CN107982223B - Atorvastatin calcium tablet and preparation method thereof - Google Patents
Atorvastatin calcium tablet and preparation method thereof Download PDFInfo
- Publication number
- CN107982223B CN107982223B CN201711207936.1A CN201711207936A CN107982223B CN 107982223 B CN107982223 B CN 107982223B CN 201711207936 A CN201711207936 A CN 201711207936A CN 107982223 B CN107982223 B CN 107982223B
- Authority
- CN
- China
- Prior art keywords
- calcium
- atorvastatin calcium
- parts
- atorvastatin
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 title claims abstract description 279
- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 279
- 238000002360 preparation method Methods 0.000 title description 25
- 239000011575 calcium Substances 0.000 claims abstract description 82
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 81
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 81
- 239000000945 filler Substances 0.000 claims abstract description 71
- 239000003623 enhancer Substances 0.000 claims abstract description 67
- 239000000314 lubricant Substances 0.000 claims abstract description 67
- 239000000853 adhesive Substances 0.000 claims abstract description 66
- 230000001070 adhesive effect Effects 0.000 claims abstract description 66
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 65
- 239000002994 raw material Substances 0.000 claims abstract description 35
- 238000002156 mixing Methods 0.000 claims description 63
- 239000000203 mixture Substances 0.000 claims description 53
- 239000007884 disintegrant Substances 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 39
- 239000008187 granular material Substances 0.000 claims description 36
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 35
- 239000002904 solvent Substances 0.000 claims description 35
- 229940079593 drug Drugs 0.000 claims description 34
- 239000013078 crystal Substances 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 29
- 229960004063 propylene glycol Drugs 0.000 claims description 29
- 239000004094 surface-active agent Substances 0.000 claims description 28
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 claims description 26
- 239000001354 calcium citrate Substances 0.000 claims description 26
- 235000013337 tricalcium citrate Nutrition 0.000 claims description 26
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 25
- 150000002500 ions Chemical class 0.000 claims description 25
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 24
- 239000001639 calcium acetate Substances 0.000 claims description 24
- 235000011092 calcium acetate Nutrition 0.000 claims description 24
- 229960005147 calcium acetate Drugs 0.000 claims description 24
- 239000012928 buffer substance Substances 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 19
- 238000005469 granulation Methods 0.000 claims description 18
- 230000003179 granulation Effects 0.000 claims description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 17
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 16
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 16
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
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- -1 sorbitan fatty acid ester Chemical class 0.000 claims description 14
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 13
- 229920002472 Starch Polymers 0.000 claims description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 13
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 13
- 235000019698 starch Nutrition 0.000 claims description 13
- 239000008107 starch Substances 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 12
- 239000001506 calcium phosphate Substances 0.000 claims description 12
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 12
- 235000011010 calcium phosphates Nutrition 0.000 claims description 12
- 239000006184 cosolvent Substances 0.000 claims description 12
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- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 12
- 239000011591 potassium Substances 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 229960003975 potassium Drugs 0.000 claims description 12
- 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 claims description 12
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 11
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 10
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 10
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 10
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- 229920002307 Dextran Polymers 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 9
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 9
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 9
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 8
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- 229960001681 croscarmellose sodium Drugs 0.000 claims description 8
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- 235000014113 dietary fatty acids Nutrition 0.000 claims description 8
- 239000000194 fatty acid Substances 0.000 claims description 8
- 229930195729 fatty acid Natural products 0.000 claims description 8
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 8
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- 235000015424 sodium Nutrition 0.000 claims description 8
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 6
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 6
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 5
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 5
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- 241000416162 Astragalus gummifer Species 0.000 claims description 4
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- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 4
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
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- 229960001462 sodium cyclamate Drugs 0.000 description 1
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- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
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- 229940013618 stevioside Drugs 0.000 description 1
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- 235000019202 steviosides Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/10—Carbonates; Bicarbonates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an atorvastatin calcium tablet which comprises the following raw materials: 1-20 parts of atorvastatin calcium, 10-80 parts of filler, 20-40 parts of disintegrating agent, 5-40 parts of adhesive, 1-15 parts of lubricant and 1-20 parts of calcium enhancer. The atorvastatin calcium tablet provided by the invention has the advantages of high stability, good dissolution performance, high bioavailability and the like, and has a good clinical application prospect.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an atorvastatin calcium tablet and a preparation method thereof.
Background
Atorvastatin calcium, the English name Atorvastatincalcium, the chemical name [ R- (R, R)]-2- (4-fluorophenyl) - β, -Dikis-5- (1-methylethyl) -3-phenyl-4- [ (phenylamine) carbonyl]-1-hydro-pyrrole-1-heptanoic acid calcium salt having the formula (C)33H34FN205)2Ca, molecular weight 1155.34. The structural formula is as follows:
atorvastatin calcium is a selective HMG-CoA reductase inhibitor that feedback mediates the activity of low density lipoprotein LDL receptors by competitively inhibiting the anabolism of cholesterol in tissue cells, thereby promoting the clearance of LDL in the plasma and lowering LDL levels in the plasma. The medicine can effectively reduce the levels of Total Cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and Triglyceride (TG) of patients with primary hypercholesterolemia and mixed hyperlipidemia (IIa and IIb), and does not influence the synthesis and metabolism of high-density lipoprotein cholesterol (HDL-C).
Atorvastatin calcium has definite clinical curative effect and obvious effect, but the atorvastatin calcium has strong bitter taste, is very slightly soluble in water, has poor stability and is highly sensitive to moisture, heat, light and acid environments. Currently, atorvastatin calcium is used clinically and is often prepared as tablets.
For example, chinese patent document CN102309462A discloses an atorvastatin calcium tablet comprising atorvastatin calcium, a filler, a disintegrant and a lubricant. The filler is selected from one or more of the following: starch, lactose, powdered sugar, mannitol, dextrin, cyclodextrin, microcrystalline cellulose, and sucrose; the disintegrant is selected from one or more of the following: sodium carboxymethyl starch, crospovidone, croscarmellose sodium, sodium croscarmellose, pregelatinized starch, and low-substituted hydroxypropylcellulose; the lubricant is selected from one or more of the following: magnesium stearate, talcum powder and silica gel micropowder.
Chinese patent document CN105168162A discloses an atorvastatin calcium oral rapidly disintegrating tablet, which comprises the following components: 5-30 parts of atorvastatin calcium, 50-90 parts of a framework material, 1-10 parts of a suspending agent, 0.1-5 parts of a surfactant, 0.1-5 parts of a flavoring agent and 0.1-2 parts of a pH regulator. The framework material is selected from any one or a mixture of any two of mannitol, sorbitol, lactose, dextran and starch according to any proportion; the suspending agent is any one or a mixture of any two of polyvinyl alcohol, tragacanth, sodium alginate, gelatin, shellac, acacia, methylcellulose, ethylcellulose, agar or hydroxypropyl methylcellulose in any proportion; the surfactant is selected from any one or a mixture of any two of sodium dodecyl sulfate, carbomer, poloxamer and polysorbate according to any proportion; the pH regulator is selected from any one or a mixture of two of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and potassium bicarbonate according to any proportion.
