CN101973922B - Atorvastatin semi-strontium salt polymorphs as well as preparation and application thereof as HMG-CoA enzyme inhibitor - Google Patents
Atorvastatin semi-strontium salt polymorphs as well as preparation and application thereof as HMG-CoA enzyme inhibitor Download PDFInfo
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Abstract
The invention discloses atorvastatin semi-strontium salt polymorphs as well as preparation and application thereof as HMG-CoA an enzyme inhibitor. The invention discloses polymorphs HA, HB and HC or solvates of atorvastatin semi-strontium salt, which are shown as a formula (I). When used as HMG-CoA enzyme inhibitor medicines, the polymorphs HA, HB or HC, or the solvates of atorvastatin semi-strontium salt in the formula (I) are better choices for hypercalcemia syndrome, since the selected polymorphs HA, HB or HC, or the solvates of atorvastatin semi-strontium salt shown as the formula (I) notonly can achieve the purpose of controlling blood cholesterol, but also can avoid the extra intake of calcium.
Description
Technical field
The invention discloses atorvastatin semi strontium salt polymorphic form, its preparation method and as the application of HMG-CoA enzyme inhibitors.
Background of invention
The mechanism of action that statins reduces low-density lipoprotein in the body is clear and definite.The HMG-CoA enzyme can make HMG change into first hydroxyl penta salt, and this is the deciding step of biosynthesizing cholesterol in the liver.Extremely low low-density lipoprotein (VLDL) can be transferred to the cholesterol in the liver and tri-glyceride in the outside cell.VLDL is decomposed release fat acid by outside cell.VLDL will be converted into the lipoprotein (IDL) of intermediate density so, and IDL can be shifted or be transformed into LDL by low-density lipoprotein (LDL) acceptor.The content of reducing cholesterol can increase number and the corresponding amount that reduces the LDL that is changed by IDL of ldl receptor.By suppressing the HMG-CoA enzyme, statins can effectively be blocked cholesterol synthesizing in liver, thereby effectively reduces low-density lipoprotein.High LDL level can cause coronary heart disease, causes thrombus.Therefore, reduce low-density lipoprotein and can effectively prevent cardiovascular diseases, especially coronary heart disease or other hypercholesteremia syndromes.
Zarator (Atorvastatin, i.e. compound shown in the formula II) is most popular kind in the statins.The earliest, the lactone of Zarator and its calcium salt forms in the patent (US-4681893, US-5273995) of the U.S., have been mentioned.The atorvastatin semi-calcium salt trihydrate is by Pfizer called after Lipitor (LIPITOR), and 2007 annual sales amounts are above 12,000,000,000 dollars.
The patent No. is: 2002/0099224; 5273995; 5298627; 5003080; 5097045; 5124482; 5149837 United States Patent (USP) discloses the preparation process of Zarator.Half calcium salt of Zarator is seen patent US-5273995.The I of atorvastatin semi-calcium salt is disclosed in the United States Patent (USP) (US-5959156, US-6121462), II, III, IV crystal formation.The V crystal formation of atorvastatin semi-calcium salt is announced in patent WO-01/36384.Other crystal formation of atorvastatin semi-calcium salt is at patent WO-02/43732, and WO-02/41834 announces among the WO-03/070702.
Single molecule can form various salt or crystal type, such as Zarator I type or its salt (II) type, because neighboring molecule intermolecular interaction and direction is different in the crystal, different salt or the polymorphic of same molecule can have different physical propertiess.An important physical properties of medicine is its solvability, especially can dissolve in gastric juice.The drug effect of medicine is relevant with the drug level that medicine can reach in blood, and same a part, the solubility property in gastric juice and intestinal juice directly affect medicine by the absorption of GI system.Thereby the salt or the crystal formation that have the medicine of proper solubility energy may have better result for the treatment of than slower salt or the crystal formation of dissolving.The atorvastatin semi-calcium salt trihydrate is water-soluble lower, and its oral administration biaavailability only is 12%.The highly water-soluble salt of research and development Zarator can improve the oral administration biaavailability of Zarator.Thereby salt or polymorphic form that the research and development Zarator is new are very valuable.
