CN102276445A - Colloidal bismuth tartrate compound, medicaments thereof, preparation method thereof and application thereof - Google Patents
Colloidal bismuth tartrate compound, medicaments thereof, preparation method thereof and application thereof Download PDFInfo
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Abstract
The invention relates to a colloidal bismuth tartrate compound (poly bismuth potassium tartrate), and especially relates to a poly bismuth potassium tartrate tetrahydrate (the molecular formula is C20H19O29Bi2K3.4H2O), medicaments thereof, a preparation method thereof, and an application thereof. The compound can form a stable colloidal solution in water with a settlement volume ratio of equal to or more than 99%, and is not dissolved in organic solvents of ethanol, acetone and the like. The compound can be treated as an active component of the medicaments to prepare into pharmaceutical compositions of a capsule, a tablet, a particulate agent, a solution and the like by adding with pharmaceutically acceptable accessories, the pharmaceutical compositions can be used for treating chronic non-specific ulcerative colonitis which is difficult to treat on clinic, easy to recur, and has a tendency to cancerization, chronic colonitis, irritable bowel syndrome, chronic diarrhoea, helicobacter pylori correlated digestive ulcer, chronic erosive gastritis, and chronic atrophic gastritis.
Description
Technical field
The present invention relates to a kind of Colloidal Bismuth Tartrate compound (promptly poly-tartaric acid bismuth complex potassium salt), (its molecular formula is C to particularly poly-tartaric acid bismuth complex potassium salt tetrahydrate
20H
19O
29Bi
2K
34H
2O) and its production and application.Described compound is as the pharmaceutical composition of active constituents of medicine with the preparation of acceptable auxiliary material pharmaceutically, can be used for treating incidence height, the course of disease chronic colon diseases long, that easily recur and have canceration to be inclined to clinically, also can treat peptide ulceration and gastritis.Belong to field of medicaments.
Background technology
Nineteen twenty-eight United States Patent (USP) (U.S.pad.1663,201) discloses and British Pharmacopoeia in 1949 has recorded Bismuth Sodium Tartrate (Bismuthi Sodium Tartate) and is used for the treatment of hyperchlorhydria and maldigestion medicine.Britain's Glan restrained plain company has applied for relating to Bismuth tartrate in China process for preparation of furan derivatives patent in 1993.Preparation method's Chinese invention patent (patent No.: ZL 92114664.7) of the quick acquisition jellied bismuth tartrate of Medicine Inst. of Datong City researcher Yu Xue in 1992.The structural formula of the Bismuth Sodium Tartrate of above-mentioned patent disclosure or Colloidal Bismuth Tartrate compound is:
Molecular formula C
8H
90
12Bi or C
8H
8O
12BiNa, molecular weight 506 or 529, bi content 35%-75% is generally at 70%-74%.Ultimate analysis measured value: C, 18.44%; H, 1.81%; O, 39.04%; Bi, 40%.Calculated value: C, 18.70%; H, 1.93%; O, 38.70%; Bi, 40.7%; Record moisture content 1.54%, be equivalent to 0.43 mole.
(application number 200810004304.X contriver: Yu Xuemin) " a kind of colloidal bismuth tartrate medicine and its production and use ", disclosed colloidal bismuth tartrate medicine is patent of invention: by the oxide compound of tartrate and trivalent metal bismuth or its salt and pharmaceutical composition and capsule that low-methoxyl-the D-polygalacturonic acid forms.
Summary of the invention
One of the object of the invention is to provide a kind of Colloidal Bismuth Tartrate compound (poly-tartaric acid bismuth complex potassium salt).Particularly, the invention provides a kind of poly-Bismuth tartrate potassium compound, particularly poly-tartaric acid bismuth complex potassium salt aquo compound, obviously different with aforementioned patent.
For achieving the above object, technical solution of the present invention is as follows:
The invention provides compound, its pharmaceutical salts or the hydrate of a kind of following formula (I):
The aforesaid compound of the present invention is preferably hydrate.
As preferred compound as mentioned above, it is that molecular formula is C suc as formula the Colloidal Bismuth Tartrate of (I) (poly-tartaric acid bismuth complex potassium salt hydrate)
20H
19O
29Bi
2K
3NH
2O, wherein whether n for or not 0 integer.
As one of most preferred compound of the present invention, aforesaid compound, it is the poly-tartaric acid bismuth complex potassium salt tetrahydrate as above-mentioned formula (I), molecular formula is C
20H
19O
29Bi
2K
34H
2O, its molecular weight are 1330.Have colloid property, therefore be also referred to as Colloidal Bismuth Tartrate.It forms translucent colloidal solution in water, settling volume is insoluble to organic solvents such as ethanol, acetone, ether than 〉=99.99%, is soluble in ammoniacal liquor, Na
2CO
3, alkaline solutions such as NaOH, KOH.The aqueous solution is acid, and the pH value is 3.5-5.5, bi content 30-34%.
