CN102232935A - Novel oral mecobalamin sustained-release tablets and preparation method thereof - Google Patents
Novel oral mecobalamin sustained-release tablets and preparation method thereof Download PDFInfo
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- CN102232935A CN102232935A CN 201010156237 CN201010156237A CN102232935A CN 102232935 A CN102232935 A CN 102232935A CN 201010156237 CN201010156237 CN 201010156237 CN 201010156237 A CN201010156237 A CN 201010156237A CN 102232935 A CN102232935 A CN 102232935A
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Abstract
The invention relates to novel oral mecobalamin sustained-release tablets and a preparation method thereof. The novel mecobalamin sustained-release tablets are used for treating diseases such as peripheral neuropathy and megaloblastic anemia caused by vitamin B12 deficiency. The release per hour, release per 2 hours and release per 4 hours of the mecobalamin sustained-release tablets are 15 to 45 percent, 45 to 80 percent and over 80 percent respectively; the action of the sustained-release tablets lasts long and stability, peak and trough phenomena are avoided, and the sustained-release tablets have small side effect and are convenient for administration and suitable for patients who need to take medicines for a long time; and conventional auxiliary materials for sustained-release tablets are used in the formula, so the formula is very practical, convenient for industrial product and suitable for the patients who need to take the medicines for a long time.
Description
Technical field
The present invention relates to a kind of novel mecobalamin oral sustained release sheet and preparation method thereof, be used for the treatment of peripheral neuropathy or the B that is deficient in vitamin
12Diseases such as the megaloblastic anemia that causes belong to field of pharmaceutical preparations.
Background technology
Mecobalamin (Mecobalamin) is the endogenous coenzyme vitamin B that Japanese Eisai Co., Ltd develops
12Derivative formulations.Its chemical name is α-(5,6-dimethylbenzimidazole base)-Co-first cobalt amide, English chemistry α by name-(5,6-dinethylbenzimidazolyl)-Co-methyl-cobamide, molecular formula is C
63H
91CoN
13O
14P, molecular weight 1344.38, chemical formula is:
Clinical research shows that mecobalamin has better curative effect to diseases such as neuropathy and megaloblastic anemia around treatment diabetic neuropathy, the polyneuritis etc., and can treat following some diseases:
1. peripheral facial paralysis (PFP).Adopt vitamin B
12Reach steroid hormone treatment PFP and can obtain certain curative effect, but the part patient still can leave sequela in various degree.
2. coronary heart disease (CHD) homocysteine (Hcy) mass formed by blood stasis.Merge high Hcy mass formed by blood stasis patient for CHD, use mecobalamin and can reduce its Plasma Hcy level.
3. cubital tunnel syndrome.Mecobalamin can improve the postoperative symptom, and curative effect is better than vitamin B
1, show that mecobalamin has certain promotion post-operative recovery effect to cubital tunnel syndrome.
4. lower lumbar spine illness.Mecobalamin is very fast to nervous tissue's repair of damage, and the function of nervous system that can reverse can recover rapidly in a short time in medication, and mecobalamin can improve the pain relevant with the lower lumbar spine illness, numbness and other nervous symptoms safely and effectively.
5. traumatic levator palpebrae superioris paralysis.The traumatic levator palpebrae superioris paralysis of mecobalamin in treating has effect preferably, and adopting this medicine treatment in early days is helpful to recovering normal levator palpebrae superioris function.
Commercially available mecobalamin is separable tablets/capsules (dosage 0.5mg) at present, each 0.5mg, every day 3 times; Injection (dosage 0.5mg), intramuscular injection or quiet notes, the 0.5mg that is grown up a time, 1 time on the one, a week 3 times.Ten days one courses of treatment or need take for a long time.
General mecobalamin preparation often needs a number of days to take medicine for 3 times, and the mecobalamin sustained-release sheet of our invention is only with administration every day 1 time, easy to use.The general preparation effect of slow releasing tablet low, avoided general preparation frequent drug administration after, because of blood drug level excessive the fluctuated of effective blood drug concentration that occur that rise and fall, toxic and side effects therefore is little than an ordinary preparation, is fit to life-time service.