Chinese patent document CN1911209A discloses an atorvastatin calcium tablet capable of being rapidly disintegrated and a preparation method thereof, the atorvastatin calcium tablet is prepared from a main drug atorvastatin calcium and a drug carrier, the drug carrier mainly comprises an adhesive, a disintegrant, a flavoring agent, a lubricant and a filler, and the main drug and the drug carrier are proportioned according to the following weight percentage: 5-25% of atorvastatin calcium, 28-55% of disintegrating agent, 1-5% of flavoring agent, 25-50% of filling agent and 1-5% of lubricating agent; the disintegrating agent is formed by combining three components of microcrystalline cellulose, sodium dodecyl sulfate and crosslinked polyvinylpyrrolidone; the correctant is selected from one or more of fructus Citri sinensis powder essence, aspartame, sodium cyclamate, glycyrrhizin, stevioside, and saccharin; the lubricant is selected from one or more of magnesium stearate, silicon dioxide, talcum powder and polyethylene glycol; the filler is selected from one or more of pregelatinized starch, lactose, sugar powder, starch, and mannitol.
Chinese patent document CN103705484A discloses a stable atorvastatin calcium tablet, the tablet core of which comprises the following components by mass percent: 5-20% of atorvastatin calcium, 15-60% of filler, 5-20% of disintegrant, 125-45% of stabilizer, 8.0-11.0% of stabilizer 2 for adjusting the pH value of wetting agent and 0.5-1% of magnesium stearate. Wherein the filler is one or the combination of any two of lactose, microcrystalline cellulose, mannitol, sorbitol and pregelatinized starch. The disintegrant is one or combination of croscarmellose sodium, hydroxypropyl cellulose, carboxymethyl starch sodium, sodium carboxymethylcellulose, and crospovidone. The stabilizer 1 is any one of calcium carbonate, magnesium oxide and sodium bicarbonate; the stabilizer 2 is any one of sodium hydroxide, calcium hydroxide, potassium hydroxide and tromethamine. The tablet core is also added with a bonding agent, and the bonding agent is povidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose.
Chinese patent document CN104688708A discloses a preparation method of atorvastatin calcium preparation, which adopts the following components in proportion: 10-40 parts of atorvastatin calcium calculated as atorvastatin, 40-60 parts of hydrophilic diluent, 30-45 parts of alkaline diluent, 20-40 parts of microcrystalline cellulose, 5-18 parts of disintegrant, 4-10 parts of superfine silica gel powder and 1.5-4 parts of adhesive. The hydrophilic diluent is one of lactose, mannitol and sorbitol. The alkaline diluent is one of calcium carbonate, sodium bicarbonate and magnesium carbonate. The disintegrating agent is one or more of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose and crospovidone. The adhesive is one of povidone and hydroxypropyl methylcellulose. The lubricant is one or more of superfine silica gel powder, magnesium stearate and talcum powder.
Chinese patent document CN106491554A discloses a tablet containing atorvastatin calcium, the formulation of the coating film is: 10-50% of atorvastatin calcium, 30-70% of an alkalizer and 5-25% of an adhesive. The alkalizer is selected from one or more of sodium carbonate, sodium hydroxide, calcium carbonate and calcium hydrophosphate; the adhesive is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone; the disintegrant is selected from one or more of crospovidone, croscarmellose sodium and sodium carboxymethyl starch; the lubricant is selected from one or more of magnesium stearate, talcum powder and sodium stearyl fumarate.
Although the research on atorvastatin calcium preparations in the prior art mainly focuses on improving the stability, enhancing the dissolution performance and improving the cell availability of atorvastatin calcium, the problem of how to effectively improve the stability, dissolution performance and cell availability of atorvastatin calcium pharmaceutical preparations is still a technical difficulty to be solved urgently in the field.
In addition, when preparing atorvastatin calcium, due to the fact that the total amount of impurities of atorvastatin calcium in various crystal forms or non-crystal forms is high, optical purity is low, bioavailability is low, and the conventional crystal forms have the defects of sensitivity to air environmental factors, instable bioactivity, harsh preparation processing conditions and the like, the problem is difficult to solve by a preparation process, and another problem is brought to technical personnel in the field.
Disclosure of Invention
The invention aims to provide an atorvastatin calcium tablet with high stability, good dissolution performance and high cell availability and a preparation method thereof.
Therefore, the invention provides an atorvastatin calcium tablet which comprises the following raw materials:
1-20 parts of atorvastatin calcium, 10-80 parts of filler, 20-40 parts of disintegrant, 5-40 parts of adhesive, 1-15 parts of lubricant and 1-20 parts of calcium enhancer;
the calcium enhancer is one or more of calcium citrate, calcium carbonate, calcium bicarbonate, calcium acetate, calcium phosphate, calcium hydrogen phosphate and calcium sulfate.
The atorvastatin calcium tablet can be prepared into capsules, and the atorvastatin calcium tablet can be filled into the capsules after the atorvastatin calcium tablet is uniformly mixed with the atorvastatin calcium tablet.
Preferably, the calcium fortifier is a mixture of calcium citrate and calcium acetate.
More preferably, the calcium enhancer is calcium citrate and calcium acetate according to the proportion of (1-3): 1 by weight ratio of the mixture.
Preferably, the atorvastatin calcium tablet comprises the following raw material components:
10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
Preferably, the atorvastatin calcium is a solvate stable crystal having a structure shown in formula (I):
further preferably, the molar ratio of atorvastatin calcium to solvent molecules is 1: 1.
Preferably, the filler is one or more of pregelatinized starch, microcrystalline cellulose, lactose, sucrose, corn starch, mannitol, sorbitol, dextrin, crospovidone, dextran, polyvinylpyrrolidone, sodium alginate, povidone, carboxymethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, and methyl cellulose;
the disintegrating agent is one or more of pregelatinized starch, crospovidone, polyvinylpyrrolidone, sodium alginate, maltodextrin, croscarmellose sodium, cross-linked carboxymethyl starch, magnesium aluminum silicate, potassium polyacrylate and low-substituted hydroxypropyl cellulose;
the adhesive is one or more of pregelatinized starch, gelatinized starch, lactose, dextrin, dextran, maltodextrin, sodium alginate, sucrose, polyethylene glycol, hydroxypropyl methylcellulose, ethyl cellulose, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, sodium carboxypropyl cellulose, gelatin, acacia, tragacanth, polyvinylpyrrolidone and magnesium aluminum silicate;
the lubricant is one or more of magnesium stearate, calcium stearate, zinc stearate, calcium behenate, sodium stearyl fumarate, talcum powder, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax and silicon dioxide.
Preferably, the atorvastatin calcium tablet further comprises one or more of 0.1-0.03 parts by weight of surfactant, 10-40 parts by weight of inorganic salt ion balancing agent and 10-20 parts by weight of buffer substance.
Further preferably, the surfactant is one or more of sodium dodecyl sulfate, poloxamer, lecithin, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated hydrogenated castor oil, polyoxyethylene stearate and cetyl pyridinium chloride;
the inorganic salt ion balancing agent is one or more of sodium carbonate or potassium, sodium bicarbonate or potassium, sodium phosphate or potassium, disodium hydrogen phosphate or dipotassium, sodium dihydrogen phosphate or potassium, calcium citrate, calcium carbonate, calcium bicarbonate, calcium acetate, calcium phosphate and calcium hydrogen phosphate;
the buffer substance is one or more of sodium citrate, disodium phosphate, calcium carbonate, phosphate, sulfate, magnesium carbonate, potassium citrate, potassium sorbate, sodium ascorbate, bicarbonate and hydrogen phosphate.
