CN101584676B - Matrine sustained release preparation and preparing method thereof - Google Patents
Matrine sustained release preparation and preparing method thereof Download PDFInfo
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- CN101584676B CN101584676B CN2009100831409A CN200910083140A CN101584676B CN 101584676 B CN101584676 B CN 101584676B CN 2009100831409 A CN2009100831409 A CN 2009100831409A CN 200910083140 A CN200910083140 A CN 200910083140A CN 101584676 B CN101584676 B CN 101584676B
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Abstract
A matrine sustained release preparation comprises the following componets in the formula: matrine, lactose, mlcrocrystalline cellulose, 10% of polyvidone K30 ethanol solution, hydroxypropyl methyl cellulose, aerosil, magnesium stearate and stomach-dissolve type film coating powder. The matrine sustained release preparation is prepared with a method of preparing the granule with a wet method and additionally adding the mlcrocrystalline cellulose. The method of film coating is adopted so that the appearance of the sustained release tablet is more beautiful and the quality is more stable.
Description
Technical field
The present invention relates to a kind of matrine sustained release preparation and preparation method thereof, belong to technical field of Chinese medicines.
Background technology
Viral hepatitis is a kind of infectious disease of serious harm people's life health.Popular scope is wide, the sickness rate height be other infectious disease can not compare.The Asia, hepatitis b virus carrier is up to 15%～20% among Africa and area, southern Europe crowd, and China is the district occurred frequently of hepatitis B virus, and according to statistics, the hepatitis B patient who increases newly every year just has 1,000,000.The whole world has 750,000 people to die from the hepatocarcinoma that chronic hepatitis B causes approximately.The medicine that is used for viral hepatitis, the whole world is estimated to reach more than 600 kinds at present, but does not still have the important breakthrough progress so far.
The main component kurarinone of Kurarinol slow-release sheet is the alkaloid that extracts by in Chinese medicine Herba Sophorae alopecuroidis or the Radix Sophorae Flavescentis, and kurarinone has been confirmed as treating the viral hepatitis emphasis and has promoted the engineering medicine at present.Domestic kurarinone dosage form commonly used has injection, capsule etc. now.
The half-life of kurarinone is short.Local pain is obvious when injection intramuscular injection or intravenous injection, needs patient's medication inconvenience of long-term prescription for treatment chronic hepatitis B or leukopenia etc.The kurarinone capsule need repeatedly be taken medicine every day, and life-time service also has inconvenience, and the blood drug level fluctuating is big, and " peak valley " phenomenon is obvious, affects the treatment.For reducing the oral administration number of times, eliminate " peak valley " phenomenon, being convenient to the patient uses, the suitable slow releasing preparation of making of kurarinone, existing patent CN1212840C discloses " matrine sustained release preparation and preparation method thereof ", its lasting medicine, stable, the patient can take secondary on the 1st, avoid " peak valley " phenomenon simultaneously, side effect is little, needing to be particularly useful for the hepatitis B patient of long-term prescription.
Kurarinol slow-release sheet of the present invention is by adding to the control of the screening of supplementary product kind and consumption thereof in the prescription, preparation technology's strictness, with hydrophilic skeleton etc., made a day clothes Kurarinol slow-release sheet once, its drug effect is lasting stability more, and side effect is little, and patient's compliance is better.
Simultaneously,, be convenient to take, also, improve stability of drug, the Kurarinol slow-release sheet is made Film coated tablets in order to protect medicine to avoid the influence of humidity, illumination and airborne oxygen in order to cover the bitterness of medicine itself.
Summary of the invention
The object of the present invention is to provide a kind of Kurarinol slow-release sheet, this slow releasing tablet has slow release long-acting, and release is abundant, and blood drug level is steady, the advantage that bioavailability is high.
Kurarinol slow-release sheet provided by the present invention, rate of release are release about 30% in 0-2 hour; Discharged about 60% in 6 hours; Discharged about 80% in 12 hours; Release about 90% in 16 hours (" 2005 editions appendix X of Chinese pharmacopoeia D, first method);
Though adjuvant provided by the present invention is the adjuvant that those skilled in the art use always, the present invention makes that by the method that hydrophilic skeleton material and other adjuvant add the release of prepared Kurarinol slow-release sheet is abundant, blood drug level is steady, the bioavailability height.
Another object of the present invention is to provide a kind of preparation method of Kurarinol slow-release sheet, supplementary product kind and consumption thereof in the prescription are screened, and among the preparation technology each step all carried out strict control.
The present invention is achieved through the following technical solutions:
A kind of Kurarinol slow-release sheet is that the proportioning raw materials by following weight portion forms:
Kurarinone 300 weight portions, lactose 50-60 weight portion, microcrystalline Cellulose 40-50 weight portion, 10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution 50-70 parts by volume, hydroxypropyl methylcellulose K100M100-140 weight portion, micropowder silica gel 5-6 weight portion, magnesium stearate 2-3 weight portion, stomach dissolution type film coating powder 10-12 weight portion.
Described weight portion/parts by volume is corresponding to g/ml.
