CN1088433A - Jellied bismuth tartrate medicine - Google Patents
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Abstract
The invention relates to a kind of new bismuth salt medicine jellied bismuth tartrate for the treatment of gastrointestinal disease.Once compared with this medicine and existing various bismuth salt prefs, and carried out a series of animal experiments and hundred routine gastrointestinal patient clinical treatment observations, the result proves that this medicine all has obvious curative effects to gastric and duodenal ulcers and inflammation, is 93.3% to the peptic ulcer effective percentage.Especially for the persistent ailment ulcerative colitis that is difficult at present treat obvious curative effects is arranged, total effective rate is 86%, and existing bismuth salt medicine is all invalid to this disease.This medicine of evidence has no side effect to human body.This medicine raw material is easy to get, product is inexpensive, production equipment and technology are simple, quality controllable.
Description
The invention belongs to the bismuth salt medicine and the manufacture method thereof of treatment gastrointestinal disease.
Bismuth salt is the active drug of treatment gastrointestinal disease.Being applied to clinical bismuth salt pref the earliest is bismuth subcarbonate (clinical medicine handbook, volumes such as Nanjing pharmaceutical college, Science and Technology of Shanghai publishing house, 1979).After this there are many bismuth salt prefs to come out one after another again, as bismuth subnitrate (American Pharmacopeia, 1985), bismuth aluminate compound (Germany central authorities big pharmaceutical factory product), roter tablets (Holland readily take the opportunity to big pharmaceutical factory ROTER B.V. permission BeiJing, China pharmaceutical factory produce product), colloidal state time citric acid bismuth (Dutch product, abbreviated name CBS; Chinese commodity name " must be happy ", Zhuhai pharmaceutical factory).The back belongs to natural organic acids bismuth salt for two kinds, is close with jellied bismuth tartrate of the present invention.In the bismuth salt medicine of treatment gastrointestinal disease, colloidal state citric acid bismuth is better person, has obtained extensive use at present.But evidence, colloidal state citric acid bismuth salt (must be happy) does not have therapeutical effect to ulcerative colitis.
Foreign literature has been reported drug effect, toxicity and the clinical research of many relevant bismuth salt.It is generally acknowledged that various bismuth preparations can form a kind of protecting film on gastrointestinal mucosa, become isolated gastric acid, gastric enzyme and food to the erosive barrier of ulcer mucosa, thereby make ulcer be repaired voluntarily, heal.CBS is inclined under acid condition and with the amino acid residue of ulcer spot chelation is taken place and condense; also can chelation be taken place and make this enzyme deactivation with pepsin; bismuth ion can promote gastrointestinal mucosa epithelial cell secreting mucus simultaneously, and this mucus has protective effect to gastrointestinal mucosa.The several animal models result of the test all shows the anti-gastroenteritic ulcer activity of bismuth salt.The stress ulcer of rat needs 40 days ability normal healings approximately, but gives can obviously shorten healing stage after the bismuth salt.For example give 32,16 respectively, 8mg(kgd) bismuth salt is (with Bi
2O
3Meter), healing time foreshortens to 20 days respectively, 30 days, 35 days.To the rat ulcer disease, give CBS with 407mg/kg dosage, to observe in 20 hours, ulcer incidence rate and mortality rate are 0, and the blank group ulcer incidence rate of giving normal saline is 100%, mortality rate (due to the perforation) is 75%.Use aspirin, cortisone etc. carry out the drug-induced ulcer result of the test and also show, the bismuth salt pref reduces the sickness rate of drug-induced ulcer, on average reduces by 55%.
Pharmacokinetic studies result shows that bismuth salt forms infusible precipitate under one's belt, is difficult to digestive tract and absorbs, and only has the bismuth of trace to be absorbed.To with the ulcerated dog of aspirin, treated for three weeks with 20 times of CBS to people's therapeutic dose, the blood bi concns is lower than 0.5ppm, and the urine bi concns is 15.3ppm.With the routine dose administration, stable state blood bi concns is between 5～14mg/L.
The toxicity test result shows the deadly dosage of dying of bismuth salt LD50(50%) meaningless.Promptly give the rat mice with the CBS that is higher than 315 times of human therapy dosage and 175 times respectively, observing after 24 hours does not all have intoxicating phenomenon.Long term toxicity test shows, gives rat and mice with the bismuth subnitrate that is equivalent to 35 times of human therapy dosage, successive administration 30 days, and the result does not see esophagus, stomach, intestinal, liver, kidney, adrenal gland, gonad and cerebral lesion.
