CN117281785A - Levamlodipine besylate tablet and preparation process thereof - Google Patents
Levamlodipine besylate tablet and preparation process thereof Download PDFInfo
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- CN117281785A CN117281785A CN202210737083.7A CN202210737083A CN117281785A CN 117281785 A CN117281785 A CN 117281785A CN 202210737083 A CN202210737083 A CN 202210737083A CN 117281785 A CN117281785 A CN 117281785A
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- CN
- China
- Prior art keywords
- levamlodipine besylate
- tablet
- levamlodipine
- simethicone
- titanium dioxide
- Prior art date
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- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 title claims abstract description 105
- 229950008554 levamlodipine Drugs 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000002156 mixing Methods 0.000 claims abstract description 33
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229940083037 simethicone Drugs 0.000 claims abstract description 29
- 239000004408 titanium dioxide Substances 0.000 claims abstract description 24
- 239000000463 material Substances 0.000 claims abstract description 21
- 239000011248 coating agent Substances 0.000 claims abstract description 16
- 238000000576 coating method Methods 0.000 claims abstract description 16
- 238000005507 spraying Methods 0.000 claims description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 239000000945 filler Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 239000000314 lubricant Substances 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 8
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 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 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- 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 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 229920002545 silicone oil Polymers 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims 3
- 235000021355 Stearic acid Nutrition 0.000 claims 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims 1
- 229940032147 starch Drugs 0.000 claims 1
- 239000008117 stearic acid Substances 0.000 claims 1
- 239000012808 vapor phase Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 25
- 238000004090 dissolution Methods 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 4
- 239000006185 dispersion Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 229960005196 titanium dioxide Drugs 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- 238000005259 measurement Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000007865 diluting Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 229960004005 amlodipine besylate Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229960000528 amlodipine Drugs 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- NWDQBIRZEWCIMO-BVMIBZPSSA-N C(C)C1([C@H](NC(C(C1C1=C(C=CC=C1)Cl)(C(=O)O)C)C)COCCN)C(=O)O Chemical group C(C)C1([C@H](NC(C(C1C1=C(C=CC=C1)Cl)(C(=O)O)C)C)COCCN)C(=O)O NWDQBIRZEWCIMO-BVMIBZPSSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010017472 Fumbling Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- OKLAEQBUDFSNDL-UHFFFAOYSA-N calcium;1,4-dihydropyridine Chemical compound [Ca].C1C=CNC=C1 OKLAEQBUDFSNDL-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention provides a levamlodipine besylate tablet, which comprises levamlodipine besylate, simethicone, gas-phase titanium dioxide and other pharmaceutically acceptable auxiliary materials; the prepared levamlodipine besylate tablet has the advantages of uniform medicine dispersion, high dissolution speed, less impurities and obviously improved medicine stability; in addition, the raw material medicine used in the invention does not need micronization, repeated mixing steps and coating, and the preparation process is simple and convenient, thus being very suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a levamlodipine besylate tablet and a preparation process thereof.
Background
Amlodipine besylate has two isomers of levorotatory and dextrorotatory, and the antagonistic activity of calcium ions of the levorotatory body is 1000 times that of the dextrorotatory body and is twice that of the racemization body. Levamlodipine besylate is a levorotatory body of amlodipine besylate, is a 1, 4-dihydropyridine calcium ion antagonist or a slow channel blocker, and is a common medicament for treating hypertension at present. Levamlodipine besylate is white or white-like powder, is easily dissolved in methanol and ethanol, and is slightly dissolved in water; its English name is Levamlodipine Besylate the chemical name is (S) - (-) 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylic acid ester benzenesulfonate, and the molecular formula is C 20 H 25 N 2 O 5 Cl·C 6 H 6 O3S has a molecular weight of 567.1 and a structural formula as follows:
the levamlodipine besylate tablet mainly has two effects in clinical application: one is to treat hypertension in patients with mild and moderate hypertension (alone or in combination with other drugs), and the other is to treat angina, especially spontaneous angina (alone or in combination with other drugs). Levamlodipine besylate has many unique properties and unlike other calcium antagonists, it is shown to be long acting, slowly absorbed, gradually producing vasodilating effects. The effects of lowering blood pressure and resisting angina pectoris are long, the medicine is taken once a day, and the effect time can be maintained for about 24 hours. The side effects are slight, and patients can generally tolerate the side effects, so that the side effects are more and more widely applied to clinic.
