CN102138911A - Divalproex sodium sustained release tablets and preparation method thereof - Google Patents
Divalproex sodium sustained release tablets and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicinal preparations, and particularly relates to divalproex sodium sustained release tablets and a preparation method thereof. The sustained release table comprises divalproex sodium, a retarding agent, a diluent, a disintegrant, a binder, a pH regulating agent, a lubricant, an antiadherent and the like.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, specifically, relate to a kind of divalproex sodium slow releasing preparation and preparation method thereof, the invention also discloses its preparation technology's relevant parameter.
Technical background
Divalproex sodium is central nervous system's class medicine, claims two-(2-Propylpentanoic) hydrogen sodium again, is the ionic compound that is formed by a part valproic acid and a part sodium valproate.It is that molecular formula is: C
16H
31O
2Na.Molecular weight is 310.41, and structural formula is:
Divalproex sodium is crystallization of white fiber shape or powder, odorless, and it is little puckery to distinguish the flavor of; Slightly draw moist.This product is dissolved in ethanol, dissolves in the water part omitted, and is almost insoluble in ether.
Divalproex sodium is the antiepileptic by Abbot laboratory research and development listing the earliest, is the wide spectrum antiepileptic, mainly acts on the central nervous system.The pharmacological research of animal is found that this product all has anticonvulsant action to the experimental model (general and part) of various epilepsies.The all kinds epilepsy that same this product is found the people has inhibitory action, and its main mechanism of action may be relevant with the concentration that increases γ-An Jidingsuan.
Because the too fast blood drug level peak value that makes of divalproex sodium general formulation rate of releasing drug is higher, easily has side effects, and is especially common with gastrointestinal reaction; Because main medication crowd be the epileptic, patient often can not take medicine on time in fine oneself's control, thereby commonly situation such as usually occurs missing make therapeutic effect decline or not obvious in administration.Related prescription and preparation method thereof has effectively solved the problems referred to above among the present invention.
It is the divalproex sodium slow releasing tablet of composite slow release framework material that people such as bibliographical information Venkatramana M.Rao have studied with strange E100 of You Te and Mei Duo show K4M, can improve divalproex sodium onset rapidly after the rate of release of low pH environment makes its administration, reduced the inside and outside difference of slow releasing tablet release, but looking around the skeleton slow-release time, this can only reach 8 hours, sufferer still needs multiple dosing, epileptic to occur easily missing every day; There are two pieces to prepare relevant Chinese patent CN99814629 and CN200580005453.2 with the divalproex sodium slow releasing tablet, with one piece of U.S. Pat 2004/0037880, at 20-40%, the material that produces valproate ion accounts for 50～55% of gross weight as the consumption that all requires divalproex sodium slow releasing composition medium-high viscosity hydroxypropyl methylcellulose in patent 99814629 and 200580005453.2.The preparation technology of its use relates to wet granulation and dry granulation: dry granulation is because its productive rate lower (being usually less than 60%), often occur that granule was all once bad, tablet weight variation is big, content difference is big, batch between problems such as release difference is big, generally not as prefered method; Divalproex sodium is not too responsive to external environment factors such as acid, humidity, wet granulation is as the most frequently used method of granulating, be used in very much the preparation of divalproex sodium slow releasing tablet, but change to be difficult to be dried and carry out further tabletting because its physicochemical properties can appear in sodium valproate and divalproex sodium after moisture absorption, the prescription that is adopted among the present invention is fit to wet granulation, the problem of the divalproex sodium moisture absorption that preparation method may occur in the aforementioned patent can not appear in the preparation technology of Cai Yonging simultaneously, has improved preparation technology's productive rate greatly.
Summary of the invention
The purpose of this invention is to provide a kind of divalproex sodium slow releasing preparation and preparation method thereof, improve the medication compliance, the situation of avoiding the epileptic to miss repeating taking medicine takes place, and reduces the toxic and side effects that medicine brings.
