CN100420437C - Tetramethylpyrazine phosphate slow-release micro-pill and its preparing method - Google Patents
Tetramethylpyrazine phosphate slow-release micro-pill and its preparing method Download PDFInfo
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- CN100420437C CN100420437C CNB2006100965734A CN200610096573A CN100420437C CN 100420437 C CN100420437 C CN 100420437C CN B2006100965734 A CNB2006100965734 A CN B2006100965734A CN 200610096573 A CN200610096573 A CN 200610096573A CN 100420437 C CN100420437 C CN 100420437C
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Abstract
The present invention relates to the field of medicine preparation, in the concrete, it relates to a ligustrazine phosphate slow-released micropill and its preparation method. Said preparation is formed from two kind of slow-released micropills with different medicine-releasing actions, so that the medicine can be quickly released so as to obtain a certain blood concentration.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to tetramethylpyrazine phosphate slow-release micro-pill and preparation method.
Background technology
Ligustrazine phosphate, English name: tetramethylpyrazine phosphate, chemical name: 2 phosphate monohydrate, molecular formula: C
8H
12N
2H
3PO
4H
2O, structural formula is as follows:
This product is white or off-white color crystalline powder; Little smelly, bitter in the mouth.In water or ethanol, dissolve, insoluble in chloroform; Ligustrazine phosphate is a kind of calcium antagonist, has the effect of antiplatelet aggregation, and accumulative platelet is had depolymerisation, still can expand small artery, microcirculation improvement and cerebral blood flow increasing amount, the function of promoting blood circulation to disperse blood clots of formation of generation antithrombotic and thrombus dissolving.Ligustrazine phosphate absorbs rapidly, and is widely distributed, mainly eliminates rapidly in liver, and biological half-life is short, and ordinary preparation needs repeatedly take every day.The kind of listing has tablet, capsule and injection at present.This product conventional tablet dosage is the 50mg/ sheet, 3 times/day, and the 1-2 sheet/time.If it is prepared into slow releasing preparation, can reach and prolong its action time, reduce administration frequency, reduce the purpose of toxic and side effects.At present, the patent of disclosed relevant ligustrazine phosphate has controlled releasing penetrant pump of CN02156892.8 phosphoric acid ligustrazine and preparation method thereof, CN03118436.7 ligustrazine phosphoric acid sustained-release sheet and preparation method thereof, CN03149886.8 phosphoric ligustrazine drop and preparation method thereof, CN200410073664.7 Lingustrazine Phosphate soft capsule and preparation method thereof, the compound medicinal formulation and the preparation method of CN200410005679.X ligustrazine phosphate and xylitol.
The diameter that micropill is made up of medicine and adjuvant is about the miniature spherical entity of 1mm.According to different treatment requirements, micropill system is dispersed in the medicine of dose in 1,100 small circular compartments, because there is bigger contact surface on medicine and gastrointestinal tract surface, absorbs good and little to partial zest; Micropill is different with tablet simultaneously, and the former is not subjected to the gastric emptying factor affecting substantially, so the infiltration rate of medicine is even, individual bioavailability difference is also little.Micropill has particle diameter even, and good fluidity is difficult for advantages such as crushing, particularly in the fine pellet core surface coatings, makes location, slow release or controlled release preparation, and technology is simple, can avoid coatings such as other solid preparations such as tablet inhomogeneous, may cause the risk of medicine pulse.
Summary of the invention
The invention discloses a kind of sustained-release pellet preparation of ligustrazine phosphate, i.e. 24 hours sustained-release pellet preparations of the ligustrazine phosphate of administration once a day.
The sustained-release pellet preparation of ligustrazine phosphate of the present invention is made up of the slow-release micro-pill of two kinds of different drug release behaviors, find in the research, if only use a kind of micropill, its external stripping otherwise slow partially otherwise fast, cumulative release percent do not reach fixed standard, and verify that in the dog body release can cause medicine bioavailability reduction in vivo too slowly; Discharging to cause medicine not have slow release effect in vivo too soon.The present invention makes medicine can discharge the blood drug level that reaches certain rapidly by adopting the slow-release micro-pill combination of two kinds of different drug release behaviors, and release maintains on the level always, makes blood drug level steady, reaches comparatively ideal therapeutic effect.
