CN102641253A - Valsartan sustained release tablet and preparation method thereof - Google Patents
Valsartan sustained release tablet and preparation method thereof Download PDFInfo
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- CN102641253A CN102641253A CN2012101369669A CN201210136966A CN102641253A CN 102641253 A CN102641253 A CN 102641253A CN 2012101369669 A CN2012101369669 A CN 2012101369669A CN 201210136966 A CN201210136966 A CN 201210136966A CN 102641253 A CN102641253 A CN 102641253A
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- valsartan
- slow releasing
- binding agent
- releasing tablet
- diluent
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Abstract
The invention provides a preparation method of a valsartan sustained release matrix tablet. Particular prescription components (g/g) of a carbazochrome sodium sulfonate trihydrate sustained release tablet is 20-50% of valsartan, 8-20% of framework materials, 35-75% of diluent, 0-5% of binding agent and 1-4% of lubricating agent. The preparation method adopts full powder direct compression or adopts a wet granulation to achieve compression after dryimng.
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 that contains the active component valsartan and preparation method thereof.
Background technology
The valsartan chemical name is N-(1-valeryl)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-L-valine, and structural formula is following:
The English description of FDA issue: the valsartan raw material is that white arrives the off-white color fine powder, is dissolved in methanol and ethanol, is slightly soluble in water.
Crude drug import standard is: these article are white or off-white color fine powder, and hygroscopicity is arranged.These article dissolve in methanol, dissolve in the water part omitted.
Chinese Pharmacopoeia 2010 editions is: these article are white crystals or white, off-white powder; Hygroscopicity is arranged.These article are very easily dissolving in ethanol, in methanol, is prone to dissolve, and dissolves in the ethyl acetate part omitted, and are almost insoluble in water.
Analyze the reason of valsartan raw material different solubility in water: the granularity of the crude drug that uses during mensuration is variant; The imported raw material medicine is micronization, and particle diameter is a few μ m ~ tens μ m, that is to say that the import standard controls particle size range; So more help the stripping and the absorption of medicine; Make the pharmacokinetics of valsartan more stable, reduce the absorption difference between fasting and the feed, reduce the degree of fluctuation of interindividual variation and blood drug level.
The valsartan pharmacokinetics:
Absorb: can absorb rapidly after valsartan is oral, its absorbtivity is widely different, and the average absolute bioavailability is 23% (23 ± 7), and in the dosage range of research, it is linear that pharmacokinetic curve is.When taking one every day, valsartan seldom causes to be accumulated, and in masculinity and femininity, PC is similar.
Take valsartan during dining, make AUC reduce 48%, blood drug level peak value (Cmax) reduces 59%.Whether no matter obey together with food, the blood drug level after 8 hours is similar.The minimizing of AUC or Cmax does not have tangible influence to clinical efficacy, thus when valsartan can be had meal or (medicine) being taken before meal use.
Distribute: most valsartan (94～97%) combine (mainly being albumin) with serum albumin, reach stable state in the week.Vdss is about 17 liters.(30L/h) compares with hepatic blood flow, plasma clearance speed relatively slow (approximately 2L/h).
Remove: valsartan is with multi index option decay kinetics metabolism (a item half-life < 1 hour, about 9 hours of t1/>2).Valsartan is mainly drained with prototype, and 70% from the feces discharge, and 30% from the urine discharge.
According to the slow releasing preparation requirement, its delivery time should prolong than ordinary preparation to some extent.The original purpose of slow releasing preparation mainly is to improve the safety of medication and effectiveness and patient's compliance, and this mainly realizes through control drug plasma level and reduction administration frequency.With regard to ordinary preparation, most drug all exists the treatment window, and blood level is lower than the treatment window, does not then reach due therapeutic effect, is higher than the treatment window and then poisoning symptom can occurs.Therefore safe and effective for medication proposed the notion of therapeutic index (TI).So-called therapeutic index can be used 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 medicine with linearity, single compartment model characteristic, the relation between its spacing of doses (τ) and the therapeutic index (TI) as shown in the formula:
τ＜t
1/2(lnTI/ln2) formula (1)
T in the following formula (1)
1/2Be the half-life of medicine because the therapeutic index of most drug is about about 2, so the spacing of doses of most drug less than its half-life, this dosage regimen will reduce patient's compliance greatly.
Concerning the medicine with many compartments characteristic, its spacing of doses can be described with following formula.
