CN103919746A - Edoxaban sustained release tablet and preparation method thereof - Google Patents
Edoxaban sustained release tablet and preparation method thereof Download PDFInfo
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Abstract
The invention provides a preparation method of an edoxaban sustained release matrix tablet. The specific prescription of the edoxaban sustained release tablet consists of the following components in percentage by weight: 14-21 percent of edoxaban p-toluene sulfonate hydrate, 0-36 percent of hydroxypropyl methylcellulose, 0-28 percent of carbomer, 10-28 percent of lactose, 29-38 percent of diluent, 0-3 percent of povidone and 0.6-4 percent of lubricant.
Description
Technical field
The invention belongs to the technical field of medicament slow release preparation, exactly relate to a kind of sustained-release matrix tablets containing active component Yi Dushaban and preparation method thereof.
Background technology
Yi Dushaban chemical name is N-(5-chloro-2-pyridyl)-N
'-[(1S, 2R, 4S)-4-[(dimethylamino) formoxyl]-2-[[4,5,6,7-tetrahydrochysene-5-methylthiazol is [5,4-C] pyridine-2-yl also) formyl] amino] cyclohexyl] oxalamide is to benzene methanesulfonic acid salt monohydrate, structural formula is as follows:
。
In Japanese description about the dissolubility of this product: be soluble in dimethyl sulfoxine, DMF, be slightly dissolved in methanol, water, acetonitrile, be slightly soluble in ethanol (99.5), atomic acetone, the ethyl acetate of being dissolved in, almost insoluble in isopropyl alcohol.
NAM's single is oral Yi Dushaban 30mg on an empty stomach, and the pharmacokinetic parameter of Yi Dushaban and active metabolite M-4 thereof is as form 1 and form 2, and blood drug level-time graph of Yi Dushaban is shown in Figure of description 1.
Form 1 NAM's single is the pharmacokinetic parameter of oral Yi Dushaban on an empty stomach
The pharmacokinetic parameter of its active metabolite M-4 after the oral Yi Dushaban of form 2 NAM's singles empty stomach
。
According to slow releasing preparation requirement, its delivery time should extend to some extent compared with ordinary preparation.The original object of slow releasing preparation is mainly to improve safety, effectiveness and the patient's of medication compliance, and this is mainly by controlling drug plasma level and reducing administration frequency and realize.With regard to ordinary preparation, most drug all exists treatment window, and blood level, lower than treatment window, does not reach due therapeutic effect, higher than treatment window, there will be poisoning symptom.Therefore safe and effective for medication, has proposed the concept of therapeutic index (TI).So-called therapeutic index can be with the highest blood drug level (C that can tolerate
max) and can produce the minimum blood drug level (C of appropriate therapeutic effect
min) between ratio represent.
For the medicine with linearity, single compartment model characteristic, the relation between its spacing of doses (τ) and therapeutic index (TI) as shown in the formula:
τ＜t
1/2(lnTI/ln2) （1）
T in above formula
1/2for the half-life of medicine, because the therapeutic index of most drug is about 2 left and right, so the spacing of doses of most drug is less than its half-life, this dosage regimen will reduce patient's compliance greatly.
Concerning having the medicine of many compartments characteristic, its spacing of doses can be described with following formula.
τ＜0.693 MRT (lnTI/In2) （2）
MRT is mean residence time in body, and in (2) formula, the spacing of doses of gained will more be less than (1) formula, and administration is more frequent.
Generally, extending dosing interval can solve by following two approach.The first by revise medicine molecular structure, reduce medicine release rate (
k el); It two is by reducing the rate of release of medicine from preparation to reduce the infiltration rate constant of medicine
k a .These two kinds of approach all can significantly reduce the fluctuation of blood drug level in multiple dose administration.But utilize, reduce the restriction that infiltration rate delayed release will be subject to some physiologic factor, as the holdup time at absorption site, medicine is about 9～12h at the effective soak time of gastrointestinal.If infiltration rate is too slow, some medicines can not be completely absorbed.If certain drug half-life is 6h or shorter, and its therapeutic index is less than 3, designs spacing of doses and can not be greater than 12h.It will be very difficult that shorter medicine of this half-life is prepared to the preparation that 24h is administered once.