Concrete technical scheme of the present invention is as follows:
The sustained-release pellet preparation of ligustrazine phosphate of the present invention contains two kinds of micropills, and two kinds of micropills are formed and percentage by weight is:
First kind of micropill: contain pill core 50-95%
Controlled release layer 5-50%
Second kind of micropill: contain pill core 20-89%
Swell layer 3-40%
Controlled release layer 8-45%
Wherein the weight ratio of first kind of micropill and second kind of micropill is 1: 0.2-5.
The drug release rate of the pellet preparations of such two kinds of micropills combination:
2 hours 5-25%; 4 hours 15-50%; 6 hours 30-60%; 12 hours 50-85%; 16 hours greater than 75%.
In the above-mentioned micropill, the preferred hydroxypropyl emthylcellulose of swell layer, low-substituted hydroxypropyl cellulose or polyvinylpolypyrrolidone; Controlled release layer preferred, ethyl and/or acrylic resin base polymer.
Contain the main phosphoric acid ligustrazine of pill core, filler, osmotic pressure promoter.Ligustrazine phosphate shared percentage by weight in whole micropill is: 30-60%.
Containing pill core can be made up of above-mentioned three kinds of materials, also can contain binding agent again, and binding agent can be a water, and water is most of can the volatilization in preparation process, also can select other binding agents, and preferred adhesive is hydroxypropyl emthylcellulose and/or methylcellulose.Can also contain other carriers pharmaceutically commonly used.
Above-mentioned filler is one or more in starch, beta-schardinger dextrin-, microcrystalline Cellulose or dextrin preferably; Osmotic pressure promoter is one or more in lactose, sucrose, fructose, glucose or mannitol preferably.Binding agent is hydroxypropyl emthylcellulose and/or methylcellulose.
The preferred prescription of the present invention is formed:
First kind of micropill: contain pill core ligustrazine phosphate 30-60%
Microcrystalline Cellulose or starch 10-50%
Lactose or sucrose 5-50%
Hydroxypropyl emthylcellulose or methylcellulose 0-2.5%
Controlled release layer Aquacoat or acrylic resin 10-40%
Second kind of micropill: contain pill core ligustrazine phosphate 30-60%
Microcrystalline Cellulose or starch 10-46%
Lactose or sucrose 4-40%
Hydroxypropyl emthylcellulose or methylcellulose 0-2.5%
Swell layer hydroxypropyl emthylcellulose 5-30%
Controlled release layer Aquacoat or acrylic resin 15-40%
Below respectively organize percentage ratio all in the gross weight of this kind micropill.
The weight ratio of above-mentioned contained first kind of micropill and second kind of micropill is preferably 1: 0.5-3.
Above-mentioned preferred prescription is formed the release in vitro degree and is about:
First kind of micropill: 2 hours 4 hours 6 hours 12 hours 16 hours
5-15％ 10-20％ 20-45％ 50-70％ 60-85％
Second kind of micropill: 2 hours 4 hours 6 hours 12 hours 16 hours
7-20％ 30-55％ 55-75％ 70-97％ 90-99％
After two kinds of combinations: 2 hours 4 hours 6 hours 12 hours 16 hours
6-20％ 17-48％ 35-55％ 60-80％ 80-95％
By the release profiles of first kind of micropill as can be seen, the whole dispose procedure of this micropill is all very slow, and blood concentration is difficult to the treatment level that reaches certain in vivo; And second kind of micropill discharges comparatively fast in earlier stage, can reach blood concentration rapidly in vivo but can not keep a period of time, slow release effect preferably not has only first kind of micropill and the second kind of micropill concentration that could reach certain in vivo rapidly that combines can be kept a constant time again.
After two kinds of micropills of the present invention make up in proportion, can directly be filled in the hard capsule, in the packaging bag of also can packing into, can also add other pharmaceutic adjuvant and be pressed into tablet, these follow-up preparation methoies all are customary ways pharmaceutically.
The preparation method of tetramethylpyrazine phosphate slow-release micro-pill preparation of the present invention is as follows:
With ligustrazine phosphate and adjuvant mix homogeneously, make behind the soft material that preparation contains pill core in extruding spheronizator; The solution that perhaps will contain ligustrazine phosphate is sprayed onto on celphere or the blank adjuvant by fluid bed; Perhaps ligustrazine phosphate and adjuvant are mixed, in fluid bed, spray into the solution that contains binding agent, promptly get and contain pill core.