Clinical research and applicable cases show that the bismuth salt pref is effective to stomach and duodenal ulcer, can also promote ulcer healing by relief of symptoms, and relapse rate are low, and side reaction is slight.From double blind controling test, most bismuth preparations are effective to gastric and duodenal ulcers, have significant difference (P＜0.05) statistically with placebo.Healing rate and H
2-receptor antagonist cimetidine compares, and both are there was no significant difference (P＞0.05) statistically.But can reach more than 80% with bismuth salt pref treatment healing rate the tolerific ulcer of cimetidine (being the invalid ulcer of routine dose cimetidine of 1g/d).Be lower than H with the relapse rate after the bismuth preparation healing ulcer
2-receptor antagonist is respectively 13～39% and 48～70%, and there is significant difference (P＜0.05) statistically in both.
To studies show that of clinical adverse, the blood bi concns of taking bismuth preparation never finds to surpass the case history of 50mg/l.The serum check result, liver, renal function are all normal.All patient's feces of taking bismuth preparation are black, may be bismuth ion and H
2S forms Bi
2S
3Cause, promptly disappear after the drug withdrawal, so the feces blackening is a normal phenomenon.
Though above-mentioned known bismuth preparation is all effective to peptic ulcer disease and gastritis, and toxicity extremely low (actual avirulence), have no side effect, the protection and the therapeutical effect of ulcer only is confined to the harmonization of the stomach duodenum, ulcerative colitis is not then had effect.Analyzing reason may be to lose colloid property when arriving colons owing to these medicines, can not form protecting film to intestinal mucosa in the intestinal juice alkaline medium, therefore non-specific colonic ulcer is not had therapeutical effect.
The objective of the invention is to: (1) nonspecific ulcerative colitis at present is obstinate clinically and difficult doctor's disease.The medicine for this disease of treatment of generally acknowledging at present only has sulfasalazine (SASP).Because this poison of drug side effect is big, clinical practice is restricted.New drug of the present invention is suitable to the therapeutical effect and the SASP of ulcerative colitis, but does not have the toxic and side effects of SASP.And should the disease course of disease grow, easily recur, the medicine of low toxicity has special important value in the treatment of this disease.(2) suffer from the patient of ulcerative colitis, have quite a few to suffer from gastritis or peptic ulcer simultaneously.The medicine of most at present treatment gastropathy can produce antagonism with the medicine SASP of treatment ulcerative colitis.The present invention integrates treatment gastropathy and colonic diseases.This medicine is to cure the effective new method of suffering from gastropathy and colonic diseases patient simultaneously.
Purpose of the present invention be intended to seek treatment ulcerative colitis effectively, low toxicity and treat effective new drug of gastropathy and colonic diseases simultaneously.The characteristics such as dissolubility, colloid of bismuth preparation have been changed by the acid group that changes bismuth salt; thereby its decapacitation is formed outside the protecting film in acid medium to gastrointestinal mucosa; also can in the intestinal alkaline medium, form protecting film, with intestinal tract diseases such as treatment ulcerative colitiss to mucosa.For achieving the above object; a large amount of investigative tests had once been carried out; the bismuth salt that has successively prepared various different acid groups; screen with zoopery; find that the acid Bismuth tartrate. can also can form protecting film simultaneously on gastric mucosa on mucous membrane of colon, put to death animal in administration after 16 hours; peel off mucous membrane of colon and gastric mucosa, after nitrated, show the identification of bismuth salt.On this basis the acid Bismuth tartrate. is added suitable adjuvant such as pectin, alginic acid and make multiple dosage forms such as capsule, electuary, water preparation, give and to suffer from colitis and suffer from volunteer people more than 20 of gastropathy simultaneously and take, scattered clinical test results shows that this medicine all has the obvious treatment effect to ulcerative colitis and gastritis.And other bismuth salt medicine only has certain therapeutical effect to disease of stomach, and is then invalid to ulcerative colitis.
The invention provides a kind of new drug jellied bismuth tartrate for the treatment of ulcerative colitis stomach function regulating, duodenal ulcer, chronic gastritis simultaneously, its chemistry acid Bismuth tartrate. by name or COLLOIDAL BISMUTH TARTRATE, (English name: Colloidal Bismuth Tartrate, Latin literary fame: Bismuthi Tartras Colloidalis).The chemical constitution that this product is determined through mass spectrum, infrared spectrum and ultraviolet spectral analysis is as follows:
Its molecular formula is C
8H
9O
12Bi, or BiH(C
4H
4O
6)
2
Molecular weight is 506.
