CN1660123A - Sustained release preparation for treating cardiovascular diseases, adn preparation method, quality control method - Google Patents
Sustained release preparation for treating cardiovascular diseases, adn preparation method, quality control method Download PDFInfo
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- CN1660123A CN1660123A CN 200410004449 CN200410004449A CN1660123A CN 1660123 A CN1660123 A CN 1660123A CN 200410004449 CN200410004449 CN 200410004449 CN 200410004449 A CN200410004449 A CN 200410004449A CN 1660123 A CN1660123 A CN 1660123A
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- preparation
- slow releasing
- weight portion
- standard solution
- puerarin
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- 238000003908 quality control method Methods 0.000 title claims abstract description 12
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 68
- 239000003405 delayed action preparation Substances 0.000 title 1
- 229930003944 flavone Natural products 0.000 claims abstract description 41
- 235000011949 flavones Nutrition 0.000 claims abstract description 41
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 claims abstract description 37
- 150000002212 flavone derivatives Chemical class 0.000 claims abstract description 37
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 claims abstract description 37
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 16
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 11
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 4
- ZQSIJRDFPHDXIC-UHFFFAOYSA-N daidzein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC=C2C1=O ZQSIJRDFPHDXIC-UHFFFAOYSA-N 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 38
- 239000012086 standard solution Substances 0.000 claims description 33
- RXUWDKBZZLIASQ-UHFFFAOYSA-N Puerarin Natural products OCC1OC(Oc2c(O)cc(O)c3C(=O)C(=COc23)c4ccc(O)cc4)C(O)C(O)C1O RXUWDKBZZLIASQ-UHFFFAOYSA-N 0.000 claims description 32
- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 25
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000005251 capillar electrophoresis Methods 0.000 claims description 15
- 230000014759 maintenance of location Effects 0.000 claims description 15
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- UZJOVZNBAJPLFU-UHFFFAOYSA-N 3'-methoxypuerarin Natural products COc1cc(ccc1O)C2=COc3c(OC4OC(CO)C(O)C(O)C4O)c(O)cc(O)c3C2=O UZJOVZNBAJPLFU-UHFFFAOYSA-N 0.000 claims description 5
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- YCUNGEJJOMKCGZ-UHFFFAOYSA-N Pallidiflorin Natural products C1=CC(OC)=CC=C1C1=COC2=CC=CC(O)=C2C1=O YCUNGEJJOMKCGZ-UHFFFAOYSA-N 0.000 claims description 3
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- Medicinal Preparation (AREA)
Abstract
A slowly-releasing medicine for treating cardiovascular disease is prepared through pulverizing pueraria flavone, sieving, proportionally mixing it with hydroxypropyl methylcellulose, adding alcohol, granulating by sieving, drying, proportionally mixing with magnesium stearate and SiO2, stirring and tabletting. Its quality control method is also disclosed.
Description
Technical field
The present invention relates to a kind of slow releasing preparation for the treatment of cardiovascular disease, particularly the Radix Puerariae total flavones slow releasing preparation belongs to formulation art.
Background technology
Clinical practice has proved that yufeng ningxin tablets, yufeng ningxin pian is the comparatively ideal Chinese patent medicine of cardiovascular disease, the neck pain that this medicine causes releasing hypertension, and dizziness headache, coronary heart disease, diseases such as angina pectoris are evident in efficacy.Yet its production technology is also more original at present, and the controllability of quality is relatively poor, and dosage form is single, and active constituent content is lower in the preparation, and taking dose is big.The needs of modern clinical application can not be satisfied and adapt to the existence of these problems, in order to improve the quality of this medicine, gives full play to its effectiveness, is necessary very much to develop convenient and long lasting novel form.
Summary of the invention
One object of the present invention is to disclose a kind of Radix Puerariae total flavones slow releasing preparation for the treatment of cardiovascular disease; Another object of the present invention is a kind of preparation method for the treatment of the Radix Puerariae total flavones slow releasing preparation of cardiovascular disease of open preparation; Another object of the present invention is to disclose the method for quality control of this slow releasing preparation.
The crude drug that pharmaceutical composition of the present invention is made slow releasing preparation form and part by weight as follows:
Extract product of general flavone of kudzuvine root 300-600 weight portion
Hydroxypropyl emthylcellulose 50-200 weight portion
Magnesium stearate 1-4 weight portion.
Crude drug composition and part by weight that pharmaceutical composition of the present invention is made slow releasing preparation are preferably:
Extract product of general flavone of kudzuvine root 350-500 weight portion
Hydroxypropyl emthylcellulose 80-150 weight portion
Magnesium stearate 1-3 weight portion.
The crude drug group that pharmaceutical composition of the present invention is made slow releasing preparation can also be:
Extract product of general flavone of kudzuvine root 300-600 weight portion
Hydroxypropyl emthylcellulose 50-200 weight portion
Magnesium stearate 1-4 weight portion
Silica 1-6 weight portion.