If second kind of micropill, then after obtaining containing pill core, the swell layer coating solution is sprayed onto and contains on the pill core, the pill core skin that contains of this moment has wrapped swell layer, again spray controlled release layer coating solution on swell layer.If first kind of micropill, then directly spray controlled release layer coating solution gets final product on the pill core containing.
After two kinds of micropills are made, be mixed in proportion and promptly get tetramethylpyrazine phosphate slow-release micro-pill preparation of the present invention.
Description of drawings
Blood concentration when Fig. 1 is the beasle dog oral administration of 24 hours sustained-release micro-pill capsules of ligustrazine phosphate of the present invention and commercially available ordinary tablet through the time curve (n=3)
The specific embodiment
Embodiment 1
First kind of micropill:
Consumption
Contain pill core starch 85mg
Sucrose 15mg
Ligustrazine phosphate 130mg
Hydroxypropyl emthylcellulose E3 5mg
The controlled release layer Aquacoat (
) 60mg (in solid content)
Second kind of micropill:
Consumption
Contain pill core starch 85mg
Sucrose 15mg
Ligustrazine phosphate 130mg
Hydroxypropyl emthylcellulose E3 5mg
Swelling layer hydroxypropyl emthylcellulose E5 50mg
The controlled release layer Aquacoat (
) 85mg (in solid content)
Above weight is every weight that capsule is contained.
Preparation method: feed intake by 1000 capsular amounts.The preparation of first kind of micropill, step 1 is dissolved in ligustrazine phosphate in the distilled water that contains hydroxypropyl emthylcellulose E3, the dissolving back is as the pastille solution for standby, and other takes by weighing sucrose, and the mixed accessories of starch places fluid bed, to contain drug solns then and be sprayed onto on the mixed accessories, obtain containing pill core; Step 2, take by weighing Aquacoat (
) be diluted to certain solid content with deionized water, stir evenly, as the controlled release layer coating solution, then coating solution is sprayed onto in the step 1 on the gained micropill, promptly.
The preparation of second kind of micropill, step 1 is dissolved in ligustrazine phosphate in the distilled water that contains hydroxypropyl emthylcellulose E3, the dissolving back is as the pastille solution for standby, and other takes by weighing sucrose, and the mixed accessories of starch places fluid bed, to contain drug solns then and be sprayed onto on the mixed accessories, obtain containing pill core; Step 2 takes by weighing hydroxypropyl emthylcellulose E5, adds a certain amount of deionized water, stirs evenly, and as swelling layer coating solution, then swelling layer coating solution is sprayed onto step 1 and prepares and contain on the pill core, be the swelling layer as the second layer; Step 3, take by weighing Aquacoat (
) be diluted to certain solid content with deionized water, stir evenly, as the controlled release layer coating solution, then coating solution is sprayed onto in the step 2 on the gained micropill, promptly.
Is to pack at 1: 1 in No. 1 hard capsule case promptly first kind of micropill and second kind of micropill according to weight ratio.
Result of the test:
First kind of micropill dissolution:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 6% 15% 23% 52% 68%
The twoth kind of micropill dissolution:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 10% 50% 65% 97% 99%
Mix back micropill dissolution at 1: 1:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 8% 33% 44% 75% 84%
First kind of micropill:
Consumption
Contain pill core microcrystalline Cellulose 85mg
Lactose 15mg
Ligustrazine phosphate 120mg
Hydroxypropyl emthylcellulose E3 5mg
The controlled release layer Aquacoat (
) 30mg (in solid content)
Second kind of micropill:
Consumption
Contain pill core microcrystalline Cellulose 85mg
Lactose 25mg
Ligustrazine phosphate 120mg
Hydroxypropyl emthylcellulose E3 5mg
Swelling layer hydroxypropyl emthylcellulose E5 70mg
The controlled release layer Aquacoat (
) 95mg (in solid content)
Above weight is every weight that capsule is contained.
