CN1329414C - Bismuth potassium hyalurate and its preparation method and uses - Google Patents
Bismuth potassium hyalurate and its preparation method and uses Download PDFInfo
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- CN1329414C CN1329414C CNB200510125668XA CN200510125668A CN1329414C CN 1329414 C CN1329414 C CN 1329414C CN B200510125668X A CNB200510125668X A CN B200510125668XA CN 200510125668 A CN200510125668 A CN 200510125668A CN 1329414 C CN1329414 C CN 1329414C
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- hyalurate
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Abstract
The present invention relates to a bismuth potassium hyalurate of which the molecular formula is (C14O13NH21Bi)m(C14O11NH19K)n; in the molecular formula, the ratio of m to n is from 1:0.01 to 20. A preparation method of the bismuth potassium hyalurate comprises the following steps: soluble hyaluronate and bismuth salt react in a ter solution which contains potassium hydroxide; through precipitation, washing operation, filtration, drying and the like, a product is obtained. The bismuth potassium hyalurate is used for preparing medicaments for preventing and treating gstrointestinal tract diseases or health care food. The bismuth potassium hyalurate is especially used for preparing medicaments for treating gstrointestinal tract canker. Animal experiments prove that the therapeutic effect of the bismuth potassium hyalurate is better than that of similar products.
Description
The invention belongs to field of medical technology, relate to a kind of bismuth hyalurate sylvite and preparation method thereof and the application aspect its preparation prevention and treatment gastrointestinal tract disease medicine and protective foods.
Hyaluronic acid claims glass acid (hyaluronic acid is hereinafter to be referred as HA) again.The regular macromole chain polysaccharide that repeats to constitute of disaccharide unit that HA is made up of D-glucuronic acid and N-ethanoyl glucose, molecular weight has the moisture retention of good lubricity, viscoelasticity, non-immunogenic and height from several ten thousand to millions of.At present, commodity HA mainly be applied to clinical with the form of sodium salt and makeup in.Hyaluronic potassium, calcium, magnesium, aluminium, ammonium, silver and the preparation of golden salt and application thereof are open in a plurality of patents; the ion salify (complexing) of hyaluronic acid and the 4th cycle the 3rd of periodic table of elements family's metal; confirmed skin ulcer, bedsore effective in cure (WO9010020) as zinc hyaluronate and Cobalt hyaluronate; it is active that zinc hyaluronate has significant stomach protection, can be used for prevention and treatment peptide ulceration (CN1126548).Bismuth hyalurate sylvite (mixture) and preparation thereof and application yet there are no document and openly report.
Gastrointestinal tract disease comprises chronic gastritis, peptide ulceration, functional dyspepsia and cancer of the stomach etc., and wherein peptide ulceration is a kind of high morbidity kind, and it is the major incentive that causes gastrointestinal tract inflammation, gastrointestinal hemorrhage, maldigestion and gastrointestinal cancer.The pathogeny of peptide ulceration is comparatively complicated, and local mucous membrane infringement (the causing ulcer) factor of itself and stomach and intestine that studies show that in recent years and mucous membrane protection (mucous membrane barrier) factor are unbalance and it is relevant to infect Hp.At present clinical the associating uses microbiotic, antacid and mucous membrane protective material treatment peptic ulcer disease to obtain good result; wherein the bismuth agent is the maximum class mucous membrane protective material of clinical use, and commonly used have Bismuth Potassium Citrate, bismuth subsalicylate, bismuth subnitrate and a Colloidal Bismuth Pectin etc.The pharmacological action of bismuth agent can reduce and produce precipitation under the hydrochloric acid in gastric juice condition, attaches to mucosa surface and forms protective layer, and protection gastric mucosa (ulcer surface) reduces the pessimal stimulation of stomach, promotes regeneration of ulcer mucous membrane and ulcer healing; Regulate secretion, as reduce pepsic activity, increase mucoprotein secretion, promote mucous membrane to discharge PGE
2Absorption bacteriocin (enterotoxin that toxin that produces as colon bacillus or vibrio cholerae produce) and to the direct anti-microbial activity of pathogenic microbes (Hp).The agent of biomacromolecule bismuth, as Colloidal Bismuth Pectin with its stronger selectivity of sticking, promptly to the special avidity of gastroenteritic ulcer face and inflammation surface, curative effect obviously surpasses other small molecules bismuth agent in treatment of diseases such as gastric and duodenal ulcer, chronic superficial gastritis, chronic atrophic gastritis, digestive tract hemorrhage.Bismuth potassium hyalurate also belongs to the agent of macromole bismuth, and HA is the biological glutinous polysaccharide of animal body inherent macromole, and its structure does not have the kind difference, has good viscoelasticity, oilness and film-forming properties.The present HA that studies show that has participated in various kinds of cell activity and physiological process, migrates as migration and differentiation, wound healing, the cancer cells of cell, influences the generation of effect, embryo's formation and the growth and the inflammation of somatomedin.Have test to confirm that HA has directed accumulative trend in inflammation and damage location, polymer HA has anti-inflammatory activity by the function that suppresses scavenger cell.Under acidic conditions, the HA solution viscosity increases, and forms macromolecular reticulated structure, is gel, has stronger tack.Therefore, bismuth potassium hyalurate compared with similar products, has unrivaled superiority as the mucous membrane protective material.