Another object of the present invention is to solve the excessive problem that is not easy to swallow of divalproex sodium oral slow-releasing preparation volume.
The present invention is the improvement of divalproex sodium ordinary preparation, experiment shows that taking a divalproex sodium slow releasing preparation every day can guarantee that 24 hours interior concentrations of body are in effective treatment window in its human body, and can stablize control plasma drug level peak value, reduce the side effect that medicine brings, improve bioavailability of medicament to guarantee curative effect.By in the Chinese Pharmacopoeia 2010 editions investigation is tested in the requirement of preparation stability, its release performance stable uniform, choose three batches and carry out the measuring of release in vitro degree, the release relative standard deviation is less than 3% between batch, and experiment shows in release in vitro percent and the body and is absorbed with good linear relationship in the body.
The technical solution used in the present invention is:
A kind of divalproex sodium slow releasing preparation is characterized in that described preparation has certain sustained release performance, and its slow release principle is mainly matrix sustained release tablet.Selected adjuvant and preparation method all are easy to get feasible, and the method favorable reproducibility, suitability for industrialized production.
For this reason, the invention provides a kind of divalproex sodium sustained-release tablet composition, it is characterized in that, form by divalproex sodium, blocker, binding agent, diluent, disintegrating agent, lubricant, antiplastering aid, pH regulator agent.Preferred composition of the present invention, the mass percent of each component is:
In the preferred composition of the present invention, wherein blocker is two kinds of different compositions, is blocker 1 and blocker 2, and both are respectively at the mass percent in compositions:
Blocker 1 5%-35%
Blocker 2 3%-15%.
In the composition of the present invention, wherein said blocker 1 is selected one or several the mixture in ethyl cellulose, hypromellose, carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, polyacrylic acid, stearic acid, palm wax, the chitosan for use.Preferred hydroxypropyl methylcellulose, wherein the substitution value to its methyl and hydroxypropyl has requirement, and the methyl substituted ratio is at 15%-25%, and hydroxypropyl replaces ratio at 5%-15%, and its solution viscosity of 2% should be greater than 10000 centipoises.
Described blocker 2 is selected hydroxypropyl methylcellulose, hydroxypropyl cellulose, pregelatinized Starch, cellulose acetate, ethyl cellulose, polyglutamic acid, carbomer for use.Preferred carbomer, and select other oral type carbomer of high-purity-grade for use, as carbomer 934 P, carbomer 974P.
Described diluent is selected from the mixture of selecting one or more in the following adjuvant: lactose, starch, microcrystalline Cellulose, pregelatinized Starch, mannitol, chitosan, dextrin, preferable absorbent are pregelatinized Starch.
Selected binding agent is selected from mixture, the starch slurry of the second alcohol and water of polyvidone, water, dehydrated alcohol, different proportion, the aqueous dispersion of a certain proportion of hypromellose; Preferred alcohol solution, concentration is at 80%-99%.
Described lubricant is selected one or more the mixture in magnesium stearate, Pulvis Talci, hydrogenated vegetable oil, the stearyl alcohol, preferably talc powder for use.
Described antiplastering aid is selected Pulvis Talci, micropowder silica gel, stearyl alcohol, magnesium stearate for use, preferred micropowder silica gel, preferred micropowder silica gel.
Tricalcium phosphate, calcium hydrogen phosphate, dalcium biphosphate, dibastic sodium phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate or similar phosphate, carbonate are selected in described pH regulator agent for use.