Preparation method: feed intake by 1000 capsular amounts.The preparation of first kind of micropill, step 1 takes by weighing ligustrazine phosphate, microcrystalline Cellulose and lactose, mix homogeneously places centrifugal granulator, and the aqueous solution with hydroxypropyl emthylcellulose E3 is sprayed onto as binding agent on the mixture of medicine and adjuvant in addition, obtains containing pill core; Step 2, take by weighing Aquacoat (
) be diluted to certain solid content with deionized water, stir evenly, as the controlled release layer coating solution, then coating solution is sprayed onto in the step 1 on the gained micropill, promptly.
The preparation of second kind of micropill, step 1 takes by weighing ligustrazine phosphate, microcrystalline Cellulose and lactose, mix homogeneously places centrifugal granulator, and the aqueous solution with hydroxypropyl emthylcellulose E3 is sprayed onto as binding agent on the mixture of medicine and adjuvant in addition, obtains containing pill core; Step 2 takes by weighing hydroxypropyl emthylcellulose E5, adds a certain amount of deionized water, stirs evenly, and as swelling layer coating solution, then swelling layer coating solution is sprayed onto containing on the pill core of step 1 preparation, is the swelling layer as the second layer; Step 3, take by weighing Aquacoat (
) be diluted to certain solid content with deionized water, stir evenly, as the controlled release layer coating solution, then coating solution is sprayed onto in the step 2 on the gained micropill, promptly.
Is to pack at 1: 1.5 in No. 1 hard capsule case promptly first kind of micropill and second kind of micropill according to weight ratio.
Result of the test:
First kind of micropill dissolution:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 15% 30% 40% 65% 75%
The twoth kind of micropill dissolution:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 7% 28% 65% 77% 89%
Mix back micropill dissolution:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 10% 30% 55% 72% 83%
Embodiment 3
First kind of micropill:
Consumption
Contain pill core microcrystalline Cellulose 95mg
Mannitol 25mg
Ligustrazine phosphate 120mg
The controlled release layer Aquacoat (
) 40mg (in solid content)
Second kind of micropill:
Consumption
Contain pill core microcrystalline Cellulose 95mg
Mannitol 20mg
Ligustrazine phosphate 120mg
Swelling layer hydroxypropyl emthylcellulose E5 60mg
The controlled release layer Aquacoat (
) 75mg (in solid content)
Above weight is every weight that capsule is contained.
Preparation method: feed intake by 1000 capsular amounts.The preparation of first kind of micropill, step 1 takes by weighing ligustrazine phosphate, microcrystalline Cellulose and mannitol, mix homogeneously prepares soft material with deionized water as binding agent, places then to extrude spheronizator, and is round as a ball, obtains containing pill core; Step 2, take by weighing Aquacoat (
) be diluted to certain solid content with deionized water, stir evenly, as the controlled release layer coating solution, then coating solution is sprayed onto in the step 1 on the gained micropill, promptly.
The preparation of second kind of micropill, step 1 takes by weighing ligustrazine phosphate, microcrystalline Cellulose and mannitol, mix homogeneously prepares soft material with deionized water as binding agent, places then to extrude spheronizator, and is round as a ball, obtains containing pill core; Step 2 takes by weighing hydroxypropyl emthylcellulose E5, adds a certain amount of deionized water, stirs evenly, and as swelling layer coating solution, then swelling layer coating solution is sprayed onto containing on the pill core of step 1 preparation, is the swelling layer as the second layer; Step 3, take by weighing Aquacoat (
) be diluted to certain solid content with deionized water, stir evenly, as the controlled release layer coating solution, then coating solution is sprayed onto in the step 2 on the gained micropill, promptly.
Is to pack at 1: 1.2 in No. 1 hard capsule case promptly first kind of micropill and second kind of micropill according to weight ratio.
Result of the test:
First kind of micropill dissolution:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 10% 18% 26% 57% 68%
The twoth kind of micropill dissolution:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 11% 45% 69% 97% 97%
Mix back micropill dissolution:
Time: 2 hours 4 hours 6 hours 12 hours 16 hours
Cumulative release percent: 11% 33% 50% 79% 85%
Tetramethylpyrazine phosphate slow-release micro-pill capsule beasle dog body giving drugs into nose is for the examination of kinetic property:
A. administration with get the blood scheme:
3 of beasle dogs, male, body weight 10-12kg, the difference commercially available ligustrazine phosphate ordinary tablet of oral administration gavage (according to 15mg/kg dosage), respectively at 0.17,0.33,0.5,0.67,1,1.5,2,3,4,6,8h gets blood after the administration, each 0.5ml.Institute's blood-sample withdrawal is all used anticoagulant heparin, and separated plasma immediately.After one week, irritate 24 hours sustained-release micro-pill capsules (embodiment 3 makes) of stomach ligustrazine phosphate of the present invention at the first-class dosage of same animal, respectively at 0.5,1,1.5,2,3,4,6,8,12,16,24h gets blood after the administration, places the centrifuge tube of heparinization.
