CN102048706B - Darifenacin hydrobromide sustained-release tablet and preparation method - Google Patents
Darifenacin hydrobromide sustained-release tablet and preparation method Download PDFInfo
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- CN102048706B CN102048706B CN2011100053185A CN201110005318A CN102048706B CN 102048706 B CN102048706 B CN 102048706B CN 2011100053185 A CN2011100053185 A CN 2011100053185A CN 201110005318 A CN201110005318 A CN 201110005318A CN 102048706 B CN102048706 B CN 102048706B
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- darifenacin hydrobromide
- darifenacin
- sustained release
- lactose
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Abstract
The invention belongs to the field of new medicament technologies, and in particular relates to a darifenacin hydrobromide sustained-release tablet and a preparation method. The darifenacin hydrobromide sustained-release tablet adopts carbomer as a new retardant, and the dosage of the carbomer is 1-5% by weight of the preparation and can reach considerable vitro release and bioavailability compared with the dosage of the retardant in the prior art, which is more than half of the dosage of a prescription. The dosage of the retardant in the new method is greatly reduced so that the consumption of materials can be greatly reduced, the process is simpler, the controllability is better, the efficiency is improved, and the production cost is greatly reduced.
Description
Technical field
The invention belongs to the medicine new technical field, be specifically related to a kind of darifenacin hydrobromide sustained release tablets and method for preparing that adopts carbomer as blocker.
Background technology
Darifenacin hydrobromide sustained release tablets is used to treat bladder hyperkinesia diseases (OAB) such as urinary incontinence, urgent micturition and frequent micturition, and U.S. FDA is in the darifenacin hydrobromide sustained release tablets (Enablex of December in 2004 approval on the 22nd Novartis
) listing.Darifenacin plays a role through blocking main M3 receptor to the bladder muscle contractile response; It is the strong malicious deep alkali receptor blocking agent of imitating; Help to alleviate the incidence rate of urinary incontinence, increase bladder urine reserves, reduce number of micturitions and reduce the constriction and the urgency of being eager to urinate.The M3 of darifenacin hydrobromide acts in all OAB medicines has uniqueness, processes the incidence rate that slow releasing tablet can reduce nervus centralis and cardiovascular adverse effects.
The open Enablex of the orange book of U.S. FDA (Orange Book)
Be to adopt the formulation and technology of patent US6106864 to prepare, it adopts high-molecular weight hypromellose as blocker, the large usage quantity of hypromellose, and the ratio that accounts for the tablet total weight amount is up to 56 ~ 58%.Though said method has reached ideal external slow release effect and bioavailability; But the use of high weight and a high proportion of blocker had both caused the increase greatly of the consumption of material, thereby had increased cost; Make that also the adjustable space of prescription is less, the production poor controllability.
Summary of the invention
The object of the invention is exactly the defective to above-mentioned existence, provides a kind of novel blocker to be used to prepare the method for darifenacin hydrobromide sustained release tablets.
Use the novel auxiliary material carbomer as blocker, only account for 1% ~ 5% of weight of formulation, for example: consumption is merely 1mg ~ 5mg, and sheet heavily is 100mg; Perhaps the carbomer consumption is merely 2mg ~ 10mg, and sheet heavily is 200mg, can reach release in vitro effect and the bioavailability suitable with existing method.Because the minimizing significantly of the consumption of blocker in the new method, can reduce the consumption of material, also make the prescription adjustability obviously strengthen, thereby can make technology simpler, controllability is better, and efficient improves, and production cost significantly reduces.
Darifenacin hydrobromide sustained release tablets of the present invention adopts novel blocker carbomer; Consumption only accounts for 1% ~ 5% of weight of formulation; The calcium hydrogen phosphate and the lactose that adopt compressibility simultaneously be as diluent, and magnesium stearate is as lubricant, and adopt powder mixes direct compression technology.
Technical scheme of the present invention is: a kind of darifenacin hydrobromide sustained release tablets, adopt the blocker of carbomer as slow releasing preparation.
1% ~ 5% of described blocker carbomer comprises weight of formulation.
Described a kind of darifenacin hydrobromide sustained release tablets, comprise by weight following drug component:
Darifenacin hydrobromide 1%-20%;
Carbomer 1%-5%;
Calcium hydrogen phosphate 16%-91%;
Lactose 5%-51%;
Magnesium stearate 0.1%-10%.
