CN103193700A - Benzenesulfonic acid levamlodipine crystal and pharmaceutical composition containing same - Google Patents
Benzenesulfonic acid levamlodipine crystal and pharmaceutical composition containing same Download PDFInfo
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- CN103193700A CN103193700A CN2013101062119A CN201310106211A CN103193700A CN 103193700 A CN103193700 A CN 103193700A CN 2013101062119 A CN2013101062119 A CN 2013101062119A CN 201310106211 A CN201310106211 A CN 201310106211A CN 103193700 A CN103193700 A CN 103193700A
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- levamlodipine besylate
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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 148
- 229950008554 levamlodipine Drugs 0.000 title claims abstract description 148
- 239000013078 crystal Substances 0.000 title claims abstract description 105
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 39
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 title abstract description 7
- 229940092714 benzenesulfonic acid Drugs 0.000 title abstract 6
- 238000002360 preparation method Methods 0.000 claims abstract description 60
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 46
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 23
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 22
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 22
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 22
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 22
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 22
- 239000011734 sodium Substances 0.000 claims abstract description 22
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 22
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 6
- 229910017488 Cu K Inorganic materials 0.000 claims abstract description 5
- 229910017541 Cu-K Inorganic materials 0.000 claims abstract description 5
- 230000005260 alpha ray Effects 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 37
- 239000000843 powder Substances 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 24
- 238000002156 mixing Methods 0.000 claims description 12
- 238000005303 weighing Methods 0.000 claims description 10
- 238000005070 sampling Methods 0.000 claims description 5
- 239000000890 drug combination Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 abstract description 3
- 229920002472 Starch Polymers 0.000 abstract 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 abstract 1
- 239000008107 starch Substances 0.000 abstract 1
- 235000019698 starch Nutrition 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- 239000003814 drug Substances 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 238000012360 testing method Methods 0.000 description 22
- 238000009472 formulation Methods 0.000 description 19
- 229940079593 drug Drugs 0.000 description 16
- 230000000694 effects Effects 0.000 description 14
- 239000012046 mixed solvent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229960004005 amlodipine besylate Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 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
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 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 description 1
- VCOYRKXQRUGBKS-UHFFFAOYSA-N N.[Cl] Chemical compound N.[Cl] VCOYRKXQRUGBKS-UHFFFAOYSA-N 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003257 anti-anginal 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
- 239000002981 blocking agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- OKLAEQBUDFSNDL-UHFFFAOYSA-N calcium;1,4-dihydropyridine Chemical group [Ca].C1C=CNC=C1 OKLAEQBUDFSNDL-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
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- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000005955 light diet Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960000519 losartan potassium Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 238000009702 powder compression Methods 0.000 description 1
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- 235000019633 pungent taste Nutrition 0.000 description 1
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- 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
- 238000010998 test method Methods 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to a benzenesulfonic acid levamlodipine crystal, a preparation method thereof and a brand new pharmaceutical composition containing the crystal. According to an X-ray powder diffraction pattern obtained by measuring the benzenesulfonic acid levamlodipine crystal by utilizing a Cu-K alpha ray, characteristic peaks are displayed when 2theta is equal to 8.0 degrees, 12.1 degrees, 15.4 degrees, 17.0 degrees, 19.8 degrees, 21.6 degrees, 23.0 degrees, 24.3 degrees, 25.7 degrees, 27.4 degrees, 30.7 degrees and 33.5 degrees. The pharmaceutical composition contains the benzenesulfonic acid levamlodipine crystal and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials are microcrystalline cellulose, carboxymethyl starch sodium and magnesium stearate. According to the benzenesulfonic acid levamlodipine crystal, the dissolubility of benzenesulfonic acid levamlodipine is improved, and a tablet prepared from the crystal has an improved biological availability.
Description
The application is dividing an application of Chinese patent application 201110238802.2.
Original application day: 2011-8-19
Original applying number: 201110238802.2
Original application invention and created name: a kind of Levamlodipine besylate crystal, its preparation method and contain the breakthrough drug compositions of this crystal
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of Levamlodipine besylate crystal, its preparation method and contain the breakthrough drug compositions of this crystal.
