CN103396328A - Meclofenoxate hydrochloride compound and pharmaceutical composition thereof - Google Patents
Meclofenoxate hydrochloride compound and pharmaceutical composition thereof Download PDFInfo
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- CN103396328A CN103396328A CN2013103658460A CN201310365846A CN103396328A CN 103396328 A CN103396328 A CN 103396328A CN 2013103658460 A CN2013103658460 A CN 2013103658460A CN 201310365846 A CN201310365846 A CN 201310365846A CN 103396328 A CN103396328 A CN 103396328A
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- meclofenoxate hydrochloride
- hydrochloride compound
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- meclofenoxate
- drug combination
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- 229960001637 meclofenoxate hydrochloride Drugs 0.000 title claims abstract description 168
- -1 Meclofenoxate hydrochloride compound Chemical class 0.000 title claims abstract description 87
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 6
- 239000000843 powder Substances 0.000 claims abstract description 41
- 239000002775 capsule Substances 0.000 claims abstract description 25
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 7
- 239000013078 crystal Substances 0.000 claims abstract description 4
- XZTYGFHCIAKPGJ-UHFFFAOYSA-N Meclofenoxate Chemical compound CN(C)CCOC(=O)COC1=CC=C(Cl)C=C1 XZTYGFHCIAKPGJ-UHFFFAOYSA-N 0.000 claims description 84
- 238000002360 preparation method Methods 0.000 claims description 65
- 238000003756 stirring Methods 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 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 24
- 229930195725 Mannitol Natural products 0.000 claims description 24
- 239000000594 mannitol Substances 0.000 claims description 24
- 235000010355 mannitol Nutrition 0.000 claims description 24
- 239000000706 filtrate Substances 0.000 claims description 22
- 238000012856 packing Methods 0.000 claims description 22
- 239000000470 constituent Substances 0.000 claims description 20
- 239000000890 drug combination Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 238000010792 warming Methods 0.000 claims description 18
- 239000008215 water for injection Substances 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000007919 dispersible tablet Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 206010013786 Dry skin Diseases 0.000 claims description 11
- 229920000881 Modified starch Polymers 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 238000005374 membrane filtration Methods 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 229960001701 chloroform Drugs 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- 238000005262 decarbonization Methods 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 238000011068 loading method Methods 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 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 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 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 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
- 238000002347 injection Methods 0.000 abstract description 16
- 239000007924 injection Substances 0.000 abstract description 16
- 239000002552 dosage form Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
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- 238000000034 method Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 10
- 238000011835 investigation Methods 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- SODPIMGUZLOIPE-UHFFFAOYSA-N (4-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1 SODPIMGUZLOIPE-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000008967 Enuresis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010039987 Senile psychosis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000002131 composite material Substances 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
- 150000002148 esters Chemical class 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
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Abstract
A meclofenoxate hydrochloride compound is a crystal. Determined by X-ray powder diffraction, the meclofenoxate hydrochloride compound has characteristic peaks at 2theta +/- 0.2 degree of 6.1 degrees, 7.7 degrees, 9.3 degrees, 12.2 degrees, 14.3 degrees, 17.8 degrees, 18.9 degrees, 20.5 degrees, 22.2 degrees, 23.3 degrees, 24.5 degrees, 25.8 degrees and 27.0 degrees in the spectrum pattern. The invention also discloses a pharmaceutical composition of the meclofenoxate hydrochloride compound. The dosage forms of the pharmaceutical composition comprise dispersing tablets, capsules, freeze-dried powder injection, and aseptic powder for injection. The meclofenoxate hydrochloride compound has extremely good fluidity as well as stable quality. The benefits comprise that the dispersing tablets, the capsules and the freeze-dried powder injection of the prepared meclofenoxate hydrochloride compound has good stability and low impurity content.
Description
Technical field
The invention belongs to medical technical field, meclofenoxate hydrochloride compound and pharmaceutical composition thereof.
Background technology
Meclofenoxate hydrochloride, chemical name: 2-(dimethylamino) ethyl parachlorophen-oxyacetic acid ester hydrochloride.The meclofenoxate hydrochloride Main Function is in pallium, and it can promote the redox of brain cell, regulates the metabolism of neurocyte, and the utilization that increases carbohydrate has excitation to downtrod nervus centralis.Be applicable to traumatic stupor, children enuresis, the disturbance of consciousness, senile psychosis, various dementia, alcoholism etc.