A kind of Kurarinol slow-release sheet is that the proportioning raw materials by following weight portion forms:
Kurarinone 300 weight portions, lactose 54.5 weight portions, microcrystalline Cellulose 46.4 weight portions, 10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, 60 parts by volume, hydroxypropyl methylcellulose K100M136.4 weight portion, micropowder silica gel 5.4 weight portions, magnesium stearate 2.7 weight portions, stomach dissolution type film coating powder 10.9 weight portions.
Hydroxypropyl methylcellulose K100M adopts outer addition in the Kurarinol slow-release sheet of the present invention; The Kurarinol slow-release sheet adopts wet granulation to obtain; The Kurarinol slow-release sheet can be used stomach dissolution type coating material coating.
The preparation method of above-mentioned Kurarinol slow-release sheet:
Step 1: take by weighing kurarinone and lactose by recipe quantity, mix homogeneously adds 10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, stirs, and makes suitable soft material, crosses the 16-24 mesh sieve and granulates;
Step 2: granule is dried under 50-70 ℃ of condition, crosses 16-24 mesh sieve granulate;
Step 3: measure the content of kurarinone in the granule, determine that sheet is heavy;
Step 4: add hydroxypropyl methyl fiber K100M, microcrystalline Cellulose, micropowder silica gel, the magnesium stearate of recipe quantity in the dried granule, mix homogeneously;
Step 5: tabletting, coating;
Step 6: check, packing.
The preparation method of Kurarinol slow-release sheet is preferably:
Step 1: kurarinone was pulverized 100 mesh sieves, lactose, hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, magnesium stearate were crossed 100 mesh sieves, standby;
Step 2: take by weighing kurarinone and lactose by recipe quantity, mix homogeneously adds the about 60ml of 10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, stirs, and makes suitable soft material, crosses 18 mesh sieves and granulates;
Step 3: granule is dried under 60 ℃ of conditions, crosses 18 mesh sieve granulate;
Step 4: measure the content of kurarinone in the granule, determine that sheet is heavy;
Step 5: add hydroxypropyl methyl fiber K100M, microcrystalline Cellulose, micropowder silica gel, the magnesium stearate of recipe quantity in the dried granule, mix homogeneously;
Step 6: tabletting, coating;
Step 7: check, packing.
Kurarinone is a kind of medicine of taking for a long time, should make slow releasing preparation, existing patent CN1212840C, denomination of invention is " matrine sustained release preparation and preparation method thereof ", this disclosure of the Invention took twice matrine sustained release preparation in one day, the present invention obtains a kind of day clothes matrine sustained release preparation once by a large amount of tests, and patient's compliance is better.
The capsular specification of commercially available kurarinone is the 0.1g/ grain, and usage and dosage every day three times, is obeyed 0.3g in case of necessity for the each 0.2g of adult at every turn.According to adult's the custom of generally taking medicine, many 7-9 points in the morning of taking medicine for the first time, many 12-14 points at noon of taking medicine for the second time, the 18-20 points of how at night taking medicine were for the third time taken dose on the one in promptly general about 12 hours and to be finished.It is the 0.3g/ sheet that this slow releasing tablet is drafted specification, and usage and dosage is drafted to once-a-day, one time 2, design principal agent rate of release is basic consistent medicine time with common oral preparation.The absorbing state of kurarinone different parts in intestinal that the present invention has passed through the experimental study of isolated rat intestinal absorption, show equal energy good absorption between duodenum, jejunum, ileum, each section of colon, there was no significant difference helps preparing slow releasing preparation of the present invention, as shown in Figure 1.With reference to the requirement of Chinese Pharmacopoeia version appendix in 2005 XIX D slow release, controlled release preparation guideline, the rate of release of this preparation of Preliminary design is simultaneously: discharged about 30% in 0.5-2 hour; Discharged about 60% in 6 hours; Discharged about 80% in 12 hours; Discharged greater than 90% in 16 hours.
The selection of test example 1 sustained-release matrix material
Kurarinone is soluble in water, and character is more stable.According to above character, we select it is made as hydrogel matrix tablet, use full-bodied hydroxypropyl methylcellulose (HPMC) K100M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K4M, sodium carboxymethyl cellulose, carbopol, ethyl cellulose as framework material respectively.
It is 20% that preliminary definite framework material accounts for the heavy ratio of sheet.Investigate of the influence of sustained-release matrix material to the release of tablet.The consumption of considering micropowder silica gel and magnesium stearate is little to the release influence of Kurarinol slow-release sheet, but can improve particulate flowability, guarantees tablet weight variation.Therefore, the consumption of just deciding micropowder silica gel is 1.0%, and the consumption of magnesium stearate is 0.5%.
Release inspection method: get this product, according to drug release determination method (Chinese Pharmacopoeia version appendix in 2005 X D first method), adopt the device of dissolution method (Chinese Pharmacopoeia version appendix in 2005 X C second method), adding water 900ml is solvent, rotating speed is that per minute 50 changes, operation in accordance with the law.Through 1,2,6,12,16,20,24 hour, respectively get solution 5ml (replenishing the solvent of uniform temp, equal volume simultaneously), filter, get subsequent filtrate as need testing solution; It is an amount of that other gets the oxymatrine reference substance, and water is made the solution that every 1ml contains 0.3mg, in contrast product solution.With octadecylsilane chemically bonded silica is filler; 0.02mol/L potassium dihydrogen phosphate (adding 0.3% triethylamine, phosphoric acid adjust pH to 3.2 ± 0.05)-acetonitrile (92: 8) is a mobile phase; The detection wavelength is 210nm.Theoretical cam curve ammoxidation matrine peak calculates should be not less than 2000, and the peak-to-peak separating degree of oxymatrine peak and impurity should be greater than 1.5.Get each 20 μ l of above-mentioned two kinds of solution and inject chromatograph of liquid, press external standard method with every burst size of calculated by peak area at different time.