Usually, the salt that the metal ion that organic acid and nucleidic mass are large forms water-soluble lower than low atomic weight metal cation salt of the same clan is lower than the acetylsalicylic acid calcium salt such as acetylsalicylic acid barium salt water-soluble.Yet when our salt at the screening Zarator, what be surprised to find polymorphic HA, the HB of atorvastatin semi strontium salt and HC water-solublely is higher than commercially available atorvastatin semi-calcium salt trihydrate widely.
Summary of the invention
Correspondingly, the invention discloses the polymorphic form HA of compound shown in the formula I, HB, HC or its solvate, the water-soluble of the polymorphic form HA of compound shown in the formula I disclosed by the invention or its solvate is 0.706mg/ml, the water-soluble of the polymorphic form HB of compound shown in the formula I or its solvate is 0.38mg/ml, the water-soluble of the polymorphic form HC of compound shown in the formula I or its solvate is 0.43mg/ml, under same testing method, the water-soluble of atorvastatin semi-calcium salt trihydrate only is 0.198mg/ml.Therefore, polymorphic form HA, the HB of compound shown in the formula I disclosed by the invention, HC or its solvate are all much higher than atorvastatin semi-calcium salt trihydrate.
The polymorphic form HA of compound shown in the formula I disclosed by the invention or the X-ray powder diffraction collection of illustrative plates of its solvate have following peak:
| Angle of diffraction (2 θ, °) | Intensity (I/I 0) | Angle of diffraction (2 θ, °) | Intensity (I/I 0) |
| 5.340 | 29.0 | 8.680 | 47.8 |
| 18.339 | 100.0 | 18.739 | 74.7 |
| 19.099 | 37.2 | 22.742 | 12.1 |
The polymorphic form HB of compound shown in the formula I disclosed by the invention or the X-ray powder diffraction collection of illustrative plates of its solvate have following peak:
| Angle of diffraction (2 θ, °) | Intensity (I/I 0) | Angle of diffraction (2 θ, °) | Intensity (I/I 0) |
| 8.639 | 83.9 | 9.842 | 33.4 |
| 11.520 | 39.5 | 16.399 | 100 |
| 17.619 | 15.4 | 19.986 | 24.5 |
| 20.218 | 31.7 | 21.718 | 30.5 |
| 29.860 | 12.3 |
The polymorphic form HC of compound shown in the formula I disclosed by the invention or the X-ray powder diffraction collection of illustrative plates of its solvate have following peak:
| Angle of diffraction (2 θ, °) | Intensity (I/I 0) | Angle of diffraction (2 θ, °) | Intensity (I/I 0) |
| 3.760 | 100.0 | 11.420 | 12.4 |
| 7.662 | 24.8 | 16.359 | 17.8 |
| 8.379 | 27.9 | 19.261 | 16.6 |
| 9.381 | 15.3 | 19.678 | 24.1 |
Polymorphic form HA, the HB of compound shown in the formula I disclosed by the invention or HC or its solvate provide the better selection of HMG-CoA enzyme inhibitors class medicine for hypercalcemia syndromes sufferer.Hypercalcemia patient need avoid the absorption of calcium as far as possible, to reduce because the harm to its heart that the raising of blood calcium concentration causes.Selecting polymorphic form HA, the HB of the compound shown in the formula I or HC or its solvate as HMG-CoA enzyme inhibitors class medicine, can reach the purpose of control blood cholesterol, can avoid again the absorption of extra calcium, is the optimal selection of this class sufferer.
But the bone density of elderly woman after absorption Effective Raise the elderly, the especially climacterium of strontium ion.Thereby polymorphic form HA, the HB of compound shown in the formula I, HC or its solvate also have the drug effect of prevention elderly woman osteoporosis.
