CN105796523A - Levofloxacin mesylate tablets and preparation process thereof - Google Patents
Levofloxacin mesylate tablets and preparation process thereof Download PDFInfo
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- CN105796523A CN105796523A CN201610244555.XA CN201610244555A CN105796523A CN 105796523 A CN105796523 A CN 105796523A CN 201610244555 A CN201610244555 A CN 201610244555A CN 105796523 A CN105796523 A CN 105796523A
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- levofloxacin
- hypromellose
- lactose
- crospolyvinylpyrrolidone
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- ZSPLOATUDIRNAS-PPHPATTJSA-N levofloxacin mesylate Chemical compound CS(O)(=O)=O.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 ZSPLOATUDIRNAS-PPHPATTJSA-N 0.000 title abstract description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 31
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 31
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 31
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 24
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 24
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 24
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 24
- 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 abstract description 23
- 239000008101 lactose Substances 0.000 claims abstract description 23
- 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 abstract description 20
- 229930195725 Mannitol Natural products 0.000 claims abstract description 20
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 20
- 239000000594 mannitol Substances 0.000 claims abstract description 20
- 235000010355 mannitol Nutrition 0.000 claims abstract description 20
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 20
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000008117 stearic acid Substances 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 31
- 229960003376 levofloxacin Drugs 0.000 claims description 31
- 229960003943 hypromellose Drugs 0.000 claims description 30
- 239000008187 granular material Substances 0.000 claims description 21
- 238000000576 coating method Methods 0.000 claims description 19
- 239000011248 coating agent Substances 0.000 claims description 18
- 239000002671 adjuvant Substances 0.000 claims description 17
- 239000002994 raw material Substances 0.000 claims description 14
- 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 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 6
- 229960001375 lactose Drugs 0.000 claims description 6
- 229960001855 mannitol Drugs 0.000 claims description 6
- 239000007779 soft material Substances 0.000 claims description 6
- -1 tabletting Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 23
- 238000004090 dissolution Methods 0.000 abstract description 15
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 230000002950 deficient Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000007907 direct compression Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 239000002932 luster Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- MAZGUESXTVKPCZ-UHFFFAOYSA-N 3h-pyrrolo[3,2-b]pyridine Chemical compound C1=CN=C2CC=NC2=C1 MAZGUESXTVKPCZ-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 235000009854 Cucurbita moschata Nutrition 0.000 description 1
- 240000001980 Cucurbita pepo Species 0.000 description 1
- 235000009852 Cucurbita pepo Nutrition 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000006101 laboratory sample Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 235000020354 squash Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- 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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to levofloxacin mesylate tablets and a preparation process thereof. The tablets are prepared from, by weight, 100 parts of levofloxacin mesylate, 150 parts of lactose, 150 parts of mannitol, 38 parts of hydroxypropyl methylcellulose, 12 parts of microcrystalline cellulose, 50 parts of crospolyvinylpyrrolidone and 6 parts of stearic acid. The tablets prepared through the process are good in stability, high in dissolution rate, good in disintegration and good in formability.
Description
Technical field
The present invention relates to a kind of Ethanesulfonic acid levofloxacin and preparation technology thereof.
Background technology
Levofloxacin M. S. A is the levo form of ofloxacin, chemical name is: (-)-(S)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen-7H-is than pyridine also [1,2,3-de] [1,4] benzimidazole dihydrochloride-6-carboxylic acid methyl sulfonate monohydrate, its antibacterial activity is about 2 times of ofloxacin.Its main mechanism, for suppressing DNA of bacteria rotation body enzymatic activity, stops the duplication of DNA of bacteria, the gram positive bacteria and gram-negative bacteria including anaerobe is all demonstrated the inside and outside antibacterial activity of good body.It is now widely used for the acute and chronic bacterial infection of light, the moderate of each tracts such as the breathing caused by sensitive organism, digestion, urinary system, reproductive system, skin soft tissue, there is broad-spectrum antibacterial action, the feature that antibacterial action is strong.The dosage form of existing market preparation is tablet and injection, but Levofloxacin M. S. A aqueous stability is poor, meets light and is extremely easy in decomposition variable color, and its little pin and infusion solutions are both needed to keep in Dark Place.And the Ethanesulfonic acid levofloxacin agent sold in the market is primarily present following deficiency: direct compression of full-powder poor fluidity, in process of production, Levofloxacin M. S. A is extremely readily adsorbed in metal surface, rubbed and extruding is easily generated bonding, therefore the extruding of low punch and the extruding of drift and mould are gone up during tabletting, slice, thin piece is bonded in rapidly on drift and the mould of tablet machine, and increasingly severe.