Adopt powder mixes direct compression technology to prepare darifenacin hydrobromide sustained release tablets of the present invention, may further comprise the steps:
1. darifenacin hydrobromide, calcium hydrogen phosphate, carbomer, lactose are sieved mix homogeneously;
2. get magnesium stearate and add above powder, mixing;
3. adopt powder mixes direct compression technology, the heavy and pressure of adjustment sheet, tabletting, coating.
Beneficial effect of the present invention is: use the novel auxiliary material carbomer as blocker, only account for 1% ~ 5% of weight of formulation, for example: consumption is merely 1mg ~ 5mg, and sheet heavily is 100mg; Perhaps the carbomer consumption is merely 2mg ~ 10mg, and sheet heavily is 200mg, can reach release in vitro effect and the bioavailability suitable with existing method.Because the minimizing significantly of the consumption of blocker, can reduce the consumption of material, also make the prescription adjustability obviously strengthen, reduced production cost simultaneously, enhance productivity.
Technology of the present invention in addition adopts calcium hydrogen phosphate and the lactose of compressibility as diluent simultaneously, and magnesium stearate is as lubricant, and preparation technology is simple for prescription, is easy to put into production; The powder flowbility that makes is better, and be more than 36 degree angle of repose, in tablet manufacture, can satisfy the requirement of high speed tabletting; The tablet hardness of compacting is better, good looking appearance, and technology is simple; Controllability is good, and efficient improves, and production cost significantly lowers.
The specific embodiment:
In order to understand the present invention better, specify technical scheme of the present invention with instantiation below, but the present invention is not limited thereto.
Embodiment 1
Darifenacin hydrobromide 8.93g
Carbomer 974P 5.6g
Calcium hydrogen phosphate 133.47g
Lactose 50.0g
Magnesium stearate 2.0g
Gross weight 200g
Process 1000
Darifenacin hydrobromide, carbomer 974P, calcium hydrogen phosphate and lactose are crossed 80 mesh sieves, the three-dimensional mixer mix homogeneously.Magnesium stearate lubricant is added above powder, mix homogeneously in three-dimensional mixer, stomach dissolution type coating powder coating is used in the stamping of f8mm scrobicula.
Embodiment 2
Darifenacin hydrobromide 8.93g
Carbomer 971P 2g
Calcium hydrogen phosphate 137.07g
Lactose 50.0g
Magnesium stearate 2.0g
Gross weight 200g
Process 1000
Darifenacin hydrobromide, carbomer 971P, calcium hydrogen phosphate and lactose are crossed 80 mesh sieves, the three-dimensional mixer mix homogeneously.Magnesium stearate lubricant is added above powder, mix homogeneously in three-dimensional mixer, stomach dissolution type coating powder coating is used in the stamping of f8mm scrobicula.
Embodiment 3
Darifenacin hydrobromide 8.93g
Carbomer 934 P 10g
Calcium hydrogen phosphate 129.07g
Lactose 50.0g
Magnesium stearate 2.0g
Gross weight 200g
Process 1000
Darifenacin hydrobromide, carbomer 934 P, calcium hydrogen phosphate and lactose are crossed 80 mesh sieves, the three-dimensional mixer mix homogeneously.Magnesium stearate lubricant is added above powder, mix homogeneously in three-dimensional mixer, stomach dissolution type coating powder coating is used in the stamping of f8mm scrobicula.
Embodiment 4
Darifenacin hydrobromide 17.86g
Carbomer 974P 5.6g
Calcium hydrogen phosphate 124.54g
Lactose 50.0g
Magnesium stearate 2.0g
Gross weight 200g
Process 1000
Darifenacin hydrobromide, carbomer 974P, calcium hydrogen phosphate and lactose are crossed 80 mesh sieves, the three-dimensional mixer mix homogeneously.Magnesium stearate lubricant is added above powder, mix homogeneously in three-dimensional mixer, stomach dissolution type coating powder coating is used in the stamping of f8mm scrobicula.