As another goal of the invention of the present invention, also providing with the The compounds of this invention is the pharmaceutical composition that activeconstituents is prepared into, and pharmaceutical composition provided by the invention comprises the compound as mentioned above and the acceptable accessories for the treatment of significant quantity.Wherein, described pharmaceutical composition for example can be formulations such as capsule, tablet, granule, control-released agent, sustained release dosage, enteric coated preparation, effervescent, suppository, pill, powder, solution, syrup, suspensoid.
As the 3rd goal of the invention of the present invention, a kind of method for preparing The compounds of this invention also is provided, it comprises the step that is generated described Colloidal Bismuth Tartrate (promptly poly-tartaric acid bismuth complex potassium salt) compound by tartrate and metabismuthic acid nak response.
Wherein, above-mentioned described method preferably also comprises by Bismuth trinitrate and potassium hydroxide and react the step that generates metabismuthic acid potassium in water.
As preferred version, described method, it comprises that with Bismuth trinitrate or oxygen Bismuth trinitrate and various tartrate optically active isomer [comprising left-handed (-), dextrorotation (+), meso (±), racemic modification (dt)] be raw material, KOH, NaOH, ammoniacal liquor exist or not in the presence of, heating or not under the heating condition adds or does not add the method that the organic solvent that dissolves each other with water prepares above-claimed cpd.Concrete steps are: (1) under agitation joins tartrate (can be various optically active isomer tartrate) in the hot pure water, stirs to make dissolving fully, puts cold.(2) under agitation Bismuth trinitrate is joined in the pure water, stir and make suspension, add the potassium hydroxide solution stirring and make hydrolysis complete (filtrate adds potassium hydroxide solution and precipitation no longer occurs).(3) centrifuging does not extremely almost have NO with the pure water repetitive scrubbing
3 -(with Sulphanilic Acid-alpha-naphthylamine test solution and zinc powder test), centrifuge dripping gets oxygen Bismuth trinitrate potassium (metabismuthic acid potassium) filter cake.(4) metabismuthic acid potassium filter cake under agitation is suspended in the pure water, under agitation adds polyvalent alcohol solubility promoters such as sorbyl alcohol, add potassium hydroxide solution, be stirred to by white precipitate and become translucent colloidal solution, 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 in poly-Bismuth tartrate potassium solution, add the heavy glue of ethanol, centrifuging, the ethanol top is washed, and must gather the wet crude product of Colloidal Bismuth Tartrate.(7) the wet crude product of Colloidal Bismuth Tartrate is under agitation joined in the pure water, heated and stirred makes into colloidal dispersion, and cooling adds the heavy glue of ethanol, centrifuging, oven dry, product, also the colloidal dispersion spraying drying can be got product.
As the 4th goal of the invention of the present invention, provide also that to comprise treatment effective dose The compounds of this invention be the method for active ingredient and acceptable accessories pharmaceutical compositions.Comprise active ingredient with ratio of adjuvant, mix, the suitable suitable amount of adhesive of adding granulates, or the dry powder blend solid orally ingestible that direct compression, encapsulated, pack etc. make of not granulating.Comprise dissolving or suspend, add liquid oral medicines such as solution that solubility promoter or suspending agent etc. make, syrup.Wherein said auxiliary material can be selected from one or more in pectin, sodium alginate, Microcrystalline Cellulose, white bole, starch, dextrin, Icing Sugar, talcum powder, stearic acid, propylene glycol, the glycerine etc.
As the 5th goal of the invention of the present invention, also provide the application of The compounds of this invention and pharmaceutical composition thereof.Specifically, above-mentioned described The compounds of this invention or pharmaceutical composition can be used for treating the purposes of gastrointestinal illness, particularly chronic non-specific ulcerative colitis, chronic colitis, irritable bowel syndrome, chronic diarrhoea, and Hp dependency stomach ulcer, duodenal bulbar ulcer, chronic erosive gastritis, chronic atrophic gastritis.
Advantage outstanding behaviours of the present invention exists: compare with existing bismuthotartrate medicine, The compounds of this invention is roughly the same on the sick kind of treatment, but because The compounds of this invention is a polymkeric substance, molecular weight is big, bi content is high, and slow depolymerization in gastrointestinal fluid disengages the Bismuth tartrate monomer as prodrug, has the sustained release preparation effect, prolong drug is the residence time in gi tract, improve the active drug concentration of medicine in target cell, reduce dosage, alleviate toxic side effect.For example, the dosage in the documents (as patent No. ZL 92114664.7) is each 165mg (in a bismuth), three times on the one, take half an hour before the meal, and add once just before going to bed.And the each taking dose of medicine of the present invention is 110mg (in a bismuth), one day twice, all can take pre/after meal.
