CN101590076B - Application of pharmacologically-acceptable metal lanthanum salt or lanthanum oxide - Google Patents
Application of pharmacologically-acceptable metal lanthanum salt or lanthanum oxide Download PDFInfo
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- CN101590076B CN101590076B CN 200810011597 CN200810011597A CN101590076B CN 101590076 B CN101590076 B CN 101590076B CN 200810011597 CN200810011597 CN 200810011597 CN 200810011597 A CN200810011597 A CN 200810011597A CN 101590076 B CN101590076 B CN 101590076B
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Abstract
The invention relates to an application of pharmacologically-acceptable metal lanthanum salt or lanthanum oxide, in particular to an application of pharmacologically-acceptable metal lanthanum salt or lanthanum oxide in preparing medicament for preventing-alimentary canal ulcer. The inventor of the invention surprisingly found that the pharmacologically-acceptable metal lanthanum salt or lanthanum oxide can be used to resist alimentary canal ulcer, including gastric ulcer, duodenal ulcer, complex ulcer, multiple ulcer, stoma ulcer and colonitis.
Description
Technical field
The present invention relates to the purposes of lanthanoid metal pharmaceutically acceptable salt or its oxide.Concretely, the invention particularly relates to lanthanoid metal pharmaceutically acceptable salt or its oxide purposes in the preparation anti-peptic ulcer drug.
Background technology
Lanthanum is rare earth metal, and its symbol of element is La, and English full name is Lanthanum.
There has been the chemical compound of multiple lanthanum to be well known, such as lanthana, Lanthanum (III) nitrate, lanthanum carbonate, lanthanum chloride etc.Active component is that the medicine of lanthanum carbonate goes on the market in the U.S., and its commodity are called FOSRENOL, and molecular formula is La
2(CO
3)
3XH
2O (x is 4-5) is the chemical compound of about 4 of lanthanum carbonate band (4-5) water of crystallization.FOSRENOL is phosphate binder, can reduce the absorption to phosphorus in the food.Simultaneously because the absorbed degree of lanthanum is very low, be safe drugs very.
Chinese invention patent ZL96193918.4 also discloses the preparation method of lanthanum carbonate tetrahydrate, lanthanum carbonate eight hydrates.With and as the effect of phosphate binder.
The people such as Japanese plum flower bud (Lanthanum (III) nitrate is to the experimentation of gastric mucosa of rat long term. the journal .2001 of Norman Bethune Medical University, 27 (2): 121-123) studied the impact of Lanthanum (III) nitrate Long-term Oral on gastric mucosa of rat, found: the Lanthanum (III) nitrate Long-term Oral of higher dosage (20 and 10mg/kg) causes the damage of gastric mucosa; Lanthanum (III) nitrate than low dosage (2,0.2 and 0.1mg/kg) has certain protective effect to gastric mucosa.This author thinks that there is " adaptability protection " phenomenon in normal gastric mucosa, directly contacts gastric mucosa than the Lanthanum (III) nitrate of low dosage through gavage, also can think a kind of low intensive stimulating factor, the protective effect that can improve gastric mucosa.The Lanthanum (III) nitrate of 10mg, the 0.1mg Lanthanum (III) nitrate is equivalent to respectively 5.02mg, the lanthanum of 0.0502mg according to its molecular formula conversion.Because for be lanthanum on the impact of normal gastric mucosa, on the knees of the gods to the effect of existing damage.
Summary of the invention
The present invention relates to lanthanoid metal pharmaceutically acceptable salt or its oxide purposes in the preparation anti-peptic ulcer drug.The inventor surprisingly finds, lanthanoid metal pharmaceutically acceptable salt or its oxide can be used for Antiulcer activity, and said digestive tract ulcer comprises gastric ulcer, duodenal ulcer, complex ulcer, multiple ulcers, stoma ulcer, colitis etc.
For essence of the present invention better is described, one embodiment of the invention have confirmed its effect as anti-ulcer medicament with lanthanum carbonate and citric acid lanthanum.What the inventor was surprised shows, bring out on the Mouse Stomach mucosa injury model at dehydrated alcohol, give the good antiulcer action that demonstrates of lanthanum carbonate or citric acid lanthanum, under the dosage in lanthanum 96.7mg/kg administration, its effect is better than the bismuth potassium citrate (bismuth potassium citrate of determined curative effect at statistical significance, wherein bismuth potassium citrate is in bismuth, is converted into dosage 169.5mg/kg corresponding to mice by the clinical daily dose of human).
Another embodiment of the invention has confirmed that mice gives respectively lanthanum carbonate (in lanthanum) 12.5mg/kg by body weight, 25.0mg/kg, and 50mg/kg demonstrates statistically significant antiulcer action during 200mg/kg.