The meclofenoxate hydrochloride less stable, and in molecule because containing ester bond, the aqueous solution is unstable, facile hydrolysis.Aqueous solution pH raises, and hydrolysis rate is accelerated.In order to address this problem, prior art generally attempts from the preparation aspect addressing this problem, and the means of use are add auxiliary material and adopt than complicated technology, and overcome its unstable.Although improving the stability of meclofenoxate hydrochloride aspect preparation, prior art have certain effect still to need to add more auxiliary material and need to coordinate the comparatively technique of complexity, although there have certain effect still to act on to be limited, limited the application of meclofenoxate hydrochloride,, because the facile hydrolysis meclofenoxate hydrochloride is unstable in feed stage, need high preservation condition.the prior art that also has attempts obtaining from changing crystal formation the meclofenoxate hydrochloride of higher stability, as: China application CN103214382A, the meclofenoxate hydrochloride compound that this application provides and drug regimen thereof are compared with prior art, have better stability in storage and mobility, the inventor finds in test, although the meclofenoxate hydrochloride that obtains in this application has stability preferably under normal temperature and acceleration environment, but less stable in the factorial experiments of other influences drug quality, especially still have higher draw moist, make the easy water of hydroscopicity solution of meclofenoxate hydrochloride.Obtained unexpectedly a kind of meclofenoxate hydrochloride compound of crystalline form in order to address this problem the inventor in long-term a large amount of research process, this compound draws moist very low, is difficult for the water of hydroscopicity solution and has high quality stability.It is composite preparation of meclofenoxate hydrochloride compound of the present invention and preparation method thereof that the present invention also provides effective constituent, the preparation that can be prepared into according to content of the present invention, keep high stability, obviously be better than commercially available kind, greatly improved security, validity that meclofenoxate hydrochloride uses.
Summary of the invention
The invention provides a kind of stable meclofenoxate hydrochloride compound and drug combination preparation thereof.
Meclofenoxate hydrochloride structural formula of compound provided by the invention is as shown in formula I:
Formula I
Described meclofenoxate hydrochloride compound is crystal, adopt the X-ray powder diffraction to measure, in its collection of illustrative plates, characteristic peak ° is 6.1 °, 7.7 °, 9.3 °, 12.2 °, 14.3 °, 17.8 °, 18.9 °, 20.5 °, 22.2 °, 23.3 °, 24.5 °, 25.8 °, 27.0 ° demonstrations in 2 θ ± 0.2.
The X-ray powder diffraction figure of described meclofenoxate hydrochloride compound sees Fig. 1.
The fusing point of described meclofenoxate hydrochloride compound is 147～152 ℃.
Meclofenoxate hydrochloride compounds process for production thereof of the present invention comprises the steps:
1) the meclofenoxate hydrochloride raw material being added volume ratio by weight 1:15～1:18 is that in the mixing solutions of the trichloromethane of 9:1 and ethanol, the regulator solution temperature is 30～35 ℃, stirring and dissolving.
2) keeping solution temperature is 30～35 ℃, and adding weight is the gac of meclofenoxate hydrochloride weight 0.7%, and 120～150 rev/mins were stirred 25 minutes, filtered carbon removal, and filtrate, through 0.22 μ m membrane filtration, is obtained filtrate.
3) regulating the filtrate temperature is 22～27 ℃, under the stirring velocity of 90～110 rev/mins, slowly at the uniform velocity drip weight in the filtrate that obtains take 50ml～75ml/min speed toward step 2 while stirring and be the ether of 8:2 and the mixing solutions of sherwood oil as the volume ratio of 10～12 times of trichloromethane in step 1 and alcohol mixtures; Simultaneously with 0.5～0.7 ℃/min speed, be cooled to 8～10 ℃, stop stirring, with 0.2～0.4 ℃/min speed, be cooled to 2～4 ℃ of standing growing the grains 6 hours, filter.
4) wash 2 times with the ether of 2 times of weight filtering the filter cake obtain in step 3,47 ℃～52 ℃ dryings 8 hours, namely obtain described meclofenoxate hydrochloride compound.
Meclofenoxate hydrochloride raw material in meclofenoxate hydrochloride compound preparation process of the present invention is the marketable material medicine.
It is the drug combination preparation of meclofenoxate hydrochloride compound of the present invention that the present invention's the second purpose is to provide effective constituent, and described drug combination preparation is dispersible tablet, capsule, freeze-dried powder and injectable sterile powder.Characteristics based on the meclofenoxate hydrochloride of the present invention preparation, can the meclofenoxate hydrochloride of the present invention's preparation be made several formulations with existing public technology, but in order to obtain the more better meclofenoxate hydrochloride preparation of high quality of stability, the preferred following technical scheme of the present invention:
Described freeze-dried powder contains pharmacy acceptable vehicle carrier, and vehicle can be one or more of N.F,USP MANNITOL, glucose, dextran, lactose, preferred N.F,USP MANNITOL, and the preparation solvent is water for injection.
Preferred every of described lyophilized injectable powder contains meclofenoxate hydrochloride compound 0.06g of the present invention, N.F,USP MANNITOL 0.24g or meclofenoxate hydrochloride compound 0.25g, N.F,USP MANNITOL 0.05g or meclofenoxate hydrochloride compound 0.1g, N.F,USP MANNITOL 0.1g and meclofenoxate hydrochloride compound 0.2g, N.F,USP MANNITOL 0.2g.