The compounds of this invention and preparation are to the therapeutic action of the experimental ulcerative colitis of rabbit, treatment back ulcer sum (individual) is 5.5 ± 1.6; length of lesion (cm) is 13.33 ± 4.89; ulcer diffusion length (cm) is 4.42 ± 1.78; diameter is 0.33 ± 0.5 greater than the ulcer number (individual) of 5cm, and ulcer inhibition rate (%) is 47.6 ± 5.77.Model control group ulcer sum, length of lesion, ulcer disperse length, big ulcer number, ulcer inhibition rate are respectively: 10.5 ± 4.2,23.97 ± 3.8,7.92 ± 2.5,1.5 ± 1.05,0; The above-mentioned documents medicine of control group is respectively 7.1 ± 2.9,16.63 ± 4.27,5.45 ± 1.11,1.33 ± 0.5,36.5 ± 4.87; Medicine of the present invention and model control group, documents medicine group comparison difference all have significance (P＜0.01), and the former curative effect is significantly better than the latter.Control group sulfasalazine (SASP) These parameters is respectively 4.6 ± 1.4,10.60 ± 3.77,2.4 ± 1.14,0.31 ± 0.4,49.2 ± 7.16, medicine of the present invention and SASP relatively difference do not have significance (P＞0.05), and both are therapeutic equivalence aspect the experimental ulcerative colitis of treatment rabbit.But medicine of the present invention does not have the toxic side effects that SASP has, and has the curative effect identical with the documents medicine aspect the experimental ulcerative colitis of treatment rabbit.
The compounds of this invention and preparation thereof are treated chronic ulcerative colitis, chronic colitis, irritable bowel syndrome aspect total effective rate clinically and are respectively: 89.5%, 84.6%, 88.8%; Contrast medicine SASP is respectively 86.7% (knot of bursting), 58.9% (knot slowly); Contrast medicine Norxin is 50.0% at total effective rate aspect the treatment chronic colitis; Contrast medicine diphenoxylate is 59.6% at total effective rate aspect the treatment irritable bowel syndrome.It is suitable with SASP that medicine of the present invention is treated chronic ulcerative colitis aspect curative effect clinically, but toxic side effect such as feeling sick of not having that SASP has, vomiting, heating, fash, granulocytopenia, aplastic anemia, spermatozoon minimizing.Curative effect is significantly better than SASP and Norxin aspect the treatment chronic colitis, and curative effect is significantly better than diphenoxylate aspect the treatment irritable bowel syndrome.It is suitable to treat peptide ulceration and chronic erosive gastritis (superficial gastritis), chronic atrophic gastritis aspect and documents bismuth preparation and Colloidal Bismuth Pectin clinically.
Embodiment
Following examples are in order to understand and technical solution of the present invention to be described, but do not constitute the invention interest field not being limited.
Embodiment 1
The 22.75g Bismuth trinitrate is under agitation joined in the 75ml water, add 12.5ml potassium hydroxide solution (amounting to solid caustic soda 4.75g), suction filtration gets filter cake, and washing leaching cake is to almost there not being NO
3 -Adding 37.5ml water adds polyvalent alcohol solubility promoters (content 20%) such as 16.2ml sorbyl alcohol in filter cake, fully stirs, and adds the stirring of 10ml potassium hydroxide solution and makes molten.16.4g tartrate is dissolved in the 28.75ml hot water, put cold after, stir down and join in the oxygen bismuth nitrate solution, cooling is stirred and is added ethanol (or acetone) down, suction filtration, oven dry gets The compounds of this invention.
The product proterties: form colloidal solution in water, sedimentation volume is than 〉=99.99%.Be insoluble to organic solvents such as ethanol, acetone, ether, the pH value is 3.5-5.5, and outward appearance is white amorphous powder.
Get the about 0.1g of this product,, drip the potassiumiodide test solution and generate dark brown solution, in excessive potassiumiodide test solution, be dissolved into orange solution with dilute sulphuric acid 3ml acidifying.
Get the about 0.1g of this product, add water 10ml and shake up, and use the dilute sulphuric acid acidifying, add 10% thiourea solution and generate yellow.
Get the about 0.2g of this product, add water 2ml and shake up, add sodium hydrogen carbonate solution and transfer to neutrality, ammonification system Silver Nitrate test solution number droplet heats in water-bath, occurs silver mirror on the test tube wall.
Results of elemental analyses:
Measured value: C, 17.72%; H, 2.27%; O, 39.02%; Bi, 32.09%; K, 8.40%; Record moisture content 4.74%, be equivalent to 3.5 moles.
