sedimentation volume ratio is ≥99.9%.

Example 2

Add 22.75g of bismuth nitrate into 75ml of water under stirring, add 12.5ml of potassium hydroxide solution (equivalent to 4.75g of solid alkali), and filter with suction to obtain a filter cake, which is washed until there is almost no NO ₃ ^- . Add 16.2ml of sorbitol and other polyalcohol co-solvents (content 20%), add an appropriate amount of ammonia water, stir well to dissolve. Dissolve 16.4g of tartaric acid in 28.75ml of hot water, let it cool, add it into the bismuth oxynitrate solution with stirring, remove ammonia by evaporation, filter, wash with water, and dry to obtain the compound of the present invention. Through spectral analysis, it is determined that its chemical structure is the same as that of the compound in Example 1.

Example 3

Add 8.5g of bismuth subnitrate into 50ml of potassium hydroxide (5%) hot solution under stirring, and heat to 90-100°C under stirring to obtain potassium bismuth oxynitrate (potassium metabismuthate) solution. Dissolve 16.4g of tartaric acid in 28.75ml of hot water, let it cool, add it into the potassium bismuth oxynitrate (potassium metabismuthate) solution under stirring, reflux until the sample is dissolved by adding ammonia water, cool, filter with suction, and add a small amount of ethanol Washing, suction filtration, drying to obtain the compound of the present invention. Through spectral analysis, it is determined that its chemical structure is the same as that of the compound in Example 1.

Example 4

Weigh 33g of the compound of Example 1 of the present invention, 16g of pectin, and 16g of starch and pulverize them through a 100-mesh sieve, fully mix 1g of magnesium stearate with the above-mentioned raw materials, calculate the loading, and load them into hollow capsules. The content is measured, and the content of each capsule is 90-110% of 55 mg (calculated as bismuth). Determination of the disintegration time limit shall not exceed 0.5h.

Example 5

Weigh 33g of the compound of Example 1 of the present invention, 15g of starch, and 15g of kaolin and pulverize them through a 100-mesh sieve, fully mix 3g of talcum powder with the above-mentioned raw materials, calculate the loading, and put them into hollow capsules. The content is measured, and the content of each capsule is 90-110% of 55 mg (calculated as bismuth). Determination of the disintegration time limit, in line with the standards of capsules.

Example 6

Weigh 33g of the compound of Example 1 of the present invention, 15g of pectin, 15g of kaolin, and 3g of talcum powder, mix and pulverize them through a 100-mesh sieve, calculate the loading, and load them into hollow capsules. The content is determined, and the content of each capsule is 90%-110% of 55 mg (calculated as bismuth). Determination of the disintegration time limit, in line with the requirements of capsules.

Example 7

Take by weighing 99g of the compound of Example 1 of the present invention, 49g pectin, 25g starch, 25g powdered sugar, mix and pulverize through a 100 mesh sieve, use starch (or dextrin) paste and ethanol mixed binder to make soft material, granulate, Dried, granulated and bagged. Each bag contains 90%-110% of 110 mg (calculated as bismuth) of the compound of the present invention. Determination of dissolution, should be 85% of 110mg.

Example 8

Weigh 33g of the compound of Example 1 of the present invention, 15g of kaolin, 15g of starch, and 3g of talcum powder, mix and pulverize them through a 100-mesh sieve, use ethanol-water as a binder, make soft materials, granulate, and compress into tablets. The content of each tablet is 90%-110% of 55 mg (calculated as bismuth). Determination of the disintegration time limit, in line with the requirements of the tablet.

Example 9

1. the therapeutic effect of colloidal bismuth tartrate of the present invention on rabbit experimental ulcerative colitis

1.1 Animal model preparation Rabbit colonic mucosal homogenate plus complete Freund's adjuvant was used to immunize animals, and boosted once after 10 days, continued to observe for 10 days, and then began to administer medicine (the compound of Example 1).

1.2 Dosage and Observation Index The dosage is 50mg/100g/d by intragastric administration. The observation indicators are the total number of ulcers, the number of ulcers with a diameter greater than 5 cm, the length of ulcer spread (the long diameter of the ulcer lesion), the length of the lesion (the total length of the lesion on the colon), and the ulcer inhibition rate [(number of ulcers in the saline control group - number of ulcers in the drug treatment group) /Number of ulcers in the saline control group].