Background technology
Levamlodipine besylate is white or off-white powder, and its chemical name is (s)-(-)-3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-the 4-(2-chloro-phenyl-)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate, molecular formula C
20H
25N
2O
5ClC
6H
6O
3S, molecular weight 567.1, structural formula is:
Levamlodipine besylate is 1,4-dihydropyridine calcium ion antagonist or slow channel blocking agent.Amlodipine besylate has left-handed and two kinds of isomer of dextrorotation, and levo form calcium ion antagonistic activity is 1000 times of dextrorotatory form, is 2 times of raceme.Levamlodipine besylate is to treat the hypertension common drug at present.The clinical application Levamlodipine beaylate tablets mainly has two kinds of effects: a kind of effect is the treatment essential hypertension, is used for hyperpietic's (using separately or with the other drug merging) of slight and moderate.Another kind of effect is treatment stenocardia, especially spontaneous angina pectoris (using separately or with the other drug merging).Levamlodipine besylate has many peculiar properties and is different with other calcium antagonist, shows as long-acting, slow absorption, produces hemangiectasis effect gradually.Hypotensive and antianginal long action time, take once and get final product every day, can keep action time nearly 24 hours.Side effect is smaller, and patient generally can both tolerate, thereby is applied to clinical more and more widely.
CN101559043A discloses a kind of Levamlodipine beaylate tablets and preparation method thereof.Levamlodipine beaylate tablets of the present invention, in 1000, it contains Levamlodipine besylate 1-10g, particularly preferably 2.5g; Lactose 50-100g, preferably, 67-87g, particularly preferably 80g; Low-substituted hydroxypropyl cellulose 5-55g, preferably 20-40g, particularly preferably 30g; Cross-linked polyvinylpyrrolidone 2-20g, preferably 5g; Magnesium Stearate 0.5-5g, preferably 1.5g.The dissolution rate of Levamlodipine besylate of the present invention more than 95%, product stability are good.
CN101721384A discloses with 1-20 weight part Levamlodipine besylate, 20-150 weight part weighting agent, 10-100 weight part disintegrating agent, 1-10 weight part lubricant, mixing, pulverize, cross the 60-100 mesh sieve, mixing, put novel tabletting machine with in the powder feed device, the Levamlodipine beaylate tablets that the method for dry powder direct tabletting method compressing tablet is made.Compare with existing tablet manufacturing technology, Levamlodipine beaylate tablets compressibility, friability, the tablet weight variation of the present invention's preparation are good, and content is even, steady quality.
CN102028662A relates to the quality controlling means of a kind of Levamlodipine beaylate tablets and preparation technology and related substance.Levamlodipine beaylate tablets of the present invention, per 1000 contain following component: Levamlodipine besylate 2.5g(is in levamlodipine); Microcrystalline Cellulose 25-45g is as weighting agent; Carboxymethylstach sodium 20-40 is as disintegrating agent; Magnesium Stearate 1-2g is as lubricant; The character that the present invention is directed to Levamlodipine besylate is made multinomial improvement, increases solubleness and the dissolution rate of medicine, improves stability of drug, reduce the pungency of medicine, significantly reduced the limit of related substance, result for the treatment of is better clinically, makes patient's step-down more steady.
CN101766582A provides tablet of a kind of Levamlodipine besylate and preparation method thereof.This tablet is by being the label of activeconstituents with the Levamlodipine besylate and being wrapped in outer field film-coat and forming, wherein the thinner in the label contains one or both in diatomite and the micropowder silica gel, also contain pharmaceutically acceptable other auxiliary materials, the outer membrane clothing accounts for the heavy 8%-12% of sheet, can play the effect of protection against the tide, lucifuge, medicine stability is greatly improved, and related substance obviously reduces; In addition, because this tablet specification is less, tablet provided by the invention has guaranteed uniformity of dosage units, has improved dissolution rate, the method simple controllable, and the water absorbability of medicine is obviously reduced.
But because Levamlodipine besylate is insoluble in water, and enough solubleness is the prerequisite that medicine obtains the good biological availability, yet Levamlodipine besylate is in water, particularly there is not enough solubleness under the state near physiological pH7.4, its solubleness in water only is 0.053mg/mL, it is absorbed in human body slowly, the time that reaches peak concentration (Cmax) after the medication is longer, the Plasma Concentration aggregate level is low, particularly the Plasma Concentration at initial stage is very low after the administration, this medicine onset is very slow, and effect slowly.