Calculated value: C, 18.04%; H, 2.02%; O, 39.70%; Bi, 31.43%; K, 8.8%; Moisture content 5.40% is equivalent to 4 moles.
Infrared spectra (KBr compressing tablet) data and analysis.At 2600cm
-1To 3000cm
-1The place has provided carboxyl and alcoholic extract hydroxyl group peak in the carboxyl, at 1730cm
-1The place is the carbonyl peak of association hydroxyl, 1590cm
-1The place is asymmetric carboxylate anion's carbonyl peak, 1380cm
-1And 1310cm
-1The place is symmetric carboxylate anion's carboxyl peak.
Carboxylic acid is at 2600cm
-1To 3000cm
-1There are charateristic avsorption band, peak value 2974.0cm in the place
-1, intensity 39.84 has clearly provided carbonyl and the hydroxyl in the carboxylic acid molecules.Free hydroxyl group is at 2400cm
-1To 2800cm
-1It is 2504.0cm that there are charateristic avsorption band, peak value in the place
-1, intensity 51.76.In addition, at 1050cm
-1To 1280cm
-1Also there is charateristic avsorption band at the place, and peak value is respectively 1066.0cm
-1, 1134.0cm
-1, 1213.0cm
-1, 1263.0cm
-1, intensity is respectively 7.74,10.40,9.61,7.69.At 1650cm
-1To 1750cm
-1It is 1725cm that there are charateristic avsorption band, peak value in the place
-1, intensity 20.91.The carboxylic acid ion is at 1500cm
-1To 1650cm
-1It is 1590cm that there are charateristic avsorption band, peak value in the place
-1, intensity is 5.70.In sum, infrared spectra clearly provides and contains carboxylic acid (carbonyl and hydroxyl), free hydroxyl group, ester bond and carboxylic acid ion (salt) in the molecule, supports to exist in the molecule
Mass-spectrometric data and analysis.In the high quality district of collection of illustrative plates, the fragment of total mass number 508 correspondences is [M+2H]
+, the fragment of total mass number 483 correspondences is [M-HCO
2H+Na]
+, the fragment of total mass number 445 correspondences is [M-CO
2H-H
2O+2H]
+, the fragment of total mass number 426 correspondences is [M-CO
2H-2H
2O+H]
+, the fragment of total mass number 416 correspondences is [M-2CO
2H]
+, the fragment of total mass number 407 correspondences is [M-CO
2H-3H
2O]
+, the fragment of total mass number 550 correspondences is [M-2CO
2H-H
2O+2H]
+, the fragment of total mass number 601 correspondences is [M-CO
2H-2H
2O+Na+3H]
+Molion and fragmention hydrogenation, adding sodium, is the feature of fast atom bombardment mass spectroscopy(FABMS).Decarboxylation, dehydration are the common fragmentation patterns of carboxylic acid.Total mass number be the fragment of 508,483,445,426,416,407 correspondences all clearly to provide the fragment molecular weight be 506, and contain hydroxyl, carboxyl in the molecule.It is 656 that the fragment of total mass number 550 and 601 correspondences clearly provides the fragment molecular weight, and has hydroxyl and carboxyl.Molecular weight is that the molecular formula of 506 correspondences is C
8H
9O
12Bi, molecular weight are that the molecular formula of 656 correspondences is C
12H
15O
18Bi, C in the product molecule
8H
9O
12Bi and C
12H
15O
18Bi connects in the mode of ester bond.
Ultraviolet spectrum data and analysis.This product has maximum absorption at the 200nm place, corresponding to carboxylate salt n-π transition.
Comprehensive ultimate analysis, Infrared spectroscopy, mass spectroscopy, ultraviolet spectral analysis, contain hydroxyl, carboxylic ions, ester bond in this compound molecule, the structure of signify hydroxy acid, the result of ultimate analysis also support to contain in the molecule five tartrate, two bismuth ions, three potassium ions and about 4 moles of moisture content (5.40%).Chemical structural formula is as follows, and its molecular formula is C
20H
19O
29Bi
2K
34H
2O, molecular weight are 1330, and bi content is 32 ± 2%.Form stable colloidal solution in water, settling volume is than 〉=99.9%.
Embodiment 2
The 22.75g Bismuth trinitrate is under agitation joined in the 75ml water, add 12.5ml potassium hydroxide solution (amounting to solid caustic soda 4.75g), suction filtration gets filter cake, and washing leaching cake is to almost there not being NO
3 -Add polyvalent alcohol solubility promoters (content 20%) such as 16.2ml sorbyl alcohol, adding ammoniacal liquor is an amount of, and fully stirring makes molten.16.4g tartrate is dissolved in the 28.75ml hot water, put cold after, stir down and join in the oxygen bismuth nitrate solution, the ammonia evaporation is removed, filter, washing, oven dry gets The compounds of this invention.Through Spectrum Analysis, determine that its chemical structure is with embodiment 1 compound.
