CN102276445B - 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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- CN102276445B CN102276445B CN 201110168696 CN201110168696A CN102276445B CN 102276445 B CN102276445 B CN 102276445B CN 201110168696 CN201110168696 CN 201110168696 CN 201110168696 A CN201110168696 A CN 201110168696A CN 102276445 B CN102276445 B CN 102276445B
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- chronic
- solution
- bismuth
- potassium
- tartrate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- -1 bismuth tartrate compound Chemical class 0.000 title claims abstract description 16
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- 208000015864 chronic erosive gastritis Diseases 0.000 claims abstract description 4
- SULICOHAQXOMED-YDXPQRMKSA-H dibismuth;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Bi+3].[Bi+3].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O.[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O.[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O SULICOHAQXOMED-YDXPQRMKSA-H 0.000 claims description 31
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 23
- 229910052797 bismuth Inorganic materials 0.000 claims description 23
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 20
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- PPNKDDZCLDMRHS-UHFFFAOYSA-N dinitrooxybismuthanyl nitrate Chemical compound [Bi+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O PPNKDDZCLDMRHS-UHFFFAOYSA-N 0.000 claims description 12
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000001087 myotubule Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- LTUDISCZKZHRMJ-UHFFFAOYSA-N potassium;hydrate Chemical compound O.[K] LTUDISCZKZHRMJ-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a colloidal bismuth tartrate compound (poly bismuth potassium tartrate), and specifically 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 (i.e. poly-tartaric acid bismuth complex potassium salt), particularly (its molecular formula is C to poly-tartaric acid bismuth complex potassium salt tetrahydrate
20H
19O
29Bi
2K
34H
2O) and its preparation method 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 that incidence clinically is high, the course of disease long, easily recurrence and the chronic colon diseases of cAMP content is arranged, 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 and is used for the treatment of hyperchlorhydria and maldigestion medicine.Britain Glan gram element company had applied for relating to the process for preparation of furan derivatives patent of Bismuth tartrate in China in 1993.Preparation method's Chinese invention patent (patent No.: ZL92114664.7) of the quick acquisition jellied bismuth tartrate of Medicine Inst. of Datong City researcher Yu Xue in 1992.The structural formula of the disclosed Bismuth Sodium Tartrate of above-mentioned patent 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 gather the tartaric acid bismuth complex potassium salt aquo compound,
Obviously different from 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 present invention's compound as above 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, compound as above, 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.Has colloid property, therefore also referred to as Colloidal Bismuth Tartrate.It forms translucent colloidal solution in water, settling volume ratio 〉=99.99% is insoluble to the organic solvents such as ethanol, acetone, ether, is soluble in ammoniacal liquor, Na
2CO
3, the 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, the pharmaceutical composition that becomes take the compounds of this invention as active fraction preparation also is provided, pharmaceutical composition provided by the invention comprises compound as mentioned above and the pharmaceutically acceptable auxiliary material for the treatment of significant quantity.Wherein, described pharmaceutical composition is such as thinking the 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 (i.e. poly-tartaric acid bismuth complex potassium salt) compound by tartrate and metabismuthic acid nak response.
Wherein, method described above 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 take Bismuth trinitrate or oxygen Bismuth trinitrate and various tartrate optically active isomer [comprising left-handed (-), dextrorotation (+), meso (±), racemic modification (dt)] as raw material, KOH, NaOH, ammoniacal liquor exist or not in the presence of, heating or not under heating condition adds or does not add the organic solvent that dissolves each other with water to prepare the method for above-claimed cpd.Concrete steps are: (1) under agitation joins tartrate (can be various optically active isomer tartrate) in hot pure water, stirs to make dissolving fully, lets cool.(2) under agitation Bismuth trinitrate is joined in pure water, stir and make suspension, add potassium hydroxide solution to stir and make hydrolysis complete (filtrate adds potassium hydroxide solution precipitation no longer to occur).(3) centrifuging uses the pure water repetitive scrubbing extremely almost without NO
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 pure water, under agitation adds the polyvalent alcohol solubility promoters such as sorbyl alcohol, add potassium hydroxide solution, be stirred to and become translucent colloidal solution by white precipitate, 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 Colloidal Bismuth Tartrate crude product that wets.(7) the wet crude product of Colloidal Bismuth Tartrate is under agitation joined in pure water, heated and stirred makes into colloidal dispersion, and is cooling, adds ethanol sink glue, and centrifuging is dried, and gets 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 pharmaceutically acceptable auxiliary material pharmaceutical compositions.Comprise active ingredient with ratio of adjuvant, mix, add suitable suitable amount of adhesive to granulate, or the dry powder blend solid orally ingestible that direct compression, encapsulated, pack etc. make of not granulating.Comprise dissolving or suspend, add the 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, 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, the compounds of this invention described above 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.