Levamlodipine besylate is unstable to moisture and light. The common tablet has poor stability of the levamlodipine besylate tablet due to the reasons of prescription, preparation process and the like, and brings potential safety hazard to clinical application. Therefore, how to improve the stability of the compound through a preparation technology so as to meet the dissolution rate and stability requirements of the preparation, thereby ensuring that the product effectively plays a role in treatment, finally achieving superior quality, and having very important significance and value.
Patent CN101559043a discloses a levamlodipine besylate tablet and a preparation method thereof, the tablet improves the stability and dissolution of the levamlodipine besylate tablet, but the stability of the drug is still not ideal.
Patent CN105412029a discloses an antihypertensive levamlodipine besylate tablet, which adopts a new crystal form structure of levamlodipine besylate different from the prior art, improves the dissolution rate of the drug, but does not improve the stability and dispersion effect of the drug.
Patent CN107375222a discloses a levamlodipine besylate tablet and a preparation method thereof, which improves the dissolution rate and stability of the drug but has poor content uniformity of the drug by optimizing the adding proportion of auxiliary materials and the type of disintegrating agent.
Patent CN103127018B discloses a levamlodipine besylate tablet, which is prepared by firstly preparing lactose pellets of levamlodipine besylate, then mixing with pharmaceutically acceptable auxiliary materials and tabletting. The method improves the stability and the dissolution rate of the levamlodipine besylate tablet, but the method needs to dissolve the raw materials in a solvent and spray the raw materials to the pill core, the loss of the raw materials is large in the process of drug loading, the dosage of the tablet auxiliary materials prepared by the method is large, the cost is high, and the drug compliance of patients is influenced by the large tablet.
Patent CN101766582B discloses a preparation method of a levamlodipine besylate coated tablet, which mainly improves the stability of the levamlodipine besylate tablet by coating, but the coating weight is larger, and the earlier-stage dissolution of the levamlodipine besylate tablet is affected.
Patent CN105106161B discloses a levamlodipine besylate tablet and a preparation process thereof, which contains levamlodipine besylate solid dispersion and other pharmaceutical grade auxiliary materials. The levamlodipine besylate tablet has high accumulated dissolution, but the preparation process is complex, and the grinding method is used for preparing the levamlodipine besylate solid dispersion, so that the dispersing effect on the medicine and the increase of the specific surface area of the medicine are limited.
In summary, the prior art cannot comprehensively overcome the defects of levamlodipine besylate. Aiming at the defects of the prior art, the dosage of the levamlodipine besylate tablet is smaller, more fumbling and experiments are necessary to be carried out on the dosage form of the levamlodipine besylate, a better formula and a preparation method are found, and the medicine effect is ensured, meanwhile, the content uniformity is controlled at a higher level, related substances are controlled at an extremely low level, and the dissolution is more complete.
Disclosure of Invention
The invention provides a levamlodipine besylate tablet and a preparation method thereof, which have the advantages of simple preparation process, remarkably improved drug stability, improved content uniformity and complete drug dissolution.
Aiming at the problems, the invention provides a levamlodipine besylate tablet, which has the following specific technical scheme:
a levamlodipine besylate tablet comprises levamlodipine besylate, simethicone, gas-phase titanium dioxide and other pharmaceutically acceptable auxiliary materials.
The weight ratio of the levamlodipine besylate to the simethicone is 1:0.1-1, preferably 1:0.3-0.6; in some embodiments, the mass ratio of the levamlodipine besylate to the simethicone is 1:0.5.
the weight ratio of the levamlodipine besylate to the gas-phase titanium dioxide is 1:0.02-0.1, preferably 1:0.04 to 0.08; in some embodiments the weight ratio of levamlodipine besylate to fumed titanium dioxide is 1:0.05.
The viscosity (cSt) of the simethicone is selected from one or more of 5, 20, 50, 100, 200, 350; preferably, the viscosity (cSt) is 20, 50, 100, 200.
The other pharmaceutically acceptable excipients include fillers, disintegrants, and lubricants.
The filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch and dextrin.
The disintegrating agent is one or more selected from sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, crosslinked povidone and low-substituted hydroxypropyl cellulose.
The lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, polyethylene glycol and silicon dioxide.
The weight ratio of the levamlodipine besylate to the filler is 1:20 to 100, preferably 1: 40-60; in some embodiments 1:50.