Embodiment 3
The 8.5g bismuth subnitrate is under agitation joined in 50ml potassium hydroxide (5%) hot solution, be heated to 90-100 ℃ under stirring, get oxygen Bismuth trinitrate potassium (metabismuthic acid potassium) solution.16.4g tartrate is dissolved in the 28.75ml hot water, put cold after, stir down and join in oxygen Bismuth trinitrate potassium (metabismuthic acid potassium) solution, back flow reaction is till the sampling adding ammonia solvent, cooling, suction filtration adds the small amount of ethanol washing, suction filtration, oven dry gets The compounds of this invention.Through Spectrum Analysis, determine that its chemical structure is with embodiment 1 compound.
Embodiment 4
Take by weighing the 33g embodiment of the invention 1 compound, 16g pectin, 16g starch separated pulverizing and cross 100 mesh sieves, 1g Magnesium Stearate and above-mentioned raw materials thorough mixing is even, calculate loading amount, the hollow capsule and pill of packing into.Measure content, every capsules content content is the 90-110% of 55mg (in bismuth).Measure disintegration, must not surpass 0.5h.
Embodiment 5
Take by weighing the 33g embodiment of the invention 1 compound, 15g starch, 15g white bole separated pulverizing and cross 100 mesh sieves, 3g talcum powder and above-mentioned raw materials thorough mixing is even, calculate loading amount, the hollow capsule and pill of packing into.Measure content, every capsules content content is the 90-110% of 55mg (in bismuth).Measure disintegration, meet the standard of capsule.
Embodiment 6
Take by weighing the 33g embodiment of the invention 1 compound, 15g pectin, 15g white bole, 3g talcum powder and mix and pulverized 100 mesh sieves, calculate loading amount, the hollow capsule and pill of packing into.Measure content, every capsules content content is the 90%-110% of 55mg (in bismuth).Measure disintegration, meet the requirement of capsule.
Embodiment 7
Take by weighing the 99g embodiment of the invention 1 compound, 49g pectin, 25g starch, 25g Icing Sugar mix and pulverized 100 mesh sieves, stick with paste with the ethanol mixed adhesive with starch (or dextrin) and make softwood, granulate oven dry, whole grain, pack.Every bag of 90%-110% that contains The compounds of this invention 110mg (in bismuth).Measure dissolution rate, should be 85% of 110mg.
Embodiment 8
Take by weighing the 33g embodiment of the invention 1 compound, 15g white bole, 15g starch, 3g talcum powder mix and pulverized 100 mesh sieves, are tackiness agent with alcohol-water, make softwood, granulate compressing tablet.Every content is the 90%-110% of 55mg (in bismuth).Measure disintegration, meet the requirement of tablet.
Embodiment 9
1. Colloidal Bismuth Tartrate of the present invention is to the therapeutic action of the experimental ulcerative colitis of rabbit
1.1 the animal model preparation adds complete Freund adjuvant with the homogenate of rabbit mucous membrane of colon, immune animal was strengthened once after 10 days, continued to observe after 10 days beginning medication (embodiment 1 compound).
1.2 dosage and observation index gastric infusion, dosage are 50mg/100g/d.Observation index is ulcer sum, diameter ulcer number, the ulcer diffusion length (the elongated footpath of Peptic Ulcers) greater than 5cm, length of lesion (total length of pathology on the colon), ulcer inhibition rate [(saline control group ulcer number-medication group ulcer number)/saline control group ulcer number].
1.3 behind the experimental result animal immune 20 days, rare just, the bloody stool of most of animal appearance, find after the postmortem that mucous membrane of colon is dispersivity inflammation, ulcer, based on neutrophil infiltration, and visible eosinophilic granulocyte, each layer of intestines wall all has in various degree congested and hemorrhage, flesh layer oedema, and visible myofiber fracture.Medication was compared with model control group after 10 days, and the ulcer number obviously reduces, and length of lesion, ulcer diffusion length obviously shorten.Ulcer sum (individual) is reduced to 5.5 ± 1.6 by 10.5 ± 4.2 of model control group; length of lesion (cm) is reduced to 13.33 ± 4.89 by 23.97 ± 3.8 of model control group; ulcer diffusion length (cm) is reduced to 4.42 ± 1.78 by 7.92 ± 2.5 of model control group; big ulcer number (individual) is reduced to 0.33 ± 0.5 by 1.5 ± 1.05 of model control group; ulcer inhibition rate is 47.6 ± 5.77%, and control group documents (patent No.: ZL 92114664.7) medicine ulcer inhibition rate is 36.5 ± 4.87%.Relatively there was a significant difference (P＜0.01) with model control group, and relatively there was a significant difference (P＜0.05) with documents medicine group.
