CN102558016A - Novel compound with high blood fat-reducing activity and preparation method thereof - Google Patents
Novel compound with high blood fat-reducing activity and preparation method thereof Download PDFInfo
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- CN102558016A CN102558016A CN2012100324143A CN201210032414A CN102558016A CN 102558016 A CN102558016 A CN 102558016A CN 2012100324143 A CN2012100324143 A CN 2012100324143A CN 201210032414 A CN201210032414 A CN 201210032414A CN 102558016 A CN102558016 A CN 102558016A
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- compound
- zinc
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- statins
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 230000003516 hyperlipidaemic effect Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
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- 208000010125 myocardial infarction Diseases 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- 229960001462 sodium cyclamate Drugs 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
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- 239000002025 wood fiber Substances 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel compound with high blood fat-reducing activity, a preparation method thereof. The compound serving as an active ingredient and pharmaceutically-acceptable pharmaceutic adjuvants are combined to prepare oral preparations such as tablets, chewable tablets, dispersible tablets, oral disintegrating tables, buccal tablets, capsules, soft capsules, pills, sustained-release tablets and sustained-release capsules. The compound is used for treating and preventing various kinds of hyperlipidemia.
Description
Technical field
The present invention belongs to medical technical field for a kind of novel active compound of height lipopenicillinase and preparation method thereof that has.
Background technology
Hyperlipidemia is meant blood cholesterol (TC) and/or triglyceride level (TG) is too high or high density lipoprotein cholesterol (HDL-C) is low excessively, this disease to the infringement of health be concealment, gradually, carrying out property and general.Its direct infringement is to quicken systemic atherosclerosis, because the vitals of whole body all will rely on artery blood supply, oxygen supply, in case artery is stopped up by atheromatous plaque, will cause serious consequence.The renal failure that arteriosclerosis causes etc., all closely related with hyperlipidemia.A large amount of research datas show that hyperlipidemia is apoplexy, coronary heart disease, myocardial infarction, cardiac sudden death is independent and important risk.In the last few years, have multiple hypolipidemic to go on the market successively, for hyperlipemic patients has increased safety control, but result of treatment is still not ideal enough, so seek a kind of good effect and stable blood lipid-lowering medicine remains the direction of new drug development from now on.
Statins is a kind of selectivity HMG-CoA reductase inhibitor.The HMG-CoA reductase inhibitor is that the transformation 3-hydroxy-3-methylglutaryl-coenzyme A is the rate-limiting enzyme of first valerate-precursor of cholesterol.The main site of action of statins is the target organs of liver-reducing cholesterol.Statins has increased liver LDL cell surface receptor number, promotes absorption and the katabolism of LDL, and the liver that has suppressed VLDL is synthetic, reduces the sum of VLDL and LDL particulate thus.Because unbodied statins poor stability, so the part statins of listing all is that form with calcium salt exists at present, such as atorvastatincalcuim, pitavastatin calcium, but the production process of calcium salt is relatively very complicated, and production cost is higher.
Summary of the invention
For improving pharmaceutical activity; Reduce toxicity; Simultaneously also in order to simplify the production process of statins; Reduce production costs, the present invention provides a kind of statins that exists with the zinc salt form and preparation method thereof, and statins is selected from atorvastatin, pitavastatin, SV, pravastatin, fluvastatin, lovastatin.
Its preparation method comprises: at first use the organic or inorganic sodium salt to change his spit of fland (acid) into his spit of fland sodium salt, again with corresponding his the spit of fland zinc salt of inorganic zinc salt (preferred zinc chloride) prepared in reaction.
Compound according to the invention can make up with acceptable accessories, processes oral prepns: comprise granule, ordinary tablet, chewable tablet, dispersible tablet, oral cavity disintegration tablet, buccal tablet, capsule, soft capsule, pill, slow releasing tablet, slow releasing capsule etc.