The preparation method of described lyophilized injectable powder comprises the steps:
1, add to by meclofenoxate hydrochloride compound 60g, N.F,USP MANNITOL 240g, water for injection that 2000ml or meclofenoxate hydrochloride compound 250g, N.F,USP MANNITOL 50g, water for injection add to 2000ml or meclofenoxate hydrochloride compound 100g, N.F,USP MANNITOL 100g, water for injection adds to 2000ml.The meclofenoxate hydrochloride compound of recipe quantity is added in the water for injection of 1400ml, and stirring and dissolving, inject water to 1600ml, then by recipe quantity, adds the N.F,USP MANNITOL stirring and dissolving, injects water to 2000ml, stirs.
2, add 0.10%(g/ml in 1) gac, stirred 20 minutes, filtering decarbonization, 0.22 μ m membrane filtration degerming, carry out intermediate and detect.
3, freeze-drying:
1. pre-freeze: filtrate packing false add in 2 is plugged in being cooled in advance-24 ℃～-22 ℃ refrigerated tanks, kept 1.5 hours, with 0.6 ℃/min～0.8 ℃/min speed, be cooled to-38 ℃～-33 ℃, be incubated 2 hours;
2. distillation: open vacuum unit, control vacuum tightness is 14～17Pa, with 0.5 ℃/min～0.7 ℃/min speed, at the uniform velocity is warming up to-14 ℃～-12 ℃, in this temperature, keeps 1 hour, at the uniform velocity be warming up to-2 ℃～3 ℃ with 0.3 ℃/min～0.5 ℃/min speed, in this temperature, kept 5 hours.
3. dry: at the uniform velocity be warming up to 40 ℃～43 ℃ with 0.7 ℃/min～0.9 ℃/min speed, dry 6 hours, packing namely obtained described meclofenoxate hydrochloride freeze-dried powder after the assay was approved.
The inventor finds that the meclofenoxate hydrochloride compound that the present invention prepares also has the fabulous characteristic of mobility except steady quality under study for action, for this characteristic, through large quantity research, screening high amount of drug auxiliary material carrier combinations comprises one or more of starch, pregelatinized Starch, talcum powder, N.F,USP MANNITOL, Microcrystalline Cellulose, lactose, Xylo-Mucine, hydroxypropylcellulose, Magnesium Stearate, sodium starch glycolate, preferred pregelatinized Starch.
When described drug combination preparation capsule, preferred specification is meclofenoxate hydrochloride 0.2g and meclofenoxate hydrochloride 0.1g.
The prescription of described meclofenoxate hydrochloride composition capsule is:
Meclofenoxate hydrochloride compound: 200g
Pregelatinized Starch: 50g
Its preparation method is:
1, will cross successively 80 mesh sieves through meclofenoxate hydrochloride compound, the pregelatinized Starch of 60 ℃ of dryings in advance.
2, each supplementary material is fully mixed rear mensuration content, according to specification, determine loading amount, with the capsule packing machine, be packed into capsule, check, packing, obtain the medicament composition capsule that effective constituent is meclofenoxate hydrochloride of the present invention.
When described drug combination preparation dispersible tablet, preferred specification is meclofenoxate hydrochloride 0.1g.
The prescription of described meclofenoxate hydrochloride composition dispersible tablet is:
Meclofenoxate hydrochloride compound: 200g
Microcrystalline Cellulose: 50g
Its preparation method is:
1, will cross successively 80 mesh sieves through meclofenoxate hydrochloride compound, the Microcrystalline Cellulose of 60 ℃ of dryings in advance.
2, each supplementary material is fully mixed rear mensuration content, according to specification, determine the sheet weight, upper machine compressing tablet, check, packing, obtain the medicament combination dispersible tablet that effective constituent is meclofenoxate hydrochloride of the present invention.
When described drug combination preparation injectable sterile powder, preferred specification is meclofenoxate hydrochloride 0.1g or 0.06g or 0.25g or 0.2g.
Its preparation method is:
Under hundred grades of aseptic conditions, the meclofenoxate hydrochloride compound is undertaken aseptic subpackaged by specification, obtain the injectable sterile powder that effective constituent is meclofenoxate hydrochloride of the present invention.
Description of drawings
Fig. 1 is the X-ray powder diffraction pattern of the meclofenoxate hydrochloride compound of the embodiment of the present invention 1 preparation.
Embodiment
The preparation of embodiment 1 meclofenoxate hydrochloride compound
1. the meclofenoxate hydrochloride raw material being added volume ratio by weight 1:15 is that in the mixing solutions of the trichloromethane of 9:1 and ethanol, the regulator solution temperature is 30 ℃, stirring and dissolving.
2. keeping solution temperature is 30 ℃, and adding weight is the gac of meclofenoxate hydrochloride weight 0.7%, and 120 rev/mins were stirred 25 minutes, filtered carbon removal, and filtrate, through 0.22 μ m membrane filtration, is obtained filtrate;
3. regulating the filtrate temperature is 22 ℃, under the stirring velocity of 90 rev/mins, slowly at the uniform velocity drip weight in the filtrate that obtains take 50ml/min speed toward step 1 while stirring and be the ether of 8:2 and the mixing solutions of sherwood oil as the volume ratio of 10 times of trichloromethane in step 1 and alcohol mixtures; Simultaneously with 0.5 ℃/min speed, be cooled to 8 ℃, stop stirring, with 0.2 ℃/min speed, be cooled to 2 ℃ of standing growing the grains 6 hours, filter.