Character of this product and chemical composition: it is slightly soluble in water, and it is acid that its aqueous solution shows, and pH is 3.5～5.5, and standard substance are 4.16～4.58, and chemistry acid Bismuth tartrate. by name or COLLOIDAL BISMUTH TARTRATE have special colloid property.It is different from diplomatic Bismuth tartrate. (Bismuth Tartrate), and latter's molecular formula is Bi
2(C
4H
4O
6)
3H
2O, the normal salt for tartaric acid and bismuth ion formation is water-insoluble; It also is different from bismuth and potassium tartrate and bismuth sodium tartrate, and back two kinds are alkali formula double salt, and soluble in water, aqueous solution shows alkalescence.
The bismuth of jellied bismuth tartrate of the present invention (Bi) constituent content is 30.0～34.0%, average 31.75%.Determination is to adopt complexiometry, makes indicator with xylenol orange under the acidity of pH＜1, with EDTA-2Na titer direct titration.
Physicochemical constant is measured: this product is a white powder, and hygroscopicity is arranged, and is slightly soluble in water, places the back and forms colloid solution; Be insoluble to organic solvents such as acetic acid, acetone, isopropyl alcohol.The thermal decomposition point of this product is 260～264 ℃, and the catabolic process color is deepened blackening gradually, arrives decomposition point and expands suddenly.This product proportion meansigma methods is 0.97g/ml.This product does not have optical activity.
Purity: the impurity that raw material and technical process may be introduced has been done check, and the result points out, lead salt content all is lower than 0.0010%, iron salt all＜0.005%, sulfate all＜0.040%, chloride＜0.05%, nitrate all＜0.3%, arsenic salt＜0.0002%.
Structure determination: this product has been carried out fast atom bombardment mass spectroscopy, infrared spectrum and ultraviolet spectroscopy.Mass spectrum is to measure on the ZAB-MS type High Resolution G C/MS/DS combined instrument that U.S. VG company produces; Infrared spectrum is to measure on U.S. Perkin-Elmer 983G infrared spectrometer; Ultraviolet spectra is to measure on Japanese Shimadzu Uv 260 ultraviolet spectrometers.Original spectrogram is attached.As follows to spectrum analysis:
Mass spectrum: the high-quality district of collection of illustrative plates has clear and definite (M+2H)
+(508) peak; The fragment of mass number 483 correspondences is (M-HCO
2H+Na); 445 peaks are corresponding to (M-CO
2H-H
2O+2H)
+; 426 peaks are corresponding to (M-CO
2H2H
2O+H)
+; 416 peaks are corresponding to (M-2CO
2H)
+; 407 peaks are corresponding to (M-CO
2H3H
2O).Molecular ion and fragment ion hydrogenation, adding sodium, is the feature of fast atom bombardment mass spectroscopy.Decarboxylation, dehydration are the common cracking modes of hydroxy acid.Molecular weight that provides and decarboxylation illustrate to still have a free carboxy to exist in the molecule.
Infrared spectrum (KBr tabletting): infrared spectrum confirms that molecule is a hydroxy-acid salt, has carboxyl and exists.Main spectrum peak such as following table.
The ownership at the main spectrum of table 1 peak
| Group | Oscillatory type | Wave number (cm) | Intensity (%T) |
| Carboxyl | The symmetrical stretching vibration carboxyl anion carbonyl symmetrical stretching vibration of the stretching vibration carboxyl anion carbonyl of association carbonyl in the stretching vibration carboxyl of carboxyl association hydroxyl | 3000～3300 1725 1590 1384 1305 | 7.36 20.91 5.70 4.08 6.13 |
| Secondary hydroxyl group | Hydroxyl stretching vibration secondary alcohol C-O stretching vibration | 3590 1134 | With carboxyl overlapping 10.84 |
| Methine | The C-H stretching vibration | 2974 | 39.84 |
Ultraviolet spectra (0.1M hydrochloric acid, 0.1M NaOH and 0.1M methanol solution):
Clear and definite absworption peak is all arranged about 220nm, and it is corresponding to the n → n of carboxylate
※Transition.
Analysis-by-synthesis: above-mentioned data spell out hydroxyl contained in the molecule, carboxyl, carboxylate group; Molecular weight is 506, and corresponding chemical constitution as mentioned above.
The technological process of production of jellied bismuth tartrate is as follows:
Molten acid → alkalization → dissolved salt → salify → adjust pH → wine sinks → refining → filtration → oven dry → pulverizing.