Though there is document description to cause the damage of normal gastric mucosa to the Lanthanum (III) nitrate Long-term Oral of: higher dosage (20 and 10mg/kg), still, the unexpected discovery of the inventor: for Ulcer Models, demonstrate antiulcer action.
Should be understood that lanthanum carbonate and citric acid lanthanum only provide the concrete form of lanthanum ion.Essence of the present invention is to give lanthanum ion in the intestinal, can help treatment or the prevention of digestive tract ulcer.
Lanthanoid metal pharmaceutically acceptable salt of the present invention includes but not limited to: lanthanum carbonate and solvate thereof, such as the disclosed lanthanum carbonate tetrahydrate of Chinese invention patent ZL96193918.4, lanthanum carbonate eight hydrates, the lanthanum carbonate monohydrate, the lanthanum carbonate anhydride, the citric acid lanthanum, lanthanum chloride, Lanthanum (III) nitrate, lanthanum acetate etc.Salt can also be prepared temporarily, such as lanthana is suspended in the water, becomes solution or suspension with the processed with acid that is fit to, and can also use its pH value of acid-alkali accommodation again.The oxide of lanthanum is lanthanum sesquioxide, has commodity can supply to buy.Wherein the citric acid lanthanum is the product that citric acid and lanthana reacted obtain, according to the people such as G.Vanhoyland (Characterization and structural study of lanthanum citrate trihydrate[La (C
6H
5O
7) (H
2O)
2] H
2O.Journal of Solid State Chemistry.2005,178 (1): 166-171) disclosed method is prepared into citric acid lanthanum trihydrate.
Although the drug effect that specific embodiments of the present invention provide is for mice, for the technical staff under this area, can take this to estimate people and the required roughly dosage of other mammal.In the reality, dosage depends on age, health status, body weight, other Therapeutic Method of jointly taking and administration frequency etc.All be suitable through the lanthanoid metal pharmaceutically acceptable salt of intestinal canal administration or the pharmaceutical composition of oxide.Such as at the chewable tablet FOSRENOL of the lanthanum carbonate of U.S. listing, every lanthanum element that contains 250mg, 500mg, 750mg, 1000mg.Can also be other dosage form administration, such as conventional tablet, dispersible tablet, capsule, powder, granule, suspensoid etc.
The specific embodiment
Embodiment 1 contains the preparation of lanthanum compound
1.1 the preparation of lanthanum carbonate
According to Chinese invention patent ZL96193918.4 method, preparation lanthanum carbonate tetrahydrate.
1.2 the preparation of citric acid lanthanum trihydrate
According to the people such as G.Vanhoyland (Characterization and structural study of lanthanum citrate trihydrate[La (C
6H
5O
7) (H
2O)
2] H
2O.Journal of Solid State Chemistry.2005,178 (1): 166-171) disclosed method prepares citric acid lanthanum trihydrate, and its structural formula is as follows: [La (C
6H
5O
7) (H
2O)
2] H
2O.
Embodiment 2 pharmacodynamic experiments
Experimental agents
Bismuth potassium citrate (bismuth potassium citrate capsule): Livzon Pharmaceutical Factory, Livzon Group production, lot number: 071105.
Lanthanum carbonate: embodiment 1 legal system is standby.
Citric acid lanthanum: embodiment 1 legal system is standby.
Laboratory animal
50 of Kunming mouses, body weight 20～22g, male and female half and half.Laboratory animal production licence number: SCXK (the Liao Dynasty) 2003-008, laboratory animal occupancy permit number: SYXK (the Liao Dynasty) 2003-0012 are provided by Shenyang Pharmaceutical University's Experimental Animal Center.
Other reagent
Sodium carboxymethyl cellulose (CMC-Na): packing factory of Solution on Chemical Reagents in Shanghai company, lot number: F20050405.
Dehydrated alcohol: Tianjin chemical industry all generations company limited, specification: 500ml, lot number: 20070825
Experimental apparatus
TG328A type electronic balance, Shanghai Precision Scientific Apparatus Co., Ltd;
DF-101B type constant-temperature heating magnetic stirring apparatus: the Ying Yu of Gongyi City gives magnificent instrument plant
Route of administration
Gastric infusion, consistent with the clinical administration approach.
Statistical method
Relatively T check between respectively employing group.