The particularly preferred compositions of the present invention is characterized in that, the quality of each component is: make 1000 divalproex sodium sustained-release tablet recipes
The most preferred compositions of the present invention is characterized in that, the quality of each component is: make 1000 divalproex sodium sustained-release tablet recipes
It is to obtain through screening that the present invention preferably fills a prescription, and screening process is as follows:
The present invention is gone on the market in the U.S. with the An Bote laboratory
The ER product is as reference preparation, by carrying out the drug release determination experiment, with similar factors F
2Be evaluation index, by orthogonal design and center-response surface method optimization prescription design, with the software match equation of each influence factor (hydroxypropyl methylcellulose consumption, pregelatinized Starch consumption, carbomer consumption etc.) with response value release similar factors (F2).Filter out multiple adjuvant and consumption proportion thereof, comprising: filleies such as starch, microcrystalline Cellulose, lactose, calcium hydrogen phosphate, tricalcium phosphate, pregelatinized Starch; Binding agents such as 30 POVIDONE K 30 BP/USP 30,5% low viscosity hydroxypropyl methylcellulose solution, dehydrated alcohol, 60～95% ethanol; Blocker such as hydroxypropyl methylcellulose, ethyl cellulose, carbomer 934 P; Fluidizer such as micropowder silica gel, Pulvis Talci, magnesium stearate.
The present invention finds about the experimental result (mainly being hardness, friability, release index) of filler, starch and pregelatinized Starch are slower than lactose and microcrystalline Cellulose to the disintegration rate later stage of divalproex sodium slow releasing tablet, but tablet hardness and slice power are lower than microcrystalline Cellulose and lactose, are unfavorable for the requirement of tablet coating, transportation, storage.
The present invention finds about the experimental result of wetting agent, polyvidone, 60% ethanol/water solution, 5% low viscosity hydroxypropyl methylcellulose are used for its granulation and will easily cause the powder body moistening inhomogeneous, be difficult to granulate or the particle size distribution that makes is wide, be not suitable for amplifying and produce tabletting (potential risk that has tablet weight variation to exceed standard); The 80%-90% ethanol that optimizes can well make and form particle between powder, the particle size distribution that productive rate higher (being higher than 70%) makes narrow (leading indicator is investigated D50), suitable tabletting.
The present invention finds about the experimental result of blocker, ethyl cellulose is the most obvious to the slow controlled-release effect of divalproex sodium, but exist the release terminal point too late, or release does not reach more than 80% in the scheduled time, has the part medicine to be wrapped in the ethyl cellulose cellulosic material; Use separately hydroxypropyl methylcellulose as slow controlled-release material, the normal existence prominently released equivalent risk, and makes the divalproex sodium slow releasing tablet with it separately and have the pH dependency, and low pH drug release is slow, and the pH back that raises discharges and quickens, and the inside and outside dependency is poor; There are two kinds of models of 934P and 974P to be suitable for slow releasing tablet in the carbomer series, because full-bodied hydroxypropyl methylcellulose viscosity in wet-granulation process commonly used is not suitable for wetting agent such as water or 15% 30 POVIDONE K 30 BP/USP, 30 solution too by force and granulates, and carbomer is fit to wet granulation and also is amplified in the suitability for industrialized production easily by the ethanol moistening of 60-95% and the suitable viscosity of generation.The present invention filters out 934P and hydroxypropyl methylcellulose pluralgel matrix sustained release tablet according to the slow-release time demand, be aided with pH dependency and the prominent risk of releasing that the agent of microenvironment pH regulator has reduced slow releasing tablet of the present invention, make the disintegrate under intestinal environment of its skeleton more complete, discharge terminal point than hydroxypropyl methylcellulose matrix sustained release tablet more near 100%, improved the interior dependency of release, by using data statistics software, adopt the amount ranges of Central Composite-Response Surface Method optimization one optimized prescription; With cross adopt in the optimization range in the prescription of minimum gross weight, can obtain than commonsense method adjuvant still less, the slow releasing tablet of small size more makes preferably the swallowing of divalproex sodium sheet of heavy dose of specification.
The present invention comprises that also preparation of compositions method of the present invention comprises the steps:
Granule intermediate preparation: get the medicine and the adjuvant of recipe quantity, mix, add binding agent, adopt fluidized bed granulation method or wave the granulation of granulator granulation.With prepared particle drying, behind the certain hour, granule is sieved, choose the suitable granule of size, measure its moisture, the qualified back of moisture adds the lubricant of recipe quantity, and mix homogeneously is inserted tablet machine, debugging pressure makes it in optimum range, tabletting is got the recipe quantity coating material and is mixed with coating solution, with coating solution atomizing carrying out coating.Coating finishes the after drying certain hour, and the divalproex sodium slow releasing tablet gets product.