From the data of above table 1, form 2 and Figure of description 1, the C of Yi Dushaban active metabolite
maxapproximately only has Yi Dushaban C
max1/10th, the half-life of Yi Dushaban and active metabolite thereof all, about 5 hours, although its using method is once a day, that is to say the non-constant width of its therapeutic index, can cause like this blood concentration fluctuation amplitude excessive, blood drug level is steady not.Although the therapeutic index of Yi Dushaban is wider, but when day is taken one time at present, the huge spread of " peak-to-valley ratio " still can make the potential untoward reaction of medicine increase, therefore Yi Dushaban is made to slow releasing tablet, object is that the fluctuating margin of Yi Dushaban blood drug level is significantly reduced, Yi Dushaban not only can not reduce therapeutic effect like this, and can greatly reduce untoward reaction.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of above-mentioned prior art, provide a kind of anticoagulation therapy effect more steady, the Yi Dushaban slow releasing tablet with framework material control drug release that untoward reaction is lower.
Another object of the present invention is to provide a kind of preparation method of Yi Dushaban sustained-release matrix tablets.
Yi Dushaban slow releasing tablet of the present invention is comprised of crude drug, hypromellose, carbomer, lactose, diluent, polyvidone and lubricant.
Prescription composition of Yi Dushaban slow releasing tablet of the present invention and preparation method thereof is as follows:
1, prescription forms (g/g):
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 14%～21%
Hypromellose 0～36%
Carbomer 0 ~ 28%
Lactose 10% ~ 28%
Diluent 29%～38%
Polyvidone 0～3%
Lubricant 0.6% ~ 4%.
2, preparation method:
Method one: while not containing binding agent polyvidone in prescription, its preparation method be after supplementary material is mixed by direct compression of full-powder, or only use wetting agent to prepare tabletting after wet granular dry granulate.
Method two: 1. crude drug is crossed to 120 mesh sieves; 2. crude drug, framework material, mixing diluents is even, add suitable amount of adhesive, wet granulation, dry; 3. granulate, adds the lubricant of recipe quantity, mixes tabletting.
The adjuvant of Yi Dushaban slow releasing tablet of the present invention is as follows:
Hypromellose refers to HPMC K4M or HPMC K15M or HPMC K100M; Carbomer refers to Carbopol 974P or Carbopol 971p or Carbopol 71G.
Diluent refers to starch or calcium hydrogen phosphate or microcrystalline Cellulose.
Wetting agent or binding agent refer to mixed solution or the polyvidone of water and alcohol.
Lubricant comprises one or both the mixing wherein such as magnesium stearate, stearic acid, sodium stearyl fumarate, Pulvis Talci.
The Yi Dushaban slow releasing tablet making according to the present invention is carried out dissolution test in water or pH6.8 buffer (according to the preparation of Chinese Pharmacopoeia method), has following drug release characteristics:
Time (hour) cumulative release amount %
1 15%~40%
4 40%~70%
8 >80%。
Accompanying drawing explanation
Accompanying drawing 1 is NAM's single blood drug level-time graph of oral Yi Dushaban on an empty stomach.
The specific embodiment
[0023]following examples feed intake by 1000 tablet recipe amounts, and specification is that 15mg(is equivalent to Yi Dushaban to benzene methanesulfonic acid salt hydrate 20.2mg) and 30mg(be equivalent to Yi Dushaban to benzene methanesulfonic acid salt hydrate 40.4mg).Following examples just describe, and do not limit invention scope.
embodiment 1
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 20.2g 20.2%
HPMC K100M 20g 20.0%
CARBOPOL 974P 10g 10.0%
Lactose 17g 17.0%
Starch 30g 30.0%
Pulvis Talci 2g 2.0%
Magnesium stearate 1g 1.0%.