The weight ratio of the levamlodipine besylate to the disintegrating agent is 1:0.5 to 4, preferably 1:1 to 3; in some embodiments 1:2.
The weight ratio of the levamlodipine besylate to the lubricant is 1:0.1 to 1; in some embodiments 1:0.5.
The types of the other pharmaceutically acceptable auxiliary materials, namely the filler, the disintegrating agent and the lubricant are not particularly limited, and other fillers, disintegrating agents and lubricants known in the art can achieve similar effects.
The invention also provides a preparation method of the levamlodipine besylate tablet, which comprises the steps of uniformly dispersing the gas-phase titanium dioxide in the simethicone, spraying the gas-phase titanium dioxide on the levamlodipine besylate, uniformly mixing the gas-phase titanium dioxide with other pharmaceutically acceptable auxiliary materials, and tabletting.
The preparation method specifically comprises the following steps: adding levamlodipine besylate into a centrifugal granulating coating machine, uniformly dispersing gas-phase titanium dioxide in dimethyl silicone oil, and slowly spraying into the levamlodipine besylate to uniformly coat the dimethyl silicone oil and the gas-phase titanium dioxide on the outer layer of the levamlodipine besylate powder; after the spraying, adding filler and disintegrating agent, mixing, adding lubricant, mixing, and tabletting.
The rotational speed of the centrifugal granulating and coating machine is 50-150r/min, preferably 100rpm/min.
The spraying speed of the simethicone suspension is 0.2g/min-1g/min, preferably 0.5g/min.
Compared with the prior art, the invention has the following beneficial effects:
the levamlodipine besylate tablet prepared by the invention has the advantages of uniform medicine dispersion, rapid dissolution, less impurities and obviously improved medicine stability; and auxiliary materials such as lactose and mannitol which are originally incompatible with the levamlodipine besylate can also be used for preparing tablets of the levamlodipine besylate and show quite good stability; in addition, the raw material medicine used in the invention does not need micronization, repeated mixing steps and coating, and the preparation process is simple and convenient, thus being very suitable for industrial production.
Detailed Description
The advantages of the invention will now be further described by the following examples, which are given for illustrative purposes only and do not limit the scope of the invention, while variations and modifications apparent to those skilled in the art in light of the present disclosure are included within the scope of the invention.
Example 1
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve for standby; uniformly dispersing gas-phase titanium dioxide in simethicone to obtain a suspension for later use; adding levamlodipine besylate into a centrifugal granulating and coating machine, setting the rotating speed to 100r/min, and starting to rotate; slowly spraying the simethicone suspension into the levamlodipine besylate, wherein the spraying speed is 0.5g/min, and keeping the machine to rotate for 10min after the spraying is finished. Taking out the materials in the centrifugal granulator, adding microcrystalline cellulose and croscarmellose sodium, uniformly mixing, adding magnesium stearate, uniformly mixing, and tabletting to obtain the tablet with the specification of 2.5 mg/tablet.
Example 2
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve for standby; uniformly dispersing gas-phase titanium dioxide in simethicone to obtain a suspension for later use; adding levamlodipine besylate into a centrifugal granulating and coating machine, setting the rotating speed to be 50r/min, and starting to rotate; slowly spraying the simethicone suspension into the levamlodipine besylate at a spraying speed of 0.2g/min, and keeping the machine to rotate for 10min after the spraying is finished. Taking out the materials in the centrifugal granulator, adding mannitol and crospovidone, uniformly mixing, adding polyethylene glycol, uniformly mixing, and tabletting to obtain the tablet with the specification of 2.5 mg/tablet.
Example 3
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve for standby; uniformly dispersing gas-phase titanium dioxide in simethicone to obtain a suspension for later use; adding levamlodipine besylate into a centrifugal granulating and coating machine, setting the rotating speed to 150r/min, and starting to rotate; slowly spraying the simethicone suspension into the levamlodipine besylate at a spraying speed of 1g/min, and keeping the machine to rotate for 10min after the spraying is finished. Taking out the materials in the centrifugal granulator, adding starch and sodium carboxymethyl starch, uniformly mixing, adding sodium stearyl fumarate, uniformly mixing, and tabletting to obtain the tablet with the specification of 2.5 mg/tablet.