Fig. 1: the technology of the present invention route and manufacturing approach craft flow chart.
Now further narrate by reference to the accompanying drawings technology path of the present invention and manufacturing approach craft, referring to Fig. 1.
Raw material: mesotartaric acid (chemical pure), bismuth nitrate (chemical pure), KOH(chemical pure), ethanol (food grade). KOH can be NaOH, NH OH, Ca(OH), Na CO etc.; Ethanol can be ethanol and the absolute ethyl alcohol more than 80%, also isopropyl alcohol, acetone.
Reaction condition:
A. the tartaric acid solution temperature is 50～100 ℃, stirs to make dissolving in 0.5～1.0 hour, adds KOH and makes alkalize;
B. 20 ℃ of bismuth nitrate solution temperatures (room temperature) stirred 1～2 hour, added the KOH neutralization Too much nitric acid;
C. alkaline tartaric acid solution is under agitation joined in the bismuth nitrate solution, 30～50 ℃ of stirring reactions 0.5～1.5 hour;
D. the ethanol with 0.5～1.2 times of amount under agitation joins in the tartro-bismuthate, 15～25 ℃ of precipitation temperatures.
Process for purification: the tartro-bismuthate crude product is joined in the deionized water, and it is 9～10 that adding KOH liquid makes pH, stirs and makes dissolving, and it is 4～7 that adding nitric acid makes pH, adds precipitation with alcohol, and centrifugal dehydration is washed several with the ethanol top, oven dry, pulverizing, packing.
Raw material proportioning and operation:
Charge ratio: water: ethanol: potassium hydroxide: nitric acid: bismuth nitrate: sorbierite: tartaric acid=2～10: 3～15: 0.1～0.5: 1: 1～2.4: 0.5～1: 1.
Operation:
Be that the water of 5～20 times in tartaric acid joins in the flask that agitator is housed with weight ratio, be heated to 50～90 ℃, under agitation add tartaric acid, stir and make moltenly, be cooled to 20～40 ℃, stirring the lower concentration that adds is 10～40% the KOH aqueous solution, and making pH is 9～12. Be equipped with in the flask of agitator at another, add the water of 3～5 times of amounts, keep 15～20 ℃, under agitation add the sorbierite of 0.5～0.9 times of amount or sweet mellow wine, glucose cosolvent, bismuth nitrate, stir and made moltenly in 1～3 hour, add the KOH solution of concentration 10～40%, making pH is 7～8. Under agitation two liquid are mixed, 30～50 ℃ of stirring reactions 0.5～2 hour, the ethanol of 0.8～1.2 times of amount is under agitation joined in the mixed liquor, suction filtration or centrifugal gets crude product. Crude product is joined in distilled water or the deionized water, adding KOH solution, to make pH be 9～10, stirs to make dissolving, and adding nitric acid, to make pH be 4～7, add precipitation with alcohol, suction filtration or centrifugal is washed for several times with ethanol top, to the mother liquor till the no nitrate anion, 60～80 ℃ of lower oven dry, be ground into 100～200 purpose fine powders, sieve, packing.
The using method of jellied bismuth tartrate medicine of the present invention is, the final drug raw material that makes is added the auxiliary materials such as pectin or alginic acid, makes the multiple formulations such as capsule, tablet, electuary, aqua, suppository, ointment, can oral or rectally.
Test of pesticide effectiveness result:
1. clinically frontly carry out pharmacology and toxicity test result of study with animal
The bismuth salt pref is used for the treatment of the gastrointestinal disease history of existing decades, and along with the discovery of helicobacter pylori, the status of bismuth salt pref in the treatment DD raises day by day in recent years. In many bismuth preparations, must find pleasure in welcome by the patient, this medicine can successfully be used for treating gastric duodenal ulcer, chronic superficial gastritis, atrophic gastritis. This colloidal state bismuth can be killed helicobacter pylori, can obviously reduce the recurrence rate of canker and improve ulcer healing rate. So CBS is a kind of safe and desirable medicine for the treatment of at present peptic ulcer. For the foregoing reasons, we the exploitation, in the bismuth preparation process of development of new, with CBS as Positive control drug is in the hope of comparing its Different therapeutical effect.