According to taking by weighing kurarinone, lactose, microcrystalline Cellulose, micropowder silica gel, magnesium stearate shown in the table 1, totally 5 parts, add 20% following sustained-release matrix material respectively and suppress in flakes according to the method for embodiment 1.The kind of screening sustained-release matrix material.The results are shown in Table 1, Fig. 2.
The selection of table 1 sustained-release matrix material category
By table 1 and Fig. 2 as seen, hydroxypropyl methylcellulose K100M can realize slow release more than 20 hours, was better than other sustained-release matrix materials, so select hydroxypropyl methylcellulose K100M as framework material of the present invention.
The selection of test example 2 framework material consumptions
According to taking by weighing kurarinone, lactose, microcrystalline Cellulose, micropowder silica gel, magnesium stearate shown in the table 2, totally 5 parts, add the hydroxypropyl methylcellulose of weight portion shown in following table K100M respectively and suppress in flakes according to the method for embodiment 1.The release inspection method is with test example 1.The consumption of screening sustained-release matrix material.The results are shown in Table 2, Fig. 3.
The selection of table 2 sustained-release matrix material usage
By table 2 and Fig. 3 as seen, hydroxypropyl methylcellulose (HPMC) K100M is the principal element that influences release, and along with the increase of consumption, the rate of release of principal agent is slack-off.The HPMC consumption is very few in prescription 8 and the prescription 9, and drug release rate is too fast; The HPMC consumption is too much in the prescription 12, and drug release rate is slow excessively; Prescription 10, prescription 11 and writing out a prescription 12 all meets the requirements; 11 drug release rates of writing out a prescription are more moderate, and homogeneity is better, and other index check result is also better.Result in sum, hydroxypropyl methylcellulose K100M account for the heavy 20-26% of sheet.
The selection of test example 3 other adjuvants
Filler is selected lactose and microcrystalline Cellulose.The lactose stable in properties, can with the most drug compatibility, no hygroscopicity, and compression forming is fine, therefore the tablet smooth and beautiful appearance of making determines that lactose is a filler.The stable in properties of microcrystalline Cellulose, big to the principal agent saturation, have good flowability and compressibility, can be used for direct powder compression; Other sees lubricated and disintegration, determines that therefore microcrystalline Cellulose is another filler.
Binding agent is selected the alcoholic solution of 30 POVIDONE K 30 BP/USP 30.The polyvidone chemical property is stable, can water-solublely become the thickness colloidal liquid with ethanol, has good cohesive, is hydrogel matrix tablet binding agent commonly used.
Test example 4 preparation technologies' selection
4.1 tabletting method and framework material add the screening on opportunity
Preparation 13: the sample of making according to prescription and the method for making of embodiment 1;
Preparation 14: according to the prescription of embodiment 1, method for making is that kurarinone was pulverized 100 mesh sieves, and lactose, hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, magnesium stearate are crossed 100 mesh sieves, and is standby; Hardship with recipe quantity
Ginseng element, lactose, hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, magnesium stearate, mix homogeneously; Mixed supplementary material is pressed into pancake, crosses 18 mesh sieves and granulate; Punch die tabletting with diameter 12mm; Coating is to label weightening finish about 2%; The inspection of semifinished product, packing.
Preparation 15: according to the prescription of embodiment 1, method for making is that kurarinone was pulverized 100 mesh sieves, and lactose, hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, magnesium stearate are crossed 100 mesh sieves, and is standby; Take by weighing kurarinone and lactose, hydroxypropyl methylcellulose K100M, microcrystalline Cellulose by recipe quantity, mix homogeneously adds the about 60ml of binding agent, stirs, and makes suitable soft material, crosses the granulation of 18 mesh sieves; Granule is dried under 60 ℃ of conditions, crosses 18 mesh sieve granulate; Measure the content of kurarinone in the granule, determine that sheet is heavy; The micropowder silica gel, the magnesium stearate that add recipe quantity in the dried granule, mix homogeneously; Punch die tabletting with diameter 12mm; Coating is to label weightening finish about 2%; The inspection of semifinished product, packing.
Preparation 16: kurarinone 300g
Hydroxypropyl methylcellulose K100M 200g
Lactose 50g
Acrylic resin II alcoholic solution is an amount of
Magnesium stearate 5g
Opadry 17.6g
85% ethanol 278g makes 1000 of Kurarinol slow-release sheets
Method for making: be common wet granule compression tablet method, principal agent, hydroxypropyl methylcellulose K100M, lactose are pulverized the back mix homogeneously, reuse acrylic resin II alcoholic solution is made binding agent and is granulated, oven dry, the magnesium stearate of adding recipe quantity behind the granulate, tabletting behind the mixing.Use Opadry 85% alcoholic solution coating after the tablet gumming.