The unit formulation content of the zinc salt of statins is 1.25mg～120mg, is preferably 5mg～40mg.It comprises zinc salt and tackiness agent, weighting agent and the disintegrating agent of statins, and the weight composition of weighting agent and disintegrating agent is respectively 10-60%, 2-30%.Also comprise glidant, lubricant and correctives, the weight composition is respectively 1-5%, 0.2-3%, 0.01-2%.
Wherein weighting agent includes but not limited to lactose, sucrose, glucose, N.F,USP MANNITOL, sorbyl alcohol, calcium sulfate, calglucon, secondary calcium phosphate, calcium phosphate, lime carbonate, Calcium hydrogen carbonate, starch, CMS, pregelatinized Starch or Microcrystalline Cellulose; Tackiness agent includes but not limited to starch, gelatin dextrin, Star Dri 5, sucrose, gum arabic, Vinylpyrrolidone polymer, various viscosity methylcellulose gum, low viscosity carboxymethyl cellulose, various viscosity TKK 021, various viscosity Z 150PH, polyethylene glycol 6000 or TSK-Gel G 2000HXL; Disintegrating agent includes but not limited to pregelatinized Starch, Microcrystalline Cellulose, Lalgine, pure wood fiber element, sodium starch glycolate, guar gum, cross-linked polyvinylpyrrolidone, methylcellulose gum or Sodium Croscarmellose; Lubricant includes but not limited to Magnesium Stearate, calcium stearate, talcum powder, glyceryl monostearate, Macrogol 4000, polyethylene glycol 6000, polyoxyethylene glycol 8000, Sodium Benzoate, hexanodioic acid, fumaric acid, boric acid, sodium-chlor, sodium laurylsulfate or magnesium laurylsulfate; Correctives includes but not limited to Steviosin, sorbyl alcohol, maltose alcohol, glycyrrhizin, stem tea element, Sodium Cyclamate, banana flavour, flavoring pineapple essence, peppermint essence, orange flavor, fennel, vanillin food grade,1000.000000ine mesh, lemon flavour, cherry flavour or rose compound; Pharmaceutical prepn of the present invention also comprises wetting agent, is purified water or ethanol etc.
Embodiment
The preparation of embodiment 1 atorvastatin zinc:
(5.0g 8.95mmol) is dissolved in ethanol (150ml), and (9.0mmol), stirring at room slowly dripped ZnCl after 5～10 minutes to the alcohol sodium alcohol solution of adding new system for 1.0M, 9.0ml with atorvastatin
2Ethanolic soln (0.2M, 23ml).Reaction solution places 50 ℃ of stirring in water bath reactions after 2 hours, naturally cools to room temperature, filters.Filtrating is concentrated into about 20ml, adds the 200ml ether, filters the deposition of separating out, and obtains product atorvastatin zinc (6.1g, 57.7%) after the drying.
The preparation of embodiment 2 pitavastatin zinc:
(3.4g 8.07mmol) is dissolved in ethanol (100ml), and (1.0M, 8.1ml 8.1mmol), after dripping, slowly drip ZnSO to the alcohol sodium alcohol solution of adding new system with pitavastatin
4Ethanolic soln (0.2M, 20ml).Reaction solution places 50 ℃ of stirring in water bath reactions after 2 hours, naturally cools to room temperature, filters.Filtrating is concentrated into about 10ml, adds the 100ml ether, filters the deposition of separating out, and obtains product pitavastatin zinc (2.5g, 68.3%) after the drying.
The preparation of embodiment 3 SV zinc:
(5.6g 13.4mmol) is dissolved in ethanol (150ml) to SV, and (0.5M, 26.8ml 13.4mmol), regulate pH to 7 with 0.1N Hydrogen chloride behind the stirring at room reaction 30min, remove solvent under reduced pressure to add the NaOH aqueous solution.Add 60ml water and solid ZnCl in residue obtained
2(0.91g, 6.68mmol).Reaction solution places 30 ℃ of stirring in water bath reactions after 2 hours, naturally cools to room temperature, filters the deposition of separating out, and obtains product Xin Tating zinc (4.9g, 81.0%) after the drying.