Although the various medicines that contain bismuth salt for the treatment of gastrointestinal disease are come out one after another, not yet find the report with bismuth salt pref treatment non-specific ulcer colonitis. This cause of disease is not yet fully clear and definite at present, and immune deficiency may be to be accepted by people in many causes of disease. Being used for the treatment of clinically the unique active drug of ulcerative colitis is salicylazosulfapyridine (SASP), but because this medicine toxic and side effect is big, so be very limited in the use. At present, take the method for retention enema to treat this disease clinically more, not yet find a kind of ideal medicament strong, that toxicity is little that acts on, clinical still take control outbreak, mitigate the disease, anti symptom treatment as the primary treatment means. In the developmental research process of jellied bismuth tartrate, we find that this medicine not only has stomach and dudenal disease and must find pleasure in identical therapeutic action, and nonspecific ulcerative colitis is had obvious therapeutic action. This will become one of important value of this medicine of exploitation. This medicine is carried out pharmacodynamics for we and toxicity research selects SASP to contrast medicine. The result is as follows:
1. to the experimental Theatment of ulcerative of rabbit. The healthy rabbits of selecting is divided into three groups: i.e. physiological saline blank group, CBS control group and jellied bismuth tartrate group, 5～8 of every treated animals. Before formal test, carry out trial test take confirmed test with best dosage as 0.50g/kg/d, adopt without exception on an empty stomach gastric infusion in the experiment. The animal model preparation is to add that with homozoic mucous membrane of colon homogenate complete Freund adjuvant comes immune animal, and booster immunization once continues to observe 10 days after 10 days, confirms into disease. At this moment most of animal all has just rarely, and body weight obviously descends, and finds after the pathology that mucous membrane of colon is dispersivity inflammation, ulcer, and each layer of intestines wall all has in various degree congested and hemorrhage, flesh layer oedema, and visible muscle fibre fracture. Medication was found in 10 days afterwards: compare with the saline control group, the curative effect of jellied bismuth tartrate and SASP does not have marked difference (P＞0.05) all can obviously reduce the ulcer number, shortens length of lesion, dwindles ulcer disperse length; Compare P＜0.05 with saline control group and the group of must finding pleasure in, difference has significantly. Jellied bismuth tartrate group, SASP group reach to such an extent that the happy inhibiting rate of organizing ulcer is respectively 47.6%, 49.2% and 3.8%. Microscopy shows that repairing appears in jellied bismuth tartrate group ulcer surface, and pathology is light than control group, and the flesh layer does not have oedema, and connective tissue proliferation is arranged in the serous coat; Salt solution group and the no connective tissue proliferation of CBS group, the flesh layer still has oedema, and pathology is still heavier.
2. to the therapeutic action of the experimental chronic gastritis of rabbit. The preparation of morbid state animal model is to adopt immunization to copy the experimental chronic gastritis of rabbit, and the practice is with above-mentioned. The infected animal food-intake descended at that time, body weight obviously alleviates, and became celestial and found that gastric mucosa is the dispersivity inflammation, and each layer of coat of the stomach all has in various degree congested and hemorrhage. Medication found afterwards that jellied bismuth tartrate and CBS all can reduce the ulcer number, dwindle pathology area (seeing Table) in 10 days. Though the curative effect of tartro-bismuthate has obvious therapeutic action not as good as CBS, and the saline control group The result is very different. Microscopy shows: CBS group stomach lining inflammation disappears substantially, and connective tissue proliferation is arranged in the serous coat; Tartro-bismuthate group gastric mucosa still has cell infiltration in various degree, but lesion degree is light than control group; Saline control group gastric mucosa is the dispersivity inflammation, and hyperemia in various degree, hemorrhage, oedema are arranged.
Jellied bismuth tartrate, SASP and CBS are to the therapeutical effect of the experimental ulcerative colitis of rabbit
Table 2 Bismuth tartrate. and CBS are to the therapeutical effect of rabbit chronic gastritis
n＝6 °P＞0.05 °°P＜0.05 °°°P＜0.01
3. to the observation of curative effect of experimental rat acute gastritis.
Animal model preparation: in the animal fasting after 24 hours, irritate stomach with 1ml/kg dosage with the HCl of 100mMd, irritate stomach after 4 hours model make the beginning medication.Experimental result: naked eyes can be observed: obviously congested, the edema of all visible mucosa tissue of 6 rats of matched group, and part is as seen hemorrhage; Bismuth tartrate. group and CBS group gastric mucosal lesion degree are lighter, and extent of disease obviously dwindles.The pathological changes area calculates with square centimeter, and matched group is 3.30 ± 1.57, and the Bismuth tartrate. group is 0.57 ± 0.65, and the CBS group is 0.04 ± 0.10.Microscopy: the mucosal erosion of control rats lesion, a large amount of cell infiltration, and as seen be dispersed in the petechia, flesh layer edema, the fault rupture of part flesh; It is lighter that medication group and matched group are compared pathological changes, and a small amount of cell infiltration is not seen the petechia.Though the curative effect of Bismuth tartrate. still has the obvious treatment effect not as good as must be happy.