Summary of the invention
The technical problem to be solved in the present invention is: the slow releasing tablet of development mecobalamin, the ratio of prescription preferably of research mecobalamin and slow-release material, make its oral drug slow release in gastrointestinal tract, keep the required more constant blood drug level of long period of treatment thereby provide,, guarantee the effectiveness and the safety of drug use to avoid " peak, paddy " phenomenon, reduced patient's medicining times simultaneously, improve patient's compliance, easy to use, be applicable to the patient that need take medicine for a long time.
The novel mecobalamin oral sustained release sheet of our invention, day clothes can reach therapeutic purposes 1 time, from the comfortable angle of patient, preferably usually adopt the long slow releasing tablet of curative effect, because the number of times that can reduce every day like this and take medicine, thereby make the patient be easier to accept.
The manufacture method of mecobalamin sustained-release sheet provided by the invention has adopted advanced slow release control techniques, and utilize the high-affinity that medicine itself has and make the low dosage type resisting hypertension slow releasing tablet of 1.5mg/ sheet, this manufacture method is not only very simple, control easily, and do not need special production equipment, thereby small investment, cost is low.
The manufacture method of mecobalamin sustained-release sheet provided by the invention can be produced low dosage type mecobalamin sustained-release sheet, and this slow releasing tablet comprises plain sheet and coatings, and whole process of preparation need be under the lucifuge environment; Plain sheet by mecobalamin, sustained-release matrix, porogen, filler, binding agent and lubricant in 1: the ratio of 5-500: 10-200: 10-500: 1-50g: 1-10 is formed; Coatings is made up of filmogen, antiplastering aid, opacifier, plasticizer, in the ratio of 1-20: 1-20: 1-25: 1-10, is dissolved in the 50-95% ethanol, and the coating inlet temperature is 30-60 ℃, and hydrojet speed is 5-25ml/min, and plain sheet weightening finish is 1-20%.
Porogen is any one or two kinds in lactose, carboxymethyl starch sodium, Polyethylene Glycol and the microcrystalline Cellulose; Filler is any one or two kinds in sorbitol, mannitol, starch, dextrin and the Icing Sugar; Binding agent is any in 30 POVIDONE K 30 BP/USP 30, hydroxypropyl emthylcellulose, the low substituted hydroxy-propyl methylcellulose; Lubricant is any in magnesium stearate and the Pulvis Talci; Filmogen is any in hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl-cellulose and the hydroxypropyl methylcellulose; Antiplastering aid is any in Pulvis Talci and the calcium carbonate; Opacifier is any in shading color ingot and the titanium dioxide; Plasticizer is any in PEG400, Macrogol 600 and the glycerol.
The external stripping determination test of preparation of the present invention
Measure the release of the present invention's (sample is taken from the preparation of embodiment 1 preparation), its drug release determination method (appendix X D first method), according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C three therapeutic methods of traditional Chinese medicine), under the lucifuge condition, be solvent with water 100ml, rotating speed is that per minute 50 changes, operation in the time of 40 minutes, is got solution 2ml in accordance with the law, filter, get subsequent filtrate as need testing solution.Other the mecobalamin reference substance that is dried to constant weight of learning from else's experience 105 ℃ is an amount of, is dissolved in water and dilutes and make the solution that contains 5 μ g among every 1ml approximately, in contrast product solution.Measure according to the method under the assay item, get each 20 μ l of above-mentioned two kinds of solution, inject chromatograph of liquid respectively, the record chromatogram.Go out every stripping percentage amounts with calculated by peak area by external standard method.
Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D).
Instrument: Agilent 1100 type high performance liquid chromatographs
Chromatographic column: Kromasil C
18150 * 4.6mm, 5 μ m
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-acetonitrile-pH7.0 phosphoric acid triethylamine buffer (25: 85: 400) is mobile phase; The detection wavelength is 267nm; Number of theoretical plate is pressed the mecobalamin peak and is calculated, and should be not less than 2000.