τ＜0.693 MRT (lnTI/In2) formula (2)
MRT is a mean residence time in the body, will be by the spacing of doses of gained in the formula (2) more less than formula (1), and administration is more frequent.
Generally, prolonging dosing interval can solve through following two approach.The molecular structure of the first through revising medicine, the elimination speed that reduces medicine (
k El); It two is through 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 the multiple dose administration.But utilize to reduce infiltration rate and postpone to discharge the restriction that will receive some physiologic factor, as in the holdup time of absorption site, medicine is about 9～12h at the effective soak time of gastrointestinal.If infiltration rate is too slow, then some medicines can not be absorbed fully.If certain drug half-life is 6h or shorter, and its therapeutic index is less than 3, and then designing spacing of doses can not be greater than 12h.The preparation that short medication preparation 24h of this half-life is administered once will be very difficult.
About 6 ~ 9 hours of the half-life of valsartan ordinary preparation; Though its method for using is once a day, that is to say its therapeutic index broad, can cause the blood concentration fluctuation amplitude excessive like this; Blood drug level is steady inadequately; Show on the therapeutic effect can not bring high blood pressure down effectively stably more exactly, and blood pressure is produced than great fluctuation process, therefore consider development valsartan slow releasing tablet.
The method that patent CN101951902A provides a kind of valsartan solid peroral dosage form and prepared said preparation; Wherein mentioned a kind of MR tablet; The employing fusion method is granulated, and finally be pressed into oval slow releasing tablet, but the fusion method facility for granulating is not a lot of at home; Technology realizes difficult, and repeatability is relatively poor.
Summary of the invention
[0003] an object of the present invention is to overcome the shortcoming and defect of above-mentioned prior art, provide a kind of antihypertensive effect more steady, toxic and side effects is lower, the valsartan slow releasing tablet with the framework material control drug release of good patient compliance.
Another object of the present invention provides a kind of method for preparing of valsartan sustained-release matrix tablets.
Valsartan slow releasing tablet of the present invention is made up of crude drug, framework material, diluent, binding agent and lubricant.
The prescription of valsartan slow releasing tablet of the present invention is formed and preparation method thereof as follows:
1, prescription is formed (g/g):
Valsartan 20～50%
Framework material 8～20%
Diluent 35～75%
Binding agent 0～5%
Lubricant 1～4%
2, method for preparing:
Method one: 1. medicine is added an amount of dissolve with ethanol, add the part diluent and absorb; 2. add the surplus diluent, fully stir, add binding agent or wetting agent, in the high-speed stirred mixer-granulator, make wet granular, carry out drying then; 3. the granulate that sieves adds framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixing, tabletting.
Method two: 1. the particle size range with crude drug is controlled at below the tens μ m, adds diluent, fully stirs, and adds binding agent, in the high-speed stirred mixer-granulator, makes wet granular, carries out drying then; 2. the granulate that sieves adds framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixing, tabletting.
The adjuvant of valsartan slow releasing tablet of the present invention is following:
Framework material adopts Carbopol
971P or Carbopol
934P, preferred Carbopol
971P; Or employing Compritol 888 ATO (Compritol
888ATO); Or the two is mixed into framework material to adopt Carbopol and Compritol 888 ATO.
Diluent comprises one or more mixing wherein such as each kind of starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, mannitol, preferred Starch1500, lactose and calcium hydrogen phosphate; Diluent also comprises material such as porogen of scalable drug release rate etc., like fructose, sorbitol, sodium chloride, polyvidone, surfactant etc.
Wetting agent or binding agent comprise the mixed solution, hypromellose, polyvidone of water or alcohol, water and alcohol etc.;
Lubricant is magnesium stearate or calcium, Pulvis Talci, micropowder silica gel, sodium lauryl sulphate or magnesium etc.
According to the valsartan slow releasing tablet that the present invention makes, degree of release 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 45%~75%
8 >80%。
The specific embodiment
Following examples feed intake by 1000, and specification is tentative to be 80mg.Certainly, through clinical experiment, specification also can be decided to be 100mg in addition, 160mg, and 200mg or other specification, sheet heavily gets final product these needs with writing out a prescription the composition equal proportion by changing.Following examples just describe, and do not limit invention scope.