Example 4
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve for standby; uniformly dispersing gas-phase titanium dioxide in simethicone to obtain a suspension for later use; adding levamlodipine besylate into a centrifugal granulating and coating machine, setting the rotating speed to 100r/min, and starting to rotate; slowly spraying the simethicone suspension into the levamlodipine besylate at a spraying speed of 0.6g/min, and keeping the machine to rotate for 10min after the spraying is finished. Taking out the materials in the centrifugal granulator, adding lactose and low-substituted hydroxypropyl cellulose, uniformly mixing, adding sodium stearyl fumarate, uniformly mixing, and tabletting to obtain the tablet with the specification of 2.5 mg/tablet.
Example 5
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve for standby; uniformly dispersing gas-phase titanium dioxide in simethicone to obtain a suspension for later use; adding levamlodipine besylate into a centrifugal granulating and coating machine, setting the rotating speed to 100r/min, and starting to rotate; slowly spraying the simethicone suspension into the levamlodipine besylate, wherein the spraying speed is 0.5g/min, and keeping the machine to rotate for 10min after the spraying is finished. Taking out the materials in the centrifugal granulator, adding microcrystalline cellulose and croscarmellose sodium, uniformly mixing, adding silicon dioxide, uniformly mixing, and tabletting to obtain the tablet with the specification of 5.0 mg/tablet.
Example 6
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve for standby; uniformly dispersing gas-phase titanium dioxide in simethicone to obtain a suspension for later use; adding levamlodipine besylate into a centrifugal granulating and coating machine, setting the rotating speed to 100r/min, and starting to rotate; slowly spraying the simethicone suspension into the levamlodipine besylate, wherein the spraying speed is 1g/min, and keeping the machine to rotate for 10min after the spraying is finished. Taking out the materials in the centrifugal granulator, adding microcrystalline cellulose and croscarmellose sodium, uniformly mixing, adding magnesium stearate, uniformly mixing, and tabletting to obtain the tablet with the specification of 2.5 mg/tablet.
Example 7
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve for standby; uniformly dispersing gas-phase titanium dioxide in simethicone to obtain a suspension for later use; adding levamlodipine besylate into a centrifugal granulating and coating machine, setting the rotating speed to 100r/min, and starting to rotate; slowly spraying the simethicone suspension into the levamlodipine besylate, wherein the spraying speed is 0.2g/min, and keeping the machine to rotate for 10min after the spraying is finished. Taking out the materials in the centrifugal granulator, adding microcrystalline cellulose and croscarmellose sodium, uniformly mixing, adding magnesium stearate, uniformly mixing, and tabletting to obtain the tablet with the specification of 2.5 mg/tablet.
Comparative example 1
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve, added into a centrifugal granulating and coating machine, and is set at the rotating speed of 100r/min and started to rotate; slowly spraying the simethicone into the levamlodipine besylate, wherein the spraying speed is 0.5g/min, and keeping the machine to rotate for 10min after the spraying is finished. Taking out the materials in the centrifugal granulator, adding microcrystalline cellulose and croscarmellose sodium, uniformly mixing, adding magnesium stearate, uniformly mixing, and tabletting to obtain the tablet with the specification of 2.5 mg/tablet.
Comparative example 2
Prescription:
preparation process
The levamlodipine besylate is sieved by a 80-mesh sieve for standby; and uniformly mixing levamlodipine besylate, lactose, sodium carboxymethyl starch, sodium stearate fumarate and gas-phase titanium dioxide, and tabletting to obtain the tablet with the specification of 2.5 mg/tablet.
Comparative example 3
Prescription:
the preparation process comprises the following steps:
the levamlodipine besylate is sieved by a 80-mesh sieve for standby; the levamlodipine besylate, the simethicone and the gas-phase titanium dioxide are uniformly mixed, then microcrystalline cellulose and croscarmellose sodium are added to be uniformly mixed, and then magnesium stearate is added to be uniformly mixed, and then the tablet is pressed, wherein the tablet specification is 2.5 mg/tablet.
Comparative example 4
Prescription:
the preparation process comprises the following steps:
1) Granulating: weighing raw materials including levamlodipine besylate, simethicone, gas-phase titanium dioxide, microcrystalline cellulose, croscarmellose sodium and magnesium stearate which are added with a part of prescription amount, uniformly mixing, granulating by a dry method, and finishing;
2) Total mixing: mixing the prepared particles with the external auxiliary material crosslinked sodium carboxymethyl cellulose and magnesium stearate;
3) Tabletting, tablet specification 2.5 mg/tablet.