4. wash 2 times with the ether of 2 times of weight filtering the filter cake obtain in step 3,47 ℃ of dryings 8 hours, namely obtain described meclofenoxate hydrochloride compound.
The X-ray powder diffraction pattern is seen accompanying drawing 1, and in its collection of illustrative plates, characteristic peak ° is 6.1 °, 7.7 °, 9.3 °, 12.2 °, 14.3 °, 17.8 °, 18.9 °, 20.5 °, 22.2 °, 23.3 °, 24.5 °, 25.8 °, 27.0 ° demonstrations in 2 θ ± 0.2.Content: 99.90%.Fusing point: 147～152 ℃.
The preparation of embodiment 2 meclofenoxate hydrochloride compounds
1. the meclofenoxate hydrochloride raw material being added volume ratio by weight 1:18 is that in the mixing solutions of the trichloromethane of 9:1 and ethanol, the regulator solution temperature is 35 ℃, stirring and dissolving.
2. keeping solution temperature is 35 ℃, and adding weight is the gac of meclofenoxate hydrochloride weight 0.7%, and 150 rev/mins were stirred 25 minutes, filtered carbon removal, and filtrate, through 0.22 μ m membrane filtration, is obtained filtrate;
3. regulating the filtrate temperature is 27 ℃, under the stirring velocity of 110 rev/mins, slowly at the uniform velocity drip weight in the filtrate that obtains take 75ml/min speed toward step 2 while stirring and be the ether of 8:2 and the mixing solutions of sherwood oil as the volume ratio of 12 times of trichloromethane in step 1 and alcohol mixtures; Simultaneously with 0.7 ℃/min speed, be cooled to 10 ℃, stop stirring, with 0.4 ℃/min speed, be cooled to 4 ℃ of standing growing the grains 6 hours, filter.
4. wash 2 times with the ether of 2 times of weight filtering the filter cake obtain in step 3,52 ℃ of dryings 8 hours, namely obtain described meclofenoxate hydrochloride compound.
The X-ray powder diffraction pattern is consistent with embodiment.Content: 99.91%.Fusing point: 147～152 ℃.
Preparation (the specification: 0.06g) of embodiment 3 meclofenoxate hydrochloride freeze-dried powders
Prescription:
Meclofenoxate hydrochloride compound: 60g
N.F,USP MANNITOL: 240g
Water for injection adds to 2000ml
Make 1000
Technique:
1, the meclofenoxate hydrochloride of recipe quantity is added in the water for injection of 1400ml, stirring and dissolving, inject water to 1600ml, then by recipe quantity, adds the N.F,USP MANNITOL stirring and dissolving, injects water to 2000ml, stirs.
2, add 0.10%(g/ml in 1) gac, stirred 20 minutes, filtering decarbonization, 0.22 μ m membrane filtration degerming, carry out intermediate and detect.
3, freeze-drying:
1. pre-freeze: filtrate packing false add in 2 is plugged in being cooled in advance-24 ℃ of refrigerated tanks, kept 1.5 hours, with 0.6 ℃/min speed, be cooled to-38 ℃, be incubated 2 hours;
2. distillation: open vacuum unit, control vacuum tightness is 14Pa, with 0.5 ℃/min speed, at the uniform velocity is warming up to-14 ℃, in this temperature, keeps 1 hour, with 0.3 ℃/min speed, at the uniform velocity is warming up to-2 ℃, in this temperature, keeps 5 hours.
3. dry: at the uniform velocity be warming up to 40 ℃ with 0.7 ℃/min speed, dry 6 hours, packing namely obtained described meclofenoxate hydrochloride freeze-dried powder after the assay was approved.
Preparation (the specification: 0.1g) of embodiment 4 meclofenoxate hydrochloride freeze-dried powders
Prescription:
Meclofenoxate hydrochloride compound: 100g
N.F,USP MANNITOL: 100g
Water for injection adds to 2000ml
Make 1000
Technique:
1, the meclofenoxate hydrochloride of recipe quantity is added in the water for injection of 1400ml, stirring and dissolving, inject water to 1600ml, then by recipe quantity, adds the N.F,USP MANNITOL stirring and dissolving, injects water to 2000ml, stirs.
2, add 0.10%(g/ml in 1) gac, stirred 20 minutes, filtering decarbonization, 0.22 μ m membrane filtration degerming, carry out intermediate and detect.
3, freeze-drying:
1. pre-freeze: filtrate packing false add in 2 is plugged in being cooled in advance-22 ℃ of refrigerated tanks, kept 1.5 hours, with 0.8 ℃/min speed, be cooled to-33 ℃, be incubated 2 hours;
2. distillation: open vacuum unit, control vacuum tightness is 17Pa, with 0.7 ℃/min speed, at the uniform velocity is warming up to-12 ℃, in this temperature, keeps 1 hour, with 0.5 ℃/min speed, at the uniform velocity is warming up to 3 ℃, in this temperature, keeps 5 hours.