Preparation 17 kurarinone 300g
Hydroxypropyl methylcellulose K100M 150g
Magnesium stearate 4g
Opadry 14.5g
85% ethanol 227g makes 1000 of Kurarinol slow-release sheets
Method for making: principal agent and hydroxypropyl methylcellulose K100M are pulverized back and magnesium stearate mixing, direct compression behind the mixing.Use Opadry 85% alcoholic solution coating after the tablet gumming.
Table 3 tabletting method and framework material add the The selection result on opportunity
By table 3 and Fig. 4 as seen, kurarinone is mobile very poor behind crushing screening as can be seen by preparation 15 and preparation 17, so can not adopt direct compression technology, needs to adopt wet granulation; By preparation 14 and preparation 16 as can be seen hydrophilic skeleton material hydroxypropyl methylcellulose K100M in wet granulation, can make material viscosity too big, granulation is difficult to sieve; And preparation 13 is earlier with principal agent and lactose mixing granulation, and the indexs such as release of the sample that obtains of the method that hydrophilic skeleton material and other adjuvants are added all meet standards of pharmacopoeia again.Therefore, hydroxypropyl methylcellulose K100M adopts outer addition in the Kurarinol slow-release sheet of the present invention; The present invention adopts wet granulation to obtain.
4.2 the selection of slot size when granulating (crossing grit number)
Take by weighing each five parts of supplementary materials according to preparation 13, according to embodiment 1 described preparation method, granulate with 14,16,18,24,26 mesh sieves respectively, the sample that obtains the results are shown in Table 4.
The selection result of slot size when table 4 is granulated
| Index | Prescription 18 | Prescription 19 | |
Prescription 21 | Prescription 22 |
| Uniformity of dosage units | Undesirable | Meet the requirements | Meet the requirements | Meet the requirements | Meet the requirements |
| Outward appearance | Unilateral coarse, the sliver phenomenon is arranged | Smooth and beautiful appearance | Smooth and beautiful appearance | Smooth and beautiful appearance | Unilateral coarse |
By table 4 as seen because the adjuvant that need add after granulating is more, so made granule should not be too big, so as not to add adjuvant mixes uneven, so selection is with the granulation of 18 mesh sieves, granulate.
The preparation and the quality investigation of 5 three batches of lab scale samples of test example
5.1 prescription and preparation technology according to embodiment 1 prepare three batches of lab scale samples, and sample is carried out quality investigation, the release inspection method is with test example 1.The results are shown in Table 5:
Three batches of lab scale sample qualities of table 5 are investigated the result
The preparation of three batches of lab scale samples and investigation result show that selected prescription and preparation technology are rationally feasible, favorable reproducibility, and sample quality meets the requirements.Can carry out next step middle trial production.
5.2 the rate of releasing drug curve determination is with a collection of small sample product (lot number XS-3,6) release, method is as follows: get this product, according to drug release determination method (Chinese Pharmacopoeia version appendix in 2005 X D first method), adopt the device of dissolution method (Chinese Pharmacopoeia version appendix in 2005 X C second method), adding water 900ml is solvent, and rotating speed is that per minute 50 changes, operation in accordance with the law.Through 1,2,6,9,12,16,20 and 24 hour, respectively get solution 5ml (replenishing the solvent of uniform temp, equal volume simultaneously), filter, get subsequent filtrate as need testing solution; It is an amount of that other gets the oxymatrine reference substance, water is made the solution that every 1ml contains 0.3mg, product solution in contrast. according to assay item method down, get each 20 μ l of above-mentioned two kinds of solution and inject chromatograph of liquid, press external standard method with every burst size of calculated by peak area at different time.The results are shown in Table 6 and Fig. 5.
Table 6 sample rate of releasing drug curve determination result
By table 6 and Fig. 5 as seen, this product has tangible slow release characteristic, 2 hours cumulative release rates about 30%, the not prominent phenomenon of releasing.16 hours cumulative release rates are greater than 90%, and the release amount is complete substantially.
5.3 discharge the investigation of homogeneity
Measure with the release of batch (20040423) 6 samples of pilot product, investigate the homogeneity that discharges at the regulation sample point.The results are shown in Table 7.
Table 7 discharges the investigation result of homogeneity
As seen from the above table, with batches of 6 samples at the RSD of the release of regulation sample point all less than 3.0%, show that this product is good in the release homogeneity of regulation sample point.
5.4 the repeatability of three batch sample releases
Prescription and preparation technology according to embodiment 1 prepare test agent in three batches, measure three batches in the release of test agent (6 every batch), investigate batch with criticize between stable processing technique and repeatability, the results are shown in Table 8.
The repeatability of table 8 release is investigated the result
As seen from the above table, test agent all less than 2.0%, shows the repeatability that has stable processing technique and release between this product three batch samples at the release RSD of each sample point in three batches.
5.5 stability test
In the two aluminum packings of test agent, respectively in the accelerated test condition: relative humidity is 75 ± 5%, placed 6 months under 40 ± 2 ℃ of conditions of temperature, respectively at the 1st, 2,3,6 sampling at the end of month; The long term test condition: at 25 ± 2 ℃ of temperature, relative humidity is to place 12 months under 60 ± 10% conditions, respectively at the 3rd, 6,9,12,18,24 sampling at the end of month.Investigate indexs such as its character, release, related substance, content respectively, result and comparison in 0 month.The results are shown in Table 9, table 10.