The purpose of this invention is to provide a kind of bismuth agent that can be used for preparing prevention and treatment gastrointestinal tract disease medicine and protective foods and preparation method thereof, this bismuth agent is a bismuth hyalurate sylvite, prove that through preliminary animal experiment bismuth potassium hyalurate is used for the treatment of the gastrointestinal ulceration curative effect and is better than Colloidal Bismuth Pectin.
Bismuth hyalurate sylvite of the present invention is characterised in that its molecular formula is (C
14O
13NH
21Bi)
m(C
14O
11NH
19K)
n, structural formula is as follows:
M: n=1 wherein: 0.01～20
Calculate according to molecular formula, the content range of bismuth is about 2.33%～33.49% in the bismuth potassium hyalurate dry product of the present invention, and the content range of potassium is about 0.06%～8.73%, and the content range of uronic acid is about 31.39%～45.58%.
The preparation method of bismuth potassium hyalurate of the present invention, it is characterized in that making bismuth salt to be dissolved in earlier in the deionized water that contains polyvalent alcohol, be added drop-wise to simultaneously in the aqueous solution of soluble transparent matter hydrochlorate with potassium hydroxide solution then, stirring reaction is again through precipitation, washing, filtration and dry.
Among the preparation method of above-mentioned bismuth potassium hyalurate, described bismuth salt can use Bismuth trinitrate, bismuth hydroxide, bismuth chloride or bismuth oxide, described polyvalent alcohol can use sorbyl alcohol, N.F,USP MANNITOL or glycerine, described soluble transparent matter hydrochlorate can use its inorganic salt, as hyaluronate sodium, potassium hyaluronate, Calcium hyaluronate or zinc hyaluronate, also can use its organic salt, as hyaluronic quaternary ammonium salt.
The bismuth potassium hyalurate that adopts the inventive method preparation to produce, product purity is higher, foreign matter content is less.By the ratio of conditioned reaction thing, can obtain the different product of bi content, wherein bi content is more suitable for clinical treatment at 15%～30% product.
Bismuth potassium hyalurate of the present invention has excellent biological compatibility and film-forming properties; in simulated gastric fluid and simulated intestinal fluid, all can form high viscosity colloidal sol; as the protective layer of gastrointestinal tract mucosa, can avoid the stimulation of food, hydrochloric acid in gastric juice, digestive ferment and some drugs to impaired mucous membrane, promote ulcer healing.Because HA has in inflammation and damage location directed accumulative trend and certain anti-inflammatory activity are arranged, compared with similar products, the effect of bismuth potassium hyalurate prevention and treatment gastrointestinal tract disease is more remarkable.
Bismuth potassium hyalurate of the present invention can directly orally be used for gastrointestinal tract inflammation and gastrointestinal ulceration prevention and treatment; also can with other functional component and auxiliary material prescription commonly used; make the sheet that is suitable for oral administration; ball; capsule; particle; syrup; gel; pharmaceutical preparation such as solution or suspension or protective foods; oral prevention and the treatment gastrointestinal tract disease of being used for; comprise chronic gastritis; peptide ulceration; functional dyspepsia and cancer of the stomach etc.; can reach and ease the pain; symptoms such as diarrhoea and maldigestion, protection digestive tube mucous membrane; promote regeneration of ulcer mucous membrane and ulcer healing; reduce purposes such as inflammation generation.
Further specify the present invention below by embodiment.
Embodiment 1
10g hyaluronate sodium (molecular-weight average 1,090,000) is scattered in the 500ml deionized water stirring and dissolving.Other gets potassium hydroxide 10g and is dissolved in the 100ml deionized water.Get 14 gram Bismuth trinitrate [Bi (NO
3)
35H
2O] and 25 gram N.F,USP MANNITOL, add in the 500ml deionized water stirring and dissolving.Then bismuth nitrate solution and potassium hydroxide solution are added dropwise to sodium hyaluronate solution simultaneously, stirring reaction, reaction finishes and adds 3～4 times of (V/V) ethanol, stir, precipitation precipitates with 80% aqueous ethanolic solution thorough washing, with the dehydrated alcohol dehydration, 35 ℃～40 ℃ drying under reduced pressure get finished product at last.Finished product after measured, by dry product, bi content is 31.5% (W/W), potassium content is 0.51% (W/W), glucuronic acid content is 32.27% (W/W).