Existing more Ethanesulfonic acid levofloxacin commercialized product in prior art, for instance Levofloxacin Mesylate Tablets (China Resources Shuan He Medicine stock Co., Ltd), but this tablet exists dissolution is bad, stability is bad problem.
Summary of the invention
The present invention provides a kind of novel Ethanesulfonic acid levofloxacin agent, by screening relevant auxiliary materials, obtains than prior art good stability, dissolution is good, disintegrative is good, the tablet of good moldability.
One, screening process
1. the selection of tablet weight
The sheet of listing sample Levofloxacin Mesylate Tablets weighs about 100mg, and the theoretical tablet weight of design this product is also 100mg；In actual production process, adopting φ 4.0mm shallow concave punch tabletting, theoretical tablet weight 100mg, tablet is of moderate size, taking convenience.
2. the selection of preparation method
Selecting and the on all four supplementary product kind of former triturate, and employing grinds consistent technique (direct compression of full-powder method) with former, design proportioning is in Table 1.
Table 1 direct compression of full-powder proportion design (makes 1000)
| Each ingredient names | Proportioning 1 | Proportioning 2 | Proportioning 3 | Proportioning 4 | Proportioning 5 |
| Levofloxacin M. S. A (g) | 100 | 100 | 100 | 100 | 100 |
| Micro-crystalline lactose (g) | 300 | 280 | 290 | 305 | 310 |
| Crospolyvinylpyrrolidone (g) | 55 | 60 | 63 | 58 | 61 |
| Magnesium stearate (g) | 15 | 17 | 14 | 16 | 13 |
| Cyclamate (g) | 50 | 47 | 49 | 52 | 53 |
Preparation: 80 mesh sieves crossed by raw material, adjuvant；The raw material after sieving, adjuvant is accurately weighed by proportional quantity；Levofloxacin M. S. A raw material is mixed homogeneously with adjuvant, φ 4.0mm scrobicula stamping.Each proportioning test result is in Table 2.
Direct compression of full-powder proportioning in table 2 proportioning development process investigates result
| Proportioning | Tablet appearance | Mobility (angle of repose °) | Tablet weight variation | Whether sticking | Compressibility |
| 1 | Pitted skin, slice, thin piece takes off lid | 45.9 | Defective | Sticking is serious | Better |
| 2 | Pitted skin | 43.1 | Defective | Sticking | Better |
| 3 | Pitted skin | 42.0 | Defective | Sticking | Better |
| 4 | Pitted skin | 43.8 | Defective | Sticking | Better |
| 5 | Fineness is poor | 38.4 | Defective | Sticking | Better |
By result of the test it can be seen that there is, with direct compression of full-powder, the sticking phenomenon that tablet weight variation is defective and serious, analyzing reason is:
(1) the raw materials used I crystal product for Levofloxacin M. S. A, poor fluidity, in whole proportioning, proportion is very big, so that entirely mix the poor fluidity of powder, causes tablet weight variation defective；And feed particles is very thin, electrostatic phenomenon is serious, can stick to punch head surface and cause sticking.
(2) with Levofloxacin M. S. A crystal formation product when, lubricant does not have the effect preventing sticking.
In sum, direct compression of full-powder technique is not suitable for the proportioning making raw material of Levofloxacin M. S. A I crystal product, therefore adopts wet granule compression tablet method.
3. the selection of supplementary product kind
First select the magnesium stearate in former bedding-in ratio to make lubricant, but all cannot solve sticking problem after repeatedly adjusting usage ratio., through series of experiments, it has been found that the lubricant containing metal ion all can cause that the unknown impuritie in principal agent increases, finally screening stearic acid makees lubricant, it is metal ion not, will not principal agent be impacted, and supplementary material compatibility test also indicates that stearic acid is suitable as lubricant for this proportioning.Simple will also result in sticking with stearic acid, adds microcrystalline Cellulose and coordinates with stearic acid and can avoid sticking phenomenon.