Embodiment 5
Darifenacin hydrobromide 17.86g
Carbomer 971P 2g
Calcium hydrogen phosphate 128.14g
Lactose 50.0g
Magnesium stearate 2.0g
Gross weight 200g
Process 1000
Darifenacin hydrobromide, carbomer 971P, calcium hydrogen phosphate and lactose are crossed 80 mesh sieves, the three-dimensional mixer mix homogeneously.Magnesium stearate lubricant is added above powder, mix homogeneously in three-dimensional mixer, stomach dissolution type coating powder coating is used in the stamping of f8mm scrobicula.
Embodiment 6
Darifenacin hydrobromide 17.86g
Carbomer 934 P 10g
Calcium hydrogen phosphate 120.14g
Lactose 50.0g
Magnesium stearate 2.0g
Gross weight 200g
Process 1000
Darifenacin hydrobromide, carbomer 934 P, calcium hydrogen phosphate and lactose are crossed 80 mesh sieves, the three-dimensional mixer mix homogeneously.Magnesium stearate lubricant is added above powder, mix homogeneously in three-dimensional mixer, stomach dissolution type coating powder coating is used in the stamping of f8mm scrobicula.
Embodiment 7
Darifenacin hydrobromide 8.93g
Carbomer 974P 2.8g
Calcium hydrogen phosphate 61.77g
Lactose 25.5g
Magnesium stearate 1.0g
Gross weight 100g
Process 1000
Darifenacin hydrobromide, carbomer 974P, calcium hydrogen phosphate and lactose are crossed 80 mesh sieves, the three-dimensional mixer mix homogeneously.Magnesium stearate lubricant is added above powder, mix homogeneously in three-dimensional mixer, stomach dissolution type coating powder coating is used in the stamping of f8mm scrobicula.
Embodiment 8
Darifenacin hydrobromide 17.86g
Carbomer 974P 2.8g
Calcium hydrogen phosphate 52.84g
Lactose 25.5g
Magnesium stearate 1.0g
Gross weight 100g
Process 1000
Darifenacin hydrobromide, carbomer 974P, calcium hydrogen phosphate and lactose are crossed 80 mesh sieves, the three-dimensional mixer mix homogeneously.Magnesium stearate lubricant is added above powder, mix homogeneously in three-dimensional mixer, stomach dissolution type coating powder coating is used in the stamping of f8mm scrobicula.
Embodiment 9
The release degree relatively
Darifenacin hydrobromide sustained release tablets (the Enablex that embodiment 1-8 and Novartis Co.,Ltd produce
) carry out the release in vitro degree relatively.According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method); Adopt the device of dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C, second method); As release medium, rotating speed is 100 rev/mins with the hydrochloric acid of 900ml0.01mol/L, in accordance with the law operation.Through 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours; Get solution 10ml (and in time in operating instrument, replenishing release medium 10ml) respectively; Filter; Get subsequent filtrate, as need testing solution; It is an amount of that other gets the darifenacin hydrobromide reference substance, accurate claims surely, is dissolved in water and dilutes and process the solution that contains darifenacin 8.3 μ g among every 1ml approximately, as reference substance solution.
With the octadecylsilane chemically bonded silica is filler; With 0.05mol/l potassium dihydrogen phosphate (with triethylamine adjust pH to 6.0)-methanol (40:60) is mobile phase, 25 ℃ of column temperatures, flow velocity 1.0ml; The detection wavelength is 228nm.Precision is measured each 20 μ l of above solution, injecting chromatograph, and the record chromatogram is with every burst size at different time of calculated by peak area.Result of the test is seen table 1.
Table 1 embodiment 1-8 and listing article (Enablex
) the release in vitro degree relatively
* the f2 factorization method is to estimate the method for the similarity of stripping curve, if tried and the stripping curve of reference preparation between the f2 value be not less than 50, think that then both are similar.
Can find out the darifenacin hydrobromide sustained release tablets (Enablex that embodiment 1～8 uses the darifenacin hydrobromide sustained release tablets of 1% ~ 5% carbomer preparation to produce with the Novartis Co.,Ltd of having gone on the market by last table
) have a suitable release in vitro degree.