2. Colloidal Bismuth Tartrate of the present invention is to the therapeutic action of rat experiment chronic gastric ulcer
2.1 the Wistar female rats of body weight 200 ± 20g is selected in the animal model preparation, hungry 4h, cut open the belly, under 0.5cm place stomach serous coat above the pylorus, inject 10% acetic acid 0.05ml, sew up immediately, art finishes the ad libitum access water inlet, and began medication (embodiment 1 compound), shared medicine 8 days, the 9th day 8:00am the same day, with sacrifice of animal, observe the gastropathy situation.
2.2 dosage and observation index gastric infusion, dosage are 50mg/100g/d.Observation index is the ulcer area, ulcer inhibition rate, ulcer volume.
2.3 experimental result Colloidal Bismuth Tartrate of the present invention has the effect of the chronic gastric ulcer that obvious inhibition acetic acid brings out, and stomach ulcer area and volume are significantly dwindled.Ulcer area (mm
2) be reduced into 0.15 ± 0.10 by 0.72 ± 0.35 of model control group, ulcer volume (ul) is reduced into 9.3 ± 6.1 by 41.7 ± 19.5 of model control group, ulcer inhibition rate is 79%, and control group documents (patent No.: ZL 92114664.7) medicine ulcer inhibition rate is 70%.Relatively there was a significant difference (P＜0.01) with model control group, and relatively there was a significant difference (P＜0.05) with documents medicine group.
3. Colloidal Bismuth Tartrate of the present invention is to the therapeutic action of rat experiment duodenal bulbar ulcer
3.1 the animal model preparation is pressed the Szado method and is irritated the stomach modeling with the cysteamine salt acid solution.
3.2 dosage and observation index gastric infusion, dosage are 50mg/100g/d.Staging by Szado is divided into the 0-7 level: 0 for there not being the work change, and 1 is mucous hyperemia, and 2 is mucosal bleeding, and 3 is downright bad, and 4 are mucosal erosion, and 5 is shallow table ulcer, and 6 is deep ulcer, and 7 is intestines wall holostrome perforated ulcer.
Average is 5.33 ± 1.37 3.3 the damage of experimental result blank group rat preduodenal is kept the score, and Colloidal Bismuth Tartrate of the present invention is 2.2 ± 1.5, and control group documents (patent No.: ZL 92114664.7) medicine is 3.0 ± 1.0.Relatively there was a significant difference (P＜0.01) with the blank group, and relatively there was a significant difference (P＜0.05) with documents medicine group.
4. Colloidal Bismuth Tartrate of the present invention is to the therapeutic action of the experimental chronic gastritis of rabbit
4.1 the animal model preparation adds complete Freund adjuvant with rabbit gastric mucosa homogenate, immune animal was strengthened once after 10 days, continued to observe 10 days beginning medication (embodiment 1 compound).
4.2 dosage and observation index gastric infusion, dosage are 50mg/100g/d.Observation index is pathology area (the vertical footpath of pathology transverse diameter * pathology), ulcer number.
4.3 the experimental result medication after 10 days Colloidal Bismuth Tartrate of the present invention and control group documents (patent No.: ZL 92114664.7) medicine all can dwindle the pathology area, reduce the ulcer number.Colloidal Bismuth Tartrate of the present invention makes pathology area (cm
2) being reduced into 12.33 ± 10.9 by 80.17 ± 33.1 of model control group, ulcer number (individual) is reduced to 0.17 ± 0.4 by 0.5 ± 0.55, and relatively there was a significant difference (P＜0.01) with model control group.Documents medicine group pathology area is reduced into 17.81 ± 9.6, and the ulcer number is reduced to 0.28 ± 0.39, and two groups relatively there was a significant difference (P＜0.05).
Embodiment 10
1. the clinical efficacy of Colloidal Bismuth Tartrate treatment chronic colitis of the present invention
1.1 it is long-term stomachache, diarrhoea, Mucous Stool, tenesmus that case is selected symptom; Ight soil is cultivated negative; Endoscopy has intestinal mucosa hyperemia, oedema, mucous membrane granular injustice, but does not have typical ulcer changer.
1.2 dosage and curative effect determinate standard every day 2 times, each 110mg.Produce effects: transference cure, histological examination inflammation degree alleviates secondary person.Effectively: symptom is obviously improved, and histological examination inflammation degree alleviates one-level person.Invalid: clinical symptom and histological examination inflammation degree do not have the changer.