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K100M, CARBOPOL 974P mix homogeneously, the alcohol granulation with approximately 90%, is then dried; 3. the granulate that sieves, adds Pulvis Talci and the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 17.3%
4 48.6%
8 92.4%。
embodiment 2
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 20.2%
HPMC K100M 36g 18.0%
CARBOPOL 974P 12g 6.0%
Lactose 34g 17.0%
Starch 72g 36.0%
Pulvis Talci 4g 2.0%
Magnesium stearate 2g 1.0%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K100M, CARBOPOL 974P mix homogeneously, the alcohol granulation with approximately 90%, is then dried; 3. the granulate that sieves, adds Pulvis Talci and the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 23.6%
4 51.4%
8 90.8%。
embodiment 3
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 20.2g 20.2%
HPMC K100M 35g 35.0%
Lactose 11g 11.0%
Starch 30g 30.0%
PVP K30 3g 3.0%
Magnesium stearate 1g 1.0%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K100M mix homogeneously, with PVP K30 approximately 90% alcoholic solution, granulate, be then dried; 3. the granulate that sieves, adds the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 28.7%
4 55.8%
8 94.3%。
embodiment 4
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 20.2%
HPMC K100M 60g 30.0%
Lactose 26g 13.0%
Starch 66g 33.0%
PVP K30 6g 3.0%
Magnesium stearate 2g 1.0%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K100M mix homogeneously, with PVP K30 approximately 90% alcoholic solution, granulate, be then dried; 3. the granulate that sieves, adds the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 26.1%
4 54.4%
8 91.8%。
embodiment 5
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 20.2%
CARBOPOL 974P 26g 26.0%
Lactose 23g 23.0%
Starch 28g 28.0%
Pulvis Talci 2g 2.0%
Magnesium stearate 1g 1.0%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, CARBOPOL 974P, newborn sugar and starch mix homogeneously, the alcohol granulation with approximately 90%, is then dried; 3. the granulate that sieves, adds Pulvis Talci and the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 23.6%
4 51.4%
8 90.7%。
embodiment 6
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 20.2%
CARBOPOL 974P 40g 20.0%
Lactose 42g 21.0%
Starch 72g 36.0%
Pulvis Talci 4g 2.0%
Magnesium stearate 2g 1.0%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, CARBOPOL 974P, newborn sugar and starch mix homogeneously, the alcohol granulation with approximately 90%, is then dried; 3. the granulate that sieves, adds Pulvis Talci and the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 25.5%
4 57.6%
8 95.3%。
embodiment 7
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 20.2g 16.8%
HPMC K15M 25.0g 20.8%
CARBOPOL 971 15g 12.5%
Lactose 21g 17.4%
Microcrystalline Cellulose 36g 30.0%
Pulvis Talci 2g 1.7%
Magnesium stearate 1.2g 1.0%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K15M, CARBOPOL 971, lactose and microcrystalline Cellulose mix homogeneously, the alcohol granulation with approximately 90%, is then dried; 3. the granulate that sieves, adds Pulvis Talci and the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 18.4%
4 50.2%
8 89.7%。
embodiment 8
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 16.8%
HPMC K15M 44g 18.3%
CARBOPOL 971 22g 9.2%
Lactose 46g 19.2%
Microcrystalline Cellulose 82g 34.2%
Pulvis Talci 4g 1.7%
Magnesium stearate 1.6g 0.7%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K15M, CARBOPOL 971, lactose and microcrystalline Cellulose mix homogeneously, the alcohol granulation with approximately 90%, is then dried; 3. the granulate that sieves, adds Pulvis Talci and the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 21.7%
4 52.5%
8 93.7%。
embodiment 9
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 16.8%
HPMC K15M 42g 34.8%
Lactose 15g 12.5%
Microcrystalline Cellulose 39g 32.4%
PVP K30 3g 2.5%
Magnesium stearate 1.2g 1.0%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K15M, lactose and microcrystalline Cellulose mix homogeneously, with appropriate PVP K30 approximately 90% alcoholic solution, granulate, be then dried; 3. the granulate that sieves, adds the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 27.8%
4 57.5%
8 92.6%。