For overcoming above-mentioned defective, the inventor has made a kind of Levamlodipine besylate crystal pleasantly surprisedly after P-TOLUENE SULFO ACID 99's levamlodipine has carried out a large amount of research, this crystal can improve the solubleness of Levamlodipine besylate to a certain extent, and further finding that the preparation that adopts this crystal to make has the bioavailability of improvement in the research, thereby finished the present invention.
Summary of the invention
First purpose of the present invention is to provide a kind of Levamlodipine besylate crystal, and this crystal can improve the solubleness of Levamlodipine besylate to a certain extent, and adopts the tablet of this crystal preparation to have the bioavailability of improvement.
Second purpose of the present invention is to provide the preparation method of described Levamlodipine besylate crystal, introduced ultrasonic wave in this method, prepared crystal crystal formation is good, particle diameter is less, specific surface area increases, and has improved the solubleness of Levamlodipine besylate to a certain extent, has accelerated the absorption in human body, improve bioavailability, thereby improved curative effect.
The 3rd purpose of the present invention is to provide a kind of and contains above-mentioned Levamlodipine besylate crystal or adopt breakthrough drug compositions of the Levamlodipine besylate crystal that above-mentioned preparation method makes and preparation method thereof, said composition contains the Levamlodipine besylate crystal, and its curative effect is more remarkable than prior art formulations.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
A kind of amlodipine besylate crystal, wherein: characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that described Levamlodipine besylate crystal use Cu-K alpha-ray measures.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of Levamlodipine besylate crystal, wherein, described preparation method comprises the steps:
1) Levamlodipine besylate is dissolved in methylene dichloride and the ethanol mixed solvent, obtains the methylene dichloride/ethanolic soln of Levamlodipine besylate;
2) under ultrasonic field, in the methylene dichloride/ethanolic soln of the Levamlodipine besylate of step 1) gained, drip normal heptane, separate out to crystallization;
3) close ultrasonic field, leave standstill, filter, filter cake is used methylene dichloride, washing with alcohol respectively, and drying obtains described Levamlodipine besylate crystal.
According to aforesaid preparation method, wherein: the consumption of the methylene dichloride described in the step 1) and ethanol mixed solvent is 10～20 times of Levamlodipine besylate weight; The volume ratio of methylene dichloride and ethanol is 5:1～8:1 in described methylene dichloride and the ethanol mixed solvent.
According to aforesaid preparation method, wherein: step 2) described in the power of ultrasonic field be 0.4～0.6KW.
According to aforesaid preparation method, wherein: leaving standstill under 20～25 ℃, leaving standstill 4-8 hour described in the step 3).
For realizing the 3rd purpose of the present invention, the present invention adopts following technical scheme:
The Levamlodipine besylate crystal that a kind of breakthrough drug compositions, this pharmaceutical composition contain Levamlodipine besylate crystal of the present invention or adopt preparation method of the present invention to make.
According to aforesaid pharmaceutical composition, wherein, described pharmaceutical composition comprises Levamlodipine besylate crystal and acceptable accessories.
According to aforesaid pharmaceutical composition, wherein, described acceptable accessories is Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate.
According to aforesaid pharmaceutical composition, wherein, consisting of of described pharmaceutical composition: Levamlodipine besylate crystal 2 .5～5 weight parts, Microcrystalline Cellulose 40～120 weight parts, carboxymethylstach sodium 30～50 weight parts and Magnesium Stearate 1.5 weight parts, wherein the amount of Levamlodipine besylate crystal is in levamlodipine.
The present invention also provides described preparation of drug combination method, and this method comprises the steps:
1) Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, standby;
2) take by weighing above-mentioned standby Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate by described consumption, adopt the equivalent method of progressively increasing to carry out mixing, obtain powder mix;
3) take by weighing the Levamlodipine besylate crystal of described consumption, with the resulting powder mix mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
4) resulting pharmaceutical composition powder is carried out direct pressed powder, namely get described pharmaceutical composition.