Crude drug composition and part by weight that pharmaceutical composition of the present invention is made slow releasing preparation are preferably:
Extract product of general flavone of kudzuvine root 350-500 weight portion
Hydroxypropyl emthylcellulose 80-150 weight portion
Magnesium stearate 1-3 weight portion
Silicon dioxide 3-5 weight portion.
The method that pharmaceutical composition of the present invention is made slow releasing preparation is:
With the extract product of general flavone of kudzuvine root crushing screening, in proportion with the hydroxypropyl emthylcellulose mix homogeneously, add an amount of ethanol and make wetting agent, crossing the 15-30 mesh sieve granulates, 30-60 ℃ dry 1-3 hour, cross 24 mesh sieve granulate, add magnesium stearate and silicon dioxide in proportion, mix homogeneously, often regulation becomes clinical acceptable slow releasing preparation such as tablet, capsule, granule, micropill etc.
The above-mentioned raw materials extract product of general flavone of kudzuvine root can be selected commercially available product for use, also available following method makes: Radix Puerariae (Radix Puerariae) is measured Diluted Alcohols with 7 times, extract 3 times, each 2 hours, extracting solution concentrates to such an extent that thick paste (50 ℃ of relative densities are 1.3-1.4) adds 2 times of water dissolutioies to dose, filter, filtrate boils off ethanol, adds water and makes into 0.5～1g crude drug/ml solution and cross macroporous resin column, decontamination, the remainder washing, the effective ingredient that is adsorbed, 90% alcohol desorption, the dry extract product of general flavone of kudzuvine root that gets of ethanol liquid, its properties and characteristics is: general flavone content is 50-80% (UV method mensuration), and is soluble in water.
Extract product of general flavone of kudzuvine root is not a single component, but a class chemical substance, and its character is because of the difference of the place of production of medical material, extraction process etc., and is widely different.Slow releasing preparation is a technology content and exigent dosage form, so it is higher to the prescription that extract product of general flavone of kudzuvine root is relevant, otherwise, the prepared slow releasing tablet quality and the repeatability of technology are difficult to guarantee, following fingerprint chromatogram method can reach the Monitoring and Controlling quality, estimate slow releasing preparation multicomponent drug release behavior of the present invention, the control inherent quality.
The fingerprint chromatogram method method of quality control that pharmaceutical composition of the present invention is made slow releasing preparation is:
1. high performance capillary electrophoresis (HPCE)-[referring to accompanying drawing 1]
Chromatographic condition: efficient capillary electrophoresis apparatus,
Quartz capillary column: 50 μ m * 39cm,
Detection window: 100 * 200 μ m
Column temperature: 25 ℃
UV-detector: the detection wavelength is 254nm
Separation buffer solution: 0.1M Borax0.1M NaOH (pH10.12)
Separation voltage: 20KV
Anodal pressure sample introduction, sample injection time 5 seconds
The preparation of standard solution: preparation baicalin standard solution, puerarin standard solution, daiazi, daidzein standard solution;
The preparation sample of need testing solution: Radix Puerariae flavone slow releasing tablet (lot number: 000914)
Experimental technique: first method according to two drug release determination methods of Pharmacopoeia of the People's Republic of China version in 2000 is carried out, and the sampling time point is: 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h.
Finger printing:
Assay method: according to above-mentioned chromatographic condition sample introduction standard solution and need testing solution, write down 30 minutes chromatogram promptly.
The peak sequence of main peaks and retention time: daiazi (daidzin) 10-13min; Daidzein (daidzein) 12-16min; Baicalin (Bdicalin: 15-19min internal standard substance); Puerarin (Puerarin) 21-25min.
2. high performance liquid chromatography (HPLC)-[referring to accompanying drawing 2]
Chromatographic condition: high performance liquid chromatograph, detector: UV-1575, pump: TU-1580, automatic sampler: AS-1555
Chromatographic column: C18 (5 μ m)
Detect wavelength: 254nm
Column temperature: 20-35 ℃
Flow velocity: 1.0ml/min
Mobile phase: 0.2% aqueous acetic acid-acetonitrile binary gradient elution
The gradient program
Sample size: 20 μ l
| Time (min) | 0.2% aqueous acetic acid (%) | Acetonitrile (%) |
| 0 | ?90 | ?10 |
| 20 | ?90 | ?10 |
| 50 | ?50 | ?50 |
| 55 | ?90 | ?10 |
| 70 | ?90 | ?10 |
The preparation of standard solution: preparation puerarin, 3 '-methoxy puerarin, daiazi, daidzein, genistein, genistin standard solution;
The preparation of need testing solution: sample: Radix Puerariae flavone slow releasing tablet (lot number: 031002)
Experimental technique: first method according to two drug release determination methods of Pharmacopoeia of the People's Republic of China version in 2000 is carried out, and the sampling time point is: 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h.
Finger printing:
Assay method: according to above-mentioned chromatographic condition sample introduction standard solution and need testing solution, write down 50 minutes chromatogram promptly.
