CN102641253B

CN102641253B - Valsartan sustained release tablet and preparation method thereof

Info

Publication number: CN102641253B
Application number: CN2012101369669A
Authority: CN
Inventors: 陈修毅; 曹冲
Original assignee: MEDICINE INDUSTRY INST SHANDONG PROV
Current assignee: MEDICINE INDUSTRY INST SHANDONG PROV
Priority date: 2012-05-07
Filing date: 2012-05-07
Publication date: 2013-10-09
Anticipated expiration: 2032-05-07
Also published as: CN102641253A

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

Valsartan slow releasing tablet and preparation method thereof

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 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]-Valine, structural formula is as follows:

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: this product is white or off-white color fine powder, and hygroscopicity is arranged.This product is dissolved in methanol, slightly molten in water.

Chinese Pharmacopoeia 2010 editions is: this product is white crystals or white, off-white powder; Hygroscopicity is arranged.This product is very easily dissolved in ethanol, easily molten in methanol, slightly molten in ethyl acetate, almost insoluble in water.

Analyze the reason of valsartan raw material different solubility in water: the granularity of the crude drug used during mensuration is variant, the imported raw material medicine is micronization, particle diameter is a few μ m ~ tens μ m, that is to say that the import standard controls particle size range, so more be conducive to stripping and the absorption of medicine, make the pharmacokinetics of valsartan more stable, reduce the absorption difference between fasting and feed, reduce the degree of fluctuation of interindividual variation and blood drug level.

The valsartan pharmacokinetics:

Absorb: after valsartan is oral, can absorb rapidly, 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.While taking one every day, valsartan seldom causes and accumulates, and in masculinity and femininity, plasma concentration is similar.

Administration of Valsartan during dining, make AUC reduce 48%, and blood drug level peak value (Cmax) reduces 59%.Whether no matter with food is same, take, the blood drug level after 8 hours is similar.The minimizing of AUC or Cmax on clinical efficacy without obvious impact, therefore when valsartan can be had meal or (medicine) being taken before meal use.

Distribute: most valsartan (94～97%) are combined with serum albumin (being mainly albumin), in one week, reach stable state.Vdss is about 17 liters.Compare plasma clearance speed relatively slow (approximately 2L/h) with hepatic blood flow (30L/h).

Remove: valsartan is with multi index option decay kinetics metabolism (a item half-life<1 hour, t1/2 approximately 9 hours).Valsartan is mainly with the prototype excretion, and 70% discharges from feces, and 30% discharges from urine.

According to the slow releasing preparation requirement, its delivery time should extend to some extent than ordinary preparation.The original purpose of slow releasing preparation is mainly to improve the safety of medication and effectiveness and patient's compliance, and this is mainly by controlling the drug plasma level and reducing administration frequency and realize.With regard to ordinary preparation, most drug all exists the treatment window, and blood level, lower than the treatment window, does not reach due therapeutic effect, higher than the treatment window, there will be poisoning symptom.Therefore safe and effective for medication, 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 mean.

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) formula (1)

T in above formula (1) _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 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 mean residence time in body, and in formula (2), the spacing of doses of gained will more be less than formula (1), and administration is more frequent.

Generally, extending dosing interval can solve by following two approach.The molecular structure of the first by revising medicine, the release rate that reduces medicine ( 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.Reduce but utilize the restriction that the 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.

Approximately 6 ~ 9 hours half-life of valsartan ordinary preparation, although its using method is once a day, that is to say that its therapeutic index is wider, but can cause like this blood concentration fluctuation amplitude excessive, blood drug level is steady not, show on therapeutic effect and can not more reduce blood pressure effectively stably exactly, and make blood pressure produce larger fluctuation, therefore consider development valsartan slow releasing tablet.

A kind of method that patent CN101951902A provides valsartan solid peroral dosage form and prepared said preparation, wherein mentioned a kind of MR tablet, the employing fusion method is granulated, finally be pressed into oval slow releasing tablet, but the fusion method facility for granulating is not a lot of at home, technique realizes difficult, and repeatability is poor.

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 antihypertensive effect more steady, toxic and side effects is lower, the valsartan slow releasing tablet with framework material control drug release of good patient compliance.

Another object of the present invention is to provide a kind of preparation method of valsartan sustained-release matrix tablets.

Valsartan slow releasing tablet of the present invention is comprised of crude drug, framework material, diluent, binding agent and lubricant.

Prescription composition of valsartan slow releasing tablet of the present invention and preparation method thereof is as follows:

1, prescription forms (g/g):

Valsartan 20～50%

Framework material 8～20%

Diluent 35～75%

Binding agent 0～5%

Lubricant 1～4%

2, preparation method:

Method one: 1. medicine is added to appropriate dissolve with ethanol, add the part diluent to absorb; 2. add the surplus diluent, fully stir evenly, add binding agent or wetting agent, in the high-speed stirred mixer-granulator, make wet granular, then carry out drying; 3. the granulate that sieves, add framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixes tabletting.

Method two: 1. the particle size range of crude drug is controlled at below tens μ m, adds diluent, fully stir evenly, add binding agent, in the high-speed stirred mixer-granulator, make wet granular, then carry out drying; 2. the granulate that sieves, add framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixes tabletting.