3. dry: at the uniform velocity be warming up to 43 ℃ with 0.9 ℃/min speed, dry 6 hours, packing namely obtained described meclofenoxate hydrochloride freeze-dried powder after the assay was approved.
Preparation (the specification: 0.2g) of embodiment 5 meclofenoxate hydrochloride freeze-dried powders
Prescription:
Meclofenoxate hydrochloride compound: 100g
N.F,USP MANNITOL: 100g
Water for injection adds to 2000ml
Make 500
Technique:
1, the meclofenoxate hydrochloride compound of recipe quantity is added in the water for injection of 1400ml, stirring and dissolving, inject water to 1600ml, then by recipe quantity, adds the N.F,USP MANNITOL stirring and dissolving, injects water to 2000ml, stirs.
2, add 0.10%(g/ml in 1) gac, stirred 20 minutes, filtering decarbonization, 0.22 μ m membrane filtration degerming, carry out intermediate and detect.
3, freeze-drying:
1. pre-freeze: filtrate packing false add in 2 is plugged in being cooled in advance-22 ℃ of refrigerated tanks, kept 1.5 hours, with 0.8 ℃/min speed, be cooled to-33 ℃, be incubated 2 hours;
2. distillation: open vacuum unit, control vacuum tightness is 17Pa, with 0.7 ℃/min speed, at the uniform velocity is warming up to-12 ℃, in this temperature, keeps 1 hour, with 0.5 ℃/min speed, at the uniform velocity is warming up to 3 ℃, in this temperature, keeps 5 hours.
3. dry: at the uniform velocity be warming up to 43 ℃ with 0.9 ℃/min speed, dry 6 hours, packing namely obtained described meclofenoxate hydrochloride freeze-dried powder after the assay was approved.
Preparation (the specification: 0.25g) of embodiment 6 meclofenoxate hydrochloride freeze-dried powders
Prescription:
Meclofenoxate hydrochloride compound: 250g
N.F,USP MANNITOL: 50g
Water for injection adds to 2000ml
Make 1000
Technique:
1, the meclofenoxate hydrochloride compound of recipe quantity is added in the water for injection of 1400ml, stirring and dissolving, inject water to 1600ml, then by recipe quantity, adds the N.F,USP MANNITOL stirring and dissolving, injects water to 2000ml, stirs.
2, add 0.10%(g/ml in 1) gac, stirred 20 minutes, filtering decarbonization, 0.22 μ m membrane filtration degerming, carry out intermediate and detect.
3, freeze-drying:
1. pre-freeze: filtrate packing false add in 2 is plugged in being cooled in advance-23 ℃ of refrigerated tanks, kept 1.5 hours, with 0.7 ℃/min speed, be cooled to-35 ℃, be incubated 2 hours;
2. distillation: open vacuum unit, control vacuum tightness is 16Pa, with 0.6 ℃/min speed, at the uniform velocity is warming up to-13 ℃, in this temperature, keeps 1 hour, with 0.4 ℃/min speed, at the uniform velocity is warming up to 0 ℃, in this temperature, keeps 5 hours.
3. dry: at the uniform velocity be warming up to 41 ℃ with 0.8 ℃/min speed, dry 6 hours, packing namely obtained described meclofenoxate hydrochloride freeze-dried powder after the assay was approved.
Preparation (the specification: 0.1g) of embodiment 7 meclofenoxate hydrochloride capsules
Prescription:
Meclofenoxate hydrochloride compound: 200g
Pregelatinized Starch: 50g
Make 2000
Technique:
1, will cross successively 80 mesh sieves through meclofenoxate hydrochloride compound, the pregelatinized Starch of 60 ℃ of dryings in advance.
2, each supplementary material is fully mixed rear mensuration content, according to specification, determine loading amount, with the capsule packing machine, be packed into capsule, check, packing, obtain the medicament composition capsule that effective constituent is meclofenoxate hydrochloride of the present invention.
Preparation (the specification: 0.2g) of embodiment 8 meclofenoxate hydrochloride capsules
Prescription:
Meclofenoxate hydrochloride compound: 200g
Pregelatinized Starch: 50g
Make 1000
Technique:
1, will cross successively 80 mesh sieves through meclofenoxate hydrochloride compound, the pregelatinized Starch of 60 ℃ of dryings in advance.
2, each supplementary material is fully mixed rear mensuration content, according to specification, determine loading amount, with the capsule packing machine, be packed into capsule, check, packing, obtain the medicament composition capsule that effective constituent is meclofenoxate hydrochloride of the present invention.
Preparation (the specification: 0.1g) of embodiment 9 meclofenoxate hydrochloride dispersible tablets
Prescription:
Meclofenoxate hydrochloride compound: 200g
Microcrystalline Cellulose: 50g
Make 2000
Technique:
1, will cross successively 80 mesh sieves through meclofenoxate hydrochloride compound, the Microcrystalline Cellulose of 60 ℃ of dryings in advance.
2, each supplementary material is fully mixed rear mensuration content, according to specification, determine the sheet weight, upper machine compressing tablet, check, packing, obtain the medicament combination dispersible tablet that effective constituent is meclofenoxate hydrochloride of the present invention.