Test agent accelerated test result in the table 9
Result of the test shows: by two aluminum packings, pilot scale 3 batch samples through accelerated test after 6 months related substance increase to 2.02% by 0.96%, other every indexs have no significant change, and are up to specification.Test agent is by two aluminum packings in the explanation, is 75 ± 5% at relative humidity, basicly stable under 40 ± 2 ℃ of conditions of temperature.
Test agent long-term test results in the table 10
Result of the test shows: by two aluminum packings, pilot scale 3 batch samples through long term test after 24 months related substance increase to 2.1% by 0.96%, other every indexs have no significant change, and are up to specification.Test agent is by two aluminum packings in the explanation, be 60 ± 10% at relative humidity, place under 25 ± 2 ℃ of conditions of temperature basicly stable.
The test of test example 6 bioavailability
6.1 material and method
6.1.1 medicine and reagent
Test preparation: kurarinone 300g
Lactose 54.5g
10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution 60ml
Hydroxypropyl methylcellulose K100M 136.4g
Microcrystalline Cellulose 46.4g
Micropowder silica gel 5.4g
Magnesium stearate 2.7g makes 1000
Coating fluid prescription:
Stomach dissolution type film coating powder 10.9g
Distilled water 61.0ml
1. kurarinone was pulverized 100 mesh sieves, lactose, hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, magnesium stearate were crossed 100 mesh sieves, standby;
3. take by weighing kurarinone and lactose by recipe quantity, mix homogeneously adds the about 60ml of binding agent, stirs, and makes suitable soft material, crosses 18 order nylon mesh and granulates;
4. granule is dried under 60 ℃ of conditions, crosses 18 mesh sieve granulate;
5. the content of kurarinone in the mensuration granule determines that sheet is heavy;
6. the hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, the magnesium stearate that add recipe quantity in the dried granule, mix homogeneously;
7. use the punch die tabletting of diameter 12mm; Coating is to label weightening finish about 2%;
8. the inspection of semifinished product, packing.
Reference preparation I: make 1000 of Kurarinol slow-release sheets
Kurarinone 300g
Hydroxypropyl methylcellulose K100M 200g
Lactose 50g
Acrylic resin II alcoholic solution is an amount of
Magnesium stearate 5g
Opadry 17.6g
85% ethanol 278g
Method for making: be common wet granule compression tablet method, principal agent, hydroxypropyl methylcellulose K100M, lactose are pulverized the back mix homogeneously, reuse acrylic resin II alcoholic solution is made binding agent and is granulated, oven dry, the magnesium stearate of adding recipe quantity behind the granulate, tabletting behind the mixing.Use Opadry 85% alcoholic solution coating after the tablet gumming.
Reference preparation II: make 1000 of Kurarinol slow-release sheets
Kurarinone 300g
Hydroxypropyl methylcellulose K100M 150g
Magnesium stearate 4g
Opadry 14.5g
85% ethanol 227g
Method for making: principal agent and hydroxypropyl methylcellulose K100M are pulverized back and magnesium stearate mixing, direct compression behind the mixing.Use Opadry 85% alcoholic solution coating after the tablet gumming.
Every inspections such as test preparation and reference preparation I, II dissolution, weight differential are all up to specification.The oxymatrine standard substance are provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute, and lot number is 110780-200405.
Reagent: methanol, normal hexane, chloroform are chromatographically pure, and n-butyl alcohol, sodium hydroxide are analytical pure.
6.1.2 instrument
Tianjin, island LC-10AT highly effective liquid phase chromatographic system, Tianjin, island SPD-10AVPUV-VIS detector; N-2000 dual pathways chromatographic work station (Zhejiang University's intelligent information Graduate School of Engineering); LDZ4-08 type centrifuge (Beijing centrifuge factory); CX-250 ultrasonic cleaner (Beijing Medical Equipment Plant); Agitator (big instrument plant in Jintan City, Jiangsu) is used in the HY-4 speed governing more; AX205 prunus mume (sieb.) sieb.et zucc. Teller balance (Mettler-Toledo Instrument (Shanghai) Co., Ltd.).
6.1.3 chromatographic condition
Ultraviolet detection wavelength 220nm; Chromatographic column Luan5 μ Silica (250mm * 4.6mmI.D.); Mobile phase: methanol-normal hexane (4: 1, V/V), every 100ml adds 25% ammonia 1.2ml; Flow velocity is 2mlmin
-1 Sample size 20 μ l.
6.1.4 object of study
20 of volunteers, healthy male, year at age (21.95 ± 1.10), body weight (64.9 ± 4.11) kg, the written Informed Consent Form of signing before the test.Lab testing results such as all volunteer livers, renal function are normal, do not have acute and chronic disease and Inheritance medical history, test in preceding 2 weeks and the no medication history and the wine of banning on opium-smoking and the opium trade in experimental period.