Advantages of the present invention shows: compare with existing bismuthotartrate medicine, the compounds of this invention is roughly the same on the sick kind for the treatment of, but because the compounds of this invention is polymkeric substance, molecular weight is large, 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 documents (as patent No. ZL92114664.7) is each 165mg (in 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 bismuth), one day twice, all can take pre/after meal.
The therapeutic action to the experimental ulcerative colitis of rabbit of the compounds of this invention and preparation, after treatment, 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, large 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, relatively difference is without significance (P＞0.05) for medicine of the present invention and SASP, and both are therapeutic equivalence aspect the experimental ulcerative colitis for the treatment of rabbit.But the toxic side effects that medicine of the present invention has without SASP has the curative effect identical with the documents medicine aspect the experimental ulcerative colitis for the treatment of rabbit.
The compounds of this invention and preparation thereof are treated clinically chronic ulcerative colitis, chronic colitis, irritable bowel syndrome aspect total effective rate 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 without toxic side effect such as feeling sick of having of SASP, vomiting, heating, fash, granulocytopenia, aplastic anemia, spermatozoon minimizings.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.Treat clinically peptide ulceration and chronic erosive gastritis (superficial gastritis), chronic atrophic gastritis aspect and documents bismuth preparation and Colloidal Bismuth Pectin suitable.
Embodiment
Following examples are in order to understand and technical solution of the present invention to be described, but do not consist of, the invention interest field not being limited.
Embodiment 1
The 22.75g Bismuth trinitrate is under agitation joined in 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 extremely almost without NO
3 -Add 37.5ml water in filter cake, add the polyvalent alcohol solubility promoters (content 20%) such as 16.2ml sorbyl alcohol, fully stir, add the stirring of 10ml potassium hydroxide solution to make molten.16.4g tartrate is dissolved in 28.75ml hot water, after letting cool, joins under stirring in the oxygen bismuth nitrate solution, cooling, add ethanol (or acetone) under stirring, suction filtration, oven dry gets the compounds of this invention.
Product characteristics: form colloidal solution in water, sedimentation volume ratio 〉=99.99%.Be insoluble to the organic solvents such as ethanol, acetone, ether, the pH value is 3.5-5.5, and outward appearance is white amorphous powder.
Get approximately 0.1g of this product, with dilute sulphuric acid 3ml acidifying, drip the potassiumiodide test solution and generate dark brown solution, be dissolved into orange solution in excessive potassiumiodide test solution.
Get approximately 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 approximately 0.2g of this product, add water 2ml and shake up, add sodium hydrogen carbonate solution and transfer to neutrality, ammonification Silver Nitrate test solution processed number droplet heats in water-bath, occurs silver mirror on 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 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 symmetrical 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.Carboxylic Acid Ions 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 Ions (salt) in molecule, supports to exist in 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 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 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, settling volume ratio 〉=99.9% in water.
Embodiment 2
The 22.75g Bismuth trinitrate is under agitation joined in 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 extremely almost without NO
3 -Add the polyvalent alcohol solubility promoters (content 20%) such as 16.2ml sorbyl alcohol, add ammoniacal liquor appropriate, fully stirring makes molten.16.4g tartrate is dissolved in 28.75ml hot water, after letting cool, joins under stirring 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 28.75ml hot water, after letting cool, joins under stirring in oxygen Bismuth trinitrate potassium (metabismuthic acid potassium) solution, till back flow reaction to sampling adds ammonia solvent, cooling, suction filtration adds a small amount of washing with alcohol, 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 the 33g embodiment of the present invention 1 compound, 16g pectin, 16g starch and pulverized respectively 100 mesh sieves, 1g Magnesium Stearate and above-mentioned raw materials are fully mixed, 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 the 33g embodiment of the present invention 1 compound, 15g starch, 15g white bole and pulverized respectively 100 mesh sieves, 3g talcum powder and above-mentioned raw materials are fully mixed, 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 the 33g embodiment of the present invention 1 compound, 15g pectin, 15g white bole, 3g talcum powder co-grinding and cross 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 the 99g embodiment of the present invention 1 compound, 49g pectin, 25g starch, 25g Icing Sugar, co-grinding is crossed 100 mesh sieves, sticks with paste with the ethanol mixed adhesive with starch (or dextrin) and makes 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 the 33g embodiment of the present invention 1 compound, 15g white bole, 15g starch, 3g talcum powder, co-grinding is crossed 100 mesh sieves, is tackiness agent with alcohol-water, makes softwood, granulate, compressing tablet.Every content is the 90%-110% of 55mg (in bismuth).Measure disintegration, meet the requirement of tablet.
Embodiment 9
1. the therapeutic action of Colloidal Bismuth Tartrate of the present invention to 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 in 10 days afterwards, 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 that ulcer sum, diameter are greater than ulcer number, the ulcer diffusion length (the elongated footpath of Peptic Ulcers) of 5cm, length of lesion (total length of pathology on colon), ulcer inhibition rate [(saline control group ulcer number-medication group ulcer number)/saline control group ulcer number].