Two, proportioning process
Element sheet proportioning (1000 supplementary material amounts):
| Levofloxacin M. S. A | 100g (in levofloxacin) |
| Lactose | 150g |
| Mannitol | 150g |
| Hypromellose (inside adds) | 30g |
| Crospolyvinylpyrrolidone | 50g |
| Hypromellose (additional) | 8g |
| Microcrystalline Cellulose | 15g |
| 40% ethanol | In right amount |
| Stearic acid | 3g |
Preparation technology:
Prepared by a, wet granular: dry 3～4 hours of lactose, mannitol, microcrystalline Cellulose, hypromellose and crospolyvinylpyrrolidone 70 DEG C, and 80 mesh sieves crossed by raw material and each adjuvant, weigh by proportional quantity, and raw material first mixes with other adjuvants, mixing；With 40% ethanol soft material, 20 orders are granulated, and 40 DEG C～45 DEG C drying, 18 order granulate, granule is standby；
B, weighed the hypromellose after 80 mesh sieves, stearic acid, microcrystalline Cellulose by proportional quantity, fully mixed with granule；
C, tabletting；
D, coating, to obtain final product.
Three, proportioning correlation test data:
(1) principal agent and adjuvant compatibility test:
With reference to " chemicals medicine investigative technique guideline ", adjuvant in this product proportioning and raw material have been carried out compatibility test, in order to more clearly discriminate whether the impact being adjuvant to medicine, will place under crude drug equal conditions, there to be related substance to investigate 10 days at high temperature 40 DEG C for index.The relatively larger microcrystalline Cellulose of moisture, lactose, hypromellose be have also been made compatibility test at 70 DEG C after dry 3～4 hours.Investigate result in Table 3:
Table 3 supplementary material compatibility test result
Above result of the test is not it can be seen that the related substance that has of sample significantly changes, and in proportioning, adjuvant used is all better with the compatibility of principal agent；But the adjuvant that moisture is big can cause the increase of impurity A, analyzing and be because under the high temperature conditions, raw material is created impact by the moisture in adjuvant, therefore to reduce adjuvant and the moisture of final tablet in process of production as far as possible.
(2) investigation of coating situation:
Containing lactose in the coating solution of market products Levofloxacin Mesylate Tablets coated tablet, hypromellose etc..
This product selects commercially available coating materials, and it consists of hypromellose, titanium dioxide, PEG, Pulvis Talci, ferric oxide.Wherein hypromellose is filmogen, ferric oxide is pigment, and PEG can play the effect of plasticising and pore.The composition of this coating powder is basically identical with listing product, with reference to the compound method that producer of coating materials company provides, adopts different coating proportionings to carry out the investigation of coating situation, concrete condition such as table 4 below in coating process.
Table 4 coating experiments result
| Coating solution solvent | Operation difficulty or ease | Operating time | Tablet appearance | Label dissolution (%) | Dissolution (%) after coating |
| Water | Difficulty is big | Time is long | Unilateral pit | 99.23 | / |
| 40% ethanol | Acquire a certain degree of difficulty | Time is longer | Bright and clean, color and luster is homogeneous | 99.23 | 96.21 |
| 70% ethanol | It is easier to | Time is short | Bright and clean, color and luster is homogeneous | 99.23 | 98.56 |
By result of the test it can be seen that this coating material on the dissolution of this product almost without impact, it is contemplated that the preparation process of this product should be avoided moisture as far as possible, final select 70% alcoholic solution as the solvent of coating powder.
Four, contrast test
(1) dissolution contrast test
The tablet adopting the present invention is as follows with the dissolution contrast test of commercially available prod Levofloxacin Mesylate Tablets (China Resources Shuan He Medicine stock Co., Ltd):
With Levofloxacin Mesylate Tablets (China Resources Shuan He Medicine stock Co., Ltd) for reference preparation, measure the stripping curve of test agent in this product three batches (preparing according to the proportioning of said ratio technique and technique) the similarity of the outer dissolved corrosion of comparing bulk.Method, with reference to second the annex IA tablet requirement of " Chinese Pharmacopoeia " version in 2010, measures the accumulation dissolution of stipulated time point respectively, adopts the f2 factor to evaluate the similarity of In Vitro Dissolution behavior.The middle test agent of result this product and reference preparation are in 30min, accumulation dissolution reaches 96.34%, 97.42%, 95.91%, 89.73% respectively, all meets the limit of regulation, and RSD performance is good, doing dissolution contrast with commercially available prod Levofloxacin Mesylate Tablets, concrete test situation is shown in table 5 below:
Table 5 dissolution comparative test result
From upper table 5, the dissolution of Tablets is substantially better than commercially available prod.