Below describe the present invention:
Levamlodipine besylate is insoluble in water, and enough solubleness is the prerequisite that medicine obtains the good biological availability, yet Levamlodipine besylate is in water, particularly there is not enough solubleness under the state near physiological pH7.4, its solubleness in water only is 0.053mg/mL, it is absorbed in human body slowly, the time that reaches peak concentration (Cmax) after the medication is longer, the Plasma Concentration aggregate level is low, particularly the Plasma Concentration at initial stage is very low after the administration, this medicine onset is very slow, and effect slowly.
The inventor improves it from the refinement treatment of bulk drug in advance, after having carried out a large amount of tests, made a kind of Levamlodipine besylate crystal, this crystal has improved the solvability of Levamlodipine besylate to a certain extent, therefore, primary and foremost purpose of the present invention just is to provide this crystal.
Specifically, Levamlodipine besylate crystal provided by the present invention uses that characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that the Cu-K alpha-ray measures.
The present invention shows that by dissolubility test the solvability of Levamlodipine besylate crystal provided by the present invention significantly is better than Levamlodipine besylate of the prior art, and adopts its enhancing evident in efficacy of tablet of Levamlodipine besylate crystal preparation of the present invention as can be seen from pharmacodynamics test.
Secondly, the present invention also provides the preparation method of described Levamlodipine besylate crystal, and this method comprises the steps:
1) Levamlodipine besylate is dissolved in methylene dichloride and the ethanol mixed solvent, obtains the methylene dichloride/ethanolic soln of Levamlodipine besylate;
2) under ultrasonic field, in the methylene dichloride/ethanolic soln of the Levamlodipine besylate of step 1) gained, drip normal heptane, separate out to crystallization;
3) close ultrasonic field, leave standstill, filter, filter cake is used methylene dichloride, washing with alcohol respectively, and drying obtains described Levamlodipine besylate crystal.
Because the crystal formation difference of medicine may influence its stripping and absorption in vivo, and then influence bioavailability of medicament, clinical efficacy and security.Polymorph medicine between different crystal forms, its stability of the differentia influence of physico-chemical property.Same medicine is because the crystal formation difference, and the arrangement mode difference of drug molecule on lattice causes the difference of intracell Intermolecular Forces, causes the difference of various physico-chemical properties between the polymorph medicine different crystal forms.And the physico-chemical property of medicine and dissolution rate and its stability and bioavailability have much relations.The inventor starts with from the bulk drug Levamlodipine besylate, it is made with extra care---recrystallization, after having carried out a large amount of tests, find at first to adopt methylene dichloride and ethanol mixed solvent that it is dissolved, under ultrasonic condition, drip anti-solvent---normal heptane again, obtained a kind of Levamlodipine besylate crystal of stable crystal form.And further show that by dissolubility test the solvability of Levamlodipine besylate crystal provided by the present invention significantly is better than Levamlodipine besylate of the prior art.
The particle diameter of the left-handed ammonia chlorine of Phenylsulfonic acid provided by the present invention ground crystal is 80～120 μ m.
In addition, owing in preparation method of the present invention, introduced ultrasonic wave, prepared crystal particle diameter is less, specific surface area increases, in the research of the tablet that contains this crystal that carries out subsequently, find to adopt the prepared compound preparation of crystal of the present invention owing to contain the less crystal of described particle diameter more pleasantly surprisedly, thereby accelerated the absorption in human body, improved bioavailability, thereby improved curative effect.
Among the preparation method of the present invention: the consumption of the methylene dichloride described in the step 1) and ethanol mixed solvent is 10～20 times of Levamlodipine besylate weight; The volume ratio of methylene dichloride and ethanol is 5:1～8:1 in described methylene dichloride and the ethanol mixed solvent.
The power of ultrasonic field step 2) is 0.4～0.6KW.
Leaving standstill under 20～25 ℃, leaving standstill 4-8 hour described in the step 3).
The present invention also provides a kind of brand-new medicinal composition simultaneously, and this pharmaceutical composition contains the Levamlodipine besylate crystal that aforesaid Levamlodipine besylate crystal or aforementioned preparation method make.