1.3 Experimental results After 20 days of animal immunization, most of the animals had loose stools and bloody stools. After autopsy, it was found that the colonic mucosa showed diffuse inflammation and ulcers, mainly infiltrated by neutrophils, and eosinophils could be seen. There are different degrees of congestion and hemorrhage, muscle edema, and visible muscle fiber rupture. After 10 days of medication, compared with the model control group, the number of ulcers was significantly reduced, and the length of lesions and the length of ulcer diffusion were significantly shortened. The total number of ulcers (pieces) was reduced from 10.5±4.2 in the model control group to 5.5±1.6, the lesion length (cm) was reduced from 23.97±3.8 in the model control group to 13.33±4.89, and the ulcer spread length (cm) was reduced from 7.92 in the model control group. ±2.5 was reduced to 4.42±1.78, the number of large ulcers was reduced from 1.5±1.05 in the model control group to 0.33±0.5, and the ulcer inhibition rate was 47.6±5.77%. The ulcer inhibition rate was 36.5±4.87%. Compared with the model control group, there is a significant difference (P<0.01), and there is a significant difference (P<0.05) compared with the drug group in the comparative literature.

2. The therapeutic effect of colloidal bismuth tartrate of the present invention on experimental chronic gastric ulcer in rats

2.1 Animal model preparation Wistar female rats weighing 200±20g were selected, starved for 4 hours, laparotomed, 0.05ml of 10% acetic acid was injected into the gastric serosa at 0.5cm above the pylorus, and sutured immediately. The drug (the compound of Example 1) was started, and the drug was shared for 8 days. At 8:00 am on the 9th day, the animals were sacrificed, and the gastric lesions were observed.

2.2 Dosage and Observation Index The dosage is 50mg/100g/d by intragastric administration. The observation indexes were ulcer area, ulcer inhibition rate and ulcer volume.

2.3 Experimental results The colloidal bismuth tartrate of the present invention can significantly inhibit the chronic gastric ulcer induced by acetic acid, and significantly reduce the area and volume of the gastric ulcer. The ulcer area (mm ² ) was reduced from 0.72±0.35 in the model control group to 0.15±0.10, the ulcer volume (ul) was reduced from 41.7±19.5 in the model control group to 9.3±6.1, and the ulcer inhibition rate was 79%. (Patent No.: ZL92114664.7) The drug ulcer inhibition rate is 70%. Compared with the model control group, there is a significant difference (P<0.01), and there is a significant difference (P<0.05) compared with the drug group in the comparative literature.

3. The therapeutic effect of colloidal bismuth tartrate of the present invention on experimental duodenal ulcer in rats

3.1 Animal model preparation According to the Szado method, cysteamine hydrochloric acid solution was administered to establish the model.

3.2 Dosage and Observation Index The dosage is 50mg/100g/d by intragastric administration. According to Szado's grading method, it is divided into 0-7 grades: 0 is no change, 1 is mucosal hyperemia, 2 is mucosal hemorrhage, 3 is necrosis, 4 is mucosal erosion, 5 is superficial ulcer, 6 is deep ulcer, and 7 is ulcer. Full-thickness ulcer perforation of intestinal wall.

3.3 Experimental results The average score of duodenal injury in rats in the blank control group was 5.33±1.37, that of colloidal bismuth tartrate of the present invention was 2.2±1.5, and that of the control group (patent number: ZL92114664.7) was 3.0±1.0. Compared with the blank control group, there is a significant difference (P<0.01), and there is a significant difference (P<0.05) compared with the drug group in the comparative literature.

4. The therapeutic effect of colloidal bismuth tartrate of the present invention on rabbit experimental chronic gastritis

4.1 Animal model preparation Rabbit gastric mucosal homogenate plus complete Freund's adjuvant was used to immunize animals, and a booster was given 10 days later. The observation was continued for 10 days, and the drug (compound of Example 1) was started.

4.2 Dosage and Observation Index The dosage is 50mg/100g/d by intragastric administration. The observation indicators were lesion area (lesion transverse diameter × lesion longitudinal diameter) and number of ulcers.

4.3 Experimental results After 10 days of medication, the colloidal bismuth tartrate of the present invention and the comparative literature (Patent No.: ZL92114664.7) can reduce the lesion area and reduce the number of ulcers. The colloidal bismuth tartrate of the present invention reduces the lesion area (cm ² ) from 80.17±33.1 in the model control group to 12.33±10.9, and the number of ulcers (pieces) is reduced from 0.5±0.55 to 0.17±0.4, which is significantly different from that in the model control group (P<0.01). Compared with literature, the lesion area of the drug group was reduced to 17.81±9.6, and the number of ulcers was reduced to 0.28±0.39, and the difference between the two groups was significant (P<0.05).