The invention also discloses the preparation method of polymorphic form HA, HB, HC or its solvate of compound shown in the formula I: at first, sodium salt, sylvite, ammonium or the ammonium carbamate of Zarator are dissolved in the suitable solvent to form the Zarator salts solution, and then adding contains the solution of strontium salt, stir to such an extent that separate out white or off-white color solid at-20 °～100 ℃ behind the settled solution, filter the dry atorvastatin semi strontium salt that gets.Described solvent can be any sodium salt that can dissolve Zarator, sylvite, the solvent of ammonium or ammonium carbamate, kind difference depending on salt can make water, alcoholic solvent, ether solvent, amide solvent, ketones solvent, methyl-sulphoxide, esters solvent, the polyoxyethylene glycol kind solvent, include but not limited to methyl alcohol, ethanol, propyl alcohol, Virahol, the trimethyl carbinol, isopropylcarbinol, isopropyl ether, tetrahydrofuran (THF), dioxane, dimethyl formamide, ethanamide, N,N-dimethylacetamide, acetone, butanone, ethyl acetate, methyl acetate, ethyl formate, methyl-formiate, propyl acetate, isopropyl acetate, propyl formate, isopropyl formate, methyl propionate, ethyl propionate, methyl-butyrate, Macrogol 200, poly(oxyethylene glycol) 400, Polyethylene Glycol-600, cetomacrogol 1000, the polyoxyethylene glycol monoether, the polyoxyethylene glycol diether.Described strontium salt can be mineral acid strontium or organic acid strontium, includes but not limited to strontium nitrate, strontium chloride, Strontium Sulphate, strontium bisulfate, strontium phosphate, strontium monophosphate, sulfonic acid strontium, Strontium carbonate powder, strontium bicarbonate, strontium formate, strontium acetate, trifluoroacetic acid strontium, Succinic Acid strontium, strontium maleate, fumaric acid strontium, gluconic acid strontium, strontium tartrate, strontium salicylate.The described solution that contains strontium salt represents that organic acid strontium or mineral acid strontium are water-soluble, methyl alcohol, ethanol, propyl alcohol, Virahol, the trimethyl carbinol, isopropylcarbinol, isopropyl ether, tetrahydrofuran (THF), dioxane, dimethyl formamide, ethanamide, N,N-dimethylacetamide, acetone, butanone, ethyl acetate, methyl acetate, ethyl formate, methyl-formiate, propyl acetate, isopropyl acetate, propyl formate, isopropyl formate, methyl propionate, ethyl propionate, methyl-butyrate, Macrogol 200, poly(oxyethylene glycol) 400, Polyethylene Glycol-600, cetomacrogol 1000, the polyoxyethylene glycol monoether, the polyoxyethylene glycol diether, resulting solution in one or more the mixed solvent such as methyl-sulphoxide.
The second method of polymorphic form HA, HB, HC or its solvate of compound shown in the preparation formula I: the Zarator strontium is dissolved in the suitable solvent, stir to such an extent that add again another kind of solvent behind the settled solution and continue to stir and separate out white or off-white color solid at-20～100 ℃, filter the dry atorvastatin semi strontium salt finished product that gets.The suitable solvent of described dissolving Zarator refers to the Zarator strontium is had the solvent of better solubleness, include but not limited to one or more the mixed solvent such as methyl alcohol, ethanol, propyl alcohol, Virahol, the trimethyl carbinol, isopropylcarbinol, tetrahydrofuran (THF), dimethyl formamide, ethanamide, N,N-dimethylacetamide, Macrogol 200, poly(oxyethylene glycol) 400, Polyethylene Glycol-600, cetomacrogol 1000, polyoxyethylene glycol monoether, polyoxyethylene glycol diether, methyl-sulphoxide.The another kind of solvent of described adding is selected from one or more the mixed solvent in water, isopropyl ether, dioxane, acetone, butanone, ethyl acetate, methyl acetate, ethyl formate, methyl-formiate, propyl acetate, isopropyl acetate, propyl formate, isopropyl formate, methyl propionate, ethyl propionate or the methyl-butyrate.
The third method of polymorphic form HA, HB, HC or its solvate of compound shown in the preparation formula I: Zarator is dissolved in the suitable solvent to form Zarator solution, and then the solution of adding Strontium carbonate powder, strontium bicarbonate or strontium hydroxide, stir to such an extent that separate out white or off-white color solid at-20 °～100 ℃ behind the settled solution, filter the dry atorvastatin semi strontium salt finished product that gets.Described solvent is selected from water, methyl alcohol, ethanol, propyl alcohol, Virahol, the trimethyl carbinol, isopropylcarbinol, isopropyl ether, tetrahydrofuran (THF), dioxane, dimethyl formamide, ethanamide, N,N-dimethylacetamide, acetone, butanone, ethyl acetate, methyl acetate, ethyl formate, methyl-formiate, propyl acetate, isopropyl acetate, propyl formate, isopropyl formate, methyl propionate, ethyl propionate, methyl-butyrate, Macrogol 200, poly(oxyethylene glycol) 400, Polyethylene Glycol-600, cetomacrogol 1000, the polyoxyethylene glycol monoether, the polyoxyethylene glycol diether, one or more the mixed solvent such as methyl-sulphoxide.