Embodiment 10 meclofenoxate hydrochloride injection sterilized powder preparation (specifications: 0.1g)
Prescription:
Meclofenoxate hydrochloride compound: 100g
Make 1000
Technique:
Under hundred grades of aseptic conditions, the meclofenoxate hydrochloride compound is undertaken aseptic subpackaged by specification, obtaining effective constituent is the meclofenoxate hydrochloride injection sterilized powder of meclofenoxate hydrochloride of the present invention.
Embodiment 11 meclofenoxate hydrochloride injection sterilized powder preparation (specifications: 0.06g)
Prescription:
Meclofenoxate hydrochloride compound: 60g
Make 1000
Technique:
Under hundred grades of aseptic conditions, the meclofenoxate hydrochloride compound is undertaken aseptic subpackaged by specification, obtaining effective constituent is the meclofenoxate hydrochloride injection sterilized powder of meclofenoxate hydrochloride of the present invention.
Embodiment 12 meclofenoxate hydrochloride injection sterilized powder preparation (specifications: 0.2g)
Prescription:
Meclofenoxate hydrochloride compound: 200g
Make 1000
Technique:
Under hundred grades of aseptic conditions, the meclofenoxate hydrochloride compound is undertaken aseptic subpackaged by specification, obtaining effective constituent is the meclofenoxate hydrochloride injection sterilized powder of meclofenoxate hydrochloride of the present invention.
Embodiment 13 meclofenoxate hydrochloride injection sterilized powder preparation (specifications: 0.25g)
Prescription:
Meclofenoxate hydrochloride compound: 250g
Make 1000
Technique:
Under hundred grades of aseptic conditions, the meclofenoxate hydrochloride compound is undertaken aseptic subpackaged by specification, obtaining effective constituent is the meclofenoxate hydrochloride injection sterilized powder of meclofenoxate hydrochloride of the present invention.
Below test further illustrates the present invention:
Test method is with reference to 2010 editions two appendix XIX C bulk drugs of Chinese Pharmacopoeia and pharmaceutical preparation stability test governing principle.
Sample 1: by the meclofenoxate hydrochloride compound of the embodiment of the present invention 1 method preparation.
Sample 2: commercially available meclofenoxate hydrochloride raw material.
Sample 3: by the meclofenoxate hydrochloride of China application CN103214382A embodiment 1 method preparation.
Sample 1～sample 3 is carried out the influence factor test, respectively at 60 ℃; High light (4500lx ± 500lx); 25 ℃, placed under relative humidity 90% ± 5% condition 10 days, respectively at sampling calibrating in the 10th day, result with 0 day relatively, the stability result of the investigation sample 1～table 3 that sees the following form.
60 ℃ of test-results of table 1
Table 2 highlight test result
Table 3 high humidity test-results
The meclofenoxate hydrochloride compound of the embodiment of the present invention 1 preparation and commercially available meclofenoxate hydrochloride raw material are carried out accelerated stability investigation (40 ℃ ± 2 ℃, RH 75% ± 5%) by commercially available back, the results are shown in Table 4.
Table 4 meclofenoxate hydrochloride compound accelerated test result
The meclofenoxate hydrochloride compound of the embodiment of the present invention 1 preparation and commercially available meclofenoxate hydrochloride raw material are carried out permanent stability investigations (25 ℃ ± 2 ℃, RH 60% ± 10%) by commercially available back), the results are shown in Table 5.
Table 5 meclofenoxate hydrochloride compound long-term test results
Above-mentioned test-results shows, the meclofenoxate hydrochloride compound stability of the present invention's preparation is good, and foreign matter content is low, with prior art, compares and has obvious advantage.
The pharmaceutical composition with Meclofenoxate hydrochloride freeze-dried powder of the embodiment of the present invention 3 preparations and commercially available meclofenoxate hydrochloride injection freeze-dried powder are carried out accelerated stability investigation (40 ℃ ± 2 ℃, RH 75% ± 5%), the results are shown in Table 6.
Table 6 meclofenoxate hydrochloride freeze-dried powder accelerated test result
Above-mentioned test-results shows, the effective constituent of the present invention's preparation is the lyophilized injectable powder good stability of the meclofenoxate hydrochloride for preparing of the present invention, and foreign matter content is low to be compared and have obvious advantage with prior art.
The meclofenoxate hydrochloride capsules of the embodiment of the present invention 8 preparations and commercially available meclofenoxate hydrochloride capsules are carried out accelerated stability investigation (40 ℃ ± 2 ℃, RH 75% ± 5%), the results are shown in Table 7.
Table 7 meclofenoxate hydrochloride capsules accelerated test result
State test-results and show, the effective constituent of the present invention preparation is that the capsule stability of the meclofenoxate hydrochloride for preparing of the present invention is good, and foreign matter content is low to be compared and have obvious advantage with prior art.
The meclofenoxate hydrochloride dispersible tablet of the embodiment of the present invention 9 preparations and commercially available meclofenoxate hydrochloride dispersible tablet are carried out accelerated stability investigation (40 ℃ ± 2 ℃, RH 75% ± 5%), the results are shown in Table 8.