This method also comprises: direct compression process: get the medicine and the adjuvant of recipe quantity, respectively it is crushed to certain particle diameter, behind 80 to 120 eye mesh screens, mix homogeneously is inserted in the tablet machine tabletting.
The present invention selects the prescription of optimization for use; adopt fluidized bed granulation method, wave one or more method of granulating in granulator granulation or the wet granulator granulation; adopt pressed disc method to prepare the divalproex sodium slow releasing tablet then, also can adopt direct compressing dry granulation to prepare slow releasing tablet.
The present invention is owing to use multiple blocker to form the pluralgel skeleton, and blocker 2 can significantly reduce the consumption of blocker 1; Compound blocker has better inside and outside dependency than single blocker, meets slow-release material release behavior is more discharged near zero level.The present invention has reduced the influence of pH variation to the divalproex sodium release owing to used the pH regulator agent, thereby reduces the inside and outside difference of drug release behavior.The slow release principle of slow releasing tablet of the present invention belongs to framework controlled release, and this type slow releasing tablet stability is better than the coating type slow releasing tablet, is difficult for causing because of the variation of outer coating that the prominent of medicine release.Simultaneously thin film coating material can improve the stability of slow releasing tablet, and it is stable to ensure drug quality, and it is in class thin film coating material, the low viscosity hydroxypropyl methylcellulose one or more that above-mentioned thin film coating material can be selected Opadry for use.Because the adjuvant of employing optimization prescription ratio and principal agent are at the mixing and blending machine mix homogeneously; adopt the top-jet-type fluid bed to spray into binding agent and can obtain suitable size particles; adopt oscillating granulator to prepare the granule intermediate again after also can joining binding agent in the powder body; select the suitable granule intermediate of particle diameter; with carry out tabletting after the mix lubricant; the tablet character can be selected circle, ellipse or capsule-type, and the tablet of preferred capsule-type is convenient to sufferer and is swallowed.
The invention has the advantages that:
(1) the present invention's divalproex sodium slow releasing tablet, preparation process is simple for process, under laboratory scale, can finish the amplification production of 10000-30000 unit.
(2) slow releasing tablet of the present invention's preparation, the animal body giving drugs into nose is for dynamics research, with the ordinary preparation equivalence, do not produce the problem that reduces bioavailability because of slow releasing function, it discharges model and has reduced the plasma drug level peak value, thereby reduced the possibility that toxic and side effects produces, taken the compliance that has once improved patient's medication every day.
(3) the present invention's slow releasing preparation is investigated through accelerated test, under 40 ℃, the condition of relative humidity 75% in 6 months stable, the medicament contg of character, related substance all in controlled range, suitability for industrialized production.
The study on the stability of table 1 batch 101105 divalproex sodium slow releasing tablet
The study on the stability of table 2 batch 101103 divalproex sodium slow releasing tablet
The study on the stability of table 3 batch 101101 divalproex sodium slow releasing tablet
The screening process of the different prescriptions of table 4 (it is heavy to investigate hardness, particle size distribution, slamp value, compressibility index and total sheet)
Table 1
Table 2
Table 3
Table 4
Description of drawings
The release in vitro degree of Fig. 1 optimizing prescriptions gained divalproex sodium slow releasing tablet
The screening of the compound framework material of Fig. 2
Fig. 3 is by the process of the main controlled slowly releasing adjuncts dosage optimization of software match
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention rather than restriction the present invention.All and technical scheme equivalence of the present invention all belongs to protection scope of the present invention.