Can monitor about 16 peaks, but wherein according to going out 6 main peaks of peak sequencing quantitative analysis, wherein the chromatographic peak retention time of puerarin is 19-21min, 3 '-the chromatographic peak retention time of methoxy puerarin is 24-27min, the chromatographic peak retention time of daiazi is 28-31min, and the chromatographic peak retention time of daidzein is 38-40min.
The present invention overcomes existing preparation process difficulty, by the slow releasing preparation framework material, adjuvant and the each component consumption that are suitable for extract product of general flavone of kudzuvine root are selected, invents a kind of process stabilizing, and convenient drug administration prolongs drug effect, reduces the slow releasing agent of side effect.Slow releasing preparation of the present invention overcomes the shortcoming of present conventional tablet, active constituent content height in the preparation, taking dose is little, and the used slow-release material of the present invention is hydroxypropyl emthylcellulose (HPMC), simpler than other open source literature slow-released systems, thereby help quality control, the suitability for industrialized production safe and feasible.
Fingerprint chromatogram method method of quality control of the present invention, easy to operation saving time can be carried out effective mass control to slow releasing preparation of the present invention.
Following experimental example progress explanation the present invention.
Experimental example 1 sustained-release tablet recipe screening test of the present invention
Ratio with adjuvant and Radix Puerariae flavone extract, preparation technologies etc. are the investigation factor, a plurality of prescriptions have been designed, by estimating the release in vitro degree of tablet, according to the release designing requirement of slow releasing tablet, promptly 1,3,8 hours release can stably be controlled at 15-30% respectively, 30-50% and greater than 70%, thus filter out best prescription and preparation technology.
Through screening the present invention's prescription (No. 13) is best prescription.
| Time (h) discharges percentage rate (%) prescription and technology numbering thereof | ?0.5 | ?1 | ?2 | ?3 | ?4 | ?6 | ?8 | ?10 | ?12 |
| ?1 | ?7.92 | ?10.6 | ?18.3 | ?25.2 | ?31.5 | ?70.5 | ?86.2 | ?95.5 | ?100.5 |
| ?2 | ?8.60 | ?13.0 | ?20.5 | ?33.2 | ?39.0 | ?46.7 | ?61.9 | ?69.5 | ?79.5 |
| ?3 | ?6.76 | ?9.56 | ?20.0 | ?28.1 | ?34.0 | ?41.2 | ?46.5 | ?55.5 | ?71.5 |
| ?4 | ?8.57 | ?14.2 | ?27.3 | ?35.0 | ?41.2 | ?47.1 | ?52.5 | ?64.2 | ?77.8 |
| ?5 | ?6.19 | ?10.7 | ?17.8 | ?23.2 | ?30.9 | ?39.1 | ?48.0 | ?53.9 | ?58.6 |
| ?6 | ?5.60 | ?10.2 | ?17.7 | ?25.2 | ?37.3 | ?44.2 | ?55.4 | ?59.3 | ?63.4 |
| ?7 | ?5.32 | ?8.40 | ?14.5 | ?22.9 | ?28.4 | ?36.4 | ?45.0 | ?50.8 | ?65.5 |
| ?8 | ?7.64 | ?11.6 | ?18.8 | ?29.7 | ?36.3 | ?47.5 | ?58.1 | ?64.2 | ?70.0 |
| ?9 | ?12.4 | ?19.2 | ?33.8 | ?43.1 | ?50.6 | ?63.2 | ?74.8 | ?81.4 | ?87.4 |
| ?10 | ?12.3 | ?17.9 | ?28.6 | ?38.4 | ?46.3 | ?64.3 | ?76.1 | ?83.6 | ?96.9 |
| ?11 | ?32.4 | ?41.6 | ?55.2 | ?66.1 | ?75.4 | ?86.4 | ?84.4 | ?85.3 | ?85.6 |
| ?12 | ?8.74 | ?14.1 | ?30.8 | ?39.8 | ?48.4 | ?62.1 | ?71.8 | ?80.3 | ?86.1 |
| ?13 | ?16.9 | ?27.9 | ?39.6 | ?51.8 | ?61.9 | ?77.7 | ?86.7 | ?91.8 | ?93.1 |
| ?14 | ?20.2 | ?29.4 | ?44.0 | ?54.4 | ?64.0 | ?77.0 | ?86.2 | ?91.1 | ?90.1 |
| ?15 | ?15.5 | ?20.8 | ?38.2 | ?46.6 | ?51.1 | ?66.6 | ?78.8 | ?85.7 | ?91.5 |
| ?16 | ?15.2 | ?20.2 | ?35.5 | ?46.4 | ?65.1 | ?73.8 | ?83.9 | ?87.4 | ?89.2 |
| ?17 | ?16.0 | ?23.8 | ?37.7 | ?49.9 | ?59.5 | ?77.3 | ?85.9 | ?91.1 | ?87.6 |
| ?18 | ?15.4 | ?22.4 | ?42.0 | ?53.5 | ?68.4 | ?84.7 | ?89.2 | ?89.0 | ?87.7 |
| ?19 | ?12.4 | ?16.9 | ?27.5 | ?35.3 | ?43.6 | ?56.7 | ?69.4 | ?79.7 | ?86.0 |
| ?20 | ?11.9 | ?15.3 | ?26.6 | ?35.5 | ?43.6 | ?59.8 | ?68.0 | ?78.2 | ?82.9 |
| ?21 | ?11.3 | ?18.4 | ?28.5 | ?39.3 | ?48.3 | ?64.3 | ?79.8 | ?87.7 | ?91.3 |
| ?22 | ?14.5 | ?19.6 | ?31.5 | ?42.2 | ?54.2 | ?70.7 | ?86.5 | ?95.1 | ?96.6 |
| ?23 | ?13.2 | ?19.2 | ?31.9 | ?43.4 | ?54.4 | ?72.2 | ?85.7 | ?92.1 | ?95.1 |