Embodiment two
10g hyaluronate sodium (molecular-weight average 1,410,000) is scattered in the 500ml deionized water, stirring and dissolving, other gets potassium hydroxide 8.5g and is dissolved in the 100ml deionized water.Get 12 gram Bismuth trinitrate [Bi (NO
3)
35H
2O] and 24 gram N.F,USP MANNITOL, add in the 500ml deionized water stirring and dissolving.Then bismuth nitrate solution and potassium hydroxide solution are added dropwise to hyaluronic acid solution simultaneously, stirring reaction, reaction finishes and adds 3～4 times of ethanol (V/V), stir, precipitation precipitates with 80% aqueous ethanolic solution thorough washing, with the dehydrated alcohol dehydration, 35 ℃～40 ℃ drying under reduced pressure get finished product at last.Finished product after measured, by dry product, bi content is 27.4% (W/W), potassium content is 0.81% (W/W), glucuronic acid content is 33.65% (W/W).
Embodiment three
10g hyaluronate sodium (molecular-weight average 750,000) is scattered in the 500ml deionized water, stirring and dissolving, other gets potassium hydroxide 5g and is dissolved in the 100ml deionized water.Get 3.5g bismuth hydroxide [Bi (OH)
3] add the aqueous solution that 500ml contains 6 gram glycerine, stirring and dissolving.Then bismuth hydroxide solution and potassium hydroxide solution are slowly added hyaluronic acid solution simultaneously, stirring reaction, reaction finishes and adds 2～3 times of (V/V) acetone, precipitation with 70%～80% aqueous acetone solution thorough washing precipitation, is dewatered with acetone at last, 35 ℃～40 ℃ drying under reduced pressure get finished product.Finished product after measured, by dry product, bi content is 20.3% (W/W), potassium content is 3.45% (W/W), glucuronic acid content is 36.96% (W/W).
The preliminary results of pharmacodynamic test of the bismuth potassium hyalurate of the present invention's preparation is as follows.
1. bismuth potassium hyalurate causes the provide protection of rat gastric ulcer to acetate.
Select the female Wistar rats of body weight 150～200g for use, and the reference method (1. pharmacological experimental methodology, the 2nd edition. Beijing: People's Health Publisher, 1991; 1158～1160.2. bureau of drug administration of Ministry of Health of the People's Republic of China, new drug (Western medicine) preclinical study governing principle compilation (pharmacy, pharmacology, toxicology), 1993; 88～89) make acetate and burn the type gastric ulcer model.In the scope of the rat stomach somaplasm face diameter 5mm of etherization, handle 1.5min with the 0.2ml Glacial acetic acid and bring out stomach ulcer.Operation is divided into 6 groups and begin oral administration at random with animal next day, negative control is a distilled water, positive control is the Colloidal Bismuth Pectin bulk drug, (bi content is 31.5% to test sample for the bismuth potassium hyalurate by the embodiment of the invention 1 preparation, potassium content is 0.51%, glucuronic acid content is 32.27%) and hyaluronate sodium bulk drug (molecular-weight average 910,000, glucuronic acid content 38.9%).Rat is irritated stomach once every day, about at every turn 10ml, and successive administration was put to death animal after 10 days, got stomach, fixed with formaldehyde solution, after the dissection, in the size of microscopically measurement gastric mucosa ulcer surface, measured the vertical footpath of the maximum (d by the ulcer center
1) and maximum transverse diameter (d
2), calculate the ulcer area with following formula: S=π * (d
1/ 2) * (d
2/ 2), ulcer inhibition rate is represented with the difference percentage ratio of control group and experimental group.Test-results is listed in the table below.
Table 1 bismuth potassium hyalurate causes the provide protection of rat gastric ulcer to acetate
* compare P＜0.05 with control group
* and control group be P＜0.01 relatively
* * and control group be P＜0.001 relatively
2. bismuth potassium hyalurate is to the preventive and therapeutic effect of gastric mucosa damage due to the acidic alcohol
Select the female Wistar rats of body weight 150～200g for use, the reference method (the herbal pharmacology research methodology. Beijing: People's Health Publisher, 1994:441) water 24h is can't help in the rat fasting, random packet (the same), gastric infusion, behind the perfusion 30min, every rat gavages acidic alcohol (mixture of 50ml dehydrated alcohol and 1ml concentrated hydrochloric acid) respectively, dosage is the 0.5ml/100g body weight, behind the acidifying Ethanol Treatment 1h with sacrifice of animal, win stomach, cut off coat of the stomach along greater gastric curvature after the formaldehyde fixed, the gastric mucosa degree of impairment is observed in the washing back.Measure the length of streak hemorrhage damage, the results are shown in following table.