1.3 after experimental result animal immune 20 days, most of animal appearance is rare just, bloody stool, find after postmortem that mucous membrane of colon is dispersivity inflammation, ulcer, take neutrophil infiltration as main, 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; large 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 (patent No.: ZL92114664.7) the medicine ulcer inhibition rate is 36.5 ± 4.87% to the control group documents.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. the therapeutic action of Colloidal Bismuth Tartrate of the present invention to the 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, inject 10% acetic acid 0.05ml under 0.5cm place stomach serous coat above pylorus, sew up immediately, art finishes arbitrarily feed water inlet, and began medication (embodiment 1 compound) the same day, share medicine 8 days, the 8:00am of the 9th 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 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 (patent No.: ZL92114664.7) the medicine ulcer inhibition rate is 70% to the control group documents.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. the therapeutic action of Colloidal Bismuth Tartrate of the present invention to the rat experiment duodenal bulbar ulcer
3.1 the cysteamine salt acid solution gavage modeling of Szado method is pressed in the animal model preparation.
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 becoming without work, 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 scored, and Colloidal Bismuth Tartrate of the present invention is 2.2 ± 1.5, and (patent No.: ZL92114664.7) medicine is 3.0 ± 1.0 to the control group documents.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. the therapeutic action of Colloidal Bismuth Tartrate of the present invention to 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 in 10 days afterwards, 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 (pathology transverse diameter * pathology is indulged the footpath), ulcer number.
4.3 the experimental result medication after 10 days Colloidal Bismuth Tartrate of the present invention and control group documents (patent No.: ZL92114664.7) medicine all can dwindle the pathology area, reduces 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 reducing is 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. Colloidal Bismuth Tartrate of the present invention is treated the clinical efficacy of chronic colitis
1.1 it is long-term stomachache, diarrhoea, Mucous Stool, tenesmus that case is selected symptom; Coproculture is negative; Endoscopy has intestinal mucosa hyperemia, oedema, mucous membrane granular injustice, but without typical ulcer changer.
1.2 dosage and curative effect determinate standard every day 2 times, each 110mg.Produce effects: transference cure, the histological examination degree of inflammation alleviates secondary person.Effectively: symptom is obviously improved, and the histological examination degree of inflammation alleviates one-level person.Invalid: clinical symptom and histological examination degree of inflammation are without the changer.
1.3 the obvious effective rate for the treatment of 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).(patent No.: ZL92114664.7) the medicine obvious effective rate is 54.8% to the control group documents, and total effective rate is 78.2%, and there was a significant difference (P＜0.05).
2. Colloidal Bismuth Tartrate of the present invention is treated the clinical efficacy of chronic non-specific ulcerative colitis
2.1 it is stomachache, diarrhoea, pus and blood stool, tenesmus that case is selected symptom; Endoscopy meets ulcerative colitis and changes; Coproculture is 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 is without significance (P＞0.05).(patent No.: ZL92114664.7) the medicine obvious effective rate is 67.4% to the control group documents, 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 number of cases.Colloidal Bismuth Tartrate of the present invention and documents medicine all find no obvious toxic-side effects in treatment.
3. Colloidal Bismuth Tartrate of the present invention is treated the clinical efficacy of irritable bowel syndrome
3.1 case selects symptom for stomachache, diarrhoea, defecation after meal, alleviates after defecation, and belly flatulence; Coproculture is negative; Mild hyperaemia or the normal person of intestinal mucosa are only arranged under 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 is without change.
3.3 the total effective rate for the treatment of 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%, (patent No.: ZL92114664.7) medicine is 74.9% to the control group documents, with two control group comparison difference, significance (P＜0.01) is arranged all.
4. Colloidal Bismuth Tartrate of the present invention is treated the clinical efficacy of peptide ulceration
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: under gastroscope, ulcer disappears or only stays scar; Effectively: ulcer area before dwindles＞and 50%; Invalid: 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 after treatment, the HP negative conversion rate is 89.1%; (patent No.: ZL92114664.7) medicine is respectively 65.4%, 85.6% and 78.7% to the control group documents.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. Colloidal Bismuth Tartrate of the present invention is treated the clinical efficacy of chronic gastritis
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 after the epigastric discomfort treatment; Inflammation alleviates (pathology improvement): stomach hole histology biopsy inflammation rank is treated front reduction.
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; (patent No.: ZL92114664.7) to alleviate rate be 72.3% to drug symptom to the control group documents, and it is 73.8% that inflammation alleviates rate; Two groups relatively there was a significant difference (P＜0.05).
According to preferred embodiment, the present invention is described.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, within it all should be understood to be in 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.
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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 |
| 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 |
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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 |
-
2011
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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