Polymorphic form HA, the HB of compound shown in the formula I disclosed by the invention, HC or its solvate can be one or more the mixture among polymorphic form HA, HB or the HC when the active constituents of medicine.
The formulation when the active constituents of medicine of polymorphic form HA, the HB of compound, HC or its solvate shown in the formula disclosed by the invention (I) can be and anyly can reach the formulation with therapeutic action, include but not limited to that solid dosage is (such as tablet, powder, suppository, capsule, lozenge), suspension or pharmaceutical solutions.
Formulation when polymorphic form HA, the HB of compound shown in the formula I disclosed by the invention, HC or its solvate are used as active constituents of medicine can be sustained release preparation.
Except containing the polymorphic form HA of compound shown in the formula I disclosed by the invention, HB or HC or its solvate, preparation contains the polymorphic form HA of compound shown in the formula I disclosed by the invention, but HB or HC or its solvate are learned upper suitable pharmaceutical excipient as the formulation drug of choice of medicine, such as derivatived cellulose, include but not limited to cellulose powder, Microcrystalline Cellulose, methylcellulose gum, ethyl cellulose, Natvosol, hydroxypropylcellulose, Vltra tears, carboxyethyl cellulose salt and other replace and substituted cellulose not; Starch; Pre-gelatinized starch; Can contain in addition other additives commonly used in the pharmaceutical industry, include but not limited to paraffin, Saccharide and saccharide alcohols (such as N.F,USP MANNITOL, sorbyl alcohol), polyacrylic ester and pectin, dextrin, gelatin; Weighting agent comprises tackiness agent, such as gum arabic, pre-gelatinized starch, sodium alginate, glucose and other tackiness agents of using in granulation and compression; Used weighting agent can comprise disintegrating agent in compound, such as primojel, and Povidone, low-substituted hydroxypropyl cellulose etc.; In addition, weighting agent also comprises tablet lubricant, seasonings, sweeting agent, sanitas; Capsule preparations can contain by gelatin or other conventional capsule materials; Tablet and powder can be prepared into the enteric film wrap sheet, and described enteric film can be comprised of in the multipolymer of the multipolymer of cellulose acetate-phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalic acid, vinylbenzene and toxilic acid or methacrylic acid and methyl methacrylate one or more.
Polymorphic form HA, the HB of compound shown in the formula I disclosed by the invention or HC or its solvate can be 0.5mg-200mg as the unit using dosage of medicine; Preferred unit using dosage is 2.5mg-80mg; Most preferred unit using dosage is 10mg-80mg; The unit using dosage of most convenient is 10mg, 20mg, and 40mg, 80mg, and can take this medicine of one or many in one day.
Unit using dosage described in the present invention refers to be applied to the unit of patient and easy handling and packing, i.e. single dosage.
Polymorphic form HA, the HB of compound shown in the formula I disclosed by the invention or HC or its solvate can be used as preparation HMG-CoA enzyme inhibitor medicine, being used for the treatment of can be improved physically different by suppressing the HMG-CoA enzyme, includes but not limited to the disease that coronary heart disease, thrombosis cause, disease or the hypercholesterolemia that the low-density lipoprotein the level rise causes.
Polymorphic form HA, the HB of compound shown in the formula I disclosed by the invention or HC or its solvate can be used for preparing the medicine for the treatment of osteoporosis.
Description of drawings: Fig. 1: atorvastatincalcuim typical curve
Fig. 2: the polymorphic form HA of compound shown in the formula I or the X powder diffraction collection of illustrative plates of its solvate
Fig. 3: the polymorphic form HB of compound shown in the formula I or the X powder diffraction collection of illustrative plates of its solvate
Fig. 4: the polymorphic form HC of compound shown in the formula I or the X powder diffraction collection of illustrative plates of its solvate
Specific embodiment
Abbreviation language: THF: tetrahydrofuran (THF); MP: fusing point.