Embodiment 1
1000 divalproex sodium sustained-release tablet recipes
Preparation process and technology (waving the granulation machine granulation):
Get recipe quantity medicine, microcrystalline Cellulose, hydroxypropyl cellulose, carbomer, kindly reach, calcium hydrogen phosphate, standby by in stirring mixer, mixing behind 80 eye mesh screens after 1 hour.It is an amount of to get 15% povidone solution, is injected to stir in the standby powder to make soft material.Open and wave granulator; soft material is passed through 24 eye mesh screens; extrude the granule that forms suitable length; be positioned in the baking oven 70 degrees centigrade of dryings 60 minutes; carry out the uniformity and water content inspection, qualified after, add the magnesium stearate and the micropowder silica gel of recipe quantity; mix joining tabletting in the tablet machine after 1 hour, both got the divalproex sodium slow releasing tablet.
Embodiment 2
1000 divalproex sodium sustained-release tablet recipes
8% low viscosity hydroxypropyl methylcellulose aqueous solution is an amount of
Preparation process and technology:
With medicine and the medicine, microcrystalline Cellulose, hydroxypropyl cellulose, carbomer of getting recipe quantity, kindly reach, calcium hydrogen phosphate pulverizes, and after mixing 1 hour behind 80 eye mesh screens in stirring mixer, powder body placed the fluidized bed body.Dispose 8% low viscosity hydroxypropyl methylcellulose aqueous solution, add the micropowder silica gel of recipe quantity and stir and make it into suspension, adopt fluid bed to granulate, fluidized bed granulation technology is: the peristaltic pump transfusion speed is that 3ml/min, air compressor pressure are 35 ℃ of 2Bar, fluid bed inlet temperature; Fluidisation is got 20-40 order size particles after a period of time, behind 70 degrees centigrade of dry 1h, carry out the uniformity and water content inspection, qualified after, add the Pulvis Talci of recipe quantity, mix in the mixer to join after 1 hour and carry out tabletting in the tablet machine, both slow releasing tablet.
Embodiment 3
1000 divalproex sodium sustained-release tablet recipes
Preparation technology:
The preparation technology of slow releasing tablet label:
With medicine and the medicine, microcrystalline Cellulose, hydroxypropyl cellulose, lactose, carbomer of getting recipe quantity, kindly reach, calcium hydrogen phosphate pulverizes, after in stirring mixer, mixing 1 hour behind 80 eye mesh screens, the magnesium stearate and the Pulvis Talci that add recipe quantity, mix in the mixer to join after 0.5 hour and carry out direct compression in the tablet machine, both got slow releasing tablet.
Prescription
Preparation technology:
The preparation technology of slow releasing tablet label:
With medicine and the medicine, microcrystalline Cellulose, hydroxypropyl cellulose, carbomer of getting recipe quantity, kindly reach, calcium hydrogen phosphate pulverizes, after mixing 1 hour behind 80 eye mesh screens in stirring mixer, this powder body is standby.Dispose 15% an amount of povidone solution, make it into suspension, join and make soft material in the medicament powder as micropowder silica gel that adds recipe quantity in the solution and stirring.Open and wave granulator; soft material put into pass through sieve aperture; sieve aperture is selected the 16-20 eye mesh screen; form the granule of moderate length, be positioned in the baking oven 40 degrees centigrade of dryings 45 minutes, carry out the uniformity and water content inspection; after qualified; the Pulvis Talci that adds recipe quantity mixes in the mixer to join after 1 hour and carries out tabletting in the tablet machine, has both got slow releasing tablet.
Claims (10)
1. a divalproex sodium sustained-release tablet composition is characterized in that, is made up of divalproex sodium, blocker, binding agent, diluent, disintegrating agent, lubricant, antiplastering aid, pH regulator agent.
2. the compositions of claim 1 is characterized in that:
The mass percent of each component is:
3. the compositions of claim 2, it is characterized in that: wherein blocker is two kinds of different compositions, is blocker 1 and blocker 2, both are respectively at the mass percent in compositions:
Blocker 1 5%-35%
Blocker 2 3%-15%.