Brand-new medicinal composition of the present invention comprises significant quantity Levamlodipine besylate crystal and acceptable accessories on the pharmacology.
Described acceptable accessories is Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate.
Described pharmaceutical composition preferably is made up of following component: Levamlodipine besylate crystal 2 .5～5 weight parts, Microcrystalline Cellulose 40～120 weight parts, carboxymethylstach sodium 60～90 weight parts and Magnesium Stearate 1.5 weight parts.
More preferably, Levamlodipine besylate crystal 2 .5 weight part, Microcrystalline Cellulose 50～80 weight parts, carboxymethylstach sodium 40～60 weight parts and Magnesium Stearate 1.5 weight parts;
Perhaps, Levamlodipine besylate crystal 5 weight part, Microcrystalline Cellulose 50～100 weight parts, carboxymethylstach sodium 40～60 weight parts and Magnesium Stearate 1.5 weight parts;
Perhaps, Levamlodipine besylate crystal 5 weight part, Microcrystalline Cellulose 70～120 weight parts, carboxymethylstach sodium 40～60 weight parts and Magnesium Stearate 1.5 weight parts;
Perhaps, Levamlodipine besylate crystal 2 .5 weight part, Microcrystalline Cellulose 40～60 weight parts, carboxymethylstach sodium 40～60 weight parts and Magnesium Stearate 1.5 weight parts.
Most preferably, pharmaceutical composition of the present invention is made up of following component:
Perhaps, described pharmaceutical composition is made up of following component:
Wherein the amount of Levamlodipine besylate crystal is in levamlodipine, and namely the amount of Levamlodipine besylate crystal is 6.94 weight parts, corresponding to 5 weight part levamlodipine free alkalis.
Pharmaceutical composition of the present invention is acceptable oral dosage form on the pharmaceutics, preferred tablet.
Tablet of the present invention is to adopt following method preparation:
(1) Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross 60～80 mesh sieves, standby;
(2) take by weighing above-mentioned standby Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate by described consumption, adopt the equivalent method of progressively increasing to carry out mixing, obtain powder mix;
(3) take by weighing the Levamlodipine besylate crystal of described consumption, with the resulting powder mix mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
(4) resulting pharmaceutical composition powder is carried out direct pressed powder, namely get described pharmaceutical composition.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation of drug combination method of the present invention, wherein: this method comprises the steps:
1) Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, standby;
2) take by weighing above-mentioned standby Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate by described consumption, adopt the equivalent method of progressively increasing to carry out mixing, obtain powder mix;
3) take by weighing the Levamlodipine besylate crystal of described consumption, with the resulting powder mix mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
4) resulting pharmaceutical composition powder is carried out direct pressed powder, namely get described pharmaceutical composition.
The inventor finds that adopting the slope of repose measured result of the resulting pharmaceutical composition of aforesaid method is 36.5 °, and powder flowbility is good, satisfies the requirement of direct compression, adopts the method for direct powder compression to prepare sheet then.
Compressing tablet described in the step 5) is at 5～8kg with the slice, thin piece Hardness Control.
Compared with prior art, the present invention has following advantage:
(1) solvability of Levamlodipine besylate crystal provided by the present invention significantly is better than the Levamlodipine besylate of prior art, and adopts its curative effect of tablet of this crystal preparation more remarkable;
(2) adopted multiple dissolution with solvents among the preparation method of amlodipine besylate crystal provided by the present invention, and introduced ultrasonic wave, prepared crystal crystal formation is good, particle diameter is less, specific surface area increases, and has improved the solvability of Levamlodipine besylate to a certain extent, has accelerated the absorption in human body, improve bioavailability, thereby improved curative effect.
(3) the breakthrough drug compositions that contains above-mentioned Levamlodipine besylate crystal or adopt the Levamlodipine besylate crystal that above-mentioned preparation method makes provided by the present invention, reasonable recipe has step-down simultaneously and can reduce urinary albumin and β again
2-microglobulin is drained; improve endogenous creatinine clearance rate and target organ protection function; it is drug regimen preferably; this pharmaceutical composition has the curative effect that has very much; have good stability; disintegration is faster; thereby help to improve the advantage of the stripping of medicine; its preparation method adopts direct pressed powder, compares with dry granulation with wet granulation, has saved the process of granulating; this method is not only simpler; the more important thing is that the disintegration of tablet that adopts this method to prepare is faster, thus the stripping that helps to improve medicine, and have good stability.