Obtain following result:
The 15-45% mecobalamin discharged after 1 hour
The mecobalamin of 45-80% discharged after 2 hours
80% mecobalamin discharged after 4 hours
Mecobalamin sustained-release sheet pharmacokinetic properties comparative study test
For proving that preparation of the present invention is better than the advantage and the value of mecobalamin preparation in the prior art, measured the main pharmacokinetic parameter of commercially available mecobalamin ordinary tablet and mecobalamin sustained-release sheet, methycobal (the methylcobalamin tablet that adopts Japanese Eisai Co., Ltd to produce, 0.5mg/ sheet) be the standard reference preparation, carry out bioavailability and evaluation of bioequivalence (sample is taken from the preparation of embodiment 2 preparations).Health volunteer 6 people are divided into two groups at random, and disposable oral mecobalamin standard reference preparation 3 (1.5mg) and 1 of mecobalamin sustained-release sheet (1.5mg) are got hematometry concentration respectively, and the result is as follows:
3 of oral administration methycobal (1.5mg), the blood peak time Tmax that disappears is 3.11 ± 0.66 hours, and peak serum concentration Cmax is 0.37 ± 0.07ng/mL, t
1/2Be the once oral embodiment 2 mecobalamin sustained-release sheet 1.5mg of the healthy people of 7.2 ± 1.21h, serum peak time Tmax is 10.77 ± 1.42 hours, and peak serum concentration Cmax is 0.19 ± 0.11ng/mL, t
1/2Be 19.9 ± 1.14h.
The inherent bioavailability presentation of results of body, peak time prolongs in the present embodiment 2 slow release lamellar bodies, and the blood drug level peak-peak reduces, and the half-life prolongs, and has the good slow release effect.
Embodiment 1
Whole process of preparation need be under the lucifuge environment, and the ratio according to prescription takes by weighing supplementary material earlier, and mecobalamin and binding agent are dissolved in the 50-95% ethanol, gets binder concn and is 3-30%, and is standby; Sustained-release matrix, porogen, filler, mix homogeneously with recipe quantity added in the above-mentioned solution, stir, and granulate with the 18-30 eye mesh screen, make soft material, 60 ± 20 ℃ of dryings 4 hours; Dry back 18-30 eye mesh screen granulate, the lubricant of adding recipe quantity, mixing, tabletting get plain sheet; With 50% ethanol coating material is mixed with coating solution, in coating pan plain sheet is carried out coating, inlet temperature is 40 ℃, and hydrojet speed is 15ml/min, and plain sheet weightening finish is 4%, promptly makes the mecobalamin sustained-release sheet.
Embodiment 2
Whole process of preparation need be under the lucifuge environment, and the ratio according to prescription takes by weighing supplementary material earlier, and mecobalamin and binding agent are dissolved in the 50-95% ethanol, gets binder concn and is 3-30%, and is standby; Sustained-release matrix, porogen, filler, mix homogeneously with recipe quantity added in the above-mentioned solution, stir, and granulate with the 18-30 eye mesh screen, make soft material, 50 ± 20 ℃ of dryings 5 hours; Dry back 18-30 eye mesh screen granulate, the lubricant of adding recipe quantity, mixing, tabletting get plain sheet; With 95% ethanol coating material is mixed with coating solution, in coating pan plain sheet is carried out coating, inlet temperature is 45 ℃, and hydrojet speed is 12ml/min, and plain sheet weightening finish is 4%, promptly makes the mecobalamin sustained-release sheet.