Table 2 stomach is to the preventive and therapeutic effect of rat stomach mucosa injury due to the acidic alcohol
* compare P＜0.05 with control group
* and control group be P＜0.01 relatively
* * and control group be P＜0.001 relatively
Claims (6)
1. a bismuth potassium hyalurate is characterized in that molecular formula is (C
14O
13NH
21Bi)
m(C
14O
11NH
19K)
n, structural formula is as follows:
M: n=1 wherein: 0.01～20.
2. the preparation method of the described bismuth potassium hyalurate of claim 1, it is characterized in that: bismuth salt is dissolved in earlier in the deionized water that contains polyvalent alcohol, then bismuth salts solution and potassium hydroxide solution are added drop-wise in the aqueous solution of soluble transparent matter hydrochlorate simultaneously, stirring reaction is again through precipitating, wash, filter and being drying to obtain bismuth potassium hyalurate.
3. the preparation method of bismuth potassium hyalurate according to claim 2, it is characterized in that: described bismuth salt is Bismuth trinitrate, bismuth hydroxide, bismuth chloride or bismuth oxide.
4. the preparation method of bismuth potassium hyalurate according to claim 2, it is characterized in that: described polyvalent alcohol is sorbyl alcohol, N.F,USP MANNITOL or glycerine.
5. the preparation method of bismuth potassium hyalurate according to claim 2, it is characterized in that: described soluble transparent matter hydrochlorate is hyaluronate sodium, potassium hyaluronate, Calcium hyaluronate, zinc hyaluronate or hyaluronic acid quaternary ammonium salt.
6. the purposes of the described bismuth potassium hyalurate of claim 1 is characterized in that: the medicine or the protective foods that can be used to prepare prevention and treatment gastrointestinal tract disease.
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100348621C (en) * | 2005-12-02 | 2007-11-14 | 凌沛学 | Bismuth hyalurate and its preparation method and uses |
| CN101831004A (en) * | 2010-03-24 | 2010-09-15 | 章云 | Hyaluronic acid strontium salt compounds, preparation method thereof and application in medicine |
| CN107118285A (en) * | 2015-12-14 | 2017-09-01 | 于学敏 | High-purity colloidal bismuth pectin compound and structural formula, molecular formula, the confirmation of molecular weight |
| CN114133465B (en) * | 2020-09-03 | 2023-03-21 | 山东华熙海御生物医药有限公司 | Preparation method of potassium hyaluronate, obtained product and application |
| WO2024022447A1 (en) * | 2022-07-29 | 2024-02-01 | 上海交通大学 | Use of bismuth-polymer complex in digestive tract visualization |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1086422A (en) * | 1989-02-24 | 1994-05-11 | 格德昂·理查德化学工厂股份公司 | The preparation of drug combination method that contains the hyaluronic acid coordination compound |
| WO1998048815A1 (en) * | 1997-04-29 | 1998-11-05 | Richter Gedeon Vegyészeti Gyár Rt. | Use of zinc hyaluronate against peptic ulcer |
| CN1563108A (en) * | 2004-04-13 | 2005-01-12 | 阮春学 | Method for preparing transparent calcium hyaIuronate in low molecular weight |
-
2005
- 2005-12-02 CN CNB200510125668XA patent/CN1329414C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1086422A (en) * | 1989-02-24 | 1994-05-11 | 格德昂·理查德化学工厂股份公司 | The preparation of drug combination method that contains the hyaluronic acid coordination compound |
| WO1998048815A1 (en) * | 1997-04-29 | 1998-11-05 | Richter Gedeon Vegyészeti Gyár Rt. | Use of zinc hyaluronate against peptic ulcer |
| CN1563108A (en) * | 2004-04-13 | 2005-01-12 | 阮春学 | Method for preparing transparent calcium hyaIuronate in low molecular weight |
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Application publication date: 20060503 Assignee: SHANDONG FREDA BIOTECHNOLOGY CO., LTD. Assignor: Ling Peixue Contract record no.: 2012370000263 Denomination of invention: Bismuth potassium hyalurate and its preparation method and uses Granted publication date: 20070801 License type: Exclusive License Record date: 20121219 |
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