4. to the observation of curative effect of the impatient gastric ulcer of rat experiment.
Divide three groups with 22 male rats, irritate stomach secondary (fasting) with normal saline, Bismuth tartrate. and CBS respectively earlier, lumbar injection reserpine 5ml/kg put to death animal after 16 hours, took out stomach, poured into and immerse and observe specimen after formalin is fixed 10 minutes.Experimental result: Bismuth tartrate. and CBS all can obviously suppress the acute gastric ulcer number that reserpine brings out, and the two has identical therapeutical effect.To the suppression ratio of ulcer, Bismuth tartrate. is 42%, and CBS is 56%.
5. to the observation of curative effect of rat experiment chronic gastric ulcer.
With hungry 4 hours of Mus, cut open the belly, under 0.5cm place stomach serous coat above the pylorus, inject 10% acetic acid 0.05ml, to sew up immediately, art finishes ad libitum access and drinks water.Began medication the same day, shared 8 days, the sacrifice of animal of naming a person for a particular job the 9th day morning 8 was observed gastropathy.Experimental result: Bismuth tartrate. and CBS all can obviously suppress the chronic gastric ulcer that acetic acid brings out, and ulcer area and volume are significantly dwindled, and with contrast (saline) group highly significant difference (P＜0.01) are arranged relatively.The gastric ulcer suppression ratio of Bismuth tartrate. and CBS is respectively 79% and 81%, and the curative effect of the two is identical.
6. to the observation of curative effect of rat preduodenal ulcer.
Divide 3 groups to 20 rats, be respectively normal saline group, Bismuth tartrate. group and must find pleasure in and organize in accordance with regulations dosage and irritated stomach two days, after irritating stomach in second day 15 minutes, reuse Mercaptamine solution is irritated stomach to animal, once amount is 280mg/kg, be total to administration 3 times at interval in 3 hours, put to death animal after 48 hours, get near-end duodenum specimen and observe pathological changes from administration for the first time.Degree of injury shows that with the damage numerical table of keeping the score grade is divided into 0～7 grade: 0 becomes for there not being work, and 1 be mucous hyperemia, and 2 be mucosal bleeding, and 3 be downright bad, and 4 is mucosal erosion, and 5 is the routed treatment of shallow table, and 6 is deep ulcer, and 7 is intestinal wall holostrome perforated ulcer.Experimental result: control rats duodenal injury score value is 5.33 ± 1.37; The Bismuth tartrate. group is 2.2 ± 1.5; CBS group is 3.0 ± 1.0, the two no significant difference, and promptly therapeutical effect is identical, but the two is compared with matched group highly significant difference (P＜0.01) is all arranged.
7. the animal acute toxicity test of jellied bismuth tartrate
Pharmacology teaching and research room of Shanxi Medical College once selected 15 of the mices of animal housing of Shanxi Medical College breeding for use, and trial test is divided into 3 dosage groups: 2.5%, 5% and 12%(in bismuth), irritate stomach once on an empty stomach, observe animals survived and death condition in 72 hours.Formal experiment: be 20 of healthy mices, divide two groups, first group is 12% colloidal state Tartaric acid bismuth group, each dosage 0.5ml/10g/d(is the mice maximum tolerated dose), be equivalent to 60mg bismuth/10g/d, be 80 times of therapeutic dose, normal saline matched group for the second time, medication administration method is identical with dosage, observes the active situation of mice in 7 days, becomes celestial after 7 days and respectively organizes mice.Experimental result: none animal dead of trial test group, each organizes mice active situation and normal mouse indifference, can't measure LD.Mice is movable good in the formal test, no alopecia, none only death.Put to death and dissect animal, perusal, jellied bismuth tartrate group and saline control group do not have significant difference, and according to toxicity grading, the true border of this medicine is nontoxic.
8. organism absorbing jellied bismuth tartrate once observed with rabbit and human experimentation by the institute of materia medica, Datong City, Shanxi Province.Animal blood bi concns is 0.74ppm as a result, and human body blood bi concns is that three weeks of 0.49ppm(are average).Therefore this concentration belong to no cytotoxic drug in fact well below the concentration that toxic reaction occurs.