Embodiment 10
Bioavailability relatively
Darifenacin hydrobromide sustained release tablets (the Enablex of the tablet of embodiment 4 (A medicine) and Novartis Co.,Ltd
, the R medicine)
Self front and back 3 * 2 trial design is adopted in test.6 Beagle Canis familiaris L.s, each 3 of male and female, about 1 age, regular grade, the body weight 6.2 ~ 6.5kg when being used to test.Be divided into 2 groups by body weight, every group of 3 animals are established test sample (A medicine group) and reference substance (R medicine group), fasting 16 hours.Administration is 2 times altogether, behind the 1st administration and the finishing collecting biological sample, at interval 2 all cleaning phases, carries out medicine the 2nd time.Adopt 3 * 2 to intersect administration to reduce the influence that animal individual difference causes result of the test.Dosage is 4mg/kg.
0.5h before the administration and after the administration, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h,
, 36h gathers venous blood 1.5ml, anticoagulant heparin, 3000r/min is centrifugal, gets blood plasma and preserves in-80 ℃ and be equipped with inspection.2 weeks were cleaned after date, and two treated animal cross matchings are collected as stated above.Result of the test is seen table 2.
The bioavailability AUC of the tablet of table 2 embodiment 4 (A medicine) and listing article (Enablex, R medicine) and relative bioavailability thereof and main pharmacokinetic parameter Cmax and ratio thereof
Experimental result shows: average blood drug level-time changing curve was all close after beasle dog per os filling stomach gave A medicine and R medicine 4mg/kg, and the main pharmacokinetic parameter (mean+SD) of test sample A medicine and reference substance R medicine is respectively T
1/2: 6.79 ± 2.695 h and 6.521 ± 2.686 h, C
Max: 127.322 ± 112.703 ng/ml and 125.925 ± 101.827 ng/ml, AUC
0-t: 591.733 ± 475.623 μ gL
-1H and 607.711 ± 478.232 μ gL
-1H, T
MaxBe 6.00 h.The A medicine is 99.7 ± 13.5% with respect to the bioavailability of R medicine.
Data show, the darifenacin hydrobromide sustained release tablets (Enablex that preparation provided by the invention and the Novartis Co.,Ltd of having gone on the market produce
) bioequivalence that has.
Claims (4)
1. a darifenacin hydrobromide sustained release tablets is characterized in that, is made up of the drug component by following percentage by weight:
Darifenacin hydrobromide 1%-20%;
Carbomer 1%-5%;
Calcium hydrogen phosphate 16%-91%;
Lactose 5%-50%;
Magnesium stearate 0.1%-10%.
2. darifenacin hydrobromide sustained release tablets according to claim 1 is characterized in that, carbomer is selected from one or more among carbomer 974P, carbomer 971P, the carbomer 934 P.
3. darifenacin hydrobromide sustained release tablets according to claim 1 is characterized in that, the preferred carbomer 974P of described carbomer.
4. according to claim 1 or the described darifenacin hydrobromide sustained release tablets of 3 arbitrary claim, it is characterized in that, adopt powder mixes direct compression technology to prepare.
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|---|---|---|---|
| CN2011100053185A CN102048706B (en) | 2011-01-12 | 2011-01-12 | Darifenacin hydrobromide sustained-release tablet and preparation method |
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|---|---|---|---|
| CN2011100053185A CN102048706B (en) | 2011-01-12 | 2011-01-12 | Darifenacin hydrobromide sustained-release tablet and preparation method |
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| CN102048706B true CN102048706B (en) | 2012-02-22 |
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| CN102579379B (en) * | 2011-12-29 | 2016-08-10 | 北京科信必成医药科技发展有限公司 | A kind of medicament slow release preparation and preparation method thereof |
| CN102600096B (en) * | 2011-12-29 | 2016-08-10 | 北京科信必成医药科技发展有限公司 | A kind of darifenacin slow releasing preparation and preparation method thereof |
| CN106420647B (en) * | 2016-10-13 | 2019-11-22 | 山东创新药物研发有限公司 | A kind of sustained release preparation and preparation method thereof containing darifenacin hydrobromide |
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| GB9518953D0 (en) * | 1995-09-15 | 1995-11-15 | Pfizer Ltd | Pharmaceutical formulations |
| US20030185882A1 (en) * | 2001-11-06 | 2003-10-02 | Vergez Juan A. | Pharmaceutical compositions containing oxybutynin |
| GB0129962D0 (en) * | 2001-12-14 | 2002-02-06 | Pfizer Ltd | Method of treatment |
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