(2), stability contrast test
1, test specimen such as table 6 below:
Table 6 laboratory sample
2, stability data:
The bright stability experiment result of table 7 this law
Table 8 commercially available Levofloxacin Mesylate Tablets (Levofloxacin M. S. A) stability test result
From above-mentioned table 7-8 result it can be seen that the having good stability of Tablets, and it is better than commercialized product Levofloxacin Mesylate Tablets.
The present invention further study show that, when microcrystalline Cellulose and stearic acid take specific proportioning, can obtain beyond thought technique effect, and the test that the present invention does is such as shown in following table 9-10:
Table 9 wet method grain-making and squash method supplementary material proportioning (unit: g, in batches: 1000)
| Each ingredient names | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Levofloxacin M. S. A | 100 | 100 | 100 |
| Lactose | 150 | 150 | 150 |
| Mannitol | 150 | 150 | 150 |
| Hypromellose (inside adds) | 30 | 30 | 30 |
| 40% ethanol | In right amount | In right amount | In right amount |
| Hydroxypropyl fiber rope (additional) | 8 | 8 | 8 |
| Microcrystalline Cellulose | 12 | 10 | 9 |
| Crospolyvinylpyrrolidone | 50 | 50 | 50 |
| Stearic acid | 6 | 8 | 9 |
Table 10 tablet testing result
By result of the test it can be seen that embodiment 3 stripping curve is significantly better than other proportionings, comparing enforcement 1 and implement 2, embodiment 3 achieves beyond thought technique effect, it is thus determined that embodiment 3 is the basic scheme of the present invention.
(3) slaking test
Tablet the invention process 3 technique prepared and commercially available Levofloxacin Mesylate Tablets (Levofloxacin M. S. A) disintegrating property contrast experiment, see data below:
| The present invention | Commercially available | |
| Disintegration (min) | 12 | 22 |
| Friability (%) | 0.32 | 0.75 |
| Dissolution (%) | 99.36 | 93.24 |
Visible, its disintegrating property of the tablet that instant component and technique prepare is far superior to commercially available prod, achieves unexpected disintegrate effect.
(4) mouldability contrast test
According to real composition feature in the present invention, select the solvent and the concentration thereof that are suitable for the most, achieve unexpected technique effect.The concentration of alcohol that the present invention uses is 40%, even if under the premise that component is identical, it was found that be substantially better than 50% ethanol by the viscosity of the granule of 40% ethanol making, shaping particles is good.The granule made of 50% ethanol is loose, and formability is bad.After tabletting, the plain sheet fineness of the present invention is better than the fineness of 50% ethanol, and the friability present invention recorded is 0.32, and 50% ethanol is 0.87.Visible, although the simply slightly change of concentration of alcohol, but the mouldability of tablet is brought beyond thought effect.
Detailed description of the invention
The present invention is expanded on further below in conjunction with embodiment, but is not limitation of the present invention.
Embodiment 1
Weigh Levofloxacin M. S. A 100g, lactose 150g, mannitol 150g, hypromellose 38g, microcrystalline Cellulose 12g, crospolyvinylpyrrolidone 50g, stearic acid 6g；
Lactose, mannitol, microcrystalline Cellulose, hypromellose and crospolyvinylpyrrolidone 70 DEG C being dried 3～4 hours, 80 mesh sieves crossed by raw material and each adjuvant；Levofloxacin M. S. A and lactose, mannitol, hypromellose 30g, crospolyvinylpyrrolidone fully mix；
With 40% ethanol soft material, 20 orders are granulated, and 40 DEG C～45 DEG C drying, 18 order granulate, granule is standby；
Stearic acid is crossed 80 mesh sieves, is then sufficiently mixed with hypromellose 8g, microcrystalline Cellulose and granule；Tabletting, coating, to obtain final product.