The comparison of experimental example 2 slow releasing tablet of the present invention and conventional tablet (yufeng ningxin tablets, yufeng ningxin pian) bioavailability
Laboratory sample:
Radix Puerariae flavone slow releasing tablet (self-control, lot number 991115)
Yufeng ningxin tablets, yufeng ningxin pian (Chinese medicine refinery of Beijing Tongrentang, lot number 9120006)
Laboratory animal: 3 of healthy hybrid dogs
The screening of dosage is with definite: calculate that according to the clinical consumption of yufeng ningxin tablets, yufeng ningxin pian the dosage of dog should be 15mg/kg, but in the test, by this dosed administration, because of the blood drug level of puerarin very low, do not detect puerarin in the blood in the detectability of HPLC, so dosage is increased to 60mg/kg, above experimental result obtains under this dosage.
Experimentation: 3 of healthy hybrid dogs, fasting 24h before the experiment adopts the cross-over experiment design at random of two processing, two cycles, and the clean phase was 2 weeks.Dosage is pressed the 60mg/kg Radix Puerariae flavone and is given dog oral sustained release sheet and yufeng ningxin tablets, yufeng ningxin pian.The Radix Puerariae flavone slow releasing tablet is oral early morning, take medicine back 0.5,1,2,3,4,6,8,10,12,15,20,24h extracting vein blood 2ml, and the heparin sodium anticoagulant, centrifugal immediately 5min (4000r/min), it is standby to isolate blood plasma.Yufeng ningxin tablets, yufeng ningxin pian is handled the same.
The peak time T of yufeng ningxin tablets, yufeng ningxin pian as a result
MaxWith mean residence time MRT difference 3.3 ± 0.6h and 4.6 ± 0.4h.The T of Radix Puerariae flavone slow releasing tablet
MaxBe respectively 4.7 ± 1.2h and 7.6 ± 0.6h with MRT, slow releasing function is obvious.The relative bioavailability of Radix Puerariae flavone slow releasing tablet is 181 ± 54%, absorbs to be better than yufeng ningxin tablets, yufeng ningxin pian.
The comparison relatively of the external degree of putting of experimental example 3 invention slow releasing tablet and conventional tablet (yufeng ningxin tablets, yufeng ningxin pian)
(lot number: 000315) (Chinese medicine refinery of Beijing Tongrentang: release in vitro degree lot number 9120006) relatively with commercially available yufeng ningxin tablets, yufeng ningxin pian for slow releasing tablet of the present invention
| Time (hour) | ????0.5 | ??1 | ??2 | ??3 | ??4 | ??6 | ??8 | ??10 | ??12 |
| Commercially available average cumulative discharges percentage rate | ????1.79 | ??10.32 | ??24.69 | ??46.53 | ??65.84 | ??96.07 | |||
| Standard deviation | ????0.385 | ??2.232 | ??8.116 | ??13.006 | ??12.471 | ??2.056 | |||
| The slow releasing tablet average cumulative discharges percentage rate | ????9.81 | ??16.58 | ??27.88 | ??38.77 | ??53.04 | ??65.99 | ??80.17 | ??88.85 | ??95.24 |
| Standard deviation | ????0.173 | ??2.79 | ??2.95 | ??3.23 | ??2.47 | ??2.20 | ??2.96 | ??3.38 | ??0.81 |
As seen knot is, the self-control slow releasing tablet is compared with the release in vitro degree of commercially available yufeng ningxin tablets, yufeng ningxin pian, has tangible slow releasing function.
From drug release behavior, commercially available yufeng ningxin tablets, yufeng ningxin pian is complete release in 6 hours, and the self-control slow releasing tablet then lasted till to have slow releasing function 12 hours.
From the deviation of data, the standard deviation of each time point data of commercially available yufeng ningxin tablets, yufeng ningxin pian is bigger, and the data standard deviation of self-control slow releasing tablet is less, and quality controllability is good.
Experimental example 4 slow releasing tablet of the present invention inside and outside correlation tests
Puerarin curve when the intravital medicine of dog meets open two-compartment model, according to PA (Fa) in the Loo-Riegelman Equation for Calculating body, PA (Fa) in the same time dog body is returned with batch Radix Puerariae flavone slow releasing tablet release in vitro percentage rate (Fd), correlation coefficient is 0.9898, the inside and outside is relevant, can be according to absorbing state in the release in vitro degrees of data predictor.