Example 10

1. the clinical curative effect of colloidal bismuth tartrate of the present invention treatment chronic colitis

1.1 Selected cases with symptoms of long-term abdominal pain, diarrhea, mucus stool, tenesmus; negative stool culture; endoscopic examination showed intestinal mucosal congestion, edema, and uneven mucosal particles, but no typical ulcer changes.

1.2 Dosage and curative effect determination standard: 110mg twice a day, each time. Significantly effective: the symptoms disappeared, and the degree of inflammation was reduced by histological examination. Effective: Symptoms are significantly improved, and the degree of inflammation is relieved by histological examination. Ineffective: No change in clinical symptoms and histological examination of inflammation.

1.3 Therapeutic results The obvious efficiency of colloidal bismuth tartrate of the present invention (embodiment 1 compound) treatment chronic colitis is 66.7%, and the total effective rate is 84.6%; The obvious effective rate of SASP of the control group is 32.4%, and the total effective rate is 58.9%; The effective rate of norfloxacin was 26.9%, and the total effective rate was 50.0%, the differences were significant (P<0.01). The comparative literature (Patent No.: ZL92114664.7) of the control group had a marked effective rate of 54.8% and a total effective rate of 78.2%, with a significant difference (P<0.05).

2. The clinical efficacy of colloidal bismuth tartrate of the present invention in the treatment of chronic nonspecific ulcerative colitis

2.1 Case selection Symptoms were abdominal pain, diarrhea, bloody stool, tenesmus; endoscopic examination consistent with ulcerative colitis changes; stool culture was negative; biopsy showed erosion, ulcer, crypt abscess, glandular epithelial degeneration, hyperplasia and goblet cell reduction .

2.2 Dosage and curative effect judging criteria are the same as 1.2.

2.3 Treatment results The effective rate of colloidal bismuth tartrate (compound of Example 1) of the present invention was 73.7%, and the total effective rate was 89.5%; the effective rate of SASP in the control group was 53.3%, and the total effective rate was 86.7%. Compared with the SASP group, there was a significant difference in the effective rate (P<0.05), but there was no significant difference in the total effective rate (P>0.05). The control group compared with the literature (Patent No.: ZL92114664.7) has a marked effect rate of 67.4%, and a total effective rate of 72.7%, which is significantly different from the comparison literature (P<0.05). In clinical observation, 5 cases of nausea and vomiting, 3 cases of fever and rash, and 1 case of leukopenia occurred in the SASP group. The incidence of toxic and side effects accounted for 21% of the total cases. Neither the colloidal bismuth tartrate of the present invention nor the drug in the comparative literature has any obvious toxic and side effects in the treatment.

3. The clinical efficacy of colloidal bismuth tartrate of the present invention in the treatment of irritable bowel syndrome

3.1 Selected cases with symptoms of abdominal pain, diarrhea, defecation after meals, relief after defecation, abdominal flatulence, negative stool culture, only mild congestion or normal intestinal mucosa under endoscopy.

3.2 Dosage and Curative Effect Judgment Criteria Take 110 mg orally twice a day, each time. Markedly effective: symptoms (abdominal pain, abdominal distension, diarrhea) disappear or basically disappear; effective: symptoms are significantly relieved; ineffective: symptoms do not change.

3.3 Treatment results The total effective rate of colloidal bismuth tartrate of the present invention (the compound of Example 1) in the treatment of irritable bowel syndrome is 88.8%, and that of phenethylpiperidine in the control group is 59.6%. The drug was 74.9%, and the difference was significant compared with the two control groups (P<0.01).

4. The clinical efficacy of colloidal bismuth tartrate of the present invention in the treatment of peptic ulcer

4.1 Case selection: Gastric ulcer and duodenal ulcer diagnosed by endoscopy.

4.2 Dosage and Curative Effect Judgment Criteria Take 110 mg orally twice a day, each time. Healing: the ulcer disappears or only scars are left under the gastroscope; effective: the area of the ulcer is reduced by >50%; ineffective: the area of the ulcer is reduced by <50% or expanded.