The measuring condition of X-ray powder diffraction collection of illustrative plates is as follows among the present invention:
Sample size: about 100mg
Target: Cu
Filter disc: monochrome
Voltage/current: 40kV/100mA
1 ° of slit: SS/DS, RS 0.3mm
Sweep velocity: 8 °/minutes
Embodiment 1:
The aqueous solution that the aqueous solution of strontium nitrate (1.83g) is at room temperature added atorvastatin sodium (10g), stirring at room is to separating out solid, suction filtration is collected solid, wash filter cake with 100ml, filter cake is put into the polymorphic form HA that obtains atorvastatin semi strontium salt after vacuum drying oven (40 ℃) drying.MP:202-212 ℃ of decomposition, aes determination content of strontium 6.7%, MS:557 (M-1).Water-soluble: 0.7mg/ml.
Embodiment 2:
5g Zarator ammonium is dissolved in THF, the aqueous solution that at room temperature adds strontium acetate (1.75g), stirring at room is to separating out solid, and suction filtration is collected solid, wash filter cake with 50ml, obtain atorvastatin semi strontium salt after filter cake is put into vacuum drying oven (40 ℃) drying.MP:201-205 ℃ of decomposition, aes determination content of strontium 6.6%.
Embodiment 3:
The methanol solution that the methanol solution of methylsulfonic acid strontium (1.2g) is at room temperature added atorvastatin sodium (5g), stirring at room is to separating out solid, suction filtration is collected solid, washes filter cake with 40ml, obtains atorvastatin semi strontium salt after filter cake is put into vacuum drying oven (40 ℃) drying.MP:203-206 ℃ of decomposition, aes determination content of strontium 6.7%.
Embodiment 4:
The 4.4g Zarator is dissolved in acetone, at room temperature adds the aqueous solution of strontium bicarbonate, stirring at room is to separating out solid, and suction filtration is collected solid, washes filter cake with 40ml, obtains atorvastatin semi strontium salt after filter cake is put into vacuum drying oven (40 ℃) drying.MP:202-210 ℃ of decomposition, aes determination content of strontium 6.9%.
Embodiment 5:
The 4.4g Zarator is dissolved in THF, the aqueous solution that at room temperature adds strontium acetate (3.5g), stirring at room is to separating out solid, and suction filtration is collected solid, wash filter cake with 50ml, obtain atorvastatin semi strontium salt after filter cake is put into vacuum drying oven (40 ℃) drying.MP:203-209 ℃ of decomposition, aes determination content of strontium 7.1%.
Embodiment 6:
(the water: THF=2: 1) in the solution that the aqueous solution of 18.28g strontium nitrate is at room temperature added atorvastatin sodium (100.51g), be stirred to and separate out solid, suction filtration is collected solid, water 1000ml stirred filter cake 2 hours, suction filtration is collected solid, the polymorphic form HB that obtains atorvastatin semi strontium salt after vacuum drying oven (50 ℃) drying put into filter cake by water (400ml * 3) filter wash cake.
Embodiment 7:
The polymorphic form HA of atorvastatin semi strontium salt is placed for a long time the polymorphic form HB that (including but not limited to the room temperature placement) can be converted into atorvastatin semi strontium salt.
Embodiment 8:
Get (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate 20g adds 200ml methyl alcohol and places stirring at room, get the 2.6ml concentrated hydrochloric acid and be dissolved in the 20ml water, keep being stirred to finishing reaction.
Keeping temperature to stir adds 10%NaOH solution in the solution to keep system pH is 12 to finishing reaction down.Suction filtration keeps filtrate.Gained filtrate decompression vacuum concentration to about 130ml, is added anhydrous methanol, the mixing solutions of methyl tertiary butyl ether and water, the extraction separatory keeps water; Water adds methyl tertiary butyl ether again to be washed once, and separatory keeps water.Under stirring at room, be 8 with 6N HCl regulation system pH value with gained solution, the concentrated residual organic solvents of removing of vacuum rotary steam.