The preparation of embodiment 4 pravastatin zinc:
(5.2g 12.2mmol) is dissolved in ethanol (150ml) to pravastatin, and (0.5M, 24.5ml 12.2mmol), regulate pH to 7 with 0.1N Hydrogen chloride behind the stirring at room reaction 30min, remove solvent under reduced pressure to add the NaOH aqueous solution.Add 50ml water and solid ZnCl in residue obtained
2(0.83g, 6.1mmol).Reaction solution places 30 ℃ of stirring in water bath reactions after 2 hours, naturally cools to room temperature, filters the deposition of separating out, and obtains product Pu Tating zinc (4.9g, 87.6%) after the drying.
The preparation of embodiment 5 fluvastatin zinc:
His spit of fland is cut down in the fluorine holder, and (6.2g 15.1mmol) is dissolved in ethanol (180ml), and (1.0M, 15.0ml 15.0mmol), slowly drip ZnSO to the alcohol sodium alcohol solution of adding new system again
4Ethanolic soln (0.2M, 37.5ml).Reaction solution places 50 ℃ of stirring in water bath reactions after 2 hours, naturally cools to room temperature, filters.Filtrating is concentrated into about 20ml, adds the 200ml ether, filters the deposition of separating out, and obtains product fluvastatin zinc (5.2g, 77.6%) after the drying.
The preparation of embodiment 6 lovastatin zinc;
Luo Tuo cuts down his spit of fland, and (5.0g 12.4mmol) is dissolved in ethanol (150ml), and (0.5M, 25.0ml 12.5mmol), regulate pH to 7 with 0.1N Hydrogen chloride behind the stirring at room reaction 30min, remove solvent under reduced pressure to add the NaOH aqueous solution.Add 50ml water and solid ZnCl in residue obtained
2(0.84g, 6.2mmol).Reaction solution places 30 ℃ of stirring in water bath reactions after 2 hours, naturally cools to room temperature, filters the deposition of separating out, and obtains product lovastatin zinc (4.6g, 85.2%) after the drying.
Below each preparation specification all be in the prototype medicine
Embodiment 7 pitavastatin zinc metal sheets
The preparation method:
1. in 50 ℃ purified water, add the recipe quantity tween 80, fully stirring and dissolving adds TSK-Gel G 2000HXL and makes its aquation, forms tackiness agent.
Recipe quantity pitavastatin zinc, lime carbonate, Microcrystalline Cellulose, starch 1500, Sodium Croscarmellose is even with the equivalent method thorough mixing that progressively increases 2..
3. in the resulting mixed powder of step 2, add the resulting tackiness agent system softwood of step 1,18 mesh sieves are granulated.
4. drying step 3 resulting granules are controlled moisture and are not more than 2.0%.
5. in the resulting composite grain of step 4, add Magnesium Stearate, mix, compressing tablet promptly gets.
Embodiment 8 atorvastatin zinc capsules
The preparation method:
1. in 50 ℃ purified water, add the recipe quantity tween 80, fully stirring and dissolving adds TSK-Gel G 2000HXL and makes its aquation, forms tackiness agent.
Recipe quantity atorvastatin zinc, lime carbonate, pregelatinized Starch, starch 1500, sodium starch glycolate is even with the equivalent method thorough mixing that progressively increases 2..
3. in the resulting mixed powder of step 2, add the resulting tackiness agent system softwood of step 1,18 mesh sieves are granulated.
4. drying step 3 resulting granules are controlled moisture and are not more than 2.0%, cross the whole grain of 24 mesh sieves.
5. in step 4 resulting granules, add starch, the silicon-dioxide thorough mixing is even.