The method for preparing the atorvastatin calcium tablet comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 2-98% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, and granulating by adopting a granulating solvent to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
Preferably, the granulation in step (1) is spray granulation; the granulating solvent is one or more of water, ethanol, methanol, isopropanol, n-butanol, acetone, diethyl ether, ethyl acetate, isopropyl acetate and methyl acetate;
further preferably, the spray granulation is followed by drying; the drying adopts one of disc drying, fluidized bed drying, vacuum drying and microwave drying.
Preferably, the temperature of the drying is 60 ℃ or lower.
Preferably, the step (1) further comprises the step of taking one or more of a surfactant, an inorganic salt ion balancing agent and a buffering substance according to selected parts by weight, and mixing the surfactant, the inorganic salt ion balancing agent and the buffering substance together with the atorvastatin calcium, the filling agent, the disintegrant and the binder; and/or
The step (2) also comprises a step of mixing one or two of inorganic salt ion balancing agent and buffer substance according to selected weight parts with the lubricant, calcium enhancer and disintegrant.
Preferably, the atorvastatin calcium is atorvastatin calcium 1,2 propylene glycol solvate stable crystal, and the atorvastatin calcium 1,2 propylene glycol solvate stable crystal is obtained by the following method:
(a) firstly dissolving atorvastatin calcium raw materials in a mixed solvent;
the dissolving concentration of the atorvastatin calcium raw material is 1-3% by weight;
the mixed solvent is formed by mixing dimethyl sulfoxide and acetone according to a volume ratio of 1-2: 100; or the mixed solvent is formed by mixing dimethyl sulfoxide and methanol according to the volume ratio of 1-2: 100;
(b) adding a 1, 2-propanediol solvent to the mixed liquor obtained in step (a);
the addition amount of the 1, 2-propanediol solvent is that 0.2-0.4 ml of the 1, 2-propanediol solvent is added into every 1g of atorvastatin calcium;
(c) adding an organic cosolvent into the mixed solution obtained in the step (b);
the addition amount of the organic cosolvent is 0.1-0.2 ml of the organic solvent added into every 1g of atorvastatin calcium;
the organic cosolvent is one of butyl acetate and isoamyl acetate or a mixture in any proportion;
(d) and (c) standing, cooling, separating and drying the mixed solution obtained in the step (c) to obtain the atorvastatin calcium 1,2 propylene glycol solvate stable crystal.
Compared with the prior art, the technical scheme of the invention has the following advantages:
(1) the atorvastatin calcium tablet comprises the calcium enhancer, wherein the calcium enhancer is one or more of calcium citrate, calcium carbonate, calcium bicarbonate, calcium acetate, calcium phosphate, calcium hydrogen phosphate and calcium sulfate. The calcium enhancer is a medicinal active substance and an effective functional action factor of the pharmaceutical preparation.
Firstly, from the perspective of biological functionality, inorganic or organic calcium is used as an auxiliary material to influence human bodies, and a simple biological function is to supplement calcium, for example, calcium tablets contain a large amount of calcium carbonate, and the action mechanism is to dissociate calcium carbonate by using gastric acid to become Ca ions which are absorbed by human bodies to achieve the purpose of calcium supplement; in the invention, the calcium fortifier is used as an antacid, and after the atorvastatin calcium is taken, the antacid can neutralize part of gastric acid to keep the medicinal activity of the atorvastatin calcium. More importantly, when the calcium enhancer is organic calcium citrate, the calcium channel in the cell membrane can be adjusted, so that the atorvastatin calcium drug molecule has the function of swallowing through the cell membrane surface, and the bioavailability of the atorvastatin calcium can be improved through the change of the ion channel of the cell. Particularly, when the calcium citrate is used together with one or more of calcium carbonate, calcium bicarbonate, calcium acetate, calcium phosphate, calcium hydrogen phosphate and calcium sulfate, the calcium salts can obviously promote the calcium citrate to play the above role in the atorvastatin calcium medicament. Multiple experiments show that when the calcium citrate and the calcium acetate are used together, the calcium citrate and the calcium acetate have a synergistic effect, the effect is good, and when the calcium citrate and the calcium acetate are used together, the calcium citrate and the calcium acetate are (1-3): when the weight ratio of 1 is mixed, the effect is particularly remarkable.
Secondly, from the perspective of pharmaceutical preparations, the organic or inorganic calcium-containing compound can be used as a disintegrant in the preparation of tablets, in addition to a lubricant, an excipient and a filler, and the tablets can disintegrate quickly after the calcium enhancer is added, so that the dissolution rate is greatly improved;
(2) the atorvastatin calcium tablet of the present invention further comprises a surfactant. Amphiphilic molecules in the molecular structure of the surfactant can be adsorbed on the surface of a solid to form an adsorption layer in directional arrangement, so that the interfacial free energy is reduced, the wetting property of the surface of the solid is effectively changed, the wetting capacity of liquid can be improved, the liquid is easy to absorb water, swell and disintegrate, the disintegration time is shortened, and the disintegration of a medicament with strong hydrophobicity is promoted. By adding the surfactant, the adsorbability of the cell membrane surface in the atorvastatin calcium molecule is effectively improved, the problem of low absorption and utilization rate of the atorvastatin calcium molecule in vivo is solved, and the transport capacity and the release speed of the atorvastatin calcium in vivo are effectively improved.
It should be noted that the calcium enhancer, especially the calcium enhancer represented by calcium citrate, improves the bioavailability of atorvastatin calcium in terms of biological functions, and the surfactant improves the adsorbability of the cell membrane surface in atorvastatin calcium molecules, so that the calcium enhancer can act on cells more effectively, and the two effects act synergistically, thereby greatly improving the bioavailability of atorvastatin calcium;
(3) the atorvastatin calcium tablet also comprises an inorganic salt ion balancing agent, wherein the inorganic salt ion balancing agent can protect atorvastatin calcium molecules, keep calcium ions of the atorvastatin calcium not to be separated, and maintain the state of the atorvastatin calcium capable of passing through a calcium ion channel, so that the bioactivity of the atorvastatin calcium is better kept; the atorvastatin calcium compound has the combined action with the effect of the calcium ion enhancer, and the bioavailability of the atorvastatin calcium is better improved from different angles;
(4) the atorvastatin calcium tablet further comprises a buffer substance, and the buffer substance can play a role in balancing local pH value stabilization; the atorvastatin calcium can exert drug effect at a proper pH value and can be added into tablets as an excipient;
(5) the atorvastatin calcium tablet adopts atorvastatin calcium as a solvent stable crystal, and particularly, the atorvastatin calcium 1,2 propylene glycol solvent stable crystal. The crystal is a new crystal form, the chemical and optical purity of the prepared stable crystal is extremely high and reaches 99.9 percent, and the experiment proves that: under the conditions of high temperature, strong light and high humidity for 0-30 days, the appearance, physical and chemical properties and content of the composition are not changed, which shows that the composition has good chemical stability and is suitable for manufacturing and long-term storage of pharmaceutical preparations;
(6) the atorvastatin calcium tablet provided by the invention adopts an innovative process combining dry-wet preparation for the first time in the preparation process, and by adding a proper amount of surfactant into part of auxiliary materials in part of the component wet processing process, the problems of poor effective dispersibility and hydrophobicity of cell membrane lipid substances in the preparation process of the atorvastatin calcium tablet are effectively solved, and the affinity of atorvastatin calcium to the cell membrane surface is improved. In addition, the atorvastatin calcium tablet prepared by the dry method and the wet method has good physical appearance of the tablet, and the uniformity and the stability of the drug dosage are ensured.