4. the compositions of claim 3 is characterized in that:
Wherein said blocker 1 is selected one or several the mixture in ethyl cellulose, hypromellose, carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, polyacrylic acid, stearic acid, palm wax, the chitosan for use.Preferred hydroxypropyl methylcellulose, wherein the substitution value to its methyl and hydroxypropyl has requirement, and the methyl substituted ratio is at 15%-25%, and hydroxypropyl replaces ratio at 5%-15%, and its solution viscosity of 2% should be greater than 10000 centipoises.
Described blocker 2 is selected hydroxypropyl methylcellulose, hydroxypropyl cellulose, pregelatinized Starch, cellulose acetate, ethyl cellulose, polyglutamic acid, carbomer for use.Preferred carbomer, and select other oral type carbomer of high-purity-grade for use, as carbomer 934 P, carbomer 974P.
Described diluent is selected from the mixture of selecting one or more in the following adjuvant: lactose, starch, microcrystalline Cellulose, pregelatinized Starch, mannitol, chitosan, dextrin, preferable absorbent are lactose.
Selected binding agent is selected from mixture, the starch slurry of the second alcohol and water of polyvidone, water, dehydrated alcohol, different proportion, the aqueous dispersion of a certain proportion of hypromellose; Preferred alcohol solution, concentration is at 80%-99%.
Described lubricant is selected one or more the mixture in magnesium stearate, Pulvis Talci, hydrogenated vegetable oil, the stearyl alcohol for use, preferred magnesium stearate.
Described antiplastering aid is selected Pulvis Talci, micropowder silica gel, stearyl alcohol, magnesium stearate for use, preferred micropowder silica gel, preferred micropowder silica gel.
Tricalcium phosphate, calcium hydrogen phosphate, dalcium biphosphate, dibastic sodium phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate or similar phosphate, carbonate are selected in described pH regulator agent for use.
5. the compositions of claim 4 is characterized in that, the quality of each component is: make 1000 divalproex sodium sustained-release tablet recipes
6. the compositions of claim 5 is characterized in that, the quality of each component is: make 1000 divalproex sodium sustained-release tablet recipes
7. the preparation of compositions method of claim 1 is characterized in that, comprises the steps:
Granule intermediate preparation: get the medicine and the adjuvant of recipe quantity, mix, add binding agent, adopt fluidized bed granulation method, wave granulation of granulator granulation or shearing method granulation.With prepared particle drying, behind the certain hour, granule is sieved, choose the suitable granule of size, measure its moisture, the qualified back of moisture adds the lubricant of recipe quantity, mix homogeneously is inserted tablet machine, and debugging pressure makes it in optimum range, to be pressed into slow releasing tablet with the mix lubricant homogeneous granules: get the recipe quantity coating material and be mixed with coating solution, with coating solution atomizing carrying out coating.Coating finishes the after drying certain hour, and the divalproex sodium slow releasing tablet gets product.
8. the preparation method of claim 7 is characterized in that this method comprises the steps:
Direct compression process: get the medicine and the adjuvant of recipe quantity, respectively it is crushed to certain particle diameter, behind 80 to 120 eye mesh screens, mix homogeneously is inserted in the tablet machine tabletting.
9. the preparation method of claim 7 is characterized in that, 1000 divalproex sodium sustained-release tablet recipes
Preparation method
Get recipe quantity medicine, microcrystalline Cellulose, hydroxypropyl cellulose, carbomer, kindly reach, calcium hydrogen phosphate, standby by in stirring mixer, mixing behind 80 eye mesh screens after 1 hour.It is an amount of to get 15% povidone solution, is injected to stir in the standby powder to make soft material.Open and wave granulator; soft material is passed through 24 eye mesh screens; extrude the granule that forms suitable length; be positioned in the baking oven 70 degrees centigrade of dryings 60 minutes; carry out the uniformity and water content inspection, qualified after, add the magnesium stearate and the micropowder silica gel of recipe quantity; mix joining tabletting in the tablet machine after 1 hour, both got the divalproex sodium slow releasing tablet.