Embodiment 1
Prescription:
Valsartan 80g
Carbopol
971P 32g
Starch1500 90g
Lactose 90g
Magnesium stearate 3.0g
Pulvis Talci 3.0g
Method one: 1. medicine is added an amount of dissolve with ethanol, add Starch1500 and absorb; 2. add lactose, fully stir, in the high-speed stirred mixer-granulator, make wet granular, carry out drying then; 3. the granulate that sieves adds framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixing, tabletting.
Method two: 1. the particle size range with crude drug is controlled at below the tens μ m, adds Starch1500 and lactose, fully stirs, and adds suitable quantity of water, in the high-speed stirred mixer-granulator, makes wet granular, carries out drying then; 2. the granulate that sieves adds the Carbopol of recipe quantity
971P, magnesium stearate and Pulvis Talci, mixing, tabletting.
Method three: the particle size range of crude drug is controlled at below the tens μ m, adds direct compression adjuvant Starch1500 and lactose, add the Carbopol of recipe quantity again
971P, magnesium stearate and Pulvis Talci, mixing, tabletting.
The experiment of release degree is with two appendix X of Chinese Pharmacopoeia version in 2010 C, first subtraction unit, according to the release degree of two appendix X of Chinese Pharmacopoeia version in 2010 D, the first method working sample.Buffer salt 900ml with pH6.8 is a solvent, and rotating speed 100 changes, sampling in 1,4 and 8 hour, and the release degree of working sample, the result is following:
Time (hour) cumulative release degree %
1 30.7%
4 62.2%
8 93.4%
Embodiment 2
Prescription:
Valsartan 80g
Compritol 888 ATO (Compritol
888ATO) 26g
Calcium phosphate dibasic anhydrous 30g
Lactose 50g
PVP K30 5.0g
Magnesium stearate 3.0g
Pulvis Talci 2.0g
Method: 1. the particle size range with crude drug is controlled at below the tens μ m, with Compritol 888 ATO (Compritol
888ATO), calcium phosphate dibasic anhydrous and lactose mix, and fully stirs, and adds binding agent PVP K30 solution, in the high-speed stirred mixer-granulator, makes wet granular, carries out drying then; 2. the granulate that sieves adds the magnesium stearate and the Pulvis Talci of recipe quantity, mixing, tabletting.
The experiment of release degree is with embodiment 1, and the result is following:
Time (hour) cumulative release degree %
1 26.7%
4 60.3%
8 89.6%
Embodiment 3
Prescription:
Valsartan 80g
Carbopol 971P 15g
Compritol 888 ATO (Compritol
888ATO) 12g
Calcium phosphate dibasic anhydrous 30g
Lactose 60g
PVP K30 4.0g
Magnesium stearate 3.0g
Pulvis Talci 2.0g
Method: 1. the particle size range with crude drug is controlled at below the tens μ m, with Compritol 888 ATO (Compritol
888ATO), calcium phosphate dibasic anhydrous and lactose mix, and fully stirs, and adds binding agent PVP K30 solution, in the high-speed stirred mixer-granulator, makes wet granular, carries out drying then; 2. the granulate that sieves adds Carbopol 971P, magnesium stearate and the Pulvis Talci of recipe quantity, mixing, tabletting.
The experiment of release degree is with embodiment 1, and the result is following:
Time (hour) cumulative release degree %
1 30.2%
4 58.6%
8 92.5%
Can find out by the foregoing description; The drug release of valsartan slow releasing tablet of the present invention can continue more than 8 hours, and active drug concentration can be kept 24 hours, had overcome the shortcoming and defect of prior art; For the patient provides a kind of blood pressure lowering more steady and persistent preparation, have a extensive future.
Claims (9)
1. a sustained-release matrix tablets that contains the active pharmaceutical ingredient valsartan is characterized in that being made up of crude drug, framework material, diluent, binding agent and lubricant, and its prescription is formed as follows by weight percentage: valsartan 20～50%; Framework material 8～20%; Diluent 35～75%; Binding agent 0～5%; Lubricant 1～4%.
2. valsartan slow releasing tablet according to claim 1 is characterized in that: when not containing binding agent in the prescription, its preparation method be with behind the supplementary material mixing by direct compression of full-powder, or only use wetting agent to prepare tabletting behind wet granular and the dry granulate.
3. valsartan slow releasing tablet according to claim 1 is characterized in that: when containing binding agent in the prescription, its preparation method is 1. medicine to be added an amount of dissolve with ethanol, adds the part diluent and absorbs; 2. add the surplus diluent, fully stir, add binding agent, in the high-speed stirred mixer-granulator, make wet granular, carry out drying then; 3. the granulate that sieves adds framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixing, tabletting.