Detailed Description
Example 1
The atorvastatin calcium tablet comprises the following raw materials:
1 part by weight of atorvastatin calcium, 10 parts by weight of filler, 40 parts by weight of disintegrant, 24 parts by weight of adhesive, 8 parts by weight of lubricant and 10 parts by weight of calcium enhancer;
wherein the calcium enhancer is calcium carbonate; the filler is lactose; the disintegrant is crospovidone; the adhesive is pregelatinized starch; the lubricant is silica.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 2% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, taking water as a granulating solvent, and granulating by adopting spray granulation to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
It should be noted that, as an alternative implementation manner of this embodiment, calcium carbonate of the calcium fortifier may also be replaced by calcium bicarbonate; lactose of the filler can be replaced by one of sucrose and dextran; the pregelatinized starch of the adhesive can also be replaced by gelatinized starch. The technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 2
The atorvastatin calcium tablet comprises the following raw materials:
10 parts of atorvastatin calcium, 80 parts of filler, 30 parts of disintegrant, 5 parts of adhesive, 15 parts of lubricant and 20 parts of calcium enhancer;
wherein the calcium enhancer is calcium hydrogen phosphate; the filler is pregelatinized starch; the disintegrant is magnesium aluminum silicate; the adhesive is dextran; the lubricant is magnesium stearate.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 98% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, taking ethanol as a granulating solvent, and granulating by adopting spray granulation to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
It should be noted that, as an alternative implementation manner of this embodiment, calcium hydrogen phosphate of the calcium fortifier may also be replaced by calcium phosphate; the pregelatinized starch of the filler can be replaced by corn starch; the dextran of the adhesive can also be replaced by lactose and sucrose; the lubricant magnesium stearate can be replaced by zinc stearate, stearic acid and calcium stearate. The ethanol of the granulating solvent can be replaced by a mixture obtained by uniformly mixing ethanol and one or more of water, methanol, isopropanol, n-butanol, acetone, diethyl ether, ethyl acetate, isopropyl acetate and methyl acetate according to any weight ratio; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 3
The atorvastatin calcium tablet comprises the following raw materials:
20 parts of atorvastatin calcium, 45 parts of filler, 20 parts of disintegrant, 40 parts of adhesive, 1 part of lubricant and 1 part of calcium enhancer;
wherein the calcium enhancer is calcium sulfate; the filler is hydroxypropyl methyl cellulose; the disintegrating agent is pregelatinized starch; the adhesive is gelatin; the lubricant is talcum powder.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 50% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, taking acetone as a granulating solvent, and granulating by adopting spray granulation to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
As an alternative implementation manner of this embodiment, the hydroxypropyl methylcellulose of the filler may be replaced by one of carboxymethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, and methyl cellulose; the pregelatinized starch of the disintegrant can be replaced by maltodextrin and cross-linked carboxymethyl starch; the gelatin of the adhesive can be replaced by acacia gum and tragacanth gum. The acetone of the granulating solvent can be replaced by one of water, ethanol, methanol, isopropanol, n-butanol, diethyl ether, ethyl acetate, isopropyl acetate and methyl acetate; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 4
The atorvastatin calcium tablet comprises the following raw materials:
10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
Wherein the calcium enhancer is calcium citrate; the filler is microcrystalline cellulose; the disintegrant is low-substituted hydroxypropyl cellulose; the adhesive is dextrin; the lubricant is magnesium trisilicate; the atorvastatin calcium is a solvation stable crystal.
The solvate-stable crystal of atorvastatin calcium has the following structure:
as a preferred embodiment of this example, the stable crystalline solvate of atorvastatin calcium is a stable crystalline 1,2 propylene glycol solvate of atorvastatin calcium; the molar ratio of the atorvastatin calcium to the 1, 2-propylene glycol is 1: 1.
The stable crystallization of the 1, 2-propanediol solvate of atorvastatin calcium is obtained by the following method:
(a) firstly dissolving atorvastatin calcium raw materials in a mixed solvent;
the dissolving concentration of the atorvastatin calcium raw material is 1-3% by weight;
the mixed solvent is formed by mixing dimethyl sulfoxide and acetone according to the volume ratio of 1: 100;
(b) adding a 1, 2-propanediol solvent to the mixed liquor obtained in step (a);
the addition amount of the 1, 2-propanediol solvent is 0.2ml of the 1, 2-propanediol solvent added to every 1g of atorvastatin calcium;
(c) adding an organic cosolvent into the mixed solution obtained in the step (b);
the addition amount of the organic cosolvent is 0.2ml of the organic solvent added into every 1g of atorvastatin calcium;
the organic cosolvent is one of butyl acetate and isoamyl acetate or a mixture in any proportion;
(d) and (c) standing, cooling, separating and drying the mixed solution obtained in the step (c) to obtain the atorvastatin calcium 1,2 propylene glycol solvate stable crystal.
Taking the atorvastatin calcium 1,2 propylene glycol solvate for stable crystallization, and carrying out the atorvastatin calcium tablet, wherein the preparation method comprises the following steps:
(1) taking the atorvastatin calcium 1,2 propylene glycol solvate stable crystal, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 50% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, taking ethanol as a granulating solvent, performing spray granulation, and drying the obtained granules by vacuum drying to obtain atorvastatin calcium medicine-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
It should be noted that, as an alternative implementation manner of this embodiment, the low-substituted hydroxypropyl cellulose of the disintegrant may also be replaced by croscarmellose sodium; the dextrin of the binder may also be replaced by maltodextrin. The technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 5
The atorvastatin calcium tablet comprises the following raw materials:
10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
Wherein the calcium enhancer is calcium acetate; the filler is mannitol; the disintegrating agent is polyvinylpyrrolidone; the adhesive is hydroxypropyl methyl cellulose; the lubricant is sodium stearyl fumarate. The atorvastatin calcium is stable crystal of 1,2 propylene glycol solvate of atorvastatin calcium.
The stable crystallization of the 1, 2-propanediol solvate of atorvastatin calcium is obtained by the following method:
(a) firstly dissolving atorvastatin calcium raw materials in a mixed solvent;
the dissolving concentration of the atorvastatin calcium raw material is 1-3% by weight;
the mixed solvent is formed by mixing dimethyl sulfoxide and methanol according to the volume ratio of 2: 100;
(b) adding a 1, 2-propanediol solvent to the mixed liquor obtained in step (a);
the addition amount of the 1, 2-propanediol solvent is 0.4ml of the 1, 2-propanediol solvent added to every 1g of atorvastatin calcium;
(c) adding an organic cosolvent into the mixed solution obtained in the step (b);
the addition amount of the organic cosolvent is that 0.1ml of the organic solvent is added into every 1g of atorvastatin calcium;
the organic cosolvent is one of butyl acetate and isoamyl acetate or a mixture in any proportion;
(d) and (c) standing, cooling, separating and drying the mixed solution obtained in the step (c) to obtain the atorvastatin calcium 1,2 propylene glycol solvate stable crystal.