Embodiment 3
Whole process of preparation need be under the lucifuge environment, and the ratio according to prescription takes by weighing supplementary material earlier, and mecobalamin and binding agent are dissolved in the 50-95% ethanol, gets binder concn and is 3-30%, and is standby; Sustained-release matrix, porogen, filler, mix homogeneously with recipe quantity added in the above-mentioned solution, stir, and granulate with the 18-30 eye mesh screen, make soft material, 50 ± 20 ℃ of dryings 5 hours; Dry back 18-30 eye mesh screen granulate, the lubricant of adding recipe quantity, mixing, tabletting get plain sheet; With 95% ethanol coating material is mixed with coating solution, in coating pan plain sheet is carried out coating, inlet temperature is 45 ℃, and hydrojet speed is 12ml/min, and plain sheet weightening finish is 4%, promptly makes the mecobalamin sustained-release sheet.
Embodiment 4
Whole process of preparation need be under the lucifuge environment, and the ratio according to prescription takes by weighing supplementary material earlier, and mecobalamin and binding agent are dissolved in the 50-95% ethanol, gets binder concn and is 3-30%, and is standby; Sustained-release matrix, porogen, filler, mix homogeneously with recipe quantity added in the above-mentioned solution, stir, and granulate with the 18-30 eye mesh screen, make soft material, 50 ± 20 ℃ of dryings 5 hours; Dry back 18-30 eye mesh screen granulate, the lubricant of adding recipe quantity, mixing, tabletting get plain sheet; With 95% ethanol coating material is mixed with coating solution, in coating pan plain sheet is carried out coating, inlet temperature is 60 ℃, and hydrojet speed is 5ml/min, and plain sheet weightening finish is 4%, promptly makes the mecobalamin sustained-release sheet.
Claims (6)
1. oral mecobalamin sustained-release sheet, it is characterized in that containing mecobalamin and sustained-release matrix by weight 1: 5～500, this sustained-release matrix is to be selected to meet the polymeric material that water or aqueous solution have high swelling degree and have gelation, comprise: high viscosity and low viscous hydroxypropyl emthylcellulose (HPMC), sodium carboxymethyl cellulose, crosslinked hydroxypropyl cellulose, polymethyl methacrylate, crospolyvinylpyrrolidone and polyvinyl alcohol, methylcellulose, carboxymethyl cellulose, pectin, sodium alginate, chitin, in Glyceryl Behenate and the acrylic resin one or more.
2. according to claim 1, the additional proportion that it is characterized in that mecobalamin, sustained-release matrix, porogen, filler, binding agent and lubricant in the mecobalamin sustained-release sheet is 1: 5-500: 10-200: 10-500: 1-50: 1-10; Be preferably 1: 100-200: 100-200: 100-200: 10-20: 5-10.
3. according to claim 2, a kind of manufacture method of oral mecobalamin sustained-release sheet, it is characterized in that preparation method is as follows: whole process of preparation need be under the lucifuge environment, earlier take by weighing supplementary material according to the described ratio of claim 2, mecobalamin and binding agent are dissolved in the 50-95% ethanol, get binder concn and be 3-30%, standby; Sustained-release matrix, porogen, filler, mix homogeneously with recipe quantity added in the above-mentioned solution, stir, and granulate with the 18-30 eye mesh screen, make soft material, 60 ± 20 ℃ of dryings 4 hours; Dry back 18-30 eye mesh screen granulate, the lubricant of adding recipe quantity, mixing, tabletting get plain sheet; With 80% ethanol coating material is mixed with the coating solution of 1-10%, in coating pan, plain sheet is carried out coating, promptly.
4. according to claim 3, a kind of manufacture method of oral mecobalamin sustained-release sheet, it is characterized in that: described coating inlet temperature is 40 ℃, and hydrojet speed is 15ml/min, and plain sheet weightening finish is 1-10%.
5. according to claim 1, a kind of oral mecobalamin sustained-release sheet, it is characterized in that the release requirement, according to drug release determination method (appendix X D first method), according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C three therapeutic methods of traditional Chinese medicine), under the lucifuge condition, with water 100ml is solvent, rotating speed is that per minute 50 changes, measures and uses high performance liquid chromatography, and be mobile phase with methanol-acetonitrile-pH7.0 phosphoric acid triethylamine buffer (25: 85: 400); The detection wavelength is 267nm; Release should meet following requirement:
1) discharged the mecobalamin of 15-45% after 1 hour;
2) discharged the mecobalamin of 45-80% after 2 hours;
3) discharged 80% above mecobalamin after 4 hours.