embodiment 10
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 16.8%
HPMC K15M 70g 29.2%
Lactose 39g 16.2%
Microcrystalline Cellulose 83g 34.6%
PVP K30 6g 2.5%
Magnesium stearate 1.6g 0.7%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K15M, lactose and microcrystalline Cellulose mix homogeneously, with appropriate PVP K30 approximately 90% alcoholic solution, granulate, be then dried; 3. the granulate that sieves, adds the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 30.2%
4 58.1%
8 95.0%。
embodiment 11
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 20.2g 16.8%
CARBOPOL 971 30g 25.0%
Lactose 31g 25.8%
Microcrystalline Cellulose 35g 29.2%
Pulvis Talci 3g 2.5%
Magnesium stearate 0.8g 0.7%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, CARBOPOL 971, lactose and microcrystalline Cellulose mix homogeneously, with appropriate approximately 90% alcoholic solution, granulate, be then dried; 3. the granulate that sieves, adds Pulvis Talci and the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 24.6%
4 51.4%
8 93.8%。
embodiment 12
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 16.8%
CARBOPOL 971 55g 22.9%
Lactose 56g 23.3%
Microcrystalline Cellulose 80g 33.3%
Pulvis Talci 7g 2.9%
Magnesium stearate 1.6g 0.7%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, CARBOPOL 971, lactose and microcrystalline Cellulose mix homogeneously, with appropriate approximately 90% alcoholic solution, granulate, be then dried; 3. the granulate that sieves, adds Pulvis Talci and the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 24.6%
4 51.4%
8 93.2%。
embodiment 13
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 20.2g 14.4%
HPMC K4M 32g 22.9%
Carbopol 71G 18g 12.9%
Lactose 26g 18.6%
Calcium hydrogen phosphate 40g 28.6%
Pulvis Talci 3g 2.1%
Magnesium stearate 0.8g 0.6%
Preparation method: above mixing of materials is even, carry out direct compression of full-powder.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 20.1%
4 48.6%
8 90.2%。
embodiment 14
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 14.4%
HPMC K4M 55g 19.6%
Carbopol 71G 30g 10.7%
Lactose 54g 19.3%
Calcium hydrogen phosphate 92g 32.8%
Pulvis Talci 6g 2.1%
Magnesium stearate 2.8g 1.0%
Preparation method: above mixing of materials is even, carry out direct compression of full-powder.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 22.9%
4 53.4%
8 92.8%。
embodiment 15
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 20.2g 14.4%
HPMC K4M 50g 35.7%
Lactose 20g 14.3%
Calcium hydrogen phosphate 46g 32.9%
PVP K30 3g 2.1%
Magnesium stearate 0.8g 0.6%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K4M, lactose and calcium hydrogen phosphate mix homogeneously, with appropriate PVP K30 approximately 90% alcoholic solution, granulate, be then dried; 3. the granulate that sieves, adds the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 26.3%
4 55.7%
8 93.5%。
embodiment 16
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 14.4%
HPMC K4M 82g 29.3%
Lactose 46g 16.4%
Calcium hydrogen phosphate 103g 36.8%
PVP K30 6g 2.1%
Magnesium stearate 2.8g 1.0%
Preparation method: 1. crude drug is crossed to 120 mesh sieves; 2. by crude drug, HPMC K4M, lactose and calcium hydrogen phosphate mix homogeneously, with appropriate PVP K30 approximately 90% alcoholic solution, granulate, be then dried; 3. the granulate that sieves, adds the magnesium stearate of recipe quantity, mixes tabletting.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 24.3%
4 50.4%
8 92.1%。
embodiment 17
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 20.2g 14.4%
Carbopol 71G 38g 27.1%
Lactose 33g 23.6%
Calcium hydrogen phosphate 45g 32.1%
Pulvis Talci 3g 2.1%
Magnesium stearate 0.8g 0.6%
Preparation method: above mixing of materials is even, carry out direct compression of full-powder.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 19.8%
4 52.9%
8 90.4%。
embodiment 18
Recipe quantity percentage ratio
Yi Dushaban is to benzene methanesulfonic acid salt hydrate 40.4g 14.4%
Carbopol 71G 65g 23.2%
Lactose 76g 27.1%
Calcium hydrogen phosphate 90g 32.1%
Pulvis Talci 6g 2.1%
Magnesium stearate 2.8g 1.0%
Preparation method: above mixing of materials is even, carry out direct compression of full-powder.