Description of drawings
Fig. 1 is the X-ray powder diffraction figure of the prepared Levamlodipine besylate crystal of the present invention.
Embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
The preparation of [embodiment 1] Levamlodipine besylate crystal
1) Levamlodipine besylate is dissolved in methylene dichloride and the ethanol mixed solvent, obtains the methylene dichloride/ethanolic soln of Levamlodipine besylate;
2) under ultrasonic field, in the methylene dichloride/ethanolic soln of the Levamlodipine besylate of step 1) gained, drip normal heptane, separate out to crystallization;
3) close ultrasonic field, leave standstill, filter, filter cake is used methylene dichloride, washing with alcohol respectively, and drying obtains described Levamlodipine besylate crystal.
Characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that the Levamlodipine besylate crystal use Cu-K alpha-ray of gained measures.
Below be embodiment 2-9, the preparation method is with embodiment 1, and its concrete processing parameter sees Table 1:
Table 1
Annotate: A is that the consumption of methylene dichloride and ethanol mixed solvent is the multiple of Levamlodipine besylate weight;
B is the volume ratio of methylene dichloride and ethanol in methylene dichloride and the ethanol mixed solvent.
[FORMULATION EXAMPLE 1] Levamlodipine beaylate tablets
1, prescription
2, preparation technology:
(1) Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate were dried by the fire 2 hours under 60 ℃ of conditions respectively, cross 60 mesh sieves, standby;
(2) take by weighing above-mentioned standby Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain powder mix;
(3) take by weighing the Levamlodipine besylate crystal of embodiment 1 preparation of recipe quantity, with the resulting powder mix mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
(4) resulting pharmaceutical composition powder is carried out direct pressed powder, namely get described pharmaceutical composition.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die compressing tablet, and control tablet hardness 6kg.
[FORMULATION EXAMPLE 2] Levamlodipine beaylate tablets
1, prescription
2, preparation technology: with FORMULATION EXAMPLE 1, to be the Levamlodipine besylate crystal be the prepared Levamlodipine besylate crystal of embodiment 2, step 2 to difference) be baking 3 hours under 65 ℃ of conditions, cross 80 mesh sieves.
[FORMULATION EXAMPLE 3] Levamlodipine beaylate tablets
1, prescription
2, preparation technology: with FORMULATION EXAMPLE 1, to be the Levamlodipine besylate crystal be the prepared Levamlodipine besylate crystal of embodiment 3, step 2 to difference) be baking 4 hours under 80 ℃ of conditions, cross 80 mesh sieves.
[FORMULATION EXAMPLE 4] Levamlodipine beaylate tablets
1, prescription
2, preparation technology: with FORMULATION EXAMPLE 1, to be the Levamlodipine besylate crystal be the prepared Levamlodipine besylate crystal of embodiment 4, step 2 to difference) be baking 3.8 hours under 62 ℃ of conditions, cross 80 mesh sieves.
[FORMULATION EXAMPLE 5] Levamlodipine beaylate tablets
1, prescription
2, preparation technology: with FORMULATION EXAMPLE 1, to be the Levamlodipine besylate crystal be the prepared Levamlodipine besylate crystal of embodiment 5, step 2 to difference) be baking 2.2 hours under 76 ℃ of conditions, cross 80 mesh sieves.
[FORMULATION EXAMPLE 6] Levamlodipine beaylate tablets
1, prescription
2, preparation technology: with FORMULATION EXAMPLE 1, to be the Levamlodipine besylate crystal be the prepared Levamlodipine besylate crystal of embodiment 6, step 2 to difference) be baking 2 hours under 72 ℃ of conditions, cross 80 mesh sieves.
[FORMULATION EXAMPLE 7] Levamlodipine beaylate tablets
1, prescription
2, preparation technology: with FORMULATION EXAMPLE 1, to be the Levamlodipine besylate crystal be the prepared Levamlodipine besylate crystal of embodiment 7, step 2 to difference) be baking 3.5 hours under 66 ℃ of conditions, cross 80 mesh sieves.