10. the preparation method of claim 7 is characterized in that, 1000 divalproex sodium sustained-release tablet recipes
Preparation method
Get recipe quantity medicine, microcrystalline Cellulose, hydroxypropyl cellulose, carbomer, kindly reach, calcium hydrogen phosphate, standby by in stirring mixer, mixing behind 80 eye mesh screens after 1 hour.It is an amount of to get 15% povidone solution, is injected to stir in the standby powder to make soft material.Open and wave granulator; soft material is passed through 24 eye mesh screens; extrude the granule that forms suitable length; be positioned in the baking oven 70 degrees centigrade of dryings 60 minutes; carry out the uniformity and water content inspection, qualified after, add the magnesium stearate and the micropowder silica gel of recipe quantity; mix joining tabletting in the tablet machine after 1 hour, both got the divalproex sodium slow releasing tablet.
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| CN103230380A (en) * | 2013-05-06 | 2013-08-07 | 北京四环制药有限公司 | Divalproex sodium enteric-coated tablet core as well as preparation method and application thereof |
| CN104146976A (en) * | 2014-08-06 | 2014-11-19 | 沈阳药科大学 | Heavy-load valproic acid drug sustained release tablet and preparation method thereof |
| CN106389368A (en) * | 2015-07-29 | 2017-02-15 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained release preparation as well as preparation process and applications thereof |
| CN107028907A (en) * | 2016-02-04 | 2017-08-11 | 成都康弘药业集团股份有限公司 | A kind of Divalproex sodium sustained-release tablet |
| CN107811985A (en) * | 2016-09-13 | 2018-03-20 | 四川科瑞德制药股份有限公司 | A kind of anti-epileptic sustained release preparation and preparation method thereof and purposes |
| CN109674758A (en) * | 2019-02-25 | 2019-04-26 | 湖南博隽生物医药有限公司 | A kind of Divalproex sodium sustained-release tablet and preparation method thereof for treating epilepsy |
| CN113304117A (en) * | 2021-04-30 | 2021-08-27 | 山东京卫制药有限公司 | Preparation method of sodium valproate sustained-release tablets |
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| CN103230380A (en) * | 2013-05-06 | 2013-08-07 | 北京四环制药有限公司 | Divalproex sodium enteric-coated tablet core as well as preparation method and application thereof |
| CN103230380B (en) * | 2013-05-06 | 2015-02-18 | 北京四环制药有限公司 | Divalproex sodium enteric-coated tablet core as well as preparation method and application thereof |
| CN104146976A (en) * | 2014-08-06 | 2014-11-19 | 沈阳药科大学 | Heavy-load valproic acid drug sustained release tablet and preparation method thereof |
| CN104146976B (en) * | 2014-08-06 | 2017-02-15 | 沈阳药科大学 | Heavy-load valproic acid drug sustained release tablet and preparation method thereof |
| CN106389368A (en) * | 2015-07-29 | 2017-02-15 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained release preparation as well as preparation process and applications thereof |
| CN107028907A (en) * | 2016-02-04 | 2017-08-11 | 成都康弘药业集团股份有限公司 | A kind of Divalproex sodium sustained-release tablet |
| CN107811985A (en) * | 2016-09-13 | 2018-03-20 | 四川科瑞德制药股份有限公司 | A kind of anti-epileptic sustained release preparation and preparation method thereof and purposes |
| CN107811985B (en) * | 2016-09-13 | 2021-05-28 | 四川科瑞德制药股份有限公司 | Anti-epileptic sustained-release preparation and preparation method and application thereof |
| CN109674758A (en) * | 2019-02-25 | 2019-04-26 | 湖南博隽生物医药有限公司 | A kind of Divalproex sodium sustained-release tablet and preparation method thereof for treating epilepsy |
| CN113304117A (en) * | 2021-04-30 | 2021-08-27 | 山东京卫制药有限公司 | Preparation method of sodium valproate sustained-release tablets |
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