The dependency of experimental example 5 method of quality control of the present invention relatively
Carry out the experiment of release in vitro degree according to first method of two drug release determination methods of Pharmacopoeia of the People's Republic of China version in 2000, compare ultraviolet spectrophotometry (detection total flavones), high performance liquid chromatography (HPLC, detection puerarin), high performance capillary electrophoresis (HPCE, detection puerarin) is estimated the dependency of release in vitro degree.
Sample lot number 991115
| Time (hour) | 0.5 | ??1 | ??2 | ??4 | ??6 | ????8 | ????10 | ????12 |
| Average cumulative discharges percentage rate (UV method) | 6.91 | ??11.4 | ??22.7 | ??40.7 | ??54.5 | ????66.5 | ????84.5 | ????91.3 |
| Average cumulative discharges percentage rate (HPLC method) | 10.3 | ??15.8 | ??24.0 | ??46.3 | ??56.6 | ????65.6 | ????84.7 | ????91.1 |
| Average cumulative discharges percentage rate (HPCE method) | 10.45 | ??16.09 | ??27.8 | ???46.7 | ??62.5 | ????76.3 | ????84.5 | ????93.7 |
As seen, high performance liquid chromatography, high performance capillary electrophoresis and ultraviolet spectrophotometry compare, basically identical, good relationship.
High performance capillary electrophoresis (HPCE) method of quality control of experimental example 6 slow releasing preparation
1.1 instrument and chromatographic condition:
Instrument: P/ACE5000 type efficient capillary electrophoresis apparatus, U.S. Beckman company produces
Quartz capillary column: 50 μ m * 39cm,
Detection window: 100 * 200 μ m
Column temperature: 25 ℃
UV-detector: the detection wavelength is 254nm
Separation buffer solution: 0.1M Borax0.1M NaOH (pH10.12)
Separation voltage: 20KV
Anodal pressure sample introduction, sample injection time 5 seconds
1.2 reference substance and reagent
Puerarin (Puerarin) reference substance (lot number: 0752-9806 purchases in Chinese pharmaceutical biological product and identifies institute)
Baicalin (Bdicalin) reference substance (lot number: 0715-9708 purchases in Chinese pharmaceutical biological product and identifies institute)
Daiazi (daidzin) reference substance (lot number: C1803 purchases the company in ICC)
Daidzein (daidzein) reference substance (lot number: C1801 purchases the company in ICC)
Borax (lot number: 970203, analytical pure, Beijing Yili Fine Chemicals Co., Ltd.)
NaOH, analytical pure, Beijing Chemical Plant
Methanol, analytical pure.Water is high purity water.
1.3 the preparation of standard solution
The baicalin standard solution:
Accurately take by weighing baicalin 4.23mg, be dissolved in the 10ml methanol, get the 0.423mg/ml standard solution.The puerarin standard solution:
The puerarin methanol solution of accurately measuring concentration and be 2.11mg/ml is an amount of, and being diluted to concentration is the standard solution of 2.11 μ g/ml, 4.22 μ g/ml, 8.44 μ g/ml, 12.66 μ g/ml.
It is an amount of that precision takes by weighing daiazi, is mixed with the solution of 13.0 μ g/ml with methanol.
It is an amount of that precision takes by weighing daidzein, is mixed with the solution of 20.8 μ g/ml with methanol.
1.4 the preparation of need testing solution
Sample: Radix Puerariae flavone slow releasing tablet (lot number: 000914)
Experimental technique: first method according to two drug release determination methods of Pharmacopoeia of the People's Republic of China version in 2000 is carried out, and the sampling time point is: 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h.
1.5 finger printing (seeing accompanying drawing 1)
Assay method: according to above-mentioned chromatographic condition sample introduction standard solution and need testing solution, write down 30 minutes chromatogram promptly.
The peak sequence of main peaks and retention time: daiazi (daidzin)-Yue 12min; Daidzein (daidzein)-Yue 14min; Baicalin (Bdicalin: internal standard substance)-Yue 17min; Puerarin (Puerarin)-Yue 23min
Puerarin quantitatively: with concentration of standard solution to peak area return linear equation, correlation coefficient is 0.9993, with this Equation for Calculating.
Unknown peak quantitatively: the peak height value with the internal standard substance baicalin is denominator (hs), calculates peak A, B, C, D peak height ratios ha/hs, hb/hs, hc/hs, hd/hs.