[FORMULATION EXAMPLE 8] Levamlodipine beaylate tablets
1, prescription
2, preparation technology: with FORMULATION EXAMPLE 1, to be the Levamlodipine besylate crystal be the prepared Levamlodipine besylate crystal of embodiment 8, step 2 to difference) be baking 2.6 hours under 68 ℃ of conditions, cross 70 mesh sieves.
Test example 1
Solubility test
Test method is with reference to Levamlodipine besylate (Shandong Xinshidai Pharmaceutical Industry Co., Ltd. of " research of Levamlodipine besylate Losartan Potassium controlled release tablet " (Shandong University's master thesis) the 19th page of " mensuration of 4.LB and LP solubleness in different media " mensuration prior art, Linyi, China) and the prepared solubleness of Levamlodipine besylate crystal in water of the embodiment of the invention.
The Levamlodipine besylate solubleness of table 2, the present invention and prior art relatively
| ? | Solubleness (mg/mL) |
| Prior art | 0.053 |
| Embodiment 1 | 21.312 |
| Embodiment 2 | 21.408 |
| Embodiment 3 | 21.413 |
| Embodiment 4 | 21.416 |
| Embodiment 5 | 21.389 |
| Embodiment 6 | 21.397 |
| Embodiment 7 | 21.420 |
| Embodiment 8 | 21.386 |
| Embodiment 9 | 21.421 |
The solubleness of the prepared Levamlodipine besylate crystal of the embodiment of the invention is greater than the Levamlodipine besylate of prior art as can be seen from the above table, and visible Levamlodipine besylate crystal of the present invention can significantly improve the solvability of Levamlodipine besylate.
Test example 2
1, instrument and reagent
LCQ Advantage Max liquid chromatograph-mass spectrometer, U.S. Finnigan company product.Heraeus Biofuge stratos high speed freezing centrifuge, German Heraeus company product.WH-2 trace vortex mixed instrument, Shanghai Hu Xi analytical instrument factory product.
Be subjected to test preparation A: the Levamlodipine beaylate tablets of FORMULATION EXAMPLE 2 of the present invention, specification: 2.5mg sheet
-1, lot number: 100810;
Be subjected to test preparation B: with reference to the Levamlodipine beaylate tablets of FORMULATION EXAMPLE 2 of the present invention, difference is that used Levamlodipine besylate is the Levamlodipine besylate (Shandong Xinshidai Pharmaceutical Industry Co., Ltd., Linyi, China) of prior art;
Reference preparation: Levamlodipine besylate, trade(brand)name: Shi Huida, specification: 2.5mg sheet
-1, sky, Jilin Province wind pharmaceutical Co. Ltd produces.
2, method
2.1 the experimenter selects
18 of the China's Healthy male sex, the experimenter is the male sex, and the age is 21～27 years old, body weight 55～80kg, height is 165～181cm, no tobacco and wine hobby.Disease history inquire, physical examination and laboratory examination are not found obviously unusual before the experiment.Experimenter's medicine-less allergy history and pharmacological dependence history, the medical history that is a cup too low and other chronic medical histories.Do not obey any medicine in 2 weeks.Unified light diet during being tried.Before testing, the experimenter all signs Informed Consent Form.Testing program is approved through Ethics Committee.
2.2 dosage regimen and sample collecting
Adopt own control, with the note trial design.18 experimenters are divided into 3 groups at random, every group of 6 people, and every group of experimenter takes test preparation and reference preparation according to testing program in different tests in the cycle.The wash-out phase was 2 weeks, behind experimenter's fasting 10h, in morning next day (medicine) being taken before meals with being subjected to test preparation or reference preparation, medicine can be taken food behind the 4h with 150～200mL warm water delivery service; Every group of experimenter intersected three periodic tests at random by own control and taken test preparation or reference preparation, and dosage is 5mg.
Take medicine preceding (0h), take medicine back 1,2,3,4,5,6,8,12,24,48,72,96 and 120h from venous blood collection 4mL, centrifugal immediately, separated plasma is-40 ℃ of preservations.