Test method
50 of Kunming mouses, 20～22g, male and female half and half, be divided at random 5 groups by body weight, be solvent matched group (gavage gives 1%CMC-Na), model group (gavage gives 1%CMC-Na), bismuth potassium citrate group (gastric infusion, by bismuth 56.73mg/kg), citric acid lanthanum group (gastric infusion is by lanthanum 32.17mg/kg), lanthanum carbonate group (gastric infusion, by lanthanum 32.17mg/kg), the administration volume is 10ml/kg.Mice gastric infusion every day 1 time, for three days on end, fasting 12h before the last administration behind the last administration 1.0h, gives dehydrated alcohol 0.12ml modeling by the every 20g of body weight.Dehydrated alcohol brings out the preparation list of references of Mouse Stomach mucosa injury model
[1]Blank group does not give dehydrated alcohol.Each group is all taken off cervical vertebra and is put to death mice behind modeling 1h, get stomach, cuts along greater gastric curvature, observes the gastric mucosa injury situation, and calculates and respectively organize the Mouse Stomach damage index.The standards of grading of gastric damage index
[2]: local rubescent 1 meter 1 minute, 1 meter of petechial hemorrhage or ulcer 1 minute, 1 meter of streak-like hemorrhage or ulcer 3 minutes.Statistical result sees the following form 1.
The impact that the Mouse Stomach that 1h causes dehydrated alcohol behind the tested drug administration of table 1. damages (mean ± SD)
▲P＜0.05,
▲ ▲Compare with blank group P＜0.01; * P＜0.05, * * P＜0.01, with model group relatively
Result and discussion
Citric acid lanthanum group, lanthanum carbonate group have the effect that significantly prevents ethanol induced mice mucosal lesion in the test of ethanol induced mice mucosal lesion, and its ulcer index is starkly lower than model group, are better than the positive control drug bismuth potassium citrate.Wherein the average of citric acid lanthanum group gastric damage index total points is minimum.
The lanthanum of embodiment 3. various dose scopes is to the protective effect of stomach
Test equally with embodiment 2 methods, carry out simultaneously, what just will investigate is dose-effect relationship, and the antiulcer action when studying its various dose arranges high, normal, basic three dosage groups, and animal is raised with lanthanum carbonate, the results are shown in Table 2.Wherein dosage comes in lanthanum.
The impact that the Mouse Stomach that 1h causes dehydrated alcohol after the administration of table 2. various dose lanthanum carbonate damages (mean ± SD)
▲P＜0.05,
▲ ▲Compare with blank group P＜0.01;
*P＜0.05,
*Compare with model group P＜0.01
This shows that the lanthanum of 12.5-200mg/kg all demonstrates significant antiulcer action on the statistical significance.
List of references
[1] Guo Jieyun. red legend celebrating. Zhao Weizhong. etc. brave sweet glycosides is to the protective effect .[J of experimental acute mucosal lesion]. the time precious traditional Chinese medical science traditional Chinese medicines, 2006,17 (11): the 2183-2184 page or leaf.
[2] Xu Shuyun. Bian Rulian. old repairing. chief editor's " pharmacological experimental methodology " third edition. Beijing, People's Health Publisher .2002, the 1332nd page.
Claims (5)
1. lanthanoid metal pharmaceutically acceptable salt or its hydrate application in the preparation medicament for anti-gastric ulcer.
2. lanthanoid metal pharmaceutically acceptable salt claimed in claim 1 refers to: lanthanum carbonate or its hydrate.
3. hydrate claimed in claim 2 refers to: the lanthanum carbonate tetrahydrate.
4. lanthanoid metal pharmaceutically acceptable salt claimed in claim 1 refers to: citric acid lanthanum or its hydrate.
5. solvate claimed in claim 4 refers to: citric acid lanthanum trihydrate.
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| CN101590076B true CN101590076B (en) | 2013-04-10 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2415373A (en) * | 2004-06-23 | 2005-12-28 | Destiny Pharma Ltd | Porphyrins for sonodynamic therapy |
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2008
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2415373A (en) * | 2004-06-23 | 2005-12-28 | Destiny Pharma Ltd | Porphyrins for sonodynamic therapy |
Non-Patent Citations (2)
| Title |
|---|
| T.P.Kemmer et al..Influence of colloidal bismuth subcitrate on enzyme secretion froom isolated rat pancreatic acinar cells.《Experimental Medicine》.1992,(第192期),文章416-420页. * |
| 刘颖,陈东,陈爱军等.硝酸镧长期灌胃大鼠肝脏中HSP70的表达.《吉林大学学报(医学版)》.2003,第29卷(第6期),第727-728页. * |
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Effective date of registration: 20170823 Address after: 110121, 155, Taipei Avenue, tiger rock, Shenyang, Liaoning, Shenbei New Area Patentee after: Shenyang Funing Pharmaceutical Co. Ltd. Address before: 110014, Shenyang, Liaoning province Shenhe District Three South 67 Street 3-5 building Patentee before: Huatai Medicine Research Co., Ltd. Shenyang |