Comparative example 5
Prescription:
the preparation method comprises the following steps:
weighing amlodipine besylate, microcrystalline cellulose 112, pregelatinized starch and 2/3 of the amount of the crosslinked povidone according to the prescription amount, and uniformly mixing. And adding the rest of the crosslinked povidone, silicon dioxide and magnesium stearate, uniformly mixing, tabletting and coating the film.
Comparative example 6
Prescription:
the preparation method comprises the following steps: weighing levamlodipine besylate with prescription amount and micro-powder silica gel with 2/3 prescription amount, uniformly mixing by an equivalent progressive method, mixing with the rest auxiliary materials, mixing in a high-efficiency mixer for 30min, sieving with a 100-mesh sieve, directly tabletting, and preparing into tablets with the specification of 2.5 mg/tablet.
Verification embodiment
1. Dissolution measurement
Taking a medicine to be tested, taking 500ml of hydrochloric acid solution (0.9-1000) as a dissolution medium according to a dissolution rate and release rate measurement method (second method of the fourth rule 0931 of the 2015 edition of Chinese pharmacopoeia), operating according to the law, taking a proper amount of solution after 30 minutes, filtering (discarding at least 3ml of primary filtrate), and taking the subsequent filtrate as a solution of a sample to be tested; and taking a proper amount of levamlodipine besylate reference substance, precisely weighing, adding a proper amount of methanol to dissolve, and quantitatively diluting with a dissolution medium to prepare a solution containing about 5 mug (2.5 mg specification) or 10 mug (5 mg specification) of levamlodipine per lml as the reference substance solution. The amount of each of the test solution and the control solution was measured by a method under the content measuring item by precisely measuring 50. Mu.l each, and the elution amount of each tablet was calculated. The limit is 80% of the indicated amount. The results are shown in Table 1.
Table 1 sample dissolution test results/%
As can be seen from the above dissolution measurement results, the levamlodipine besylate tablets obtained in examples 1-5 and example 7 of the present invention can be rapidly dissolved in 5min, and can be rapidly dissolved after being accelerated for 6 months at 40 ℃ and 75% RH; example 6 shows that the dissolution is slightly slower due to the too high addition amount of the simethicone; in addition, comparative examples 1, 3, 4 dissolved out slower.
2. Related substance measurement
Taking a proper amount of fine powder (approximately equivalent to 50mg of levamlodipine) of a medicine to be detected, precisely weighing, placing the fine powder into a 50ml measuring flask, adding a proper amount of mobile phase, carrying out ultrasound for about 30 minutes to dissolve the levamlodipine besylate, cooling, diluting to a scale with the mobile phase, shaking uniformly, filtering, and taking the subsequent filtrate as a solution of a sample; precisely measuring the lml of the sample solution, placing the lml in a 100ml measuring flask, diluting to a scale with a mobile phase, and shaking uniformly to obtain a control solution; 5mg of levamlodipine besylate is taken, 5ml of concentrated hydrogen peroxide solution is added, and the mixture is heated for 10 to 30 minutes at 70 ℃ to be used as a system applicability solution. Octadecylsilane chemically bonded silica is used as filler (Hypersil GOLD column, 4.6 mm. Times.250 mm 5 μm or chromatographic column with equivalent potency); methanol-acetonitrile-0.7% triethylamine solution (7.0 ml of triethylamine is taken, water is added for dilution to 1000ml, and phosphoric acid is used for adjusting the pH value to 3.0+/-0.1) (35:15:50) is taken as a mobile phase; the detection wavelength was 237nm and the flow rate was 1.0ml per minute. And 20 mu l of the system applicability solution is injected into a liquid chromatograph, a chromatogram is recorded, the retention time of the levamlodipine peak is about 18 minutes, and the separation degree of the levamlodipine peak and the amlodipine impurity I peak (relative retention time is about 0.5) is more than 5.0. Precisely measuring 20 μl of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram to 4 times of the retention time of the main component peak. The test results are shown in tables 2 and 3.
TABLE 2 determination results of substances (influence factor experiment)
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As is clear from the measurement results of the above-mentioned related substances, the related substances of levamlodipine besylate tablets prepared in examples 1 to 6 of the present invention are less affected by high temperature, high humidity and light, and the related changes are larger in example 7. Comparative examples 1 to 6 show a large change in the substances involved under the influence of high temperature, high humidity and light.