2. clinical experiment result: jellied bismuth tartrate is the same with CBS to be the very effective medicine of treatment gastric and duodenal ulcers and inflammation.But jellied bismuth tartrate has the obvious treatment effect to experimental ulcerative colitis, and this is the unexistent pharmacological action of CBS.Through three hospitals (People's Hospital of Shanxi Prov., No.2 Affiliate Hospital, Shanxi Medical College and the 3rd the People's Hospital, Datong) clinical verification 105 cases, matched group 74 examples are set, and the result shows: to the chronic colitis obvious effective rate be 53.0%, effective percentage is 33.0%, total effective rate is 86.0%; To the peptic ulcer effective percentage is 93.3%.Can think the effective medicine of chronic colitis, chronic gastritis and peptic ulcer.Animal and human's body to this medicine absorbtivity seldom, well below the concentration that toxic reaction occurs.Animal experiment is carried out in heavy dose of administration, proves the real medicine that has no side effect that belongs to of this medicine.This medicine production technology is simple in addition, and the medicine valency is cheap.
Embodiment 1:
10g tartaric acid is dissolved in the hot water of 90 ℃ of 10ml, adding concentration and be 40% KOH solution, to make pH be 10.In addition 10g sorbitol, 1.4g bismuth nitrate are joined in the 20ml water, be stirred to moltenly entirely, adding concentration and be 40% KOH solution, to make pH be 5.The cold liquid of tartaric acid is joined in the bismuth nitrate solution, and adding a small amount of nitric acid or a small amount of KOH, to regulate pH value be 5～6.50ml ethanol is joined in the reactant liquor sucking filtration.Filter cake is suspended in the water, adds KOH and be stirred to dissolving fully in right amount, adding an amount of nitric acid, to make pH be 6～6.5, adds ethanol and make the COLLOIDAL BISMUTH TARTRATE precipitation fully, sucking filtration, washes for several times with the ethanol top, drains, dries, pulverizes, sieves.
Embodiment two:
10g tartaric acid is dissolved in the hot water of 70 ℃ of 15ml, it is 11 that adding KOH solution makes pH.In addition the 1.4g bismuth nitrate is joined in the 20ml water, making pH with 20～40%KOH neutralization is 7, and sucking filtration is suspended in filter cake in the 20ml water, adds the 10g sorbitol, adds the KOH solution stirring to dissolving fully.Tartaric acid solution is joined in the bismuth solution, regulate pH to 5～6, add 50ml ethanol and make precipitation fully, sucking filtration is washed 1～2 time with the small amount of ethanol top, drains, dries, pulverizes, sieves.
Claims (9)
1, a kind of bismuth salt medicine for the treatment of gastrointestinal disease is characterized in that it is jellied bismuth tartrate or acid Bismuth tartrate., and its chemical constitution is as follows:
Molecular formula is BiH (C
4H
4O
6)
2, molecular weight is 506, and its pH value of aqueous solution is 3.5～5.5, and proportion is 0.8～1.0g/ml.
2, a kind of bismuth salt medicine for the treatment of gastrointestinal disease as claimed in claim 1 is characterized in that bismuth (Bi) constituent content of this jellied bismuth tartrate is 30.0～34.0%.
3, a kind of bismuth salt medicine for the treatment of gastrointestinal disease as claimed in claim 1, the character and the physicochemical constant measured value that it is characterized in that it are: outward appearance is a white powder, moisture absorption and be slightly soluble in water and form colloid solution is insoluble to ethanol, isopropyl alcohol, acetone, and the thermal decomposition point is 260～264 ℃.
4, a kind of bismuth salt medicine for the treatment of gastrointestinal disease as claimed in claim 1 is characterized in that purity and impurity content are: lead salt content＜0.0010%(＜20ppm), arsenic salt＜0.0002%, iron salt＜0.005%, sulfate＜0.040%, chloride＜0.05%, nitrate＜0.3%.
5, a kind of manufacture method for the treatment of the bismuth salt medicine of gastrointestinal disease is characterized in that production technology is divided into 10 step operations: (a) molten acid, (b) alkalization, (c) dissolving bismuth salt, (d) salify, (e) precipitation, (f) dewater, (g) is refining, (h) filters, (j) is dry, (k) pulverizes.