1.3 the obvious effective rate of treatment result Colloidal Bismuth Tartrate of the present invention (embodiment 1 compound) treatment chronic colitis is 66.7%, total effective rate is 84.6%; Control group SASP obvious effective rate is 32.4%, and total effective rate is 58.9%; Control group Norxin obvious effective rate is 26.9%, and total effective rate is 50.0%, and difference all has significance (P＜0.01).Control group documents (patent No.: ZL 92114664.7) medicine obvious effective rate is 54.8%, and total effective rate is 78.2%, and there was a significant difference (P＜0.05).
2. the clinical efficacy of Colloidal Bismuth Tartrate treatment chronic non-specific ulcerative colitis of the present invention
2.1 it is stomachache, diarrhoea, pus and blood stool, tenesmus that case is selected symptom; Endoscopy meets ulcerative colitis and changes; Ight soil is cultivated negative; Examination of living tissue has erosion, ulcer, crypt abscess, glandular epithelium sex change, hyperplasia and goblet cell to reduce.
2.2 dosage and curative effect determinate standard are with 1.2.
2.3 treatment result Colloidal Bismuth Tartrate of the present invention (embodiment 1 compound) obvious effective rate is 73.7%, total effective rate is 89.5%; Control group SASP obvious effective rate is 53.3%, and total effective rate is 86.7%.There was a significant difference (P＜0.05) with the SASP group is compared obvious effective rate, and the total effective rate difference does not have significance (P＞0.05).Control group documents (patent No.: ZL 92114664.7) medicine obvious effective rate is 67.4%, and total effective rate is 72.7%, and relatively there was a significant difference (P＜0.05) with documents medicine group.In clinical observation, 5 examples appear in the SASP group feels sick, vomits, 3 example heatings, fash, and 1 routine oligoleukocythemia, the toxic side effect incidence accounts for 21% of total routine number.Colloidal Bismuth Tartrate of the present invention and documents medicine all find no obvious toxic-side effects in treatment.
3. the clinical efficacy of Colloidal Bismuth Tartrate treatment irritable bowel syndrome of the present invention
3.1 case selects symptom for stomachache, diarrhoea, defecation after meal, alleviates behind the defecation, and belly flatulence; Ight soil is cultivated negative; Mild hyperaemia or the normal person of intestinal mucosa are only arranged under the scope.
3.2 dosage and curative effect determinate standard oral every day 2 times, each 110mg.Produce effects: symptom (stomachache, abdominal distension, diarrhoea) disappears or basic the disappearance; Effectively: symptom obviously alleviates; Invalid: symptom does not have change.
3.3 the total effective rate of treatment result Colloidal Bismuth Tartrate of the present invention (embodiment 1 compound) treatment irritable bowel syndrome is 88.8%, the control group diphenoxylate is 59.6%, control group documents (patent No.: ZL 92114664.7) medicine is 74.9%, with two control group comparison difference significance (P＜0.01) is arranged all.
4. the clinical efficacy of Colloidal Bismuth Tartrate treatment peptide ulceration of the present invention
4.1 case is selected to be diagnosed as stomach ulcer and duodenal ulcer person with gastroscope.
4.2 dosage and curative effect determinate standard oral every day 2 times, each 110mg.Healing: ulcer disappears or only stays scar under the gastroscope; Effectively: the ulcer area before dwindles＞and 50%; Invalid: the ulcer area dwindles＜and 50% or enlarge.
4.3 treatment result Colloidal Bismuth Tartrate of the present invention (embodiment 1 compound) 4 all healing rates are 77.2%, total effective rate is 93.0%, and treatment back HP negative conversion rate is 89.1%; Control group documents (patent No.: ZL 92114664.7) medicine is respectively 65.4%, 85.6% and 78.7%.There was a significant difference aspect treatment of peptic ulcer healing rate and total effective rate (P＜0.05) for both, and there was a significant difference aspect the HP negative conversion rate (P＜0.05).
5. the clinical efficacy of Colloidal Bismuth Tartrate treatment chronic gastritis of the present invention
5.1 it is epigastric discomfort (secret anguish, noisy sense) that case is selected symptom, mucous hyperemia, oedema, some sheet blutpunkte person are seen in gastroscopy.
5.2 dosage and efficacy determination oral every day 2 times, each 110mg.Sx: the basic disappearance in epigastric discomfort treatment back; Inflammation alleviates (pathology improvement): stomach hole histology biopsy inflammation rank reduces before the treatment.
5.3 treatment result Colloidal Bismuth Tartrate of the present invention (embodiment 1 compound) sx rate is 85.2%, it is 82.0% that inflammation alleviates rate; It is 72.3% that control group documents (patent No.: ZL 92114664.7) drug symptom alleviates rate, and it is 73.8% that inflammation alleviates rate; Two groups relatively there was a significant difference (P＜0.05).