1.6 slow releasing tablet release
| Time (h) | 0.5 | ?1 | ??2 | ?4 | ?6 | ??8 | ??10 | ??12 |
| Average accumulated discharges percentage rate (%) | 10.45 | ?16.09 | ??27.80 | ?46.70 | ?62.48 | ??76.31 | ??84.53 | ??93.77 |
| SD | 1.568 | ??2.094 | ??3.222 | ?4.357 | ?6.486 | ??6.717 | ??5.506 | ??4.792 |
1.7 ABCD ratio of peak and time relation in the slow releasing tablet
| Time (h) | ?0.5 | ?1 | ?2 | ??4 | ??6 | ??8 | ??10 | ????12 |
| ??ha/hs | ?1.536 | ?2.434 | ?4.046 | ??8.450 | ??9.225 | ??11.678 | ??11.989 | ????12.484 |
| ??hb/hs | ?0.079 | ?0.138 | ?0.147 | ??0.515 | ??0.616 | ??0.751 | ??0.794 | ????0.828 |
| ??hc/hs | ?0.447 | ?0.710 | ?1.153 | ??2.445 | ??2.708 | ??3.412 | ??3.475 | ????3.631 |
| ??hd/hs | ?0.354 | ?0.589 | ?0.901 | ??1.769 | ??1.887 | ??2.267 | ??2.387 | ????2.283 |
As seen, A, B, C, the release characteristic at D peak and Radix Puerariae have dependency preferably.The method of quality control of experimental example 7 slow releasing preparation high performance liquid chromatography (HPLC)
2.1 instrument and chromatographic condition:
The JASCO high performance liquid chromatograph, detector: UV-1575, pump: TU-1580, automatic sampler: AS-1555
Chromatographic column: ZORBAX Extend-C18 (4.6 * 250mm, 5 μ m, Agilent)
Detect wavelength: 254nm
Column temperature: 25 ℃
Flow velocity: 1.0ml/min
Mobile phase: 0.2% aqueous acetic acid-acetonitrile binary gradient elution
The gradient program
| Time (min) | 0.2% aqueous acetic acid (%) | Acetonitrile (%) |
| 0 | ?90 | ?10 |
| 20 | ?90 | ?10 |
| 50 | ?50 | ?50 |
| 55 | ?90 | ?10 |
| 70 | ?90 | ?10 |
Sample size: 20 μ l
2.2 reference substance and reagent
Puerarin (Puerarin) reference substance (lot number: 0752-200108 purchases in Chinese pharmaceutical biological product and identifies institute)
Daiazi (daidzin) reference substance (lot number: C1803 purchases the company in ICC)
Daidzein (daidzein) reference substance (lot number: 1502-200101 purchases in Chinese pharmaceutical biological product and identifies institute)
3 '-methoxy puerarin: laboratory extracts, purification makes.
Methanol, analytical pure.Acetonitrile, chromatographically pure.Water is high purity water.Acetic acid, analytical pure.
2.3 the preparation of standard solution
The puerarin standard solution:
The puerarin methanol solution of accurately measuring concentration and be 2.11mg/ml is an amount of, and being diluted to concentration is the standard solution of 2.11 μ g/ml, 4.22 μ g/ml, 8.44 μ g/ml, 12.66 μ g/ml.
Precision takes by weighing 3 '-methoxy puerarin is an amount of, is mixed with the solution of 10 μ g/ml with methanol.
It is an amount of that precision takes by weighing daiazi, is mixed with the solution of 13.0 μ g/ml with methanol.
It is an amount of that precision takes by weighing daidzein, is mixed with the solution of 20.8 μ g/ml with methanol.
2.4 the preparation of need testing solution
Sample: Radix Puerariae flavone slow releasing tablet (lot number: 031002)
Experimental technique: first method according to two drug release determination methods of Pharmacopoeia of the People's Republic of China version in 2000 is carried out, and the sampling time point is: 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h.
2.5 finger printing (seeing accompanying drawing 2)
Assay method: according to above-mentioned chromatographic condition sample introduction standard solution and need testing solution, write down 50 minutes chromatogram promptly.
Can monitor about 16 peaks, but wherein according to going out 6 main peaks of peak sequencing quantitative analysis, the about 20.708min of chromatographic peak retention time of puerarin wherein, 3 '-the about 25.8min of chromatographic peak retention time of methoxy puerarin, the about 29.242min of chromatographic peak retention time of daiazi, the about 39.867min of chromatographic peak retention time of daidzein.
2.6 slow releasing tablet release (peak 1-6)
| Time (h) | 0.5 | ?1 | ?2 | ?3 | ?4 | ?6 | ?8 | ?10 | ?12 |
| Average accumulated discharges percentage rate (%) | 11.80 | ?18.28 | ?29.64 | ?40.13 | ?50.34 | ?68.49 | ?86.53 | ?96.44 | ?100.80 |
Description of drawings:
Fig. 1: high performance capillary electrophoresis finger printing (HPCE)
Fig. 2: high performance liquid chromatography finger printing (HPLC)
Following examples all can reach above-mentioned experimental example.
Embodiment 1Slow releasing tablet
Extract product of general flavone of kudzuvine root 220g
Hydroxypropyl emthylcellulose (K4M) 50g
Magnesium stearate 0.6g.