6, as the said a kind of manufacture method for the treatment of the bismuth salt medicine of gastrointestinal disease of claim 5, it is characterized in that respectively going on foot the operational approach and the reaction condition of operation: said (a) molten acid and (b) alkalization, be that to add weight ratio in tartaric acid be 5～20 times water, elevated temperature to 50～90 ℃ are stirred and were obtained aqueous tartaric acid solution in 0.5～1.0 hour, and being cooled to 20～40 ℃, to add concentration then under this temperature be that to make pH value be 9～12 for 10～40% KOH aqueous solution; Said (c) dissolving bismuth salt, be cosolvents such as the sorbitol that points to the water that adds 3～5 times of amounts in the bismuth nitrate and 0.5～0.9 times of amount, mannitol, glucose, solution temperature is 15～25 ℃, stirs 1～3 hour, add 10～40% KOH solution again, making pH value is 7～8; Said (d) salt-forming reaction be with pH value be 9～12 alkaline tartaric acid solution 30～50 ℃ and stir under join in the bismuth nitrate solution stirring reaction 0.5～2.0 hour; Said (e) precipitation and (f) dehydration be meant with the ethanol of 0.8～1.2 times of amount 15～25 ℃ and stir under join in the Bismuth tartrate., make Bismuth tartrate. produce precipitation, centrifuge dehydration then makes crude product; Said (g) is refining, (h) filters, (j) is dry and (k) pulverizing, be that order joins the Bismuth tartrate. crude product in the proper amount of deionized water, under 20～60 ℃, stir and make its dissolving, the ethanol that adds 0.8～1.2 times of amount then makes its precipitation, refilters or centrifuge dehydration, makes wet product, the product that will wet are washed for several times with the ethanol top, 60～80 ℃ of oven dry, be crushed at last and can be finished product by the fine powder of 100～200 mesh standard sieves.
7,, it is characterized in that wherein used KOH can be NaOH, NH as the manufacture method of the said bismuth salt of claim 6 medicine
4OH, Ca(OH)
2, Na
2CO
3, used ethanol can be the ethanol more than 80%, also dehydrated alcohol, isopropyl alcohol, acetone organic solvent.
8,, it is characterized in that raw materials used proportioning is: water: ethanol: potassium hydroxide: nitric acid: bismuth nitrate: sorbitol: tartaric acid=2～10: 3～15: 0.1～0.5: 1: 1～2.4: 0.5～1: 1 as the manufacture method of the said bismuth salt of claim 6 medicine.
9,, it is characterized in that using method is that adding pectin or alginic acid adjuvant are made capsule, tablet, electuary, water preparation, suppository, with oral or rectally as claim 1,2,6 said bismuth salt medicines.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92114664 CN1033789C (en) | 1992-12-23 | 1992-12-23 | Jellied bismuth tartrate medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92114664 CN1033789C (en) | 1992-12-23 | 1992-12-23 | Jellied bismuth tartrate medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1088433A true CN1088433A (en) | 1994-06-29 |
| CN1033789C CN1033789C (en) | 1997-01-15 |
Family
ID=4947045
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92114664 Expired - Lifetime CN1033789C (en) | 1992-12-23 | 1992-12-23 | Jellied bismuth tartrate medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1033789C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276445A (en) * | 2011-06-22 | 2011-12-14 | 于学敏 | Colloidal bismuth tartrate compound, medicaments thereof, preparation method thereof and application thereof |
| CN106860476A (en) * | 2015-12-14 | 2017-06-20 | 于学敏 | A kind of new pharmaceutical preparation Colloidal Bismuth Tartrate particle |
| CN106860418A (en) * | 2015-12-14 | 2017-06-20 | 于学敏 | A kind of new pharmaceutical preparation Colloidal Bismuth Tartrate piece |
-
1992
- 1992-12-23 CN CN 92114664 patent/CN1033789C/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276445A (en) * | 2011-06-22 | 2011-12-14 | 于学敏 | Colloidal bismuth tartrate compound, medicaments thereof, preparation method thereof and application thereof |
| CN102276445B (en) * | 2011-06-22 | 2013-11-06 | 于学敏 | Colloidal bismuth tartrate compound, medicaments thereof, preparation method thereof and application thereof |
| CN106860476A (en) * | 2015-12-14 | 2017-06-20 | 于学敏 | A kind of new pharmaceutical preparation Colloidal Bismuth Tartrate particle |
| CN106860418A (en) * | 2015-12-14 | 2017-06-20 | 于学敏 | A kind of new pharmaceutical preparation Colloidal Bismuth Tartrate piece |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1033789C (en) | 1997-01-15 |
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