6. according to claim 1, a kind of oral mecobalamin sustained-release sheet is characterized in that each dosage unit contains 1～3mg mecobalamin.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201010156237 CN102232935A (en) | 2010-04-20 | 2010-04-20 | Novel oral mecobalamin sustained-release tablets and preparation method thereof |
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| CN 201010156237 CN102232935A (en) | 2010-04-20 | 2010-04-20 | Novel oral mecobalamin sustained-release tablets and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109172625A (en) * | 2018-11-30 | 2019-01-11 | 无锡福祈制药有限公司 | A kind of compound preparation for treating diabete peripheral herve pathology |
| CN109820831A (en) * | 2019-03-26 | 2019-05-31 | 江苏四环生物制药有限公司 | A kind of method of granulating of mecobalamin dispersible tables |
| CN111084782A (en) * | 2020-01-17 | 2020-05-01 | 龚跃明 | A pharmaceutical composition for treating diabetic complication |
| CN112730658A (en) * | 2020-12-18 | 2021-04-30 | 卓和药业集团有限公司 | Method for analyzing dissolution curve of mecobalamin tablets |
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| CN1803145A (en) * | 2006-01-24 | 2006-07-19 | 深圳市资福药业有限公司 | Compound formulation containing cobamamide and mecobalamin, and its preparation method |
| CN101234104A (en) * | 2008-01-09 | 2008-08-06 | 北京润德康医药技术有限公司 | Pharmaceutical composition containing lipoic acid and mecobalamin and preparation thereof |
| CN101278935A (en) * | 2008-05-14 | 2008-10-08 | 北京润德康医药技术有限公司 | Medical composition containing derivative of vitamin B group |
| CN101305987A (en) * | 2007-05-17 | 2008-11-19 | 北京利乐生制药科技有限公司 | Compound gabapentin mecobalamin dispersible tables and preparation method thereof |
| JP2010013478A (en) * | 2002-02-07 | 2010-01-21 | Takeda Chem Ind Ltd | Film-coated tablet |
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2010
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010013478A (en) * | 2002-02-07 | 2010-01-21 | Takeda Chem Ind Ltd | Film-coated tablet |
| CN1803145A (en) * | 2006-01-24 | 2006-07-19 | 深圳市资福药业有限公司 | Compound formulation containing cobamamide and mecobalamin, and its preparation method |
| CN101305987A (en) * | 2007-05-17 | 2008-11-19 | 北京利乐生制药科技有限公司 | Compound gabapentin mecobalamin dispersible tables and preparation method thereof |
| CN101234104A (en) * | 2008-01-09 | 2008-08-06 | 北京润德康医药技术有限公司 | Pharmaceutical composition containing lipoic acid and mecobalamin and preparation thereof |
| CN101278935A (en) * | 2008-05-14 | 2008-10-08 | 北京润德康医药技术有限公司 | Medical composition containing derivative of vitamin B group |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109172625A (en) * | 2018-11-30 | 2019-01-11 | 无锡福祈制药有限公司 | A kind of compound preparation for treating diabete peripheral herve pathology |
| CN109820831A (en) * | 2019-03-26 | 2019-05-31 | 江苏四环生物制药有限公司 | A kind of method of granulating of mecobalamin dispersible tables |
| CN111084782A (en) * | 2020-01-17 | 2020-05-01 | 龚跃明 | A pharmaceutical composition for treating diabetic complication |
| CN112730658A (en) * | 2020-12-18 | 2021-04-30 | 卓和药业集团有限公司 | Method for analyzing dissolution curve of mecobalamin tablets |
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Application publication date: 20111109 |