6. in the resulting composite grain of step 5, add Magnesium Stearate, mix, filling capsule promptly gets.
Embodiment 9 atorvastatin zinc dispersible tablets
The preparation method:
Earlier raw material pulverizing is crossed 100 mesh sieves, with bulk drug, with other auxiliary material thorough mixing evenly after, compacting is in flakes.
The lipopenicillinase experiment of embodiment 10 rats
Male Wistar rat (secondary); Body weight 160～170g; Quantitatively give high fat diet 25g (high lipid food prescription: basal feed: SUV: lard: cholate: Thyreostat I=8418: 4: 10: 1: 012), continue 26d, set up the hyperlipemia rat model every day.
The animal subject that modeling is successful is divided into 13 groups at random, 10 every group.Administration is divided into groups as follows: A group: atorvastatin zinc (2mg/kg); A0 group: atorvastatincalcuim (2mg/kg); B group: pitavastatin zinc (0.2mg/kg); B0 group: pitavastatin calcium (0.2mg/kg); C group: fluvastatin zinc (2mg/kg); C0 group: fluvastatin sodium (2mg/kg); D group: pravastatin zinc (1mg/kg); D0 group: SQ-31000 (1mg/kg); E group: SV zinc (1mg/kg); E0 group: SV (1mg/kg); F group: lovastatin zinc (2mg/kg); F0 group: lovastatin (2mg/kg); And model control group, other gets 10 healthy rats as blank.Each group is all irritated stomach and is given relative medicine; All with the saline water preparation, irritate the stomach volume is the 1ml/100g body weight to medicine, once a day; Used for 4 weeks continuously; Model contrast and blank give isopyknic saline water, and 2h measures rat fat after the last weekly administration, observe the Blood Lipid situation of respectively organizing rat.
The result:
The result shows; Individual administration group all has the effect of significant reducing cholesterol; With model control group significant difference is arranged relatively, the action effect of the zinc salt of each his spit of fland medicine all is better than other salt forms of medicine of the same race, is worth so his spit of fland zinc salt of the present invention has certain exploitation.The result sees table 1.
Table 1 is respectively organized rat total cholesterol changing conditions
Claims (6)
1. one kind novelly has a height lipopenicillinase active compound, it is characterized in that, and be the statins that exists with the zinc salt form.
2. the described compound of claim 1 is characterized in that, statins is selected from atorvastatin, pitavastatin, SV, pravastatin, fluvastatin, lovastatin.
3. the described compound of claim 1, its preparation method is: make the sodium salt and inorganic zinc salt (zinc chloride, zinc sulfate, the zinc acetate etc.) reaction of statin compound, generate target zinc salt compound, through modes such as depositions it is separated from reaction mixture.
4. the described medicinal compound of claim 1 can be processed oral prepns with suitable pharmacy auxiliary material combination: comprise tablet, capsule, soft capsule, chewable tablet, oral cavity disintegration tablet, buccal tablet, pill.
5. the described medicinal compound of claim 1 is characterized in that, the unit formulation content of described statins zinc salt is 1.25mg～120mg, is preferably 5mg～40mg.
6. the described compsn of claim 1 is used for the treatment and the prevention of various hyperlipidemias.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101490015A (en) * | 2006-04-13 | 2009-07-22 | 埃吉斯药物股份公开有限公司 | Rosuvastatin zinc salt |
| CN102294032A (en) * | 2011-09-09 | 2011-12-28 | 北京阜康仁生物制药科技有限公司 | Medicinal composition containing statins existing in zinc salt mode |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101490015A (en) * | 2006-04-13 | 2009-07-22 | 埃吉斯药物股份公开有限公司 | Rosuvastatin zinc salt |
| CN102294032A (en) * | 2011-09-09 | 2011-12-28 | 北京阜康仁生物制药科技有限公司 | Medicinal composition containing statins existing in zinc salt mode |
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