Taking the atorvastatin calcium 1,2 propylene glycol solvate for stable crystallization, and carrying out the atorvastatin calcium tablet, wherein the preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 50% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, taking ethanol as a granulating solvent, granulating by adopting spray granulation, and drying the obtained granules by adopting microwave drying to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
It should be noted that, as an alternative implementation manner of this embodiment, mannitol of the bulking agent may also be replaced by sorbitol; the hydroxypropyl methylcellulose of the adhesive can be replaced by one of ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose and sodium carboxypropyl cellulose. The disc type drying can be replaced by one of disc type drying and fluidized bed drying; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 6
The atorvastatin calcium tablet comprises the following raw materials:
10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
Wherein the calcium enhancer is a mixture obtained by uniformly mixing calcium carbonate and calcium sulfate according to the weight ratio of 1: 1; the filler is sodium alginate; the disintegrant is potassium polyacrylate; the adhesive is polyvinylpyrrolidone; the lubricant is calcium behenate; the atorvastatin calcium is a solvation stable crystal.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
Example 7
The atorvastatin calcium tablet comprises the following raw materials:
10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
Wherein the calcium enhancer is a mixture obtained by uniformly mixing calcium phosphate and calcium hydrophosphate in a weight ratio of 3: 1; the filler is dextrin; the disintegrating agent is sodium alginate; the adhesive is polyethylene glycol; the lubricant is carnauba wax; the atorvastatin calcium is a solvation stable crystal.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
Example 8
The atorvastatin calcium tablet comprises the following raw materials:
10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
Wherein the calcium enhancer is a mixture obtained by uniformly mixing calcium bicarbonate, calcium sulfate and calcium phosphate according to the weight ratio of 1:3: 2; the filler is crospovidone; the disintegrating agent is sodium alginate, potassium polyacrylate and maltodextrin, and the weight ratio of the disintegrating agent to the sodium alginate to the potassium polyacrylate to the maltodextrin is 1:3: 1, and uniformly mixing to obtain a mixture; the adhesive is sodium alginate; the lubricant is palmitic acid; the atorvastatin calcium is a solvation stable crystal.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
It should be noted that, as an alternative implementation manner of this embodiment, the crospovidone of the filler may also be replaced by a mixture obtained by uniformly mixing crospovidone, microcrystalline cellulose, and lactose according to any weight ratio; the sodium alginate of the adhesive can also be replaced by a mixture obtained by uniformly mixing the sodium alginate, the cane sugar and the tragacanth according to any weight ratio; the palmitic acid of the lubricant can be replaced by a mixture obtained by uniformly mixing palmitic acid, talcum powder and magnesium trisilicate according to any weight ratio; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 9
The atorvastatin calcium tablet comprises the following raw materials:
10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
Wherein the calcium enhancer is a mixture obtained by uniformly mixing calcium acetate, calcium bicarbonate, calcium phosphate and calcium sulfate according to the weight ratio of 3:1:2: 1; the filler is polyvinylpyrrolidone; the disintegrating agent is a mixture obtained by uniformly mixing croscarmellose sodium, magnesium aluminum silicate and sodium alginate according to the weight ratio of 1:1: 1; the adhesive is magnesium aluminum silicate; the lubricant is a mixture obtained by uniformly mixing calcium stearate and talcum powder according to the weight ratio of 2: 3; the atorvastatin calcium is a solvation stable crystal.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
As an alternative implementation manner of this embodiment, the polyvinylpyrrolidone in the filler may be replaced by a mixture obtained by uniformly mixing polyvinylpyrrolidone and dextran at any weight ratio; the magnesium aluminum silicate of the adhesive can be replaced by a mixture obtained by uniformly mixing the magnesium aluminum silicate and the methyl cellulose according to any weight ratio; the lubricant calcium stearate and talcum powder can be replaced by a mixture obtained by uniformly mixing calcium stearate, talcum powder and magnesium trisilicate according to any weight ratio; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 10
The atorvastatin calcium tablet comprises the following raw materials:
10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
Wherein the calcium enhancer is a mixture obtained by uniformly mixing calcium citrate and calcium acetate according to the weight ratio of 1: 1; the filler is polyvinylpyrrolidone; the disintegrating agent is sodium alginate; the adhesive is magnesium aluminum silicate; the lubricant is silicon dioxide; the atorvastatin calcium is a solvation stable crystal.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
Example 11
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: and replacing the mixture obtained by uniformly mixing the calcium citrate and the calcium acetate according to the weight ratio of 1:1 with the mixture obtained by uniformly mixing the calcium citrate and the calcium acetate according to the weight ratio of 3: 1.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
Example 12
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: and replacing the mixture obtained by uniformly mixing the calcium citrate and the calcium acetate according to the weight ratio of 1:1 with the mixture obtained by uniformly mixing the calcium citrate and the calcium acetate according to the weight ratio of 1: 4.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
Example 13
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: the calcium enhancer is a mixture obtained by uniformly mixing calcium citrate and calcium acetate according to the weight ratio of 1:1, and is replaced by a mixture obtained by uniformly mixing calcium citrate and calcium phosphate according to the weight ratio of 3: 1.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
Example 14
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: the calcium enhancer is a mixture obtained by uniformly mixing calcium citrate and calcium acetate according to the weight ratio of 1:1, and the mixture is replaced by a mixture obtained by uniformly mixing calcium acetate and calcium phosphate according to the weight ratio of 1: 1.
The process for preparing the atorvastatin calcium tablet of this example is the same as that of example 5.
Example 15
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: also comprises 0.1 weight part of surfactant; the surfactant is sodium dodecyl sulfate.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent, an adhesive and a surfactant according to selected parts by weight, uniformly mixing 50% of the total amount of the disintegrating agent with the atorvastatin calcium, the filling agent, the adhesive and the surfactant, taking ethanol as a granulating solvent, performing spray granulation, and drying the obtained granules by vacuum drying to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
It should be noted that, as an alternative implementation manner of this embodiment, the sodium lauryl sulfate of the surfactant may also be replaced by one of poloxamer, lecithin, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated hydrogenated castor oil, polyoxyethylene stearate, and cetyl pyridinium chloride; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
In addition, the sodium dodecyl sulfate of the surfactant can be replaced by a mixture of the sodium dodecyl sulfate and one or more of sodium dodecyl sulfate, poloxamer, lecithin, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated hydrogenated castor oil, polyoxyethylene stearate and cetyl pyridine chloride which are uniformly mixed according to any weight ratio; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 16
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: also comprises 10 weight parts of inorganic salt ion balancing agent; the inorganic salt ion balancing agent is sodium carbonate.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 50% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, taking ethanol as a granulating solvent, granulating by adopting spray granulation, and drying the obtained granules by adopting vacuum drying to obtain the atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant, the calcium enhancer and the inorganic salt ion balancing agent according to the selected weight parts, adding the lubricant, the calcium enhancer, the inorganic salt ion balancing agent and the rest disintegrating agent into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
It should be noted that, as an alternative implementation manner of this embodiment, the sodium carbonate of the inorganic salt ion balancing agent may also be replaced by one of potassium carbonate, sodium bicarbonate or potassium bicarbonate, sodium phosphate or potassium phosphate, disodium hydrogen phosphate or dipotassium phosphate, sodium dihydrogen phosphate or potassium phosphate, calcium citrate, calcium carbonate, calcium bicarbonate, calcium acetate, calcium phosphate, and calcium hydrogen phosphate; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
In addition, the sodium carbonate of the inorganic salt ion balancing agent can be replaced by a mixture obtained by uniformly mixing sodium carbonate and one or more of potassium carbonate, sodium bicarbonate or potassium, sodium phosphate or potassium, disodium hydrogen phosphate or dipotassium, sodium dihydrogen phosphate or potassium, calcium citrate, calcium carbonate, calcium bicarbonate, calcium acetate and calcium hydrogen phosphate according to any weight ratio; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 17
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: also comprises 10 parts by weight of buffer substance; the buffer substance is sodium citrate.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent, an adhesive and a buffer substance according to selected parts by weight, uniformly mixing 50% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent, the adhesive and the buffer substance, taking ethanol as a granulating solvent, granulating by adopting spray granulation, and drying the obtained granules by adopting vacuum drying to obtain atorvastatin calcium medicine-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
It should be noted that, as an alternative implementation manner of this embodiment, the sodium citrate of the buffer substance may also be replaced by one of disodium phosphate, calcium carbonate, phosphate, sulfate, magnesium carbonate, potassium citrate, potassium sorbate, sodium ascorbate, bicarbonate, and hydrogen phosphate; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment. Wherein, the phosphate, sulfate, bicarbonate and hydrogen phosphate mainly refer to potassium, sodium and calcium, such as calcium sulfate, etc., and those skilled in the art can select corresponding specific substances according to common auxiliary materials of medicines.