Place 45 ℃ of oil baths to stir gained solution, getting the 4.214g strontium nitrate is dissolved in the 20ml water, under mechanical stirring, slowly splash into, drip to finish and to close heating and continue to stir centrifugal gained solution behind the 2h, the washing of gained filter cake once, keep the dry about 13h of 50 ℃ of reduced vacuum, get crude product atorvastatin strontium 15.1g.
Get gained crude product atorvastatin strontium 5g, add 25ml methyl alcohol and 25ml tetrahydrofuran (THF), ultrasonic or heating in water bath makes it dissolving, and suction filtration keeps filtrate, places 45 ℃ of oil baths to stir, and adds lentamente the water of 75ml behind temperature-stable, and solid is slowly separated out.After separating out solid, maintenance stirs 3h.Centrifugal gained solution, filter cake is washed once, and 50 ℃ of dry about 13h of reduced vacuum get 3.6g atorvastatin hemi strontium salt crystal formation HC.
The solubility test of atorvastatin calcium trihydrate and atorvastatin semi strontium salt polymorphic form HA, HB and HC
1. the foundation of typical curve
1) does typical curve take the atorvastatin calcium trihydrate as standard substance
2) to get atorvastatin calcium trihydrate 4.59mg and place the 100ml volumetric flask, constant volume after the dissolving. this moment, strength of solution was 0.0459mg/ml.
3) getting respectively concentration is that Zarator calcium solution 5ml, 10ml, the 25ml of 0.0459mg/ml is settled to 50ml again; Strength of solution is respectively 0.00459mg/ml, 0.00918mg/ml, 0.02295mg/ml.
4) getting its maximum absorption wavelength through uv scan is 241nm.
5) under 241nm, do typical curve and see accompanying drawing.
2. the solubility test of atorvastatin calcium trihydrate and atorvastatin semi strontium salt
1) prepares respectively atorvastatin calcium trihydrate and atorvastatin semi strontium salt saturated solution.
2) described saturated solution is filtered, get clear filtrate.
3) the gained clear filtrate is diluted to suitable multiple, makes its concentration readings in standard curve range.
4) measure absorbancy at the 241nm wavelength, draw concentration via typical curve, calculate solubleness.
3. measurement result:
The saturation solubility of atorvastatin calcium trihydrate: 0.1988mg/ml,
The saturation solubility of atorvastatin semi strontium salt polymorphic form HA: 0.70mg/ml,
The saturation solubility of atorvastatin semi strontium salt polymorphic form HB: 0.38mg/ml,
The saturation solubility of atorvastatin semi strontium salt polymorphic form HC: 0.43mg/ml.
Claims (10)
1. the polymorphic form HC of compound shown in the formula (I), the X-ray powder diffraction collection of illustrative plates that it is characterized by described polymorphic form HC has following peak:
2. prepare the method for the polymorphic form HC of compound shown in claim 1 Chinese style (I), it is characterized in that described method is: the sodium salt of Zarator, sylvite, ammonium salt or ammonium carbamate make with the strontium reactant salt in water, alcoholic solvent, ether solvent, amide solvent, ketones solvent, methyl-sulphoxide, esters solvent or polyoxyethylene glycol kind solvent.
3. prepare the method for the polymorphic form HC of compound shown in claim 1 Chinese style (I), it is characterized in that described method is: Zarator makes with Strontium carbonate powder, strontium bicarbonate or strontium hydroxide reaction in water, alcoholic solvent, ether solvent, amide solvent, ketones solvent, methyl-sulphoxide, esters solvent or polyoxyethylene glycol kind solvent.
4. the method for the polymorphic form HC of compound shown in preparation claim 2 Chinese style (I) is characterized in that described strontium salt is: strontium nitrate, strontium chloride, Strontium Sulphate, strontium bisulfate, strontium phosphate, strontium monophosphate, sulfonic acid strontium, Strontium carbonate powder, strontium bicarbonate, strontium formate, strontium acetate, trifluoroacetic acid strontium, Succinic Acid strontium, strontium maleate, fumaric acid strontium, gluconic acid strontium, strontium tartrate or strontium salicylate.