B. through the time curve, referring to Fig. 1.
C. the moving parameter of relevant medicine
Give commercially available ligustrazine phosphate ordinary tablet, its blood concentration data are through the match of 3P97 program, and behavior meets one-level absorption two-compartment model in the body, gives and tetramethylpyrazine phosphate slow-release micro-pill capsule of the present invention, and the interior behavior of body meets one-level and absorbs one-compartment model.
Tetramethylpyrazine phosphate slow-release micro-pill
The commercially available ligustrazine phosphate ordinary tablet of sexual life model parameter
Capsule
A 4331.51±1568.21 248.2±146.21
α 1.72±0.71 /
B 911.72±289.64 /
β 0.42±0.18 /
Ka 45.43±16.78 0.68±0.39
V/F(c) 0.03±0.0047 0.65±0.38
T1/2ka 0.015±0.0024 1.02±0.63
T1/2α 0.38±0.12 /
T1/2β 1.66±0.68 /
T1/2ke / 15.53±8.92
K21 0.65±0.38 /
K10 1.11±0.67 0.045±0.011
K12 0.38±0.17 /
AUC 4587.5±1547.32 5197.8±2167.72
CI/F(s) 0.033±0.011 0.03±0.014
Relative bioavailability %=5197.8/4587.5 * 100=113.3%
Claims (3)
1. tetramethylpyrazine phosphate slow-release micro-pill preparation is characterized in that: contain two kinds of micropills, two kinds of micropills are formed and percentage by weight is:
First kind of micropill: contain pill core ligustrazine phosphate 30-60%
Microcrystalline Cellulose or starch 10-50%
Lactose or sucrose 5-50%
Hydroxypropyl emthylcellulose or methylcellulose 0-2.5%
Controlled release layer Aquacoat or acrylic resin 10-40%
Second kind of micropill: contain pill core ligustrazine phosphate 30-60%
Microcrystalline Cellulose or starch 10-46%
Lactose or sucrose 4-40%
Hydroxypropyl emthylcellulose or methylcellulose 0-2.5%
Swell layer hydroxypropyl emthylcellulose 5-30%
Controlled release layer Aquacoat or acrylic resin 15-40%
Wherein the weight ratio of first kind of micropill and second kind of micropill is 1: 0.2-5.
2. the tetramethylpyrazine phosphate slow-release micro-pill preparation of claim 1, the weight ratio of wherein contained first kind of micropill and second kind of micropill is 1: 0.5-3.
3. the preparation method of claim 1 or 2 tetramethylpyrazine phosphate slow-release micro-pill preparation comprises:, centrifugal granulating round as a ball by extruding, celphere medicine-feeding legal system are equipped with ligustrazine phosphate and contain pill core; The swell layer coating solution is sprayed onto contains on the pill core; The controlled release layer coating solution is sprayed onto on the ball core of gained, promptly again.
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|---|---|---|---|
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| CN100420437C true CN100420437C (en) | 2008-09-24 |
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| CN1430963A (en) * | 2003-01-09 | 2003-07-23 | 武汉大学 | Slowly releasing tablet of ligustrazine of phosphoric acid and its preparing method |
| CN1546039A (en) * | 2003-12-15 | 2004-11-17 | 中国药科大学 | Sustained releasing minipills of diltiazem hydrochloride and its preparation |
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| CN1215847C (en) * | 2002-12-20 | 2005-08-24 | 北京中惠药业有限公司 | Control released osmotic pump prepn containing ligustrazine phosphate and its prepn process |
| CN1430963A (en) * | 2003-01-09 | 2003-07-23 | 武汉大学 | Slowly releasing tablet of ligustrazine of phosphoric acid and its preparing method |
| CN1546039A (en) * | 2003-12-15 | 2004-11-17 | 中国药科大学 | Sustained releasing minipills of diltiazem hydrochloride and its preparation |
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