In addition, the sodium citrate of the buffer substance can be replaced by a mixture obtained by uniformly mixing disodium phosphate with one or more of calcium carbonate, phosphate, sulfate, magnesium carbonate, potassium citrate, potassium sorbate, sodium ascorbate, bicarbonate and hydrogen phosphate according to any weight ratio; the technical effects of the above alternative technical solutions are not obviously different from those of the present embodiment.
Example 18
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: also comprises 15 weight parts of buffer substance; the buffer substance is a mixture obtained by uniformly mixing sodium ascorbate and magnesium sulfate according to the weight ratio of 1: 1.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 50% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, taking ethanol as a granulating solvent, granulating by adopting spray granulation, and drying the obtained granules by adopting vacuum drying to obtain the atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant, the calcium enhancer and the buffer substance according to the selected weight parts, adding the lubricant, the calcium enhancer, the buffer substance and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
Example 19
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: also comprises 0.07 weight part of surfactant and 25 weight parts of inorganic salt ion balancing agent.
The surfactant is lecithin; the inorganic salt ion balancing agent is calcium hydrophosphate.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent, an adhesive, a surfactant and an inorganic salt ion balancing agent according to selected parts by weight, uniformly mixing 50% of the total using amount of the disintegrating agent with the atorvastatin calcium, the filling agent, the adhesive, the surfactant and the inorganic salt ion balancing agent, taking ethanol as a granulating solvent, granulating by adopting spray granulation, and drying the obtained granules by adopting vacuum drying to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
Example 20
The atorvastatin calcium tablet of this example has the same raw material composition as example 10 except that: also comprises 0.03 weight part of surfactant, 40 weight parts of inorganic salt ion balancing agent and 20 weight parts of buffer substance.
The surfactant is lecithin; the inorganic salt ion balancing agent is calcium hydrophosphate; the buffer substance is sodium ascorbate.
The preparation method comprises the following steps:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent, an adhesive, a surfactant, an inorganic salt ion balancing agent and a buffer substance according to selected parts by weight, uniformly mixing 50% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent, the adhesive, the surfactant, the inorganic salt ion balancing agent and the buffer substance, taking ethanol as a granulating solvent, granulating by adopting spray granulation, and drying the obtained granules by adopting vacuum drying to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
Comparative example 1
The atorvastatin calcium tablet of this comparative example has the raw material composition as described in example 1 and is prepared using the process in example 1, except that: the calcium fortifier is not included.
Comparative example 2
The atorvastatin calcium tablet of this comparative example has the raw material composition as described in example 10, with the only difference that: the calcium fortifier is not included and the atorvastatin calcium is not a solvation stable crystal.
The atorvastatin calcium tablet described in the comparative example is prepared by the following method:
the atorvastatin calcium tablet is prepared by uniformly mixing the atorvastatin calcium, the filler, the disintegrant, the adhesive and the lubricant in selected parts by weight, taking ethanol as a granulating solvent, granulating by adopting spray granulation, drying the obtained granules by adopting microwave drying to obtain atorvastatin calcium drug-containing granules, and tabletting.
Experimental examples of Effect
To illustrate the technical effects of the present invention, the following comparative tests were performed on the atorvastatin calcium tablets prepared in examples 1 to 20 and comparative examples 1 to 2.
First, relative bioavailability assay:
1. test instruments and materials
Instrument LC-2030 high performance liquid chromatograph, two-channel chromatography workstation (Shimadzu, Japan). The test drugs are atorvastatin calcium tablets prepared in examples 1-20 respectively, and the specification of the atorvastatin calcium tablets is 10mg per tablet; the atorvastatin calcium tablet prepared in comparative example 1-2, the specification of which is 10 mg/tablet; the atorvastatin calcium tablets are commercially available in a specification of 10 mg/tablet, and are purchased from Xindongtong pharmaceutical Co., Ltd, Zhejiang (it should be noted that the commercially available atorvastatin calcium tablets appearing hereinafter are 10 mg/tablet, Zhejiang Xindongtong pharmaceutical Co., Ltd, and atorvastatin calcium tablets sold by different manufacturers can be used as an effect control of the commercially available group, and only the tablets are taken as examples here). Paeonol is used as reference substance, China institute for testing biological products of drugs.
2. Test method
115 SD rats (190-230 g weight) were randomly divided into 23 groups of 5 animals, and the SD rats were fasted for 12 hours and then gavaged with atorvastatin calcium of about 50mg/kg according to the serial numbers of examples 1-20, comparative examples 1-2 and commercial groups. After administration, about 0.5ml of blood was collected from each of the eyes and canthus of SD rat at 0.5h, 1h, 2h, 4h, 6h and 8h, respectively, and placed in a test tube treated with heparin sodium, after standing for 30min, centrifuged at 4000r/min for 15min, and 200. mu.l of supernatant plasma was collected and frozen at-20 ℃. After treatment with plasma samples, 20 μ l of the injection was taken to determine the concentration of atorvastatin calcium.
The chromatographic column used was a Diamonsil C18 column (250 mm. times.4.6 mm, 5 μm) with acetonitrile-ammonium acetate (pH adjusted to 4.0 with glacial acetic acid) (50: 50) as the mobile phase, flow rate 1.5mL/min, and detection wavelength 246nm at room temperature with paeonol as the internal standard. Within the range of 0.25-25 mug/mL, the linear relation between the peak area ratio of the atorvastatin calcium to the paeonol as the internal standard substance and the concentration of the atorvastatin calcium is good, r is 0.9951(n is 7), the average recovery rate is 89.4%, the daily RSD is less than or equal to 3.01% (n is 3), and the daily RSD is less than or equal to 5.73% (n is 3).