TABLE 3 determination of the substances involved (40 ℃,75% RH)
As can be seen from the measurement results of the related substances, the levamlodipine besylate tablets prepared in examples 1 to 7 of the present invention have smaller content of the related substances and little change after 6 months; comparative examples 1 to 6 show a large change in the content of the relevant substances after 6 months.
3. Content uniformity
The measurement was performed by high performance liquid chromatography (China pharmacopoeia 2015 edition four general rules 0512).
Chromatographic conditions and system suitability test: octadecylsilane chemically bonded silica is used as a filler; methanol-acetonitrile-0.7% triethylamine solution (7.0 ml of triethylamine is taken, water is added for dilution to 1000ml, and phosphoric acid is used for adjusting the pH value to 3.0+/-0.1) (35:15:50) is taken as a mobile phase; the detection wavelength was 237nm and the flow rate was 1.5ml per minute. Taking 5mg of levamlodipine besylate, placing the levamlodipine besylate into a 50ml measuring flask, adding 5ml of concentrated hydrogen peroxide solution, heating the mixture for 10-30 minutes at 70 ℃, cooling the mixture, diluting the mixture to a scale by using a mobile phase, taking 20 μl of the mixture as a system applicability solution, injecting the mixture into a liquid chromatograph, recording a chromatogram, wherein the separation degree of a levamlodipine peak and an amlodipine impurity I peak (the relative retention time is about 0.5) is greater than 2.0, and the theoretical plate number is not less than 3000 calculated according to the levamlodipine peak.
Assay: taking 10 tablets prepared in examples 1-7 and comparative examples 1-6 respectively, placing into 100ml (2.5 mg standard) or 200ml (5 mg standard) measuring bottles respectively, adding a proper amount of mobile phase, performing ultrasound for about 30 minutes to dissolve levamlodipine besylate, cooling, diluting to a scale with the mobile phase, shaking uniformly, filtering, taking the subsequent filtrate as a sample solution, precisely measuring 20 mu l, injecting into a liquid chromatograph, and recording a chromatogram. And (3) taking a proper amount of a levamlodipine besylate reference substance, precisely weighing, adding a mobile phase for dissolution, quantitatively diluting to prepare a solution containing about 25 mug of levamlodipine in each lml, and measuring by the same method. The content of each tablet is calculated according to the external standard method and the content uniformity is calculated according to the content of each tablet, which accords with the regulations (the fourth general rule 0941 of the 2015 annual edition of Chinese pharmacopoeia). The results are shown in Table 4.
TABLE 4 content uniformity measurement results
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Claims (10)
1. The levamlodipine besylate tablet is characterized by comprising levamlodipine besylate, simethicone, gas-phase titanium dioxide and other pharmaceutically acceptable auxiliary materials.
2. The tablet according to claim 1, wherein the weight ratio of the levamlodipine besylate to the simethicone is 1:0.1-1.
3. The tablet according to claim 1, wherein the weight ratio of the levamlodipine besylate to the fumed titanium dioxide is 1:0.02-0.1.
4. The tablet of claim 1, wherein the viscosity of the simethicone is selected from one or more of 5cSt, 20cSt, 50cSt, 100cSt, 200cSt, 350 cSt.
5. The tablet of claim 1, wherein the other pharmaceutically acceptable excipients comprise a filler, a disintegrant, and a lubricant.
6. The tablet of claim 5, wherein the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin.
7. The tablet of claim 5, wherein the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose.
8. The tablet of claim 5, wherein the lubricant is selected from one or more of stearic acid, sodium stearate fumarate, polyethylene glycol, and silica.
9. A method for preparing the levamlodipine besylate tablet according to any one of claims 1 to 8, which is characterized in that the vapor phase titanium dioxide is uniformly dispersed in simethicone, sprayed on the levamlodipine besylate, uniformly mixed with other pharmaceutically acceptable auxiliary materials and tabletted.
10. The preparation method according to claim 9, characterized in that it comprises in particular the following steps: adding levamlodipine besylate into a centrifugal granulating coating machine, uniformly dispersing gas-phase titanium dioxide into dimethyl silicone oil, and slowly spraying into the levamlodipine besylate to uniformly coat the dimethyl silicone oil and the gas-phase titanium dioxide on the outer layer of the levamlodipine besylate powder; after the spraying, adding filler and disintegrating agent, mixing, adding lubricant, mixing, and tabletting.
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