4. valsartan slow releasing tablet according to claim 1; It is characterized in that: when containing binding agent in the prescription, its preparation method is 1. the particle size range of crude drug to be controlled at below the tens μ m, adds diluent; Fully stir; Add binding agent, in the high-speed stirred mixer-granulator, make wet granular, carry out drying then; 2. the granulate that sieves adds framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixing, tabletting.
5. valsartan slow releasing tablet according to claim 1 is characterized in that: framework material adopts Carbopol
971P or Carbopol
934P, preferred Carbopol
971P; Or employing Compritol 888 ATO (Compritol
888ATO); Or the two is mixed into framework material to adopt Carbopol and Compritol 888 ATO.
6. valsartan slow releasing tablet according to claim 1; It is characterized in that: diluent comprises one or more mixing wherein such as each kind of starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, mannitol, preferred Starch1500, lactose and calcium hydrogen phosphate; Diluent also comprises material such as porogen of scalable drug release rate etc., like fructose, sorbitol, sodium chloride, polyvidone, surfactant etc.
7. valsartan slow releasing tablet according to claim 1 is characterized in that: wetting agent or binding agent comprise the mixed solution, hypromellose, polyvidone of water or alcohol, water and alcohol etc.
8. valsartan slow releasing tablet according to claim 1 is characterized in that: lubricant is magnesium stearate or calcium, Pulvis Talci, micropowder silica gel, sodium lauryl sulphate or magnesium, Compritol 888 ATO etc.
9. valsartan slow releasing tablet according to claim 1 is characterized in that: the drug release characteristics of this slow releasing tablet is following:
Time (hour) cumulative release amount %
1 15%~40%
4 45%~75%
8 >80% 。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2012101369669A CN102641253B (en) | 2012-05-07 | 2012-05-07 | Valsartan sustained release tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101369669A CN102641253B (en) | 2012-05-07 | 2012-05-07 | Valsartan sustained release tablet and preparation method thereof |
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| Publication Number | Publication Date |
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| CN102641253A true CN102641253A (en) | 2012-08-22 |
| CN102641253B CN102641253B (en) | 2013-10-09 |
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103919746A (en) * | 2014-04-17 | 2014-07-16 | 山东省医药工业研究所 | Edoxaban sustained release tablet and preparation method thereof |
| CN104415032A (en) * | 2013-08-27 | 2015-03-18 | 长春海悦药业有限公司 | Pharmaceutical composition containning valsartan |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101869710A (en) * | 2009-04-24 | 2010-10-27 | 北京奥萨医药研究中心有限公司 | Antihypertensive medical composite |
| CN102046154A (en) * | 2008-06-03 | 2011-05-04 | 诺瓦提斯公司 | Pulsatile release of valsartan |
-
2012
- 2012-05-07 CN CN2012101369669A patent/CN102641253B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046154A (en) * | 2008-06-03 | 2011-05-04 | 诺瓦提斯公司 | Pulsatile release of valsartan |
| CN101869710A (en) * | 2009-04-24 | 2010-10-27 | 北京奥萨医药研究中心有限公司 | Antihypertensive medical composite |
Non-Patent Citations (3)
| Title |
|---|
| > 20071231 谢百福，侯素敏 缬沙坦与美托洛尔缓释片联合治疗心房颤动的临床研究 第7259-7260页 1-9 第7卷, 第30期 * |
| IKUO SAITO,ET AL.: "Cost-effectiveness analysis:controlled-release nifedipine and valsartan combination therapy in patients with essential hypertension:the adalat CR and valsartan Cost-effectiveness combination (ADVANCE-combi) study", 《HYPERTENS RES》 * |
| 谢百福，侯素敏: "缬沙坦与美托洛尔缓释片联合治疗心房颤动的临床研究", <<中国误诊学杂志>> * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104415032A (en) * | 2013-08-27 | 2015-03-18 | 长春海悦药业有限公司 | Pharmaceutical composition containning valsartan |
| CN104415032B (en) * | 2013-08-27 | 2017-06-23 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing Valsartan |
| CN103919746A (en) * | 2014-04-17 | 2014-07-16 | 山东省医药工业研究所 | Edoxaban sustained release tablet and preparation method thereof |
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|---|---|
| CN102641253B (en) | 2013-10-09 |
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Granted publication date: 20131009 |