The adjuvant of valsartan slow releasing tablet of the present invention is as follows:

Framework material adopts Carbopol 971P or Carbopol 934P, preferably Carbopol 971P; Or employing Glyceryl Behenate (Compritol 888ATO); Or the two is mixed into framework material to adopt Carbopol and Glyceryl Behenate.

Diluent comprises the mixing of wherein one or more such as each kind of starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, mannitol, preferably Starch1500, lactose and calcium hydrogen phosphate; Diluent also comprises that the material of scalable drug release rate is as porogen etc., as 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.

The valsartan slow releasing tablet made 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 45%~75%

8 >80%。

The specific embodiment

Following examples feed intake by 1000, and specification is fixed tentatively as 80mg.Certainly, through clinical experiment, specification also can separately be decided to be 100mg, 160mg, and 200mg or other specification, these needs change sheet by prescription with forming equal proportion and heavily get final product.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 to appropriate dissolve with ethanol, add Starch1500 to absorb; 2. add lactose, fully stir evenly, in the high-speed stirred mixer-granulator, make wet granular, then carry out drying; 3. the granulate that sieves, add framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixes tabletting.

Method two: 1. the particle size range of crude drug is controlled at below tens μ m, adds Starch1500 and lactose, fully stir evenly, add suitable quantity of water, in the high-speed stirred mixer-granulator, make wet granular, then carry out drying; 2. the granulate that sieves, add the Carbopol of recipe quantity 971P, magnesium stearate and Pulvis Talci, mix, tabletting.

Method three: the particle size range of crude drug is controlled at below tens μ m, adds direct compression adjuvant Starch1500 and lactose, then add the Carbopol of recipe quantity 971P, magnesium stearate and Pulvis Talci, mix, tabletting.

The release experiment, with two appendix X C first method devices 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 100 turns, sampling in 1,4 and 8 hour, and the release of working sample, result is as follows:

Time (hour) cumulative release degree %

1 30.7%

4 62.2%

8 93.4%

Embodiment 2

Prescription:

Valsartan 80g

Glyceryl Behenate (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 of crude drug is controlled at below tens μ m, with Glyceryl Behenate (Compritol 888ATO), calcium phosphate dibasic anhydrous and lactose mix, and fully stirs evenly, and adds binding agent PVP K30 solution, in the high-speed stirred mixer-granulator, makes wet granular, then carries out drying; 2. the granulate that sieves, add magnesium stearate and the Pulvis Talci of recipe quantity, mixes tabletting.

The release experiment is with embodiment 1, and result is as follows:

Time (hour) cumulative release degree %

1 26.7%

4 60.3%

8 89.6%

Embodiment 3

Prescription:

Valsartan 80g

Carbopol 971P 15g

Glyceryl Behenate (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 of crude drug is controlled at below tens μ m, with Glyceryl Behenate (Compritol 888ATO), calcium phosphate dibasic anhydrous and lactose mix, and fully stirs evenly, and adds binding agent PVP K30 solution, in the high-speed stirred mixer-granulator, makes wet granular, then carries out drying; 2. the granulate that sieves, add Carbopol 971P, magnesium stearate and the Pulvis Talci of recipe quantity, mixes tabletting.

The release experiment is with embodiment 1, and result is as follows:

Time (hour) cumulative release degree %

1 30.2%

4 58.6%

8 92.5%

As can be seen from the above-described embodiment, the drug release of valsartan slow releasing tablet of the present invention can continue more than 8 hours, and active drug concentration can maintain 24 hours, had overcome the shortcoming and defect of prior art, for the patient provides a kind of blood pressure lowering more steady and lasting preparation, have a extensive future.

Claims

1. the sustained-release matrix tablets containing the active pharmaceutical ingredient valsartan, is characterized in that being comprised of crude drug, framework material, diluent, binding agent and lubricant, and its prescription is composed as follows by weight percentage: valsartan 20～50%; Framework material 8～20%; Diluent 35～75%; Binding agent 0～5%; Lubricant 1～4%, each component content sum is 100%, the framework material in prescription refers to carbomer or Glyceryl Behenate.

2. valsartan slow releasing tablet according to claim 1 is characterized in that: while in prescription, not containing binding agent, 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. valsartan slow releasing tablet according to claim 1, it is characterized in that: while in prescription, containing binding agent, its preparation method is 1. medicine to be added to appropriate dissolve with ethanol, adds the part diluent to absorb; 2. add the surplus diluent, fully stir evenly, add binding agent, in the high-speed stirred mixer-granulator, make wet granular, then carry out drying; 3. the granulate that sieves, add framework material, magnesium stearate and the Pulvis Talci of recipe quantity, mixes tabletting.

4. valsartan slow releasing tablet according to claim 1 is characterized in that: diluent comprises one or more the mixing in each kind of starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, mannitol.

5. valsartan slow releasing tablet according to claim 1 is characterized in that: binding agent comprises mixed solution, hypromellose, the polyvidone of water or alcohol, water and alcohol.

6. 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, Glyceryl Behenate.

7. valsartan slow releasing tablet according to claim 1, it 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 45%～75%

8 hours > 80%.