The method for measuring the concentration of the atorvastatin calcium in the plasma by adopting the HPLC method has the advantages of simple method, less reagents and low cost, and the method has higher sensitivity, accuracy and recovery rate, and uses less plasma amount in each measurement, so the method is suitable for the clinical plasma concentration measurement and pharmacokinetic research of the atorvastatin calcium.
3. Test results
The above test results show that the atorvastatin calcium of examples 1-20 has a peak reaching time of about 1.5h to 1.7h, peak concentrations of 6.80 + -0.47 mg/L to 7.44 + -0.79 mg/L, respectively, and the atorvastatin calcium of comparative examples 1-2 has peak concentrations of 4.73 + -0.84 mg/L and 4.66 + -0.43 mg/L, respectively. The relative bioavailability of the atorvastatin calcium tablet is 117.3 +/-4.1-154.1 +/-4.9%.
Statistical analysis: the Cmax and AUC are analyzed by a double unilateral t test, and the Tmax is measured by a nonparametric test, so that the results show that the Cmax, AUC and Tmax of the atorvastatin calcium in the examples and the comparative examples have significant difference (p < 0.05). The above experimental results show that the main pharmacokinetic parameters of the atorvastatin calcium Cmax, Tmax and AUC are statistically processed, and the difference is significant (p < 0.05).
Therefore, the atorvastatin calcium tablet provided by the invention has good relative bioavailability.
Second, determination of dissolution
1. The test steps are as follows:
taking atorvastatin calcium tablets prepared in examples 1-20 and comparative examples 1-2 respectively, taking 900ml of phosphate buffer solution with pH of 6.8 as a dissolution medium according to a dissolution rate and release rate measuring method, operating according to the method, taking a proper amount of solution after 45 minutes, filtering by using a 0.45 mu m filter membrane, and taking a subsequent filtrate as a test solution; precisely weighing about 11mg of atorvastatin calcium reference substance, placing the atorvastatin calcium reference substance into a 100ml measuring flask, adding a proper amount of methanol, performing ultrasonic treatment for 10min to dissolve, cooling, diluting with methanol to scale, shaking up, precisely weighing 5ml, placing the atorvastatin calcium reference substance into a 50ml measuring flask, diluting with a dissolution medium to scale, and shaking up to obtain a reference substance solution. Taking the test solution and the reference solution, respectively measuring peak areas at the wavelength of 244nm according to high performance liquid chromatography, and calculating the dissolution rate of each tablet, wherein the dissolution rate unit is% and the limit is 80% of the labeled amount.
2. And (3) test results:
the test results show that the atorvastatin calcium tablet can realize rapid dissolution. Third, drug stability test
1. Test procedure
Accelerated test of the pharmaceutical stability of the atorvastatin calcium tablets prepared in examples 1 to 20 and comparative examples 1 to 2:
the atorvastatin calcium tablets prepared in examples 1-20 and comparative examples 1-2 and the commercially available atorvastatin calcium tablets are placed at 40 +/-2 ℃ and RH 75% +/-5% in an environment, and the properties, related substances, dissolution rate and content of the atorvastatin calcium tablets in each group are measured at 0, 1,2, 3 and 6 months.
(1) Detecting appearance characters: visual inspection was carried out. The atorvastatin calcium tablets, which appeared white or off-white after removal of the coating, were each qualified and scored as being qualified in the test results, otherwise, as being unqualified.
(2) And (3) related substance detection: the related substances were measured by high performance liquid chromatography.
The chromatographic conditions were as follows: octadecylsilane chemically bonded silica is used as a filler, and a chromatographic column is 4.6mm multiplied by 25cm and 5 mu m; the column temperature was 30 ℃, the autosampler was 10 ℃, the sample volume was 20 μ l, and the detection wavelength was 244 nm. The solvent used was dimethylformamide. The mobile phases used were:
buffer solution: 5.75 g/l ammonium dihydrogen phosphate in water. Adjusting the pH to 4.3. + -. 0.05 with dilute acetic acid (10% v/v) or dilute ammonium hydroxide (10% v/v); solution A: acetonitrile and tetrahydrofuran (925: 75); solution B: solution A and buffer (42: 58); solution C: methanol, solution A and buffer (60:20: 20). The mobile phase was subjected to gradient elution.
Taking 20 tablets of atorvastatin calcium to be detected, grinding, weighing a proper amount of fine powder (about equivalent to 50mg of atorvastatin), placing the fine powder into a 50ml measuring flask, adding 30ml of diluent, carrying out ultrasonic treatment for 15min, fixing the volume by using the diluent, and shaking up. Filtering the solution with 0.45 μm filter membrane, precisely measuring the filtrate, and quantitatively diluting with diluent to obtain solution containing 2mg per 1ml as sample solution; precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, adding the diluent to dilute to a scale, and shaking up to obtain a control solution.
Precisely measuring 20 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram, wherein the control solution is 30 minutes and the test solution is 65 minutes. If an impurity peak exists in the chromatogram of the test solution, the content of the impurity is calculated.
(3) And (3) dissolution rate detection: the test was carried out according to the method described in the second test example of effect, dissolution test, and the dissolution at 45min was recorded.
(4) And (3) content detection: the content detection is determined according to high performance liquid chromatography. Wherein the atorvastatin calcium is as C66H68F2N4O10Calculated, the amount of the compound is 90.0 to 110.0 percent of the marked amount.
The chromatographic conditions were as follows: octadecylsilane chemically bonded silica is used as a filling agent; pH4.0 ammonium citrate buffer (9.62 g anhydrous citric acid dissolved in 950ml water, ammonia water to pH4.0, water diluted to 1000ml) -acetonitrile-tetrahydrofuran (53:27:20) as mobile phase; flow rate: 1.5 ml/min; the detection wavelength is 244 nm; column temperature: about 30 ℃.
Taking 5 tablets of atorvastatin calcium to be detected, placing the tablets in a 100ml measuring flask, adding a proper amount of methanol, performing ultrasonic dissolution, diluting the tablets to scale with methanol, shaking up, filtering, precisely taking 5.0ml of subsequent filtrate, placing the subsequent filtrate in a 25ml measuring flask, adding methanol to dilute the tablets to scale, shaking up to obtain a sample solution, precisely measuring 20 mu l of the sample solution, injecting the sample solution into a liquid chromatograph, and recording a chromatogram; and taking a proper amount of atorvastatin calcium reference substance, precisely weighing, dissolving and diluting by using methanol to prepare a solution containing about 0.1mg of atorvastatin in each lml, and measuring by the same method. Calculating the average marked content by peak area according to an external standard method, namely the content.
2. Test results
Test results show that the atorvastatin calcium tablet provided by the invention has good stability, and when the atorvastatin calcium is a solvation stable crystal, the stability of the bulk drug and the adaptability of a pharmaceutical preparation are obviously improved.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. The atorvastatin calcium tablet is characterized by comprising the following raw materials:
1-20 parts of atorvastatin calcium, 10-80 parts of filler, 20-40 parts of disintegrant, 5-40 parts of adhesive, 1-15 parts of lubricant and 1-20 parts of calcium enhancer;
the calcium enhancer consists of calcium citrate and calcium acetate.
2. The atorvastatin calcium tablet of claim 1, comprising the following raw material components: 10 parts of atorvastatin calcium, 30 parts of filler, 30 parts of disintegrant, 12 parts of adhesive, 3 parts of lubricant and 4 parts of calcium enhancer.