With the extract product of general flavone of kudzuvine root crushing screening, press prescription and hydroxypropyl emthylcellulose mix homogeneously, add an amount of ethanol and make wetting agent, cross 20 mesh sieves and granulate, 45 ℃ of dryings 2 hours are crossed 24 mesh sieve granulate, add magnesium stearate in proportion, mix homogeneously, tabletting promptly get 1000.Sheet heavily is 270 milligrams; Oral, 2 times on the one, 1 time 3.
Embodiment 2Slow releasing tablet
Extract product of general flavone of kudzuvine root 220g
Hydroxypropyl emthylcellulose 60g
Magnesium stearate 0.6g
Silica 1 g.
With the extract product of general flavone of kudzuvine root crushing screening,, add an amount of ethanol and make wetting agent in proportion with the hydroxypropyl emthylcellulose mix homogeneously, cross 20 mesh sieves and granulate, 50 ℃ of dryings 2 hours are crossed 24 mesh sieve granulate, add magnesium stearate and silicon dioxide in proportion, mix homogeneously, tabletting are promptly.
Claims (10)
1, a kind of slow releasing preparation for the treatment of cardiovascular disease is characterized in that this slow releasing preparation mainly made by following raw material:
Extract product of general flavone of kudzuvine root 300-600 weight portion
Hydroxypropyl emthylcellulose 50-200 weight portion
Magnesium stearate 1-4 weight portion.
2, slow releasing preparation as claimed in claim 1 is characterized in that this slow releasing preparation mainly made by following raw material:
Extract product of general flavone of kudzuvine root 350-500 weight portion
Hydroxypropyl emthylcellulose 80-150 weight portion
Magnesium stearate 1-3 weight portion.
3, slow releasing preparation as claimed in claim 1 is characterized in that this slow releasing preparation mainly made by following raw material:
Extract product of general flavone of kudzuvine root 300-600 weight portion
Hydroxypropyl emthylcellulose 50-200 weight portion
Magnesium stearate 1-4 weight portion
Silica 1-6 weight portion.
4, slow releasing preparation as claimed in claim 1 is characterized in that this slow releasing preparation mainly made by following raw material:
Extract product of general flavone of kudzuvine root 350-500 weight portion
Hydroxypropyl emthylcellulose 80-150 weight portion
Magnesium stearate 1-3 weight portion
Silicon dioxide 3-5 weight portion.
5, as the preparation method of the described slow releasing preparation of claim 3-4, it is characterized in that this method is: with the extract product of general flavone of kudzuvine root crushing screening, in proportion with the hydroxypropyl emthylcellulose mix homogeneously, add an amount of ethanol and make wetting agent, cross the 15-30 mesh sieve and granulate, 30-60 ℃ dry 1-3 hour, cross 24 mesh sieve granulate, add magnesium stearate and silicon dioxide in proportion, mix homogeneously, often regulation becomes clinical acceptable slow releasing tablet, slow releasing capsule, sustained-release granular formulation, slow-release micro-pill.
6, the preparation method of slow releasing preparation as claimed in claim 5, its feature in the slow releasing tablet preparation method is: with the extract product of general flavone of kudzuvine root crushing screening, in proportion with the hydroxypropyl emthylcellulose mix homogeneously, add an amount of ethanol and make wetting agent, cross 20 mesh sieves and granulate, 40 ℃ of dryings 2 hours, cross 24 mesh sieve granulate, add magnesium stearate and silicon dioxide in proportion, mix homogeneously, tabletting are promptly.
7, as in the described slow releasing preparation method of quality control of claim 1-4, it is characterized in that the high performance capillary electrophoresis that adopts comprises following method:
Chromatographic condition: efficient capillary electrophoresis apparatus, quartz capillary column: 50 μ m * 39cm, detection window: 100 * 200 μ m, column temperature: 25 ℃; UV-detector: the detection wavelength is 254nm, separation buffer solution: 0.1M Borax0.1M NaOH (pH10.12), separation voltage: 20KV, anodal pressure sample introduction, sample injection time 5 seconds; The preparation of standard solution, preparation baicalin, puerarin, daiazi, daidzein standard solution; The preparation of need testing solution, sample: the Radix Puerariae flavone slow releasing tablet is carried out according to first method of two drug release determination methods of Pharmacopoeia of the People's Republic of China version in 2000, and the sampling time point is: 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h; Assay method: according to above-mentioned chromatographic condition sample introduction standard solution and need testing solution, write down 30 minutes chromatogram promptly.
8, as the described slow releasing preparation of claim 1-4, it is characterized in that the high performance capillary electrophoresis that adopts, chromatographic condition: efficient capillary electrophoresis apparatus, quartz capillary column: 50 μ m * 39cm, detection window: 100 * 200 μ m, column temperature: 25 ℃ of UV-detector: the detection wavelength is 254nm, separation buffer solution: 0.1MBorax0.1M NaOH (pH10.12), separation voltage: 20KV, anodal pressure sample introduction, sample injection time 5 seconds; The preparation of standard solution, preparation baicalin standard solution, puerarin standard solution, daiazi, daidzein standard solution;
The preparation of need testing solution, sample: the Radix Puerariae flavone slow releasing tablet is carried out according to first method of two drug release determination methods of Pharmacopoeia of the People's Republic of China version in 2000, and the sampling time point is: 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h; Assay method: according to above-mentioned chromatographic condition sample introduction standard solution and need testing solution, write down 30 minutes chromatogram, the peak sequence and the retention time of gained finger printing main peaks: daiazi (daidzin) 10-13min; Daidzein (daidzein) 12-16min; Baicalin (Bdicalin: 15-19min internal standard substance); Puerarin (Puerarin) 21-25min.