5. the application of the polymorphic form HC of compound shown in claim 1 Chinese style (I) in being prepared into HMG-CoA enzyme inhibitors class medicine is characterized in that being prepared into the suitable preparation that is used for the treatment of hypercholesterolemia by the polymorphic form HC of compound shown in the formula (I) and suitable pharmaceutical adjunct.
6. the application of the polymorphic form HC of compound shown in claim 5 Chinese style (I) in being prepared into HMG-CoA enzyme inhibitors class medicine is characterized in that described preparation is tablet, powder agent, capsule, aqua, emulsion, suspensoid.
7. the application of the polymorphic form HC of compound shown in claim 5 Chinese style (I) in being prepared into HMG-CoA enzyme inhibitors class medicine is characterized in that the unit using dosage scope of described preparation is for containing the polymorphic form HC 0.5mg-200mg of compound shown in the formula (I).
8. the polymorphic form HC of compound shown in claim 1 Chinese style (I) is characterized in that being prepared into the suitable preparation that is used for the treatment of osteoporosis by the polymorphic form HC of compound shown in the formula (I) and suitable pharmaceutical adjunct being prepared into the application that improves in the bone density class medicine.
9. the polymorphic form HC of compound shown in claim 8 Chinese style (I) is characterized in that being prepared into the application that improves in the bone density class medicine described preparation is tablet, powder agent, capsule, aqua, emulsion, suspensoid.
10. the polymorphic form HC of compound shown in claim 8 Chinese style (I) is being prepared into the application that improves in the bone density class medicine, it is characterized in that the unit using dosage scope of described preparation is for containing the polymorphic form HC 0.5mg-200mg of compound shown in the formula (I).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| US6605729B1 (en) * | 2001-06-29 | 2003-08-12 | Warner-Lambert Company | Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) |
| WO2005123193A2 (en) * | 2004-06-17 | 2005-12-29 | Osteologix A/S | Treatments comprising strontium for rheumatic and arthritic diseases and pain |
| WO2008093951A1 (en) * | 2007-01-29 | 2008-08-07 | Hanmi Pharm. Co., Ltd. | Atorvastatin strontium salt and pharmaceutical composition comprising same |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO20014746D0 (en) * | 2001-09-28 | 2001-09-28 | Clas M Kjoelberg | Pain reliever |
| ES2553107T3 (en) * | 2003-03-27 | 2015-12-04 | Santosolve As | Anti-inflammatory composition based on strontium compounds |
| CA2465693A1 (en) * | 2003-06-12 | 2004-12-12 | Warner-Lambert Company Llc | Pharmaceutical compositions of atorvastatin |
| CA2585836A1 (en) * | 2004-10-28 | 2006-05-04 | Warner-Lambert Company Llc | Process for forming amorphous atorvastatin |
| WO2009007856A2 (en) * | 2007-07-11 | 2009-01-15 | Actavis Group Ptc Ehf | Novel polymorph of atorvastatin calcium and use thereof for the preparation of amorphous atorvastatin calcium |
| US20110142883A1 (en) * | 2007-07-20 | 2011-06-16 | Actavis Group Ptc Ehf | Amorphous Coprecipitates of Atorvastatin Pharmaceutically Acceptable Salts |
-
2010
- 2010-05-25 CN CN201210521245.XA patent/CN102976996B/en active Active
- 2010-05-25 CN CN 201010194233 patent/CN101973922B/en not_active Expired - Fee Related
- 2010-05-25 CN CN2012105212638A patent/CN102976997A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| US6605729B1 (en) * | 2001-06-29 | 2003-08-12 | Warner-Lambert Company | Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) |
| WO2005123193A2 (en) * | 2004-06-17 | 2005-12-29 | Osteologix A/S | Treatments comprising strontium for rheumatic and arthritic diseases and pain |
| WO2008093951A1 (en) * | 2007-01-29 | 2008-08-07 | Hanmi Pharm. Co., Ltd. | Atorvastatin strontium salt and pharmaceutical composition comprising same |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102976996A (en) | 2013-03-20 |
| CN101973922A (en) | 2011-02-16 |
| CN102976996B (en) | 2015-08-19 |
| CN102976997A (en) | 2013-03-20 |
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