Embodiment 2
Weigh Levofloxacin M. S. A 100g, lactose 150g, mannitol 150g, hypromellose 38g, microcrystalline Cellulose 10g, crospolyvinylpyrrolidone 50g, stearic acid 8g；
Lactose, mannitol, microcrystalline Cellulose, hypromellose and crospolyvinylpyrrolidone 70 DEG C being dried 3～4 hours, 80 mesh sieves crossed by raw material and each adjuvant；Levofloxacin M. S. A and lactose, mannitol, hypromellose 30g, crospolyvinylpyrrolidone fully mix；
With 40% ethanol soft material, 20 orders are granulated, and 40 DEG C～45 DEG C drying, 18 order granulate, granule is standby；
Stearic acid is crossed 80 mesh sieves, is then sufficiently mixed with hypromellose 8g, microcrystalline Cellulose and granule；Tabletting, coating, to obtain final product.
Embodiment 3
Weigh Levofloxacin M. S. A 100g, lactose 150g, mannitol 150g, hypromellose 38g, microcrystalline Cellulose 9g, crospolyvinylpyrrolidone 50g, stearic acid 9g；
Lactose, mannitol, microcrystalline Cellulose, hypromellose and crospolyvinylpyrrolidone 70 DEG C being dried 3～4 hours, 80 mesh sieves crossed by raw material and each adjuvant；Levofloxacin M. S. A and lactose, mannitol, hypromellose 30g, crospolyvinylpyrrolidone fully mix；
With 40% ethanol soft material, 20 orders are granulated, and 40 DEG C～45 DEG C drying, 18 order granulate, granule is standby；
Stearic acid is crossed 80 mesh sieves, is then sufficiently mixed with hypromellose 8g, microcrystalline Cellulose and granule；Tabletting, coating, to obtain final product.
Claims (3)
1. an Ethanesulfonic acid levofloxacin agent, it is characterized in that supplementary material consists of Levofloxacin M. S. A 100 weight portion, lactose 150 weight portion, mannitol 150 weight portion, hypromellose 38 weight portion, microcrystalline Cellulose 12 weight portion, crospolyvinylpyrrolidone 50 weight portion, stearic acid 6 weight portion, be prepared from as steps described below:
A lactose, mannitol, microcrystalline Cellulose, hypromellose and crospolyvinylpyrrolidone 70 DEG C are dried 3～4 hours by (), 80 mesh sieves crossed by raw material and each adjuvant；
B () Levofloxacin M. S. A and lactose, mannitol, hypromellose 30 weight portion, crospolyvinylpyrrolidone fully mix；
C () with 40% ethanol soft material, 20 orders are granulated, and 40 DEG C～45 DEG C drying, 18 order granulate, granule is standby；
D stearic acid is sufficiently mixed by () with hypromellose 8 weight portion, microcrystalline Cellulose and step (c) gained granule, tabletting, and coating to obtain final product.
2. tablet according to claim 1, it is characterized in that supplementary material consists of: Levofloxacin M. S. A 100g, lactose 150g, mannitol 150g, hypromellose 38g, microcrystalline Cellulose 12g, crospolyvinylpyrrolidone 50g, stearic acid 6g, make 1000, tablet.
3. the preparation method of an Ethanesulfonic acid levofloxacin agent, it is characterized in that supplementary material consists of Levofloxacin M. S. A 100 weight portion, lactose 150 weight portion, mannitol 150 weight portion, hypromellose 38 weight portion, microcrystalline Cellulose 9 weight portion, crospolyvinylpyrrolidone 50 weight portion, stearic acid 9 weight portion, be prepared from as steps described below:
A lactose, mannitol, microcrystalline Cellulose, hypromellose and crospolyvinylpyrrolidone 70 DEG C are dried 3～4 hours by (), 80 mesh sieves crossed by raw material and each adjuvant；
B () Levofloxacin M. S. A and lactose, mannitol, hypromellose 30 weight portion, crospolyvinylpyrrolidone fully mix；
C () with 40% ethanol soft material, 20 orders are granulated, and 40 DEG C～45 DEG C drying, 18 order granulate, granule is standby；
D stearic acid is sufficiently mixed by () with hypromellose 8 weight portion, microcrystalline Cellulose and step (c) gained granule, tabletting, and coating to obtain final product.
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