9,, it is characterized in that adopting high performance liquid chromatography to comprise following method as the fingerprint pattern quality control method of the described slow releasing preparation of claim 1-4:
Chromatographic condition: high performance liquid chromatograph, detector: UV-1575, pump: TU-1580, automatic sampler: AS-1555, chromatographic column: C18 (5 μ m) detects wavelength: 254nm, and column temperature: 20-35 ℃, flow velocity: 1.0ml/min;
Mobile phase: 0.2% aqueous acetic acid-acetonitrile binary gradient elution gradient program
10, as the described slow releasing preparation of claim 1-4, it is characterized in that adopting high performance liquid chromatography, chromatographic condition: high performance liquid chromatograph, detector: UV-1575, pump: TU-1580, automatic sampler: AS-1555, chromatographic column: C18 (5 μ m), detect wavelength: 254nm, column temperature: 20-35 ℃, flow velocity: 1.0ml/min;
Mobile phase: 0.2% aqueous acetic acid-acetonitrile binary gradient elution gradient program
Time (min) 0.2% aqueous acetic acid (%) Acetonitrile (%)
????0 ????90 ????10
????20 ????90 ????10
????50 ????50 ????50
????55 ????90 ????10
????70 ????90 ????10
, sample size: 20 μ l, the preparation of standard solution: preparation puerarin, 3 '-methoxy puerarin, daiazi, daidzein, genistein, genistin standard solution; The preparation of need testing solution: sample: the Radix Puerariae flavone slow releasing tablet, experimental technique: first method according to two drug release determination methods of Pharmacopoeia of the People's Republic of China version in 2000 is carried out, and the sampling time point is: 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h; Assay method: according to above-mentioned chromatographic condition sample introduction standard solution and need testing solution, write down 50 minutes chromatogram promptly; Gained finger printing: can monitor about 16 peaks, but wherein according to going out 6 main peaks of peak sequencing quantitative analysis, wherein the chromatographic peak retention time of puerarin is 19-21min, 3 '-the chromatographic peak retention time of methoxy puerarin is 24-27min, the chromatographic peak retention time of daiazi is 28-31min, and the chromatographic peak retention time of daidzein is 38-40min.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100429997C (en) * | 2005-12-02 | 2008-11-05 | 甘肃凯源生物技术开发中心 | Alcohol-relieving tablet containing kudzu root and spirulina spp. ,and its preparation method |
| CN103800428A (en) * | 2012-11-15 | 2014-05-21 | 吉林吉春制药股份有限公司 | Medicine for treating yin deficiency and yang excess syndrome of hypertension and coronary heart disease and preparation method thereof |
| CN105012528A (en) * | 2015-08-10 | 2015-11-04 | 深圳市泛谷药业有限公司 | Traditional Chinese medicine composition with slow release effect, heart and brain preserving pill and method and preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS62126185A (en) * | 1985-11-28 | 1987-06-08 | Tsumura Juntendo Inc | Production of isoflavone derivative |
| CN1033914C (en) * | 1991-11-06 | 1997-01-29 | 河南省医学科学研究所 | Kudzu vine root extract, its preparation and use |
| CN1177603C (en) * | 2002-03-22 | 2004-12-01 | 山西亚宝药业集团股份有限公司 | Gingko leaf slow-releasing table and preparation process thereof |
| CN1250242C (en) * | 2002-05-20 | 2006-04-12 | 郭建平 | Kudzu vine flavone capsule, and its prepn. method |
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2004
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100429997C (en) * | 2005-12-02 | 2008-11-05 | 甘肃凯源生物技术开发中心 | Alcohol-relieving tablet containing kudzu root and spirulina spp. ,and its preparation method |
| CN103800428A (en) * | 2012-11-15 | 2014-05-21 | 吉林吉春制药股份有限公司 | Medicine for treating yin deficiency and yang excess syndrome of hypertension and coronary heart disease and preparation method thereof |
| CN105012528A (en) * | 2015-08-10 | 2015-11-04 | 深圳市泛谷药业有限公司 | Traditional Chinese medicine composition with slow release effect, heart and brain preserving pill and method and preparation thereof |
| CN105012528B (en) * | 2015-08-10 | 2016-12-07 | 深圳市泛谷药业股份有限公司 | The tool Chinese medicine composition of slow releasing function, the glad ball of heart and brain and its method and preparation |
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| CN1296049C (en) | 2007-01-24 |
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