6.1.5 EXPERIMENTAL DESIGN
Be single agent dual crossing oral test design, 30 volunteers are divided into two groups at random by the body weight pairing.Three groups of volunteer's personal informations and lab testing data credit are by statistics analysed and are not had showing property difference.The volunteer is numbered 1-30, absolute fasting after test 10 o'clock evenings of the previous day, and after morning on the same day was extracted blank blood sample in test, oral drugs on an empty stomach immediately.The 1-10 st volunteer is taken test preparation (T) 600mg, took once in 1st, the 11-20 st volunteer is taken reference preparation I (R I) 300mg, took twice in 1st, the 21-30 st volunteer is taken reference preparation II (R II) 300mg, took twice on 1st, feed (standard is identical) low fat, low albumen breakfast are taken a week continuously behind the 2h.Test preparation (T) and reference preparation I (R I), reference preparation II (R II) in the back of repeatedly taking medicine take medicine the 2nd, 3,4,5,6 day morning preceding and take medicine the 6th day morning preceding and take medicine after 1.0,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10.0,11.0,12.0,15.0,24.0h extracts ulnar vein blood 4ml, two groups of samples all move in the calparine pipe immediately, the centrifugal 10min of 3000rpm, get blood plasma, preserve down in-20 ℃.Three groups of volunteer's second all 1-10 st volunteer are taken reference preparation I (R I) 300mg, took twice in 1st, the 11-20 st volunteer is taken reference preparation II (R II) 300mg, took twice in 1st, the 21-30 st volunteer is taken test preparation (T) 600mg, took once in 1st, the HPLC method is measured oxymatrine concentration in the blood plasma, repeats above-mentioned test.Three groups of volunteer's the 3rd week back 1-10 st volunteer are taken reference preparation II (RII) 300mg, took twice in 1st, the 11-20 st volunteer is taken test preparation (T) 600mg, took once in 1st, the 21-30 st volunteer is taken reference preparation I (R I) 300mg, took twice on 1st, the HPLC method is measured oxymatrine concentration in the blood plasma, repeats above-mentioned test.
6.1.6 sample process
Get 1ml blood plasma, add 0.8molL
-1Perchloric acid 1ml, vortex vibration 1min, the centrifugal 5min of 3000rpm, pipette supernatant, add 20% NaOH0.5ml, extracting solution chloroform-n-butyl alcohol (49: 1, V/V) 4ml, vortex vibration 2min, the centrifugal 5min of 3000rpm pipettes the upper strata and repeats as stated above to extract 1 time, merge organic facies 6ml altogether, water-bath nitrogen dries up, and residue dissolves with 50 μ l mobile phases, sample introduction 20 μ l.
6.1.7 standard curve preparation
Add the oxymatrine standard solution of variable concentrations in the 10ml test tube with ground stopper, nitrogen dries up, and adds blank plasma 1ml again, and the final concentration that is mixed with oxymatrine is 0.025,0.05,0.1,0.15,0.3,0.6,1.2 μ gml
-1Standard series, handle each concentration sample introduction 5 times by " 6.1.6 sample process " method.With sample concentration X (μ gml
-1) oxymatrine peak area Y is carried out linear regression, get regression equation, be Y=247.69277+23245.99612X, r=0.99961, oxymatrine is at 0.025～1.2 μ gml
-1Scope internal linear relation is good.
6.1.8 the precision and the response rate
With high, medium and low (1.2,0.3, the 0.05 μ gml of blank plasma preparation
-1) the oxymatrine standard series of 3 variable concentrations, by " 6.1.6 sample process " operation down, calculate in a few days, the coefficient of variation, relative recovery in the daytime the precision of evaluation methodology.Plasma sample in a few days RSD is (2.91 ± 0.93) %, and RSD is (2.19 ± 0.47) % in the daytime, and relative recovery is (95.87 ± 7.38) %.
6.1.9 date processing
According to institute's oxygen determination matrine blood drug level-time data, adopt trapezoidal computing method, calculate the main pharmacokinetic parameters of test preparation (T) and reference preparation (R) oxymatrine, and carry out variance analysis, two one-side t method of inspection and (1-2a) put interval analysis, estimate the bioequivalence of two kinds of preparations.
6.2 result
6.2.1 method specificity
Get blank plasma, press " 6.1.6 sample process " method extraction back sample introduction analysis down, get blank plasma chromatogram (A); The finite concentration oxymatrine with mobile phase dissolving back sample introduction, is got oxymatrine standard substance chromatogram (B); The finite concentration oxymatrine is added blank plasma,, must extract rear oxidation matrine standard substance and add blank plasma chromatogram (C) by " 6.1.6 sample process " method extraction back sample introduction analysis down; Get volunteer's plasma sample,, must extract back volunteer's plasma sample chromatogram (D), see Fig. 6 by " 6.1.6 sample process " extraction back sample introduction analysis down.