Table 8 meclofenoxate hydrochloride dispersible tablet accelerated test result
Above-mentioned test-results shows, the effective constituent of the present invention's preparation is the dispersible tablet good stability of the meclofenoxate hydrochloride for preparing of the present invention, and foreign matter content is low to be compared and have obvious advantage with prior art.
The commercially available meclofenoxate hydrochloride injection sterilized powder of meclofenoxate hydrochloride injection sterilized powder of the embodiment of the present invention 10 preparations is carried out accelerated stability investigate (40 ℃ ± 2 ℃, RH 75% ± 5%), the results are shown in Table 9.
Table 9 meclofenoxate hydrochloride injection sterilized powder accelerated test result
Above-mentioned test-results shows, the effective constituent of the present invention's preparation is the meclofenoxate hydrochloride injection sterilized powder good stability of the meclofenoxate hydrochloride for preparing of the present invention, and foreign matter content is low to be compared and have obvious advantage with prior art.
Claims (10)
1. meclofenoxate hydrochloride compound, its structural formula is as follows:
It is characterized in that: described meclofenoxate hydrochloride compound is crystal, adopt the X-ray powder diffraction to measure, in its collection of illustrative plates, characteristic peak ° is 6.1 °, 7.7 °, 9.3 °, 12.2 °, 14.3 °, 17.8 °, 18.9 °, 20.5 °, 22.2 °, 23.3 °, 24.5 °, 25.8 °, 27.0 ° demonstrations in 2 θ ± 0.2.
2. meclofenoxate hydrochloride compound according to claim 1, it is characterized in that: the fusing point of described meclofenoxate hydrochloride compound is 147～152 ℃.
3. the preparation method of the described meclofenoxate hydrochloride compound of claim 1 or 2, comprise the steps:
It is in the mixture of the trichloromethane of 9:1 and ethanol that the meclofenoxate hydrochloride raw material is added volume ratio by weight 1:15～1:18, then 30～35 ℃ of stirring and dissolving, obtains the solution I;
Keeping solution I temperature is 30～35 ℃, add weight be the gac of meclofenoxate hydrochloride weight 0.7% in the solution I, 120～150 rev/mins were stirred 25 minutes, filtered carbon removal by 0.22 μ m membrane filtration, obtained filtrate;
Regulating the filtrate temperature is 22～27 ℃, under the stirring velocity of 90～110 rev/mins, slowly at the uniform velocity drip weight in while stirring take 50ml～75ml/min speed toward filtrate and be the ether of 8:2 and the mixing solutions of sherwood oil as the volume ratio of 10～12 times of trichloromethane in step 1) and alcohol mixtures; Simultaneously with 0.5～0.7 ℃/min speed, be cooled to 8～10 ℃, stop stirring, with 0.2～0.4 ℃/min speed, be cooled to 2～4 ℃ of standing growing the grains 6 hours, filter;
Wash 2 times with the ether of 2 times of weight filtering the filter cake obtain in step 3,47 ℃～52 ℃ dryings 8 hours, namely obtain described meclofenoxate hydrochloride compound.
4. contain the drug combination preparation of meclofenoxate hydrochloride compound, it is characterized in that: the effective constituent of described drug combination preparation is the described meclofenoxate hydrochloride compound of claim 1 or 2.
5. drug combination preparation according to claim 4, it is characterized in that: described drug combination preparation is dispersible tablet, capsule, freeze-dried powder or injectable sterile powder.
6. drug combination preparation according to claim 5, it is characterized in that: described freeze-dried powder contains pharmacy acceptable vehicle carrier, and vehicle is one or more in N.F,USP MANNITOL, glucose, dextran and lactose.
7. the preparation method of drug combination preparation claimed in claim 6, comprise the steps:
1) adding to 2000ml or meclofenoxate hydrochloride compound 250g, N.F,USP MANNITOL 50g, water for injection by meclofenoxate hydrochloride compound 60g, N.F,USP MANNITOL 240g, water for injection adds to 2000ml or meclofenoxate hydrochloride compound 100g, N.F,USP MANNITOL 100g, water for injection and adds to the recipe quantity of 2000ml, the meclofenoxate hydrochloride compound is added in the water for injection of 1400ml, stirring and dissolving, inject water to 1600ml, then add the N.F,USP MANNITOL stirring and dissolving by recipe quantity, inject water to 2000ml, stir;
2) toward 1) in add the gac of 0.10g/100ml, stirred 20 minutes, filtering decarbonization, 0.22 μ m membrane filtration degerming obtains filtrate;
3) freeze-drying:
1. pre-freeze: with 2), filtrate packing false add plugs in being cooled in advance-24 ℃～-22 ℃ refrigerated tanks, keeps 1.5 hours, with 0.6 ℃/min～0.8 ℃/min speed, is cooled to-38 ℃～-33 ℃, is incubated 2 hours;
2. distillation: open vacuum unit, control vacuum tightness is 14～17Pa, with 0.5 ℃/min～0.7 ℃/min speed, at the uniform velocity is warming up to-14 ℃～-12 ℃, in this temperature, keeps 1 hour, at the uniform velocity be warming up to-2 ℃～3 ℃ with 0.3 ℃/min～0.5 ℃/min speed, in this temperature, kept 5 hours;
3. dry: as with 0.7 ℃/min～0.9 ℃/min speed, at the uniform velocity to be warming up to 40 ℃～43 ℃, dry 6 hours, to obtain described meclofenoxate hydrochloride freeze-dried powder.