Release experiment, with two appendix X C the second subtraction units of Chinese Pharmacopoeia version in 2010, according to the release of two appendix X D first method working samples of Chinese Pharmacopoeia version in 2010.The buffer salt 900ml of pH6.8 of take is solvent, and rotating speed 50 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:
Time (hour) cumulative release degree %
1 21.5%
4 54.2%
8 91.6%。
Claims (4)
1. containing a sustained-release matrix tablets of active pharmaceutical ingredient Yi Dushaban, it is characterized in that its prescription is composed as follows by weight percentage: Yi Dushaban is to benzene methanesulfonic acid salt hydrate 14%～21%; Hypromellose 0～36%; Carbomer 0 ~ 28%; Lactose 10% ~ 28%; Diluent 29%～38%; Polyvidone 0～3%; Lubricant 0.6～4%; Wherein hypromellose refers to HPMC K4M or HPMC K15M or HPMC K100M; Carbomer refers to Carbopol 974P or Carbopol 971p or Carbopol 71G; Diluent refers to starch or microcrystalline Cellulose or calcium hydrogen phosphate.
2. Yi Dushaban slow releasing tablet according to claim 1, it is characterized in that: while not containing binding agent polyvidone in prescription, its preparation method be after supplementary material is mixed by direct compression of full-powder, or only use wetting agent to prepare tabletting after wet granular dry granulate.
3. Yi Dushaban slow releasing tablet according to claim 1, is characterized in that: while containing binding agent polyvidone in prescription, its preparation method is 1. crude drug to be crossed to 120 mesh sieves; 2. crude drug, hypromellose, carbomer, lactose, mixing diluents is even, add suitable amount of adhesive solution, wet granulation, dry; 3. granulate, adds the lubricant of recipe quantity, mixes tabletting.
4. Yi Dushaban slow releasing tablet according to claim 1, is characterized in that: the drug release characteristics of this slow releasing tablet is as follows:
Accumulated time burst size %
1 hour 15%～40%
4 hours 40%～70%
8 hours >80%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410153345.0A CN103919746A (en) | 2014-04-17 | 2014-04-17 | Edoxaban sustained release tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410153345.0A CN103919746A (en) | 2014-04-17 | 2014-04-17 | Edoxaban sustained release tablet and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103919746A true CN103919746A (en) | 2014-07-16 |
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Cited By (11)
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| CN104382874A (en) * | 2014-11-21 | 2015-03-04 | 哈尔滨圣吉药业股份有限公司 | Apixaban sustained-release tablets and preparation method thereof |
| WO2017107857A1 (en) * | 2015-12-24 | 2017-06-29 | 江苏恒瑞医药股份有限公司 | Solid pharmaceutical composition comprising diamine derivative or salt thereof |
| JP2017523149A (en) * | 2014-08-06 | 2017-08-17 | サンド・アクチエンゲゼルシヤフト | Edoxaban pharmaceutical composition |
| CN108743556A (en) * | 2018-02-02 | 2018-11-06 | 重庆植恩药业有限公司 | A kind of Yi Dushaban tablets and preparation method thereof |
| CN109793715A (en) * | 2019-03-15 | 2019-05-24 | 南京卡文迪许生物工程技术有限公司 | A kind of Eliquis oral solid formulation and preparation method thereof |