3. The atorvastatin calcium tablet of claim 1 or 2, wherein the atorvastatin calcium is a solvate stable crystal having a structure according to formula (I):
the molar ratio of the atorvastatin calcium to the solvent molecules is 1: 1.
4. The atorvastatin calcium tablet of claim 1 or 2, wherein:
the filler is one or more of pregelatinized starch, microcrystalline cellulose, lactose, sucrose, corn starch, mannitol, sorbitol, dextrin, crospovidone, dextran, sodium alginate, carboxymethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and methyl cellulose;
the disintegrating agent is one or more of pregelatinized starch, crospovidone, polyvinylpyrrolidone, sodium alginate, maltodextrin, croscarmellose sodium, cross-linked carboxymethyl starch, magnesium aluminum silicate and low-substituted hydroxypropyl cellulose;
the adhesive is one or more of pregelatinized starch, gelatinized starch, dextrin, dextran, sodium alginate, sucrose, polyethylene glycol, hydroxypropyl methylcellulose, ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxypropyl cellulose, gelatin, acacia, tragacanth, polyvinylpyrrolidone, copovidone, and magnesium aluminum silicate;
the lubricant is one or more of magnesium stearate, calcium stearate, zinc stearate, calcium behenate, sodium stearyl fumarate, talcum powder, stearic acid, palmitic acid and silicon dioxide.
5. The atorvastatin calcium tablet of claim 1 or 2, wherein:
also comprises one or more of 0.1 to 0.03 weight portion of surfactant, 10 to 40 weight portions of inorganic salt ion balancing agent and 10 to 20 weight portions of buffer substance.
6. The atorvastatin calcium tablet of claim 5, wherein:
the surfactant is one or more of sodium dodecyl sulfate, poloxamer, lecithin, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester and polyoxyethylene stearate;
the inorganic salt ion balancing agent is one or more of sodium carbonate or potassium, sodium bicarbonate or potassium, sodium phosphate or potassium, disodium hydrogen phosphate or dipotassium, sodium dihydrogen phosphate or potassium, calcium citrate, calcium carbonate, calcium bicarbonate, calcium acetate, calcium phosphate and calcium hydrogen phosphate;
the buffer substance is one or more of sodium citrate, calcium carbonate, phosphate, magnesium carbonate, potassium citrate, bicarbonate and hydrogen phosphate.
7. A process for preparing the atorvastatin calcium tablet of any one of claims 1 to 6 comprising the steps of:
(1) taking atorvastatin calcium, a filling agent, a disintegrating agent and an adhesive according to selected parts by weight, uniformly mixing 2-98% of the total consumption of the disintegrating agent with the atorvastatin calcium, the filling agent and the adhesive, and granulating by adopting a granulating solvent to obtain atorvastatin calcium drug-containing granules;
(2) and (2) taking the lubricant and the calcium enhancer according to the selected weight parts, adding the lubricant, the calcium enhancer and the rest disintegrant into the atorvastatin calcium drug-containing granules in the step (1), uniformly mixing, and tabletting to obtain the atorvastatin calcium tablet.
8. The process for preparing atorvastatin calcium tablets of claim 7, wherein the granulation in step (1) is spray granulation; the granulating solvent is one or more of water, ethanol, isopropanol and acetone;
drying after the spray granulation; the drying adopts one of disc drying, fluidized bed drying, vacuum drying and microwave drying.
9. The process for preparing atorvastatin calcium tablets according to claim 7 or 8, wherein the step (1) further comprises the step of mixing one or more of a surfactant, an inorganic salt pH ion balancing agent and a buffering substance with the atorvastatin calcium, the filler, the disintegrant and the binder in selected weight parts; and/or
The step (2) also comprises a step of mixing one or two of inorganic salt pH ion balancing agent and buffer substance according to selected weight parts with the lubricant, calcium enhancer, disintegrant and adhesive.
10. The process for preparing atorvastatin calcium tablets of claim 9, wherein the atorvastatin calcium is stable crystals of a 1,2 propylene glycol solvate of atorvastatin calcium, and the stable crystals of the 1,2 propylene glycol solvate of atorvastatin calcium are obtained by the following method:
(a) firstly dissolving atorvastatin calcium raw materials in a mixed solvent;
the dissolving concentration of the atorvastatin calcium raw material is 1-3% by weight;
the mixed solvent is formed by mixing dimethyl sulfoxide and acetone according to a volume ratio of 1-2: 100; or the mixed solvent is formed by mixing dimethyl sulfoxide and methanol according to the volume ratio of 1-2: 100;
(b) adding a 1, 2-propanediol solvent to the mixed liquor obtained in step (a);
the addition amount of the 1, 2-propanediol solvent is that 0.2-0.4 ml of the 1, 2-propanediol solvent is added into every 1g of atorvastatin calcium;
(c) adding an organic cosolvent into the mixed solution obtained in the step (b);
the addition amount of the organic cosolvent is 0.1-0.2 ml of the organic solvent added into every 1g of atorvastatin calcium;
the organic cosolvent is one of butyl acetate and isoamyl acetate or a mixture in any proportion;
(d) and (c) standing, cooling, separating and drying the mixed solution obtained in the step (c) to obtain the stable crystal of the 1, 2-propylene glycol solvate of the atorvastatin calcium.
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| CN111603452B (en) * | 2020-06-24 | 2021-03-23 | 宜春万申制药机械有限公司 | Application of beta-glucan as binder in preparation of tablets or granules |
| CN112263560A (en) * | 2020-10-10 | 2021-01-26 | 湖南迪诺制药股份有限公司 | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof |
| CN113546050B (en) * | 2021-07-07 | 2022-11-29 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method thereof |
| CN114392242A (en) * | 2021-12-22 | 2022-04-26 | 海南海灵化学制药有限公司 | Atorvastatin calcium tablet and preparation process thereof |
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| WO2009140341A2 (en) * | 2008-05-13 | 2009-11-19 | Dr. Reddy's Laboratories Ltd. | Atorvastatin compositions |
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| US20080038332A1 (en) * | 2006-08-10 | 2008-02-14 | Cai Gu Huang | Stable pharmaceutical formulation comprising atorvastatin calcium |
| CN102139115B (en) * | 2011-03-30 | 2012-12-05 | 天津红日药业股份有限公司 | Preparation method for atorvastatin cyclodextrin inclusion compound and oral solid preparation thereof |
| CN102920675B (en) * | 2012-11-29 | 2016-03-23 | 河南润弘制药股份有限公司 | A kind of atorvastatin and preparation method thereof |
| CN104069078B (en) * | 2014-05-22 | 2019-06-11 | 西藏九瑞健康股份有限公司 | Atorvastatin calcium medicine compound and preparation method thereof |
| CN104230779A (en) * | 2014-08-26 | 2014-12-24 | 诺唯德(天津)制药有限公司 | Atorvastatin calcium solvate stable crystal and preparation method thereof |
| CN105168162A (en) * | 2015-09-06 | 2015-12-23 | 合肥华方医药科技有限公司 | Atorvastatin calcium rapidly disintegrating oral tablet and preparation method thereof |
| CN106389370A (en) * | 2016-10-20 | 2017-02-15 | 北京嘉林药业股份有限公司 | Stable atorvastatin calcium tablet |
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