8. the preparation method of the described drug combination preparation of claim 5, is characterized in that: when described drug combination preparation is capsule
1) will cross successively 80 mesh sieves through meclofenoxate hydrochloride compound, the pregelatinized Starch of 60 ℃ of dryings in advance;
2) ratio that is 4:1 in meclofenoxate hydrochloride compound and pregelatinized Starch weight ratio is fully mixed rear mensuration content with meclofenoxate hydrochloride compound and pregelatinized Starch, determine loading amount according to specification, be packed into capsule with the capsule packing machine, check, packing, obtain the medicament composition capsule that effective constituent is the described meclofenoxate hydrochloride compound of claim 1 or 2.
9. the preparation method of the described drug combination preparation of claim 5, is characterized in that: when described drug combination preparation is dispersible tablet
1) will cross successively 80 mesh sieves through meclofenoxate hydrochloride compound, the Microcrystalline Cellulose of 60 ℃ of dryings in advance;
2) ratio that is 4:1 in meclofenoxate hydrochloride compound and Microcrystalline Cellulose weight ratio is fully mixed rear mensuration content with meclofenoxate hydrochloride compound and Microcrystalline Cellulose, each supplementary material is fully mixed rear mensuration content, determine the sheet weight according to specification, upper machine compressing tablet, check, packing, obtain the medicament combination dispersible tablet that effective constituent is the described meclofenoxate hydrochloride compound of claim 1 or 2.
10. the preparation method of the described drug combination preparation of claim 5, it is characterized in that: when described drug combination preparation was injectable sterile powder, its preparation method was:
Under hundred grades of aseptic conditions, the meclofenoxate hydrochloride compound is undertaken aseptic subpackaged by specification, obtain the injectable sterile powder that effective constituent is the described meclofenoxate hydrochloride compound of claim 1 or 2.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104058979A (en) * | 2014-07-02 | 2014-09-24 | 江苏汉斯通药业有限公司 | Purification process of meclofenoxate hydrochloride |
| CN105106190A (en) * | 2015-10-09 | 2015-12-02 | 杨献美 | Central stimulant meclofenoxate hydrochloride composition |
| CN105106189A (en) * | 2015-09-30 | 2015-12-02 | 杨献美 | Meclofenoxate hydrochloride pharmaceutical composition capable of promoting brain energy metabolism |
| CN105287409A (en) * | 2015-12-01 | 2016-02-03 | 青岛华之草医药科技有限公司 | Medicinal meclofenoxate hydrochloride composition freeze-dried powder injection for treating senile dementia |
| CN105287410A (en) * | 2015-12-01 | 2016-02-03 | 青岛华之草医药科技有限公司 | Medicinal meclofenoxate hydrochloride composition freeze-dried powder injection for treating traumatic coma |
| CN105434384A (en) * | 2016-01-05 | 2016-03-30 | 濮阳市仲亿药业有限公司 | Aceclofenac dispersible tablets and preparation method |
| CN113133975A (en) * | 2021-04-22 | 2021-07-20 | 海南通用三洋药业有限公司 | Preparation method of meclofenoxate hydrochloride freeze-dried powder injection |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104058979A (en) * | 2014-07-02 | 2014-09-24 | 江苏汉斯通药业有限公司 | Purification process of meclofenoxate hydrochloride |
| CN105106189A (en) * | 2015-09-30 | 2015-12-02 | 杨献美 | Meclofenoxate hydrochloride pharmaceutical composition capable of promoting brain energy metabolism |
| CN105106190A (en) * | 2015-10-09 | 2015-12-02 | 杨献美 | Central stimulant meclofenoxate hydrochloride composition |
| CN105287409A (en) * | 2015-12-01 | 2016-02-03 | 青岛华之草医药科技有限公司 | Medicinal meclofenoxate hydrochloride composition freeze-dried powder injection for treating senile dementia |
| CN105287410A (en) * | 2015-12-01 | 2016-02-03 | 青岛华之草医药科技有限公司 | Medicinal meclofenoxate hydrochloride composition freeze-dried powder injection for treating traumatic coma |
| CN105434384A (en) * | 2016-01-05 | 2016-03-30 | 濮阳市仲亿药业有限公司 | Aceclofenac dispersible tablets and preparation method |
| CN113133975A (en) * | 2021-04-22 | 2021-07-20 | 海南通用三洋药业有限公司 | Preparation method of meclofenoxate hydrochloride freeze-dried powder injection |
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|---|---|
| CN103396328B (en) | 2014-10-15 |
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