6.2.2 pharmacokinetic parameters is calculated
According to institute's oxygen determination matrine plasma concentration-time data, AUC
SSFor multiple dosing reaches the area under the drug-time curve of a dosing interval after the stable state, adopt trapezoidal method to calculate; Peak concentration (C
Max) and paddy concentration (C
Min) blood drug level-time data of recording continuously after the last administration directly obtains C
MinAll directly obtain C with the blood drug level-time data that records continuously after the art time administration
MinAll use 24h numerical value after the last administration, other parameters are tried to achieve by following formula:
Average steady state blood drug level C
Av=AUC
Ss/ τ, τ are the administration time interval, and this test is 24 hours;
Blood concentration fluctuation coefficient DF=(C
Max-C
Min)/C
Av* 100%;
Relative bioavailability is according to AUC
0-24h(T)/AUC
0-24h(R) * 100% calculate.
The main pharmacokinetic parameters of table 11 test preparation (T) and reference preparation I (R I), reference preparation II (R II)
| Parameter | Test preparation (T) | Reference preparation I (R I) | Reference preparation II (R II) |
| t 1/2(h) | 2.144±0.453 | 2.066±0.439 | 2.026±0.513 |
| t max(h) | 5.275±0.716 | 5.175±0.654 | 5.105±0.541 |
| C max(μg·ml -1) | 0.284±0.144 | 0.370±0.132 | 0.368±0.132 |
| C min(μg·ml -1) | 0.178±0.117 | 0.054±0.120 | 0.055±0.056 |
| C av(μg·ml -1) | 0.071±0.052 | 0.057±0.085 | 0.056±0.102 |
| AUC ss(μg·ml -1·h) | 1.698±0.278 | 1.365±0.389 | 1.352±0.057 |
| AUC 0-24h(μg·ml -1·h) | 1.698±0.278 | 1.365±0.389 | 1.352±0.057 |
| AUC 0-∞(μg·ml -1·h) | 2.116±0.292 | 1.500±0.271 | 1.489±0.172 |
| DF(％) | 149.296±10.210 | 554.386±6.281 | 558.928±5.724 |
| F(％) | -- | 124.405±5.245 | 125.601±2.457 |
6.2.3 evaluation of bioequivalence
Adopt trapezoidal computing method, test preparation (T) and reference preparation I (R I), the main pharmacokinetic parameters of reference preparation II (R II) oxymatrine are carried out evaluation of bioequivalence.The result shows, test preparation (T) and reference preparation I (R I), the oral dual crossing test of reference preparation II (R II) multi-agent oxymatrine main showing property of pharmacokinetic parameter difference (P＜0.05), the relative bioavailability of slow releasing tablet of the present invention and reference preparation I (R I) is (124.405 ± 5.245) %, with the relative bioavailability of reference preparation II (R II) be (125.601 ± 2.457) %, all apparently higher than reference preparation.
Description of drawings
The absorbing state of Fig. 1 kurarinone different parts in intestinal
The write out a prescription release curve of 1-7 of Fig. 2
The write out a prescription release curve of 8-12 of Fig. 3
The write out a prescription release curve of 13-17 of Fig. 4
Fig. 5 medicine rate of releasing drug of the present invention curve (6 meansigma methodss)
Fig. 6 high-efficient liquid phase chromatogram
A. blank plasma B. oxymatrine standard substance
C. blank plasma+oxymatrine standard substance D. volunteer plasma sample
The specific embodiment
Kurarinone 300g
Lactose 60g
10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution 60ml
Hydroxypropyl methylcellulose K100M 130g
Microcrystalline Cellulose 50g
Micropowder silica gel 6.0g
Magnesium stearate 3.0g makes 1000
Coating fluid prescription:
Stomach dissolution type film coating powder 10.9g
Distilled water 61.0ml
1. take by weighing kurarinone and lactose by recipe quantity, mix homogeneously adds the about 60ml of binding agent, stirs, and makes suitable soft material, crosses 18 mesh sieves and granulates;
2. granule is dried under 50 ℃ of conditions, crosses 18 mesh sieve granulate;
3. the content of kurarinone in the mensuration granule determines that sheet is heavy;
4. the hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, the magnesium stearate that add recipe quantity in the dried granule, mix homogeneously;
5. use the punch die tabletting of diameter 12mm; Coating is to label weightening finish about 2%;
6. the inspection of semifinished product, packing.
Kurarinone 300g
Lactose 50g
10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution 60ml
Hydroxypropyl methylcellulose K100M 139.4g
Microcrystalline Cellulose 43.4g
Micropowder silica gel 6.0g
Magnesium stearate 2.7g makes 1000
Coating fluid prescription:
Stomach dissolution type film coating powder 11.3g
Distilled water 61.0ml
1. take by weighing kurarinone and lactose by recipe quantity, mix homogeneously adds the about 60ml of binding agent, stirs, and makes suitable soft material, crosses 24 mesh sieves and granulates;
2. granule is dried under 60 ℃ of conditions, crosses 16 mesh standard sieve granulate;
3. the content of kurarinone in the mensuration granule determines that sheet is heavy;
4. the hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, the magnesium stearate that add recipe quantity in the dried granule, mix homogeneously;
5. use the punch die tabletting of diameter 12mm; Coating is to label weightening finish about 2%;
6. the inspection of semifinished product, packing.