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (10)
1. the Colloidal Bismuth Tartrate of following formula (I) (promptly poly-tartaric acid bismuth complex potassium salt) compound, its pharmaceutical salts or hydrate:
2. compound according to claim 1, it is a hydrate, molecular formula is C
20H
19O
29Bi
2K
3NH
2O, wherein n is not 0 integer.
3. compound according to claim 2, it is Colloidal Bismuth Tartrate (the promptly poly-tartaric acid bismuth complex potassium salt) tetrahydrate of formula (I), molecular formula is C
20H
19O
29Bi
2K
34H
2O.
4. a pharmaceutical composition is characterized in that comprising each described compound of claim 1-3 as active constituents of medicine and acceptable accessories.
5. composition according to claim 4, wherein said auxiliary material can be selected from one or more in pectin, sodium alginate, Microcrystalline Cellulose, white bole, starch, dextrin, Icing Sugar, talcum powder, stearic acid, propylene glycol, the glycerine etc.
6. according to the described composition of claim 4-5, it is pharmaceutical preparations such as capsule, tablet, granule, powder, suspensoid, solution or suppository.
7. the preparation method of each described compound of claim 1-3 is characterized in that comprising the step that is generated described Colloidal Bismuth Tartrate (promptly poly-tartaric acid bismuth complex potassium salt) compound by tartrate and metabismuthic acid nak response.
8. method according to claim 7 wherein also comprises by Bismuth trinitrate and potassium hydroxide and react the step that generates metabismuthic acid potassium in water.
9. described compound of above-mentioned each claim or composition are used to prepare the purposes of treatment gastrointestinal illness medicine.
10. purposes according to claim 9, wherein said gastrointestinal illness be 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 etc. preferably.
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Cited By (4)
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| CN106860418A (en) * | 2015-12-14 | 2017-06-20 | 于学敏 | A kind of new pharmaceutical preparation Colloidal Bismuth Tartrate piece |
| CN106860476A (en) * | 2015-12-14 | 2017-06-20 | 于学敏 | A kind of new pharmaceutical preparation Colloidal Bismuth Tartrate particle |
| CN108250244A (en) * | 2018-01-19 | 2018-07-06 | 于学敏 | COLLOIDAL BISMUTH TARTRATE-β-macrolide compounds and preparation method thereof, its pharmaceutical composition and their purposes |
| WO2024228342A1 (en) * | 2023-05-01 | 2024-11-07 | 三菱瓦斯化学株式会社 | Polymerizable composition, resin obtained by polymerizing and curing same, and optical material comprising said resin |
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| CN1088433A (en) * | 1992-12-23 | 1994-06-29 | 于学敏 | Jellied bismuth tartrate medicine |
| US6482865B1 (en) * | 2000-04-12 | 2002-11-19 | Gastropal Partners | Method for preparing colloidal solution of bismuth sodium tartrate |
| CN101491507A (en) * | 2008-01-21 | 2009-07-29 | 于学敏 | Colloidal bismuth tartrate medicine and preparation method and use thereof |
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Patent Citations (4)
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| GB229946A (en) * | 1924-08-26 | 1925-03-05 | Boehringer & Soehne Gmbh | Process for the preparation of sodium-tri-bismuth tartrate |
| CN1088433A (en) * | 1992-12-23 | 1994-06-29 | 于学敏 | Jellied bismuth tartrate medicine |
| US6482865B1 (en) * | 2000-04-12 | 2002-11-19 | Gastropal Partners | Method for preparing colloidal solution of bismuth sodium tartrate |
| CN101491507A (en) * | 2008-01-21 | 2009-07-29 | 于学敏 | Colloidal bismuth tartrate medicine and preparation method and use thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106860418A (en) * | 2015-12-14 | 2017-06-20 | 于学敏 | A kind of new pharmaceutical preparation Colloidal Bismuth Tartrate piece |
| CN106860476A (en) * | 2015-12-14 | 2017-06-20 | 于学敏 | A kind of new pharmaceutical preparation Colloidal Bismuth Tartrate particle |
| CN108250244A (en) * | 2018-01-19 | 2018-07-06 | 于学敏 | COLLOIDAL BISMUTH TARTRATE-β-macrolide compounds and preparation method thereof, its pharmaceutical composition and their purposes |
| CN108250244B (en) * | 2018-01-19 | 2020-11-06 | 于学敏 | Bismuth bitartrate-beta-cyclic lactone compound, preparation method thereof, pharmaceutical composition thereof and application thereof |
| WO2024228342A1 (en) * | 2023-05-01 | 2024-11-07 | 三菱瓦斯化学株式会社 | Polymerizable composition, resin obtained by polymerizing and curing same, and optical material comprising said resin |
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|---|---|
| CN102276445B (en) | 2013-11-06 |
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