2.3 blood sample mensuration, evaluation of methodology and data processing
Referring to " levo-amlodipine is at pharmacokinetics and the bioequivalence of healthy human body " (Central-South pharmacy the 6th the 5th phase of volume of October in 2008).
3, result
Main pharmacokinetic parameter behind 18 Chinese healthy volunteers oral test preparations and the reference preparation sees Table 3.
Main pharmacokinetic parameter behind table 3, the oral Levamlodipine besylate of experimenter
As can be seen from the above table, compare than reference preparation, be subjected to test preparation A and the t that is subjected to test preparation B
MaxTime is shorter, maximum plasma concentration is higher, and compare with being subjected to test preparation B, be subjected to test preparation A---namely adopt the tablet of Levamlodipine besylate crystal preparation of the present invention then to demonstrate better pharmacokinetics character, show that the tablet release that contains Levamlodipine besylate crystal of the present invention is faster, it is better to absorb, bioavailability is higher in the body.
The Levamlodipine beaylate tablets prepared to other FORMULATION EXAMPLE of the present invention also carried out above-mentioned test, and the result of its acquisition is similar.
Claims (6)
1. Levamlodipine besylate crystal, it is characterized in that characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that described Levamlodipine besylate crystal use Cu-K alpha-ray measures.
2. a pharmaceutical composition is characterized in that, described pharmaceutical composition contains the described Levamlodipine besylate crystal of claim 1.
3. pharmaceutical composition according to claim 2 is characterized in that, described pharmaceutical composition comprises Levamlodipine besylate crystal and acceptable accessories.
4. pharmaceutical composition according to claim 3 is characterized in that, described acceptable accessories is Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate.
5. pharmaceutical composition according to claim 4, it is characterized in that, consisting of of described pharmaceutical composition: Levamlodipine besylate crystal 2 .5～5 weight parts, Microcrystalline Cellulose 40～120 weight parts, carboxymethylstach sodium 30～90 weight parts and Magnesium Stearate 1.5 weight parts, wherein the amount of Levamlodipine besylate crystal is in levamlodipine.
6. the described preparation of drug combination method of claim 5 is characterized in that this method comprises the steps:
1) Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, standby;
2) take by weighing above-mentioned standby Microcrystalline Cellulose, carboxymethylstach sodium and Magnesium Stearate by described consumption, adopt the equivalent method of progressively increasing to carry out mixing, obtain powder mix;
3) take by weighing the Levamlodipine besylate crystal of described consumption, with the resulting powder mix mixing of step 3), obtain the pharmaceutical composition powder, sampling detects;
4) resulting pharmaceutical composition powder is carried out direct pressed powder, namely get described pharmaceutical composition.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103755643A (en) * | 2013-12-31 | 2014-04-30 | 连云港金康医药科技有限公司 | Rosuvastatin calcium I crystal form |
| WO2022247063A1 (en) * | 2021-05-28 | 2022-12-01 | 海南锦瑞制药有限公司 | Levamlodipine besylate tablet and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6846932B1 (en) * | 2003-11-20 | 2005-01-25 | Council Of Scientific And Industrial Research | Process for preparation of chiral amlodipine salts |
| CN101481348A (en) * | 2009-01-07 | 2009-07-15 | 南昌弘益科技有限公司 | Production method of levamlodipine besylate |
| CN101805284A (en) * | 2010-04-19 | 2010-08-18 | 海南美兰史克制药有限公司 | Levamlodipine compound prepared in novel method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6846932B1 (en) * | 2003-11-20 | 2005-01-25 | Council Of Scientific And Industrial Research | Process for preparation of chiral amlodipine salts |
| CN101481348A (en) * | 2009-01-07 | 2009-07-15 | 南昌弘益科技有限公司 | Production method of levamlodipine besylate |
| CN101805284A (en) * | 2010-04-19 | 2010-08-18 | 海南美兰史克制药有限公司 | Levamlodipine compound prepared in novel method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755643A (en) * | 2013-12-31 | 2014-04-30 | 连云港金康医药科技有限公司 | Rosuvastatin calcium I crystal form |
| WO2022247063A1 (en) * | 2021-05-28 | 2022-12-01 | 海南锦瑞制药有限公司 | Levamlodipine besylate tablet and preparation method therefor |
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