Kurarinone 300g
Lactose 59g
10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution 70ml
Hydroxypropyl methylcellulose K100M 130.4g
Microcrystalline Cellulose 40g
Micropowder silica gel 5.8g
Magnesium stearate 2.0g makes 1000
Coating fluid prescription:
Stomach dissolution type film coating powder 12g
Distilled water 61.0ml
1. take by weighing kurarinone and lactose by recipe quantity, mix homogeneously adds the about 60ml of binding agent, stirs, and makes suitable soft material, crosses 16 order nylon mesh and granulates;
2. granule is dried under 60 ℃ of conditions, crosses 24 mesh standard sieve granulate;
3. the content of kurarinone in the mensuration granule determines that sheet is heavy;
4. the hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, the magnesium stearate that add recipe quantity in the dried granule, mix homogeneously;
5. use the punch die tabletting of diameter 12mm; Coating is to label weightening finish about 2%;
6. the inspection of semifinished product, packing.
Kurarinone 300g
Lactose 54.5g
10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution 60ml
Hydroxypropyl methylcellulose K100M 136.4g
Microcrystalline Cellulose 46.4g
Micropowder silica gel 5.4g
Magnesium stearate 2.7g makes 1000
Coating fluid prescription:
Stomach dissolution type film coating powder 10.9g
Distilled water 61.0ml
1. take by weighing kurarinone and lactose by recipe quantity, mix homogeneously adds the about 60ml of binding agent, stirs, and makes suitable soft material, crosses 18 order nylon mesh and granulates;
2. granule is dried under 60 ℃ of conditions, crosses 18 mesh sieve granulate;
3. the content of kurarinone in the mensuration granule determines that sheet is heavy;
4. the hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, the magnesium stearate that add recipe quantity in the dried granule, mix homogeneously;
5. use the punch die tabletting of diameter 12mm; Coating is to label weightening finish about 2%;
6. the inspection of semifinished product, packing.
Kurarinone 300g
Lactose 54.5g
10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution 50ml
Hydroxypropyl methylcellulose K100M 100g
Microcrystalline Cellulose 46.4g
Micropowder silica gel 5.0g
Magnesium stearate 2.7g makes 1000
Coating fluid prescription:
Stomach dissolution type film coating powder 10g
Distilled water 61.0ml
1, take by weighing kurarinone and lactose by recipe quantity, mix homogeneously adds the about 60ml of binding agent, stirs, and makes suitable soft material, crosses 20 mesh sieves and granulates;
2, granule is dried under 70 ℃ of conditions, crosses 16 mesh sieve granulate;
3, measure the content of kurarinone in the granule, determine that sheet is heavy;
4, the hydroxypropyl methylcellulose K100M, microcrystalline Cellulose, micropowder silica gel, the magnesium stearate that add recipe quantity in the dried granule, mix homogeneously;
5, use the punch die tabletting of diameter 12mm; Coating is to label weightening finish about 2%;
6, the inspection of semifinished product, packing.
Claims (4)
1. Kurarinol slow-release sheet, the proportioning raw materials that it is characterized in that this slow releasing tablet is: kurarinone 300 weight portions, lactose 50-60 weight portion, microcrystalline Cellulose 40-50 weight portion, 10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution 50-70 parts by volume, hydroxypropyl methylcellulose K100M100-140 weight portion, micropowder silica gel 5-6 weight portion, magnesium stearate 2-3 weight portion, stomach dissolution type film coating powder 10-12 weight portion, addition outside hydroxypropyl methylcellulose K100M adopts in preparation process, described weight portion/parts by volume is corresponding to g/ml.
2. Kurarinol slow-release sheet as claimed in claim 1 is characterized in that the proportioning raw materials of this slow releasing tablet is:
Kurarinone 300 weight portions, lactose 54.5 weight portions, microcrystalline Cellulose 46.4 weight portions, 10% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution, 60 parts by volume, hydroxypropyl methylcellulose K100M136.4 weight portion, micropowder silica gel 5.4 weight portions, magnesium stearate 2.7 weight portions, stomach dissolution type film coating powder 10.9 weight portions.
3. the preparation method of Kurarinol slow-release sheet as claimed in claim 1 or 2 is characterized in that the Kurarinol slow-release sheet adopts wet granulation to obtain.
4. the preparation method of Kurarinol slow-release sheet as claimed in claim 1 or 2 is characterized in that Kurarinol slow-release sheet stomach dissolution type film coating liquid coating.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100831409A CN101584676B (en) | 2009-05-05 | 2009-05-05 | Matrine sustained release preparation and preparing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100831409A CN101584676B (en) | 2009-05-05 | 2009-05-05 | Matrine sustained release preparation and preparing method thereof |
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|---|---|
| CN101584676A CN101584676A (en) | 2009-11-25 |
| CN101584676B true CN101584676B (en) | 2011-01-05 |
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ID=41369249
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|---|---|---|---|
| CN2009100831409A Expired - Fee Related CN101584676B (en) | 2009-05-05 | 2009-05-05 | Matrine sustained release preparation and preparing method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202100016784A1 (en) * | 2021-06-25 | 2022-12-25 | Natural Way Laboratories Srl | Composition for the release of Magnesium ions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103565779A (en) * | 2013-09-11 | 2014-02-12 | 中国药科大学 | Oxymatrine biological adhering sustained release preparation and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202100016784A1 (en) * | 2021-06-25 | 2022-12-25 | Natural Way Laboratories Srl | Composition for the release of Magnesium ions |
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