| CN110302167A (en) * | 2019-06-27 | 2019-10-08 | 慧生医学科技(徐州)有限公司 | A kind of Eliquis sustained release tablets and preparation method thereof |
| CN112494489A (en) * | 2020-12-18 | 2021-03-16 | 浙江诺得药业有限公司 | Apixaban-containing compound sustained-release preparation and preparation method thereof |
| CN112675136A (en) * | 2019-10-18 | 2021-04-20 | 苏州特瑞药业有限公司 | Composition for reducing rivaroxaban bleeding risk and preparation method thereof |
| CN112791057A (en) * | 2021-02-07 | 2021-05-14 | 齐飞 | Slow release preparation containing edoxaban and preparation method thereof |
| EP3838267A1 (en) * | 2019-12-19 | 2021-06-23 | Biohorm, S.L. | Edoxaban tablets |
| WO2022129535A1 (en) | 2020-12-18 | 2022-06-23 | Krka, D.D., Novo Mesto | Edoxaban formulation containing no sugar alcohols |
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Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017523149A (en) * | 2014-08-06 | 2017-08-17 | サンド・アクチエンゲゼルシヤフト | Edoxaban pharmaceutical composition |
| CN104382874A (en) * | 2014-11-21 | 2015-03-04 | 哈尔滨圣吉药业股份有限公司 | Apixaban sustained-release tablets and preparation method thereof |
| CN107405342B (en) * | 2015-12-24 | 2021-05-14 | 江苏恒瑞医药股份有限公司 | Solid pharmaceutical composition containing diamine derivative or salt thereof |
| WO2017107857A1 (en) * | 2015-12-24 | 2017-06-29 | 江苏恒瑞医药股份有限公司 | Solid pharmaceutical composition comprising diamine derivative or salt thereof |
| CN107405342A (en) * | 2015-12-24 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | A kind of solid composite medicament containing diamine derivative or its salt |
| CN108743556A (en) * | 2018-02-02 | 2018-11-06 | 重庆植恩药业有限公司 | A kind of Yi Dushaban tablets and preparation method thereof |
| CN109793715A (en) * | 2019-03-15 | 2019-05-24 | 南京卡文迪许生物工程技术有限公司 | A kind of Eliquis oral solid formulation and preparation method thereof |
| CN109793715B (en) * | 2019-03-15 | 2022-02-15 | 南京卡文迪许生物工程技术有限公司 | Apixaban oral solid preparation and preparation method thereof |
| CN110302167A (en) * | 2019-06-27 | 2019-10-08 | 慧生医学科技(徐州)有限公司 | A kind of Eliquis sustained release tablets and preparation method thereof |
| CN112675136A (en) * | 2019-10-18 | 2021-04-20 | 苏州特瑞药业有限公司 | Composition for reducing rivaroxaban bleeding risk and preparation method thereof |
| EP3838267A1 (en) * | 2019-12-19 | 2021-06-23 | Biohorm, S.L. | Edoxaban tablets |
| WO2021123192A1 (en) * | 2019-12-19 | 2021-06-24 | Biohorm, S.L. | Edoxaban tablets |
| CN112494489B (en) * | 2020-12-18 | 2021-09-03 | 浙江诺得药业有限公司 | Apixaban-containing compound sustained-release preparation and preparation method thereof |
| CN112494489A (en) * | 2020-12-18 | 2021-03-16 | 浙江诺得药业有限公司 | Apixaban-containing compound sustained-release preparation and preparation method thereof |
| WO2022129535A1 (en) | 2020-12-18 | 2022-06-23 | Krka, D.D., Novo Mesto | Edoxaban formulation containing no sugar alcohols |
| CN112791057A (en) * | 2021-02-07 | 2021-05-14 | 齐飞 | Slow release preparation containing edoxaban and preparation method thereof |
| CN112791057B (en) * | 2021-02-07 | 2022-03-18 | 齐飞 | Slow release preparation containing edoxaban and preparation method thereof |
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