4.3 Treatment results The healing rate of colloidal bismuth tartrate of the present invention (the compound of Example 1) was 77.2% in 4 weeks, the total effective rate was 93.0%, and the negative rate of HP after treatment was 89.1%. ) drugs were 65.4%, 85.6% and 78.7% respectively. There is a significant difference between the two in the healing rate and total effective rate of peptic ulcer treatment (P<0.05), and there is a significant difference in the HP negative conversion rate (P<0.05).

5. The clinical efficacy of colloidal bismuth tartrate of the present invention in the treatment of chronic gastritis

5.1 Selected cases with symptoms of epigastric discomfort (dull pain, noisy feeling), and gastroscopic examination showed mucosal hyperemia, edema, and flaky bleeding points.

5.2 Dosage and curative effect determination Take 110mg orally twice a day, each time. Relief of symptoms: epigastric discomfort basically disappeared after treatment; inflammation reduced (pathological improvement): the level of inflammation in gastric antrum biopsy was lower than that before treatment.

5.3 Treatment results The symptom relief rate of colloidal bismuth tartrate (Example 1 compound) of the present invention is 85.2%, and the inflammation relief rate is 82.0%; The rate was 73.8%; the difference between the two groups was significant (P<0.05).

The invention has been described in terms of preferred embodiments. It should be understood that the foregoing description and examples are by way of illustration only of the invention. Without departing from the spirit and scope of the present invention, those skilled in the art can design various alternatives and improvements of the present invention, all of which should be understood as falling within the protection scope of the present invention.

Claims (7)

1. poly-tartaric acid bismuth complex potassium salt tetrahydrate, its molecular formula is C ₂₀H ₁₉O ₂₉Bi ₂K ₃4H ₂O, poly-tartaric acid bismuth complex potassium salt are as shown in the formula (I):

2. a pharmaceutical composition, is characterized in that comprising poly-tartaric acid bismuth complex potassium salt tetrahydrate claimed in claim 1 as active constituents of medicine and pharmaceutically acceptable auxiliary material.

3. composition according to claim 2, wherein said auxiliary material is selected from one or more in pectin, sodium alginate, Microcrystalline Cellulose, white bole, starch, dextrin, Icing Sugar, talcum powder, stearic acid, propylene glycol, glycerine.

4. according to claim 2 or 3 described compositions, it is capsule, tablet, granule, powder, suspensoid, solution or suppository.

5. the preparation method of poly-tartaric acid bismuth complex potassium salt tetrahydrate claimed in claim 1, its step is as follows:

(1) tartrate is under agitation joined in hot pure water, stir and make dissolving fully, let cool;

(2) under agitation Bismuth trinitrate is joined in pure water, stir and make suspension, add potassium hydroxide solution to stir and make hydrolysis fully;

(3) centrifuging uses the pure water repetitive scrubbing extremely almost without NO ₃ ^-, centrifuge dripping gets metabismuthic acid potassium filter cake;

(4) metabismuthic acid potassium filter cake under agitation is suspended in pure water, under agitation adds the sorbyl alcohol solubility promoter, add potassium hydroxide solution, be stirred to by white precipitate and become translucent colloidal solution, get the metabismuthic acid potassium solution;

(5) tartaric acid solution is under agitation joined in the metabismuthic acid potassium solution, reaction 0.5-1h, cooling, must gather the Bismuth tartrate potassium solution;

(6) under agitation add in the poly-Bismuth tartrate potassium solution ethanol to sink glue, centrifuging, the ethanol top is washed, and must gather the tartaric acid bismuth complex potassium salt crude product that wets;

(7) will gather the wet crude product of tartaric acid bismuth complex potassium salt and under agitation join in pure water, heated and stirred makes into colloidal dispersion, and is cooling, adds ethanol to sink glue, and product is dried to get in centrifuging, perhaps the colloidal dispersion spraying drying is got product.

6. poly-tartaric acid bismuth complex potassium salt tetrahydrate claimed in claim 1 or the described composition of claim 2-4 any one are for the preparation of the purposes for the treatment of gastrointestinal illness medicine.

7. purposes according to claim 6, wherein said gastrointestinal illness is selected from chronic non-specific ulcerative colitis, chronic colitis, irritable bowel syndrome, chronic diarrhoea, Hp dependency stomach ulcer, duodenal bulbar ulcer, chronic erosive gastritis, chronic atrophic gastritis.